PÉCSI TUDOMÁNYEGYETEM
Orvostudományi és Egészségtudományi Centrum
Szak- és Továbbképző Központ
H-7624 Pécs, Szigeti út 12.
Tel.: (72) 512-643
Fax: (72) 512-683
IGAZGATÓ: PROF. DR. ERTL TIBOR
SZAKORVOSI TOVÁBBKÉPZÉS
TÉMA:
Szerkesztette:
CLINICAL NEPHROLOGY
DR. NÉMETH LÁSZLÓ
Cím: Petz Aladár Megyei Oktató Kórház – Rendelőintézet
I.sz. Belgyógyászati Szakrendelés
9024 Győr, Szent Imre u. 41. Tel.: (96) 418-244/1494
IRODALOM:
2006. JÚLIUS 1. – SZEPTEMBER 30.
GYŐR, 2006. OKTÓBER 6.
CONTENTS
Part One
SECTIONS
I.
EPIDEMILOGY
II.
ETIOPATHOGENESIS
III. CLINICAL PRESENTATION
IV. TREATMENT
V.
TRANSPLANTATION
TITLE OF PUBLICATIONS – AUTHORS – PUBLICATIONS
Part One
I.
EPIDEMIOLOGY
1. DNA polymorphisms and renal disease: a critical appraisal of studies presented at the annual
ERA/EDTA and ASN conferences in 2004 and 2005.
Mondry A, Loh M, Laurence KB, Low N.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
2. Lessons in ethnonephrology.
Hoy WE.
Kidney Int.
2006 70 (2): 251-7.
3. Racial disparities in the association between birth weight in the term infant and blood presure at
age 7 years: Results from Collaborative Perinatal Project.
Hemachandra AH, Klebanoff MA, Furth SL.
J Am Soc Nephrol.
2006 Jul 26; [Epub ahead of print]
4. The enigma of hypertensive ESRD: Observation on incidence and trends in 18 European,
Canadian, and Asian-Pacific populations, 1998 to 2002.
Stewart JH, McCredie MR, Williams SM; Canadian Organ Replacement Register; Fenton SS, Trepski
L; Australia and New Zealand Dialysis and Transplant Registry; McDonald SP; European Renal
Association-European Dialysis and Transplant Association Registry; Jager KJ, van Dijk PC; Finnish
Registry for Kidney Diseases; Finne P; Swedish Registry for Active Treatment of Uremia; Schon S;
Norwegian Renal Registry; Leivestad T; Danish National Registry on Regular Dialysis and
Transplantation; Lokkegaard H; Dutch-speaking Belgian Society of Nephrology; Billiouw JM; Austrian
Dialysis and Transplant Registry; Kramer R; Basque Renal Patients’ Registry; Magaz A; Catalan
Renal Registry; Vela E; Valencian Renal Registry; Garcia-Blasco MJ; Hellenic Renal Registry;
Ioannidis GA; Malaysian National Renal Registry; Lim YN.
Am J Kidney Dis.
2006 48 (2): 183-91.
5. Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension:
The HARVEST.
Palatini P, Mormino P, Dorigatti F, Santonastaso M, Mos L, De Toni R, Winnicki M, Follo MD, Biasion
T, Garavelli G, Pessina AC.
Kidney Int.
2006 Jun 21; [Epub ahead of print]
6. Prevalence and risk factor analysis of microalbuminuria in Japanese general population: The
Takahata study.
Konta T, Hao Z, Abiko H, Ishikawa M, Takahashi T, Ikeda A, Ichikawa H, Takasaki S, Kubota I.
Kidney Int.
2006 Jun 28; [Epub ahead of print]
7. Traditional and emerging cardiovascular and renal risk factors: An epidemiologic perspective.
Zoccali C.
Kidney Int.
2006 70 (1): 26-33.
8. Cardiovascular disease in early stages of chronic kidney disease in a Chinese population.
Zhang L, Zuo L, Wang F, Wang M, Wang S, Lv J, Liu L, Wang H.
J Am Soc Nephrol.
2006 Aug 2; [Epub ahead of print]
9. Identifying genetic susceptibilities to diabetes-related complications among individuals at low risk of
complications: An application of tree-structured survival analysis.
Costacou T, Chang Y, Ferrell RE, Orchard TJ.
Am J Epidemiol.
2006 Aug 23; [Epub ahead of print]
10. A cohort analysis of type 1 diabetes mortality in Havana and Allegheny County, Pittsburgh, PA.
Barcelo A, Bornyak Z, Orchard T.
Diabetes Res Clin Pract.
2006 Jul 27; [Epub ahead of print]
11. Diabetic microvascular complications -- can the presence of one predict the development of
another?
Girach A, Vignati L.
J Diabetes Complications.
2006 20 (4): 228-37.
12. Relationship between common functional polymorphisms of the p22phox gene (-930A > G and
+242 > T) and nephropathy as a result of type 2 diabetes in a Chinese population.
Lim SC, Goh SK, Lai YR, Tee WW, Koh A, Xu XH, WuYS, Yap E, Subramaniam T, Sum CF.
Diabet Med.
2006 23 (9): 1037-41.
13. Metabolic syndrome and CKD in a general Japanese population: The Hisayama Study.
Ninomiya T, Kiyohara Y, Kubo M, Yonemoto K, Tanizaki Y, Doi Y, Hirakata H, Iida M.
Am J Kidney Dis.
2006 48 (3): 383-91.
14. The relationship of microalbuminuria with metabolic syndrome.
Choi HS, Ryu SH, Lee KB.
Nephron Clin Pract.
2006 104 (2): c85-93.
15. Racial differences in the prevalence of chronic kidney disease among participants in the Reasons
for Geographic and Racial Differences in Stroke (REGARDS) cohort study.
McClellan W, Warnock DG, McClure L, Campbell RC, Newsome BB, Howard V, Cushman M, Howard
G.
J Am Soc Nephrol.
2006 17 (6): 1710-5.
16. International comparison of the relationship of chronic kidney disease prevalence and ESRD risk.
Hallan SI, Coresh J, Astor BC, Asberg A, Romundstad S, Hallan HA, Lydersen S, Holmen J.
J Am Soc Nephrol.
2006 Jun 21; [Epub ahead of print]
17. Ethnic disparities in cardiovascular risk factors and coronary disease prevalence among
individuals with chronic kidney disease: Findings from the Third National Health and Nutrition
Examination Survey.
Nguyen HT, Stack AG.
J Am Soc Nephrol.
2006 17 (6): 1716-23.
18. Trends in treatment and outcomes of survival of adolescents initiating end-stage renal disease
care in the United States of America.
Ferris ME, Gipson DS, Kimmel PL, Eggers PW.
Pediatr Nephrol.
2006 21 (7): 1020-6.
19. Chronic kidney disease and mortality risk: A systematic review.
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX.
J Am Soc Nephrol.
2006 17 (7): 2034-47.
20. Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark.
Sorensen VR, Hansen PM, Heaf J, Feldt-Rasmussen B.
Kidney Int.
2006 70 (1): 187-91.
21. Paulista registry of glomerulonephritis: 5-year data report.
Malafronte P, Mastroianni-Kirsztajn G, Betonico GN, Romao JE, Alves MA, Carvalho MF, Neto OM,
Cadaval RA, Bergamo RR, Woronik V, Sens YA, Marrocos MS, Barros RT.
Nephrol Dial Transplant.
2006 Sep 12; [Epub ahead of print]
22. A scoring system to predict renal outcome in IgA nephropathy: From a nationwide prospective
study.
Wakai K, Kawamura T, Endoh M, Kojima M, Tomino Y, Tamakoshi A, Ohno Y, Inaba Y, Sakai H.
Nephrol Dial Transplant.
2006 Jul 5; [Epub ahead of print]
23. Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk
cancer association.
Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C, Rossert J.
Kidney Int.
2006 Aug 30; [Epub ahead of print]
24. Genetic kidney diseases in the pediatric population of southern Israel.
Finer G, Shalev H, Landau D.
Pediatr Nephrol.
2006 21 (7): 910-6.
25. Spectrum of clinical features and type IV collagen {alpha}-chain distribution in Chinese patients
with Alport syndrome.
Wei G, Zhihong L, Huiping C, Caihong Z, Zhaohong C, Leishi L.
Nephrol Dial Transplant.
2006 Aug 29; [Epub ahead of print]
26. Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: Another chain
of link?
Huang JF, Chuang WL, Dai CY, Ho CK, Hwang SJ, Chen SC, Lin ZY, Wang LY, Chang WY, Yu ML.
J Intern Med.
2006 260 (3): 255-62.
27. Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for
renal disease and hypertension.
Hoy WE, Hughson MD, Singh GR, Douglas-Denton R, Bertram JF.
Kidney Int.
2006 70 (1): 104-10.
28. Epidemiology and prognostic implications of contrast-induced nephropathy.
McCullough PA, Adam A, Becker CR, Davidson C, Lameire N, Stacul F, Tumlin J; CIN Consensus
Working Panel.
Am J Cardiol.
2006 98 (6 Suppl 1): 5-13.
II.
ETIOPATHOGENESIS
1. Cis and trans regulatory elements in NPHS2 promoter: Implictions in proteinuria and progression of
renal diseases.
Di Duca M, Olegginin R, Sanna-Cherchi S, Pasquali L, Di Donato A, Parodi S, Bertelli R, Caridi G,
Frasca G, Cerullo G, Amoroso A, Schena FP, Scolari F, Ghiggeri GM.
Kidney Int.
2006 Aug 9; [Epub ahead of print]
2. Collapsing glomerulopathy.
Albaqumi M, Soos TJ, Barisoni L, Nelson PJ.
J Am Soc Nephrol.
2006 Aug 16; [Epub ahead of print]
3. The molecular biology of thrombotic microangiopathy.
Tsai HM.
Kidney Int.
2006 70 (1): 16-23.
4. Renal vascular sclerosis is associated with inherited thrombophilias.
Goforth RL, Rennke H, Sethi S.
Kidney Int.
2006 Jun 7; [Epub ahead of print]
5. Polycystic kidney disease: Cell division without a c(l)ue?
Simons M, Walz G.
Kidney Int.
2006 Jun 28; [Epub ahead of print]
6. Renal cystic diseases: Diverse phenotypes converge on the cilium/centrosome complex.
Guay-Woodford LM.
Pediatr Nephrol.
2006 Jul 6; [Epub ahead of print]
7. Understanding pathogenic mechanisms in polycystic kidney disease provides clues for therapy.
Harris PC, Torres VE.
Curr Opin Nephrol Hypertens.
2006 15 (4): 456-63.
8. mRNA translation: Unexplored territory in renal science.
Kasinath BS, Mariappan MM, Sataranatarajan K, Lee MJ, Feliers D.
J Am Soc Nephrol.
2006 Sep 7; [Epub ahead of print]
9. Further insights into the role of angiotensin II in kidney development.
Lasaitiene D, Chen Y, Adams MA, Friberg P.
Clin Physiol Funct Imaging.
2006 (26): 197-204.
10. Physiology of local renin-angiotensin systems.
Paul M, Poyan Mehr A, Kreutz R.
Physiol Rev.
2006 86 (3): 747-803.
11. The podocyte’s response to injury: Role in proteinuria and glomerulosclerosis.
Shankland SJ.
Kidney Int.
2006 69 (12): 2131-47.
12. Erythropoietin and the cardiorenal syndrome: Cellular mechanisms on the cardiorenal connectors.
Jie KE, Verhaar M, Cramer MJ, Van Der Putten K, Gaillard C, Doevendans P, Koomans HA, Joles J,
Braam B.
Am J Physiol Renal Physiol.
2006 Aug 1; [Epub ahead of print]
13. Common mechanisms in nephropathy induced by toxic metals.
Sabolic I.
Nephron Physiol.
2006 104 (3): p107-14.
14. Meeting report: ISN forefronts in nephrology on endothelial biology and renal disease: From
bench to prevention.
Goligorsky MS, Rabelink T.
Kidney Int.
2006 70 (2): 258-64.
15. Role of endothelin and endothelin receptor antagonists in renal disease.
Neuhofer W, Pittrow D.
Eur J Clin Invest.
2006 36 (Suppl 3): 78-88.
16. Cross-talk between the kidney and the cardiovascular system.
Amann K, Wanner C, Ritz E.
J Am Soc Nephrol.
2006 17 (8): 2112-9.
17. Heme oxygenase-1: A provenance for cytoprotective pathways in the kidney and other tissues.
Nath KA.
Kidney Int.
2006 70 (1): 432-43.
18. Oxidants and iron in progressive kidney disease.
Shah SV.
J Ren Nutr.
2006 16 (3): 185-9.
19. The role of urotensin II in cardiovascular and renal physiology and diseases.
Zhu YC, Zhu YZ, Moore PK.
Br J Pharmacol.
2006 (148): 834-901.
20. Eicosanoids and renal vascular function in diseases.
Imig JD.
Clin Sci (Lond).
2006 111 (1): 21-34.
21. TGF-beta1 induces COX-2 expression and PGE (2) synthesis through MAPK and PI3K pathways
in human mesangial cells.
Rodriguez-Barbero A, Dorado F, Velasco S, Pandiella A, Banas B, Lopez-Novoa JM.
Kidney Int.
2006 Jul 5; [Epub ahead of print]
22. Interferon-gamma enhances superoxide production in human mesangial cells via the JAK-STAT
pathway.
Moriwaki K, Kiyomoto H, Hitomi H, Ihara G, Kaifu K, Matsubara K, Hara T, Kondo N, Ohmori K,
Nishiyama A, Fukui T, Kohno M.
Kidney Int.
2006 70 (4): 788-93.
23. A critical look at growth factors and epithelial-to-mesenchymal transition in the adult kidney.
Interrelationships between growth factors that regulate EMT in the adult kidney.
Wahab NA, Mason RM.
Nephron Exp Nephrol.
2006 104 (4): e129-34.
24. Consequences of intrauterine growth restriction for the kidney.
Schreuder M, Delemarre-van de Waal H, van Wijk A.
Kidney Blood Press Res.
2006 29 (2): 108-25.
25. Matrix metalloproteinase 2 and basement membrane integrity: A unifying mechansims for
progressive renal injury.
Cheng S, Pollock AS, Mahimkar R, Olson JL, Lovett DH.
FASEB J.
2006 20 (11): 1898-900.
26. Mechanisms of development and progression of cyanotic nephropathy.
Inatomi J, Matsuoka K, Fujimaru R, Nakagawa A, Iijima K.
Pediatr Nephrol.
2006 Aug 11; [Epub ahead of print]
27. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical
hemolytic uremic syndrome.
Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, Arzouk N,
Cleper R, Francois M, Guest G, Pourrat J, Seligman R, Fridman WH, Loirat C, Atkinson JP.
J Am Soc Nephrol.
2006 17 (7): 2017-25.
28. Microbial nucleic acids pay a toll in kidney disease.
Pawar RD, Patole PS, Wornle M, Anders HJ.
Am J Physiol Renal Physiol.
2006 291 (3): F509-16.
29. Immunohistochemical expression of activated caspase-3 as a marker of apoptosis in glomeruli of
human lupus nephritis.
Jeruc J, Vizjak A, Rozman B, Ferluga D.
Am J Kidney Dis.
2006 48 (3): 410-8.
30. Association of alpha-actinin-binding anti-double-stranded DNA antibodies with lupus nephritis.
Renaudineau Y, Croquefer S, Jousse S, Renaudineau E, Devauchelle V, Gueguen P, Hanrotel C,
Gilburd B, Saraux A, Shoenfeld Y, Putterman C, Youinou P.
Arthritis Rheum.
2006 54 (8): 2523-32.
31. Characterization of the expanded T-cell populations in patients with Wegener’s granulomatosis.
Giscombe R, Wang XB, Kakoulidou M, Lefvert AK.
J Intern Med.
2006 260 (3): 224-30.
32. Persistent expansion of CD4 (+) effector memory T cells in Wegener’s granulomatosis.
Abdulahad WH, van der Geld YM, Stegeman CA, Kallenberg CG.
Kidney Int.
2006 Jul 12; [Epub ahead of print]
33. B lymphocyte maturation in Wegener’s granulomatosis: A comparative analysis of VH genes from
endonasal lesions.
Voswinkel J, Mueller A, Kraemer JA, Lamprecht P, Herlyn K, Holl-Ulrich K, Feller AC, Pitann S, Gause
A, Gross WL.
Ann Rheum Dis.
2006 65 (7): 859—64.
34. Henoch-Schonlein purpura: Polymorphisms in thrombophilia genes.
Dagan E, Brik R, Broza Y, Gershoni-Baruch R.
Pediatr Nephrol.
2006 21 (8): 1117-21.
35. Role of podocyte slit diaphragm as a filtration barrier.
Kawachi H, Miyauchi N, Suzuki K, Han GD, Orikasa M, Shimizu F.
Nephrology (Carlton).
2006 11 (4): 274-81.
36. Tissue factor pathway inhibitor in childhood nephrotic syndrome.
Al-Maugeiren MM, Abdel Gader AG, Al-Rasheed SA, Al-Salloum AA.
Pediatr Nephrol.
2006 21 (6): 771-7.
37. Low protein Z levels in children with nephrotic syndrome.
Ozkaya O, Bek K, Fisgin T, Aliyazicioglu Y, Sultansuyu S, Acikgoz Y, Albayrak D, Baysal K.
Pediatr Nephrol.
2006 21 (8): 1122-6.
38.
Nephrotic syndrome associated with chronic graft-versus-host disease after allogenic
hematopoietic stem cell transplantation.
Reddy P, Johnson K, Uberti JP, Reynolds C, Silver S, Ayash L, Braun TM, Ratanatharathorn V.
Bone Marrow Transplant.
2006 38 (5): 351-7.
39. Renal corpuscle morphometry with increased reliability and high level of automation.
Caruntu ID, Covic A.
Pathol Res Pract.
2006 Sep 6; [Epub ahead of print]
40. Mechanisms of neutrophil transmigration across renal proximal tubular HK-2 cells.
Bijuklic K, Sturn DH, Jennigns P, Kountchev J, Pfaller W, Wiedermann CJ, Patsch JR, Joannidis M.
Cell Physiol Biochem.
2006 17 (5-6): 233-44.
41. Loss of podocyte dysferlin expression is associated with minimal change nephropathy.
Izzedine H, Brocheriou I, Eymard B, Le Charpentier M, Romero NB, Lenaour G, Bourry E, Deray G.
Am J Kidney Dis.
2006 48 (1): 143-50.
42.
Proliferating cells in HIV and pamidronate-associated
glomerulosclerosis are parietal epithelial cells.
collapsing
focal
segmental
Dijkman HB, Weening JJ, Smeets B, Verrijp KC, van Kuppevelt TH, Assmann KK, Steenbergen EJ,
Wetzels JF.
Kidney Int.
2006 70 (2): 338-44.
43. Cell-cycle regulator proteins in the podocyte in collapsing glomerulopathy in children.
Srivastava T, Garola RE, Singh HK.
Kidney Int.
2006 Jun 14; [Epub ahead of print]
44. Glomerular clusterin is associated with PKC-alpha/beta regulation and good outcome of
membranous glomerulonephritis in humans.
Rastaldi MP, Candiano G, Musante L, Bruschi M, Armelloni S, Rimoldi L, Tardanico R, Cherci SS,
Ferrario F, Montinaro V, Haupt R, Parodi S, Carnevali ML, Allegri L, Camussi G, Gesualdo L, Scolari
F, Ghiggeri GM.
Kidney Int.
2006 Jun 14. [Epub ahead of print]
45. Study of hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B virusassociated membranous nephropathy.
Kim SE, Park YH, Chung WY.
Pediatr Nephrol.
2006 21 (8): 1097-103.
46. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are
associated with membranoproliferative glomerulonephritis type II (dense deposit disease).
Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C,
Jozsi M, Zipfel PF, Hageman GS, Smith RJ.
J Med Genet.
2006 43 (7): 582-9.
47. Mycoplasma pneumoniae detection with PCR in renal tissue of a patients with acute
glomerulonephritis.
Del Carmen Laso M, Cadario ME, Haymes L, Grimoldi I, Balbarrey Z, Casanueva E.
Pediatr Nephrol.
2006 Jul 4; [Epub ahead of print]
48. Relationship between PAI-1 gene 4G/5G polymorphism and clinical profile of IgA nephropathy.
Ding R, Chen X, Liu S, Lv Y, Wu J.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi.
2006 (4): 449-51.
49. Impact of selectin gene polymorphisms on rapid progression to end-stage renal disease in
patients with IgA nephropathy.
Watanabe Y, Inoue T, Okada H, Kotaki S, Kanno Y, Kikuta T, Suzuki H.
Intern Med.
2006 45 (16): 947-51.
50. Association of uteroglobin G38A polymorphism with IgA nephropathy: A meta-analysis.
Yong D, QingQing W, Hua L, Yang LX, QingLing Z, Ying H, QiaoJing Q, HanChao S.
Am J Kidney Dis.
2006 48 (1): 1-7.
51. Roles of TGF-beta1 and apoptosis in the progression of glomerulosclerosis in human IgA
nephropathy.
Chihara Y, Ono H, Ishimitsu T, Ono Y, Ishikawa K, Rakugi H, Ogihara T, Matsuoka H.
Clin Nephrol.
2006 65 (6): 385-92.
52. Histological differences in newly onset IgA nephropathy between children and adults.
Ikezumi Y, Suzuki T, Imai N, Ueno M, Narita I, Kawachi H, Shimizu F, Nikolic-Paterson DJ, Uchiyama
M.
Nephrol Dial Transplant.
2006 Aug 25; [Epub ahead of print]
53. 24h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of
NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes.
Fava C, von Wowern F, Berglund G, Carlson J, Hedblad B, Rosberg L, Burri P, Almgren P, Melander
O.
Kideny Int.
2006 Jun 21; [Epub ahead of print]
54. Research into the glomerular podocyte – is it relevant to diabetic nephropathy?
White KE.
Diabet Med.
2006 23 (7): 715-9.
55. A disease haplotype for advanced nephropathy in type 2 diabetes at the ACE locus.
Ng DP, Placha G, Choo S, Chia KS, Warram JH, Krolewski AS.
Diabetes.
2006 55 (9): 2660-3.
56. Impact of renin-angiotensin system modulation on the hyperfiltration state in type 1 diabetes.
Sochett EB, Cherney DZ, Curtis JR, Dekker MG, Scholey JW, Miller JA.
J Am Soc Nephrol.
2006 17 (6): 1703-9.
57. The relationship between genetic and haemodynamic factors in diabetic nephropathy (DN): Casecontrol study in type 1 diabetes mellitus (T1DM).
Shestakova MV, Vikulova OK, Gorashko NM, Voronko OE, Babunova NB, Nosikov VV, Dedov II.
Diabetes Res Clin Pract.
2006 Jul 24; [Epub ahead of print]
58. Connective tissue growth factor plays an important role in advanced glycation end productinduced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease.
Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME,
Kantharidis P.
J Am Soc Nephrol.
2006 17 (9): 2484-94.
59. Aberrant heparan sulfate profile in the human diabetic kidney offers new clues for therapeutic
glycomimetics.
Wijnhoven TJ, Lensen JF, Rops AL, van der Vlag J, Kolset SO, Bangstad HJ, Pfeffer P, van den
Hoven MJ, Berden JH, van den Heuvel LP, van Kuppevelt TH.
Am J Kidney Dis.
2006 48 (2): 250-61.
60. Association of lipoprotein lipase S447X, apolipoprotein E exon 4, apoC3 -455T>C polymorphisms
on the susceptibility to diabetic nephropathy.
Ng M, Baum L, So WY, Lam V, Wang Y, Poon E, Tomlinson B, Cheng S, Lindpaintner K, Chan J.
Clin Genet.
2006 70 (1): 20-8.
61. MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of
diabetic nephropathy in type 2 diabetes patients.
Mtiraoui N, Ezzidi I, Chaieb M, Marmouche H, Aouni Z, Chaieb A, Mahjoub T,Vaxillaire M, Almawi WY.
Diabetes Res Clin Pract.
2006 Jul 4; [Epub ahead of print]
62. Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in
patients with type 2 diabetes and overt nephropathy.
Sawai K, Mukoyama M, Mori K, Yokoi H, Koshikawa M, Yoshioka T, Takeda R, Sugawara A,
Kuwahara T, Saleem MA, Ogawa O, Nakao K.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
63. ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease.
Caglar K, Yilmaz MI, Sonmez A, Cakir E, Kaya A, Acikel C, Eyileten T, Yenicesu M, Oguz Y, Bilgi C,
Oktenli C, Vural A, Zoccali C.
Kidney Int.
2006 Jul 5; [Epub ahead of print]
64. Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and
senescent phenotypes in type 2 diabetes.
Sampson MJ, Hughes DA.
Diabetologia.
2006 49 (8): 1726-31.
65. Lipotoxicity.
Weinberg JM.
Kidney Int.
2006 Sep 6; [Epub ahead of print]
66. Alterations of uromodulin biology: a common denominator of the genetically heterogenous
FJHN/MCKD syndrome.
Vylet’al P, Kublova M, Kalbacova M, Hodanova K, Baresova V, Stiburkova B, Sikora J, Hulkova H,
Zivny J, Majewski J, Simmonds A, Fryns JP, Venkat-Raman G, Elleder M, Kmoch S.
Kidney Int.
2006 70 (6): 1155-69.
67. Update on HIV-associated nephropathy.
Shah SN, He CJ, Klotman P.
Curr Opin Nephrol Hypertens.
2006 15 (4): 450-5
68. Quantitative imaging of basic functions in renal (patho) physiology.
Kang JJ, Toma I, Sipos A, McCulloch F, Peti-Peterdi J.
Am J Physiol Renal Physiol.
III.
2006 291 (2): F495-502.
CLINICAL PRESENTATION
1. Cardiovascular biomarkers in CKD: Pathophysiology and implications for clinical management of
cardiac disease.
Roberts MA, Hare DL, Ratnaike S, Ierino FL.
Am J Kidney Dis.
2006 48 (3): 341-60.
2. Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress.
Schaufele TG, Schlaich MP, Delles C, Klingbeil AU, Fleischmann EH, Schmieder RE.
Kidney Int.
2006 Aug 2; [Epub ahead of print]
3. Microalbuminuria as an early marker for cardiovascular disease.
De Zeeuw D, Parving HH, Henning RH.
J Am Soc Nephrol.
2006 17 (8): 2100-5.
4. Macroalbuminuria is a better risk marker than low estimated GFR to identify individuals at risk for
accelerated GFR loss in population based screening.
Halbesma N, Kuiken DS, Brantsma AH, Bakker SJ, Wetzels JF, De Zeeuw D, De Jong PE,
Gansevoort RT.
J Am Soc Nephrol.
2006 Aug 9; [Epub ahead of print]
5. Adiponectin and mortality in patients with chronic kidney disease.
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Goumenos DS, Tsagalis G, El Nahas AM, Shortland JR, Davlouros P, Vlachojannis JG, Brown CB.
Nephron Clin Pract.
2006 104 (2): c75-82.
30. Cyclosporin-A in the treatment of nephrotic syndrome: The importance of monitoring C0 (trough)
and C2 (two hours after its administration) blood levels.
Goumenos DS, Kalliakmani P, Tsakas S, Savidaki I, Vlachojannis JG.
Med Chem.
2006 2 (4): 391-3.
31. Induction and long-term treatment with cyclosporine in membranous nephropathy with the
nephrotic syndrome.
Alexopoulos E, Papagianni A, Tsamelashvili M, Leontsini M, Memmos D.
Nephrol Dial Transplant.
2006 Sep 12; [Epub ahead of print]
32. Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic
syndrome.
Fujinaga S, Kaneko K, Muto T, Ohtomo Y, Murakami H, Yamashiro Y.
Arch Dis Child.
2006 91 (8): 666-70.
33. Steroid pulse therapy impaired endothelial function while increasing plasma high molecule
adiponectin concentration in patients with IgA nephropathy.
Uchida HA, Nakamura Y, Kaihara M, Norii H, Hanayama Y, Sugiyama H, Maeshima Y, Yamasaki Y,
Makino H.
Nephrol Dial Transplant.
2006 Sep 2, [Epub ahead of print]
34. Succesful therapeutic use of rituximab in refractory membranous glomerulonephritis.
Cobo M, Hernández D, Rodrigez C, Pérez-Tamajón L.
Clin Nephrol.
2006 66 (1): 54-7.
35. Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome.
Westhoff TH, Schmidt S, Zidek W, Beige J, van der Giet M.
Clin Nephrol.
2006 65 (6): 393-400.
36. Meta-analysis: Anti-viral therapy of hepatitis B virus-associated glomerulonephritis.
Fabrizi F, Dixit V, Martin P.
Aliment Pharmacol Ther.
2006 24 (5): 781-8.
37. Nephrotoxicity as a complication of antiretroviral therapy.
Valle R, Haragsim L.
Adv Chronic Kidney Dis.
2006 13 (3): 314-9.
38. HIV-associated nephropathy.
Khan S, Haragsim L, Laszik ZG.
Adv Chronic Kidney Dis.
2006 13 (3): 307-13.
39. Antiretroviral therapy in the treatment of HIV-associated nephropathy.
Atta MG, Gallant JE, Hafizur Rahman M, Nagajothi N, Racusen LC, Scheel PJ, Fine DM.
Nephrol Dial Transplant.
2006 Jul 24; [Epub ahead of print]
40. FK506 in the treatment of children with nephrotic syndrome of different pathological types.
Xia Z, Liu Y, Gao Y, Fan Z, Fu Y, Zhang LF, Ren X, Gao C.
Clin Nephrol.
2006 66 (2): 85-8.
41. Modulator of bone morphogenetic protein activity in the progression of kidney diseases.
Yanagita M.
Kidney Int.
2006 70 (6): 989-93.
42. Effect of tranilast in early-stage diabetic nephropathy.
Soma J, Sato K, Saito H, Tsuchiya Y.
Nephrol Dial Transplant.
2006 Jul 4. [Epub ahead of print]
43. The management of tumor lysis syndrome.
Rampello R, Fricia T, Malaguarnera M.
Nat Clin Pract Oncol.
2006 3 (8): 438-47.
44. Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult
human kidneys.
Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M,
Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani
S, Romagnani P.
J Am Soc Nephrol.
2006 Aug 2; [Epub ahead of print]
45. Regrow or repair: Potential regenerative therapies for the kidney.
Little MH.
J Am Soc Nephrol.
2006 Jul 26; [Epub ahead of print]
46. Secondary failure of plasma therapy in factor H deficiency.
Nathanson S, Ulinski T, Fremeaux-Bacchi V, Deschenes G.
Pediatr Nephrol.
2006 Aug 15; [Epub ahead of print]
47. Neutrophil gelatinase-associated lipocalin-mediated iron traffic in kidney epithelia.
Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, Paragas N, Nicholas T, Devarajan P, Barasch J.
Curr Opin Nephrol Hypertens.
V.
2006 15 (4): 442-9.
TRANSPLANTATION
1. Subclinical rejection impairs glomerular adaptation after renal transplantation.
Ibernon M, Goma M, Moreso F, Fulladosa X, Hueso M, Cruzado JM, Torras J, Bestard O, Grinyo JM,
Seron D.
Kidney Int.
2006 70 (3): 557-61.
2. Experience with an organ procurement organization-based non-directed living kidney donation
programme.
Mark PJ, Baker K, Aguayo C, Sorensen JB.
Clin Transplant.
2006 20 (4): 427-37.
3. Kidney transplantation without prior dialysis in children: The eurotransplant experience.
Cransberg K, Smits JM, Offner G, Nauta J, Persijn GG.
Am J Transplant.
2006 6 (8): 1858-64.
4. Reflux nephropathy in kidney transplants, demonstrated by dimercaptosuccinic acid scanning.
Coulthard MG, Keir MJ.
Transplantation.
2006 82 (2): 205-10.
5. Pediatric live-donor kidney transplantation in Mansoura Urology & Nephrology Center: A 28-year
perspective.
El-Husseinin AA, Foda MA, Shokeir AA, Sobh MA, Ghonein MA.
Pediatr Nephrol.
2006 Jun 22; [Epub ahead of print]
6. The advantage of allocating kidneys from old cadaveric donors to old recipients: A single-center
experience.
Bodingbauer M, Pakrah B, Steininger R, Berlakovich G, Rockenschaub S, Wekerle T, Muehlbacher F.
Clin Transplant.
2006 20 (4): 471-5.
7. Early posttransplant serum osteoprotegerin levels predict long-term (8-year) patient survival and
cardiovascular death in renal transplant patients.
Hjelmesaeth J, Ueland T, Flyvbjerg A, Bollerslev J, Leivestad T, Jenssen T, Hansen TK, Thiel S,
Sagedal S, Roislien J, Hartmann A.
J Am Soc Nephrol.
2006 17 (6): 1746-54.
8. Color Doppler ultrasonography in the diagnostic evaluation of renal allografts.
Schwenger V, Hinkel UP, Nahm AM, Morath C, Zeier M.
Nephron Clin Pract.
2006 104 (3): c107-12.
9. Agreement of immunosuppression regimens described in Medicare pharmacy claims with the
Organ Procurement and Transplantation Network Survey.
Stirnemann PM, Takemoto SK, Schnitzler MA, Brennan DC, Abbott KC, Salvalaggio P, Burroughs TE,
Gavard JA, Willoughby LM, Lentine KL.
J Am Soc Nephrol.
2006 Jul 6; [Epub ahead of print]
10. Effect of induction therapy protocols on transplant outcomes in crossmatch positive renal allograft
recipients desensitized with IVIG.
Vo AA, Toyoda M, Peng A, Bunnapradist S, Lukovsky M, Jordan SC.
Am J Transplant.
2006 Jul 25; [Epub ahead of print]
11. Living donor transplantation using alemtuzumab induction and tacrolimus monotherapy.
Tan HP, Kaczorowski DJ, Basu A, Unruh M, McCauley J, Wu C, Donaldson J, Dvorchik I, Kayler L,
Marcos A, Randhawa P, Smetanka C, Starzl TE, Shapiro R.
Am J Transplant.
2006 Aug 4; [Epub ahead of print]
12. Pharmacodynamics of rituximab in kidney allotransplantation.
Genberg H, Hansson A, Wernerson A, Wennberg L, Tyden G.
Am J Transplant.
2006 Aug 21; [Epub ahead of print]
13. Late corticosteroid withdrawal can be safely performed for kidney recipients with stable graft
function under pathological confirmation.
Harada H, Miura M, Ogawa Y, Seki T, Taniguchi A, Takenouchi T, Togashi M, Hirano T.
Clin Transplant.
2006 Jul 20; [Epub ahead of print]
14. Steroid-free immunosuppression after renal transplantation - - long-term experience from a single
centre.
El-Faramawi M, Rohr N, Jespersen B.
Nephrol Dial Transplant.
2006 21 (7): 1966-73.
15. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation.
Harmon W, Meyers K, Ingelfinger J, McDonald R, McIntosh M, Ho M, Spaneas L, Palmer JA, Hawk M,
Geehan C, Tinckam K Hancock WW, Sayegh MH.
J Am Soc Nephrol.
2006 17 (6): 1735-45.
16. Long-term safety and efficacy after conversion of maintenance renal transplant recipients from
mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS), myfortic®).
Budde K, Knoll G, Curtis J, Chan L, Pohanka E, Gentil M, Seifu Y, Marrast A.-C, Neumayer H.-H on
behalf of the ERL B302 Study Group.
Clin Nephrol.
2006 66 (2): 103-11.
17. Tacrolimus and quality of life after kidney transplantation - - A multicenter study.
Bohlke M, Rocha M, Gomes RH, Marini SS, Terhorst L, Barcellos FC, Hallal PC, Casarini D, Irigoyen
MC.
Clin Transplant.
2006 20 (4): 504-8.
18. A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without
basiliximab in pediatric renal transplantation.
Grenda R, Watson A, Vondrak K, Beattie J, Fitzpatrick M, Saleem MA, Trompeter R, Milford DV,
Moghal NE, Hughes D, Perner F, Friman S, Van Damme-Lombaerts R, Janssen F.
Am J Transplant.
2006. 6 (7): 1666-72.
19. Ketoconazole-tacrolimus coadministration in kidney transplant recipients: Two-year results of a
prospective randomized study.
El-Dahshan KF, Bakr MA, Donia AF. Badr AE, Sobh MA.
Am J Nephrol.
2006 26 (3): 293-8.
20. Everolimus in clinical practice - - renal transplantation.
Pascual J.
Nephrol Dial Transplant.
2006 21 Suppl 3: iii18-23.
21. Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients.
Andres V, Castro C, Campistol JM.
Nephrol Dial Transplant.
2006 21 (Suppl 3): iii14-7.
22. Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: A randomized,
double-blind, placebo-controlled, crossover trial.
Sharma RK, Prasad N, Gupta A, Kapoor R.
Am J Kidney Dis.
2006 48 (1): 128-33.
23. Soluble CD30 concentrations in ESRD patients with and without panel reactive HLA antibodies.
Vaidya S, Partlow D, Barnes T, Thomas P, Gugliuzza K.
Clin Transplant.
2006 20 (4): 461-4.
24. Late and early C4d-positive acute rejection: Different clinico-histopathological subentities in renal
transplantation.
Sun Q, Liu ZH, Ji S, Chen J, Tang Z, Zeng C, Zheng C, Li LS.
Kidney Int.
2006 70 (2): 377-83.
25. Association of high pretransplant sIL-6R plasma levels with acute tubular necrosis in kidney graft
recipients.
Sadeghi M, Daniel V, Naujokat C, Mehrabi A, Opelz G.
Transplantation.
2006 81 (12): 1716-24.
26. Noninvasive immune monitoring assessed by flow cytometry and real time RT-PCR in urine of
renal transplantation recipients.
Galante NZ, Camara NO, Kallas EG, Salomao R, Pacheco-Silva A, Medina-Pestana JO.
Transpl Immunol.
2006 16 (2): 73-80.
27. Upregulation of ADAM19 in chronic allograft nephropathy.
Melenhorst WB, van den Heuvel MC, Stegeman CA, van der Leij J, Huitema S, van den Berg A, van
Goor H.
Am J Transplant.
2006 6 (7): 1673-81.
28. Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: Impact of
different immunosuppressive regimens.
Weimer R, Susal C, Yildiz S, Staak A, Pelzl S, Renner F, Dietrich H, Daniel V, Kamali-Ernst S, Ernst
W, Padberg W, Opelz G.
Am J Transplant.
2006 6 (8): 1865-74.
29. Post-transplant anti-HLA class II antibodies as risk factor for late kidney allograft failure.
Campos EF, Tedesco-Silva H, Machado PG, Franco M, Medina-Pestana JO, Gerbase-Delima M.
Am J Transplant.
2006 Aug 21; [Epub ahead of print]
30. Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched renal
allografts from chronic rejection.
Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, Pezzotta A, Azzollini N, Noris M,
Conti S, Abbate M, Giacca M, Remuzzi G.
J Am Soc Nephrol.
2006 17 (6): 1665-72.
31. Hepatocyte growth factor: New arsenal in the fights against renal fibrosis?
Liu Y, Yang J.
Kidney Int.
2006 70 (2): 238-40.
32. HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatoryinduced mechanisms.
Herrero-Fresneda I, Torras J, Franquesa M, Vidal A, Cruzado JM, Lloberas N, Fillat C, Grinyo JM.
Kidney Int.
2006 70 (2): 265-74.
33. Recurrent glomerulonephritis after kidney transplantation.
Choy BY, Chan TM, Lai KN.
Am J Transplant.
2006 Aug 29; [Epub ahead of print]
34. Secondary focal segmental glomerulosclerosis following kidney transplantation in a patient with
type I diabetes mellitus.
Yamamoto I, Yamamoto H, Mitome J, Tanno Y, Utsunomiya Y, Miyazaki Y, Yamaguchi Y, Hosoya T.
Clin Transplant.
2006 20 Suppl (15): 7-10.
35. IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation.
Bamoulid J, Courivaud C, Deschamps M, Mercier P, Ferrand C, Penfornis A, Tiberghien P, Chalopin
JM, Saas P, Ducloux D.
J Am Soc Nephrol.
2006 Jul 12; [Epub ahead of print]
36. Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine
nephrotoxicity.
Perez-Rojas J, Blanco JA, Cruz C, Trujillo J, Vaidya VS, Uribe N, Bonventre JV, Gamba G, Bobadilla
NA.
Am J Physiol Renal Physiol.
2006 Jul 11; [Epub ahead of print]
37. Infectious complications after kidney transplantation: Current epidemiology and associated risk
factors.
Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Garnick J, El-Amm JM, West MS, Sillix DH,
Chandrasekar PH, Haririan A.
Clin Transplant.
2006 20 (4): 401-9.
38. The prevalence of BK viremia and urinary viral shedding in a pediatric renal transplant population:
A single-center retrospective analysis.
Alexander RT, Langlois V, Tellier R, Robinson L, Hebert D.
Pediatr Transplant.
2006 10 (5): 586-92.
39. Clinical utility of histological features of polyomavirus allograft nephropathy.
Gaber LW, Egidi MF, Stratta RJ, Lo A, Moore LW, Gaber AO.
Transplantation.
2006 82 (2): 196-204.
40. De novo gastrointestinal tumours after renal transplantation: Role of CMV and EBV viruses.
Adani GL, Baccarani U, Lorenzin D, Gropuzzo M, Tulissi P, Montanaro D, Curro G, Sainz M, Risaliti A,
Bresadola V, Bresadola F.
Clin Transplant.
2006 20 (4): 457-60.
41. Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.
Wada T, Azuma H, Furuichi K, Sakai N, Kitagawa K, Iwata Y, Matsushima K, Takahara S, Yokoyama
H, Kaneko S.
Am J Nephrol.
..
2006 26 (4): 319-25.
CONTENTS
Part Two
SECTIONS
I.
EPIDEMILOGY
II.
ETIOPATHOGENESIS
III. CLINICAL PRESENTATION
IV. TREATMENT
V.
TRANSPLANTATION
TITLE OF PUBLICATIONS – AUTHORS – SUMMARY OF PUBLICATIONS
..
Part Two
I.
EPIDEMIOLOGY
1. DNA polymorphisms and renal disease: A critical appraisal of studies presented at the annual
ERA/EDTA and ASN conferences in 2004 and 2005.
Mondry A, Loh M, Laurence KB et al.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
Countless studies try to associate single DNA polymorphisms with disease, while there is growing
evidence that many of these studies are of flawed design. Based on the Journal of the American
Society of Nephrology (JASN) requirements for gene-disease association study quality, the abstracts
presented at the two major international nephrology conferences in 2004 and 2005 organized by
European Renal Association/European Dialysis and Transplantation Association (ERA/EDTA) and
American Society of Nephrology (ASN) are analysed to show how this problem affects nephrology.
Over time, average sample numbers have increased, as have the numbers of abstracts compliant with
JASN requirements. This indicates a potential beneficial effect of the published stricter guidelines on
study quality. Alternative options include pre-registration of studies in dedicated databases, secondary
assessment of association studies through meta-analysis and participation in network approaches,
such as Human Genome Epidemiology Network (HuGE Net) and the Renal Genome Network.
2. Lessons in ethnonephrology.
Hoy WE.
Kidney Int.
2006 70 (2): 251-7.
Only recently has the nephrology community moved beyond singular focus on terminal kidney failure
to embrace population-based studies of early stages of disease, its markers and risk factors, and of
interventions. Observations in developing countries, and in minority, migrant, and disadvantaged
groups in westernized countries, have promoted these developments. We are only beginning to
interpret renal disease in the context of public health history, social and health transitions, changing
population demography, and competing mortality. Its intimate reletionships to other health issues are
being progressively exposed. Perspectives on the multideterminant etiology of most disease and the
pedestrian nature of most risk factors are maturing. We are challenged to reconcile epidemilogic
patterns with morphology in diseased renal tissue, and to consider structural markers, such as
nephron number and glomerular size, as determinants of disease susceptibility. New work force
models are mandated for population-based studies and intervention programs. Intervention programs
need to be integrated with other chronic disease initiatives and nested in a matrix of systematic pimary
care, and although flexible to changing needs, must be sustained over the long term. Crossdisciplinary collaboration is essential in designing those programs, and in promoting them to healthcare funders. Substatntial expansion and restructuring of the discipline is need for the nephrology
community to participate effectively in those processes.
3. Racial disparities in the association between birth weight in the term infant and blood pressure at
age 7 years: Results from the Collaborative Perinatal Project.
Hemachandra AH, Klebanoff MA, Furth SL.
J Am Soc Nephrol.
2006 Jul 26; [Epub ahead of print]
BP has been inversely associated with birth weight in studies worldwide, but few studies have included
black individuals. The US National Collaborative Project followed 58,960 pregnant women and their
resultant offspring for 7 yr. In this post hoc analysis, all term white or black children without kidney or
heart disease were included (n = 29,710). The effect of birth weight and other risk factors on systolic
(SBP) and diastolic BP (DBP) was evaluated at 7 yr. Mean birth weight and body mass index at 7 yr
were slightly lower for black compared with white children (birth weight 3.14 +/- 0.48 versus 3.32 +/0.46 kg [P < 0.001]; body mass index 15.8 +/- 2.0 versus 16.3 +/- 2.0 [P < 0.001]). Compared with
white mothers, black mothers were less likely to smoke (41 versus 52%), were more anemic (23
versus 7%), and were more likely to live in poverty (72 versus 39%). In linear regression, there was
significant interaction between race and birth weight in predicting SBP (P = 0.002). In bivariate
analysis, birth weight was positively associated SBP (beta = 0.87) and DBP (beta = 1.14) in black
children (P < 0.001) but not associated with either in white children. With maternal poverty,
educational level, and anemia during pregnancy added to the model, birth weight remained a
significant positive predictor of SBP (beta = 0.89, P < 0.001) in black but not in white children (beta =
0.02, P = 0.17). The association between birth weight and SBP differs between black and white
children. The cause of intrauterine growth restriction-associated hypertension seems to be race
sensitive; therefore, future studies of racial disparities in the „Barker hypothesis” may help in the
understanding of the mechanism of fetal programming of hypertension.
4. The enigma of hypertensive ESRD: Observation on incidence and trends in 18 European,
Canadian, and Asian-Pacific populations, 1998 to 2002.
Stewart JH, McCredie MR, Williams SM et al.
Am J Kidney Dis.
2006 48 (2): 183-91.
Background Despite improved of hypertension and decreasing rates of stroke and coronary heart
disease, the reported incidence of hypertensive end-stage renal disease (ESRD) increased during the
1990s. However, bias, particularly from variations in acceptance into ESRD treatment (ascertainment)
and diagnosis (classification), has been a major source of error when comparing ESRD incidences or
estimating trends. Methods Age-standardized rates were calculated in persons aged to 44, 45 to 64,
and 65 to 74 years for 15 countries or region (separately for the Europid and non-Europid populations
of Canada, Australia, and New Zealand), and temporal trends were estimated by means of Poisson
regression. For 10 countries or regions, population-based estimates of mean systolic blood pressure
and prevalences of hypertension were extracted from published sources. Results Hypertensive
ESRD, comprising ESRD attributed to essential hypertension or renal artery occlusion, was least
common in Finland, non-Aboriginal Australians, and non-Polynesian New Zealanders; intermediate in
most European and Canadian populations; and most common in Aboriginal Australians and New
Zealand Maori and Pacific Island people. Rates correlated with the incidence of all other nondiabetic
ESRD, but not with diabetic ESRD or community rates of hypertension. Between 1998 and 2002,
hypertensive ESRD did not increase in Northwestern Europe or non-Aboriginal Canadians, although it
did so in Australia. Conclusion Despite the likelihood of classification bias, the probability remains of
significant variation in incidence of hypertensive ESRD within the group of Europid populations. These
between-population differences are not explained by community rates of hypertension or
ascertainment bias.
5. Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension:
The HARVEST.
Palatini P, Mormino P, Dorigatti F et al.
Kidney Int.
2006 Jun 21; [Epub ahead of print]
Factors related to the development of microalbuminuria in hypertension are not well known. We did a
prospective study to investigate wether glomerular hyperfiltration precedes the development of
microalbuminuria in hypertension. We assessed 502 never-treated subjects screened for stage 1
hypertension without microalbuminuria at baseline and followed up for 7.8 years. Creatinine clearence
was measured at entry. Urinary albumin and ambulatory blood pressure were measured at entry and
during follow-up until subjects developed sustained hypertension needing antihypertensive treatment.
Subjects with hyperfiltration (creatinine clearence > 150 ml/min/1.73 m(2), top quintile of the
distribution) were younger and heavier than the rest of the group and had a greater follow-up increase
in urinary albumin than subjects with normal filtration (P<0.001). In multivariable linear regression,
creatinine clearence adjusted for confounders was a strong independent predictor of final urinary
albumin (P < 0.001). In multivariable Cox regression, patients with hyperfiltration had an adjusted
hazard ratio for the development of microalbuminuria based on the least one positive measurement of
4.0 (95% confidence interval (CI), 2.1-7.4, P < 0.001) and an adjusted hazard ratio for the
development of microalbuminuria based on two consecutive positive measurements of 4.4 (95% CI,
2.1-9.2, P < 0.001), as compared with patients with normal filtration. Age, female gender, and 24 h
systolic blood pressure were other significant predictors of microalbuminuria. In conclusion, stage 1
hypertensive subjects with glomerular hyperfiltration are at increased risk of developing
microalbuminuria. Early intervention with medical therapy may be beneficial in these subjects even if
their blood pressure falls below normal limits during follow-up.
6. Prevalence and risk factor analysis of microalbuminuria in Japanese general population: The
Takahata study.
Konta T, Hao Z, Abiko H et al.
Kidney Int.
2006 Jun 28; [Epub ahead of print]
Microalbuminuria, an indicator of glomerular injury, is associated with increased risk of progressive
renal deterioration, cardiovascular disease, and mortality. However, the prevalence of
microalbuminuria in Japanese general population is less certain. Thus, we examined the prevalence of
microaluminuria and its associated risk factors in Japan. Subjects of this cross-sectional study were
asymptomatic individuals over 40 years in Takahata, Japan. Urine albumin-creatinine ratio was
calculated from a single-spot urine specimen collected in the morning. Creatinine clearence (CCr) was
obtained by Cockcroft-Gault equation. Multivariate logistic regression analysis was used to determine
which risk factors (i.e., age, hypertension, diabetes, obesity, and salt intake) might predict the
presence of microalbuminuria. A total of 2321 subjects (mean age, 64 years; men, 1034; women,
1287) were entered into the final analysis. Among them, the prevalence of microalbuminuria,
macroalbuminuria, and proteinuria by dipstick test (>/=1+) were 317 (13.7%), 39 (1.7%), and 103
(4.4%), respectively. Age, hypertension, and diabetes were independently associated with
microalbuminuria in men. In addition to the classical risk factors detected in men, estimated 24-h
urinary sodium excretion and uric acid were also independently associated with microalbuminuria in
women. Among the 668 subjects with renal insufficiency (CCr <60 ml/min/1.73 m(2), the prevalence of
microalbuminuria and macroalbuminuria were 119 (17.8%) and 18 (2.7%), respectively. In conclusion,
microalbuminuria is prevalent across all age groups and is associated with lifestyle-related risk factors
in Japanese general population. However, there are a substantial number of subjects with renal
insufficiency accompanying no microalbuminuria.
7. Traditional and emerging cardiovascular renal risk factors: An epidemiologic perspective.
Zoccali C.
Kideny Int.
2006 70 (1): 26-33.
Patients with chronic kidney disease (CKD) represent an important segment of the population (7-10%)
and, mostly because of the high risk of cardiovascular complications associated with renal
insufficiency, detection and treatment of CKD is now a public health priority. Traditional risk factors can
incite renal dysfunction and cardiovascular damage as well. As renal function deteriorates, nontraditional risk factors play an increasing role both in glomerular filtration rate (GFR) loss and
cardiovascular damage. Secondary analyses of controlled clinical trials suggest that inflammation may
be a modifiable risk both for cardiac ischemia and renal disease progression in patients with or at risk
of coronary heart disease. Homocysteine predicts renal function loss in the general population and
cardiovascular events in end-stage renal disease (ESRD), but evidence that this sulfur amino acid is
directly implicated in the progression of renal disease and in the cardiovascular mortality of uremic
patients is still lacking. High sympathetic activity and raised plasma concentration of asymmetric
dimethylarginine (ADMA) have been associated to reduced GFR in patients with CKD and to
cardiovascular complications in those with ESRD but again we still lack clinical trials targeting these
risk factoras. Presently, the clinical management of CKD patients remains largely unsatisfactory
because only a minority of these attain the treatment goals recommended by current guidelines. Thus,
in additon to research into new and estabilished risk factors, it is important that nephrologists make the
best use of knowledge already available to optimize the follow-up of these patients.
8. Cardiovascular disease in early stages of chronic kidney disease in a Chinese population.
Zhang L, Zuo L, Wang F et al.
J Am Soc Nephrol.
2006 Aug 2; [Epub ahead of print]
Cardiovascular disease (CVD) is one of the most serious complications of kidney disease, yet studies
of CVD in early stage of chronic kidney disease (CKD) in Asian patients are very limited. Therefore,
this study determined the prevalence and the spectrum of CVD in individuals with early-stage CKD
and compared them with data of individuals without CKD. Compared with individuals with estimated
GFR (eGFR) > 90 ml/min per 1.73 m (2), the prevalence of myocardial infarction, stroke, and total
CVD of individuals with eGFR 60 to 89 ml/min per 1.73 m (2) was increased by 91.4, 71.7 and 67.6%,
respectively. For individuals with eGFR 30 to 59 ml/min per 1.73 m (2), the percentage was 105.2,
289.1, and 200%, respectively. For each eGFR category, stroke was more prevalent than myocardial
infarction. Compared with individuals with eGFR > 90 ml/min per 1.73 m (2), participants with eGFR
60 to 89 and 30 to 59 ml/min per 1.73 m (2) tended to have more cardiovascular risk factors, and there
were strong unadjusted and adjusted associations between CVD with different stages of eGFR (eGFR
> 90 ml/min per 1.73 m (2) as reference). This first report on the prevalence and spectrum of CVD in
early stages of CKD in a community-based Chinese population. The spectrum of CVD in this Chinese
population is different from reports of Western countries. Individuals with subtle decreased renal
function seem much more likely to have multiple cardiovascular risk factors and have higher
prevalence of CVD than those without CKD.
9. Identifying genetic susceptibilities to diabetes-related complications among individuals at low risk of
complications: An application of tree-structured survival analysis.
Costacou T, Chang Y, Ferrell RE et al.
Am J Epidemiol.
2006 Aug 23; [Epub ahead of print]
The authors hypothesized that genetic predisposition to diabetes complications would be more evident
among low-risk individuals and aimed to identify genes related developing complications (confirmed
distal symmetric polyneuropathy, overt nephropathy, or coronary artery disease) in low-risk groups.
Participants in the Pittsburgh, Pennsylvania, Epidemiology of Diabetes Complications Study of
childhood-onset type 1 diabetes, first seen in 1986-1988 (mean age, 28 years; diabetes duration, 19
years), were reexamined biennially for 10 years. For each complication, subgroups with lowest
disease risk were identified by using tree-structured survival analysis, and 15 candidate genes were
compared between subjects with and without complications. In the group with the lowest incidence of
confirmed distal symmetric polyneuropathy (n = 123), confirmed distal symmetric polyneuropathy risk
increased fivefold for those with the eNOS GG genotype (p < 0.05). In the group with lowest risk of
overt nephropathy (n = 340), the ACE D polymorphism increased overt nephropathy risk twofold (p =
0.05), whereas a protective effect was observed for the LIPC CC genotype (p < 0.05). In the group
with the lowest incidence of coronary arterty disease (n = 331), the MTHFR CC genotype increased
coronary artery disease risk threefold (p < 0.05). Tree-structured analysis may help identify genetic
predispositions among individuals who, despite low risk, develop diabetes-related complications.
10. A cohort analysis of type 1 diabetes mortality in Havana and Allegheny County, Pittsburgh, PA.
Barcelo A, Bosnyak Z, Orchard T.
Diabetes Res Clin Pract.
2006 Jul 27; [Epub ahead of print]
Objective To examine the mortality of type 1 diabetes (T1D) in two countries with very different health
care systems using two population-based registries of childhood-onset T1D one in Havana (HA),
Cuba, and the other in Allegheny County (AC), USA. Research Design Methods Cases diagnosed
with T1D between 1965 and 1980 in HA and between 1965 and 1979 in AC were included. Follow-up
started with diagnosis in each individual and ended as of 1 January 1991, or with death. Life-table
analyses were used to examine the mortality rates in both populations by duration of diabetes.
Results Cumulative mortality by January 1991 in HA (14% in males and females, respectively) was
higher than in AC (7% in males and 9% in females) for both genders (males, p = 0.0005; females, p =
0.0491). Mortality rates were considerably higher in HA for both men and women than in AC however,
among females confidence intervals overlapped. Overall mortality rate for Caucasians (AC) was
significantly lower than that for African-Americans (AC) or Hispanics (HR). An analysis of causes of
death showed a greater proportion of deaths attributed to nephropathy (48.6%) in HA while acute
complications (36%) and infections (27%) were frequent in AC. Conclusions This study shows a twofold greater mortality among people with childhood-onset T1D in Havana, Cuba, than Allegheny, USA.
Different strategies may be needed to increase survival among those with type 1 diabetes in the USA
and Cuba.
11. Diabetic microvascular complications - - can the presence of one predict the development of
another?
Girach A, Vignati L.
J Diabetes Complications.
2006 20 (4): 228-37.
The number of people with diabetes is increasing dramatically worldwide. The rising prevalence of
obesity in childhood and adolescence has also been linked to a startling increase in the number of
diagnosed cases of type 2 diabetes in these younger age groups. Despite the introduction of treatment
strategies, diabetes remains a major cause of new-onset blindness, end-stage renal disease, and
lower lag amputation, all of which contribute to the excess morbidity and mortality in people with
diabetes. Furthermore, the management of diabetes-related complications generates substantial
costs. In order that timely treatment can be given, it is essential that patients at risk for the
development of diabetic microvascular complications are identified earlier. Diabetes duration and
glycemic, blood pressure, and lipid control have consisitently been shown to correlate with diabetic
retinopathy, neuropathy, nephropathy, but to date, the relationship of one diabetic microvascular
complication to another has not been clearly described. A review of the literature has raised the
question that apart from known risk factors, there is a possible relationship among the diabetic
microvascular complications themselves, and this appears to be much stronger than the sparse
published data on it would suggest. A scoring system that can predict the development of diabetic
microvascular complications may facilitate the early identification of those patients at risk and,
consequently, have a positive impact on patients’ quality of life and reduce the economic burden of
diabetes and its complications.
12. Relationship between common functional polymorphisms of the p22phox gene (-930A > G and
+242C > T) and nephropathy as a result of type 2 diabetes in a Chinese population.
Lim SC, Goh SK, Lai YR et al.
Diabet Med.
2006 23 (9): 1037-41.
Objective Genetic determinants are important in diabetic nephropathy (DN). Oxidative stress has also
emerged as an important pathogenic factor in DN and vascular NADH oxidase is a major source of
reactive oxygen species (ROS). Previous small studies reported a strong but contradictory association
between functional genetic variation of p22(phox), an important subcomponent of NADH oxidase, and
DN. We investigated the association between two common functional single nucleotide polymorphisms
(SPNs) (-930 A > G and +242 C > T) and DN in a much larger group of Chinese patients with type 2
diabetes mellitus (T2DM). Research and Methods Case-control study of Chinese subjects with longstanding T2DM (> 10 years). Cases (n = 306) were subjects with a spot urinary albumin : creatinine
ratio (ACR) of > 113 mg/mmol or elevated serum creatinine. Control subjects (n = 306) had ACR < 3.3
mg/mmol and normal serum creatinine. Genotyping was carried out by standard PCR and restriction
fragment length polymorphism analysis. Results Gender distribution, age, duration of diabetes and
HbA(1c) were similar in case and control subjects. Distribution of genotypes in the control subjects for
both SNPs was consistent with the Hardy-Weinberg equilibrium. Disturbation of genotypes did not
differ significantly between cases and control subjects for both polymorphisms-+2424 C > T: cases CC
84.6%, CT 15.0%, TT 0.4% and control subjects CC 87.6%, CT 11.8%, TT 0.6% (P = 0.45); -930A >
G: cases AA 40.5%, AG 41.8%, GG 17.7% and control subjects AA 38.2%, AG 49.0%, GG 12.8% (P
= 0.12). Distribution of alleles was also similar-2424 C > T: cases C 92.2%, T 7.8% and control
subjects C 93.5%, T 6.5% (P = 0.66); -930 A > G cases A 61.4%, G 38.6% and control subjects A
62.7%, G 37.3% (P = 0.38). We estimated that our study has approximately 80% power to detect a
relative risk of 1.65 (for +242 C > T) and 1.35 (for –930 A > G) conferred by the minor allele,
respectively. Conclusions In contrast with prevoius small studies, our data suggest that these SNPs
do not confer significantly increased susceptibility to DN secondary to T2DM in Chinese subjects.
13. Metabolic syndrome and CKD in a general Japanese population: The Hisayama Study.
Ninomiya T, Kiyohara Y, Kubo M et al.
Am J Kidney Dis.
2006 48 (3): 383-91.
Background Metabolic syndrome has been linked with various atherosclerotic disease, but has not
been evaluated sufficiently as a risk for the development of chronic kidney disease (CKD) in the
general population. Methods We followed up 1,440 community-dwelling individuals without CKD aged
40 years or older for 5 years and examined the effects of metabolic syndrome, defined by the modified
National Cholesterol Education Program Adult Treatment Panel III criteria, on the development of
CKD. Results During follow-up, 88 subjects experienced CKD. The age- and sex-adjusted 5-year
cumulative incidence of CKD was significantly greater in subjects with than without metabolic
syndrome (10.6% versus 4.8%; P < 0.01). In multivariate analysis, even after adjusment for other
confounding factors, including insulinemia, metabolic sydrome remained an independent risk factor for
occurence of CKD (odds ratio, 2.08; 95% confidence interval [CI], 1.23 to 3.52). Compared with
subjects with 1 or fewer metabolic syndrome component, multivariate-adjusted odd ratios for CKD in
subjects with 2, 3, and 4 or more metabolic syndrome components were 1.13 (95% CI, 0.60 to 2.12),
1.90 (95% CI, 0.98 to 3.69), and 2.79 (95% CI, 1.31 to 9.90), respectively. The rate of change in
kidney function during 5 years decreased significantly in subjects with 4 or more metabolic sndrome
components compared with those with 1 or fewer component in the age group of 40 to 59 years,
whereas it also was significantly low in subjects with 3 metabolic syndrome components in the group
aged 60 years or older. Conclusion Our findings suggest that metabolic syndrome is a significant risk
factor for the development of CKD in the general population.
14. The relationship of microalbuminuria with metabolic syndrome.
Choi HS, Ryu SH, Lee KB.
Nephron Clin Pract.
2006 104 (2): c85-93.
Background/Aims Microalbuminuria and the metabolic syndrome are risk factors for cardiovascular
disease. The aim of this study is to examine the prevalence of microalbuminuria and to document the
relationship of microalbuminuria with the metabolic syndrome in a large population of Korean subjects.
Methods We examined the cross-sectional association of microalbuminuria with the components of
the matabolic syndrome and with other cardiovascular risk factors in 6,588 Korean adults who took
part a health examination program. Results The prevalence of microalbuminuria was 4.2% in the nonmetabolic syndrome group (n = 5,902), and 14.8% in the metabolic group ( n = 686). The odds ratio of
microalbuminuria in the adults with the metabolic syndrome compared with those adults without the
metabolic syndrome was 1.53 (1.13-2.07 95% CI). In the multiple logistic regression analysis, as
compared with the subjects without an elevated blood pressure, a low high-density lipoprotein
cholesterol level, a high triglyceride level, a high plasma glucose level and a large waist
circumference, the odds ratios for microalbuminuria with these components, after adjusment was
made for the body mass index, the high-sensitivity C-reactive protein level and the homeostasis model
assessment, were 2.17 (95% CI 1.71-2.76), 2.84 (95% CI 1.55-5.21), 1.30 (95% CI 1.03-1.65) and
2.68 (95% CI 2.04-3.51), respectively. The corresponding multivariate-adjusted odds ratios of
microalbuminuria for the participants with 1, 2, 3, and 4 and 5 components of metabolic syndrome
were 1.79 (95% CI 1.24-2.59), 2.35 (95% CI 1.58-3.51), 3.23 (95% CI 2.07-5.25), and 4.22 (95% CI
2.13-8.35), respectively. Conclusion There was a significantly graded relationship between the
number of metabolic syndrome components and the corresponding prevalence of microalbuminuria.
These findings suggest microalbumnuria is strongly related with the components of the metabolic
syndrome.
15. Racial differences in the prevalence of chronic kidney disease among participants in the Reasons
for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study.
McClellan W, Warnock DG, McClure L et al.
J Am Soc Nephrol.
2006 17 (6): 1710-5.
The racial disparity in the incidence of ESRD exemplified by the three- to four fold excess risk among
black compared with white individuals in the United States is not reflected in the prevalence of less
severe degrees of impaired kidney function among black compared with white individuals. The fourvariable Modification of Diet in Renal Disease study equation was used to evaluate the black-to-white
prevalence of impaired kidney function with increasing severity of impairment among participants in
the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationally,
representative, population-based cohort of individuals who are 45 yr and older. An estimated GFR
(eGFR) <60 ml/min per 1.73 m(2) was present in 43.3% of the 20,667 REGARDS participants and
was slightly less prevalent among black than white patients (33.7 versus 49.9%; prevalence odds ratio
0.51; 95í% confidence interval [CI] 0.48 to 0.54). The lower prevalence among black patients was not
uniform as eGFR declined. After controlling for other patients characteristics, the the black-to-white
odds ratio was 0.42 (95% CI 0.40 to 0.46) at an eGFR of 50 to 59 ml/min per 1.73 m(2) and increased
to 1.73 (95% CI 1.02 to 2.94) at an eGFR of 10to 19 ml/min per 1.73 m(2). The disparity in prevalence
of impaired kidney function among white compared with black patients reversed as the severity of
impaired kidney function increase. Factors that are responsible for the increasing prevalence of
severely impaired kidney function among black patients remain to be determined.
16. International comparison of the relationship of chronic kidney disease prevalence and ESRD risk.
Hallan SI, Coresh J, Astor BC et al.
J Am Soc Nephrol.
2006 Jun 21; [Epub ahead of print]
ESRD incidence is much lower in Europe compared with the United States. This study investigated
whether this reflects a difference in the prevalence of earlier stages of chronic kidney disease (CKD)
or other mechanisms. CKD prevalence in Norway was estimated from the population-based Health
Survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997
(participation rate 70.4%). Data were analyzed using the same methods as two US National Health
and Nutrition Examination Surveys in 1988 through 1994 (n = 15,488) and 1999 through 2000 (n =
4101). The primary analysis used gender-specific cutoffs in estimating persistent albuminuria for CKD
stages 1 and 2. ESRD rates and other relevant data were extracted from national registries. Total CKD
prevalence in Norway was 10.2% (SE 0.5) : CKD stage 1 (GFR >90 ml/min per 1.73 m(2) and
albuminuria, 2.7% (SE 0.3); stage 2 (GFR 60 to 89 ml/min per 1.73 m(2) and albuminuria), 3.2% (SE
0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m(2), 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min
per 1.73 m(2), 0.2% (SE 0,01). This closely approximates reported US CKD prevalence (11.0% in
1988 through 1994 and 11.7% in 1999 through 2000). The relative risk for progression from CKD
stages 3 or 4 to ESRD in US white patients compared with Norwegian patients was 2.5. This was only
modestly modified by adjusment for age, gender, and diabetes. AGE and GFR at start of dialysis were
similar, hypertension and cardiovascular mortality in the populations were comparable, but US white
patients were referred later to a nephrologist and had higher prevalence of obesity and diabetes. In
conclusion, CKD prevalence in Norway was similar to that in the United States, suggesting that lower
progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence
of ESRD in Norway.
17. Ethnic disparities in cardiovascular risk factors and coronary disease prevalence among
individuals with chronic kidney disease: Findings from the Third National Health and Nutrition
Examination Survey.
Nguyen HT, Stack AG.
J Am Soc Nephrol.
2006 17 (6): 1716-23.
Differences in coronary disease have been reported among ethnic minorities in the US population.
Whether these persist in patients with chronic kidney disease is unknown. The prevalence of
myocardial infarction (MI) and angina was compared by race and GFR in the Third National Health
and Nutrition Examination Survey using the Modification of Diet in Renal Disease Study equation.
Age-gender standardized estimates were computed for each GFR category (>/=90, 60 to 89, and <60
ml/min per 1.73 m(2) ), and odds ratios were compared using weighted multivariable logistic
regression for each race. The age-gender standardized prevalence of MI was 3.0, 3.1 and 4.9% in
white individuals; 2.8, 3.8, and 9.9% in black individuals; and 1.9, 2.9, and 3.8% in Mexican-American
individuals in each category: >/=90, 60to 89, and <60 ml/min, respectively. Compared with the referent
(Mexican-American; GFR >/=90 ml/min; odds ratio 1.00), Mexican-American individuals with GFR of
60 to 89 and <60 ml/min had more than four and nine times the odds dor MI; black individuals at
successively lower GFR had 1.6, 6.1, and 16.3 times the odds for MI, whereas white individuals had
1.9, 4.7, and 20.2 times that of the referent, respectively. After adjusment for traditional risk factors,
the inverse association of GFR with MI was substantially attenuated in black and white individuals and
completely abolished in Mexican-American individuals. The burden of coronary disease is lower in
Mexican-American than in white and black individuals with reduced kidney function even accounting
for differences in traditional risk factors.
18. Trends in treatment and outcomes of survival adolescents initiating end-stage renal disease care
in the United States of America.
Ferris ME, Gipson DS, Kimmel PL et al.
Pediatr Nephrol.
2006 21 (7): 1020-6.
This study characterizes treatment and outcome trends of adolescent patients initiating renal
replacement therapy in the USA from 1978 to 2002. This is a retrospective analysis of data from the
US Renal Data System (USRDS) of incident end-stage renal disease (ESRD) patients, ages 12 years
through 19 years, initiating renal replacement therapy between 1978 and 2002. Survival analyses
were conducted from either the first date of kidney failure or date of transplantation until death or 31
December 2002. The ESRD incidence per million adolescents increased from 17.6 in 1978 to 26.0 in
1990, with no change in incidence in the ensuing 12 years. Incidence was sligthly higher among males
than females and was twice as great in black than in white populations. The major cause of ESRD was
glomerulonephritis followed by cystic /congenital diseases and focal segmental glomerulosclerosis
(FSGS). Incidence increased with age, from 13.0 per million for children aged 13 years to 32.6 per
million for 19 year olds. Three-quarters of all adolescent patients received at least one transplant, and
one-fifth of patients received two or more transplants. Ten percent of incident adolescent patients
received a preemptive transplant. The 10-year survival rate was lowest in the 1978-1982 incident
cohort (77.6%) and improved to approximately 80% for later cohorts. Survival was better for younger
adolescents, transplant recipients, preemptive transplant recipients, males, Caucasian, and Asian
patients. The primary mode of renal replacement therapy is transplantation in most adolescent ESRD
patients. The 80% 10-year survival rate for adolescent-onset ESRD is very good when compared with
adult onset ESRD. However, this represents a 30-fold increase in mortality compared to the general
US adolescent population.
19. Chronic kidney disease and mortality risk: A systemic review.
Tonelli M, Wiebe N, Culleton B et al.
J Am Soc Nephrol.
2006 17 (7): 2034-47.
Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for
cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a
comprehensive summary of this risk would be potentially useful for planning public health policy. A
systemic review of the association between non-dialysis-dependent CKD and the risk for all-cause and
cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the
magnitude of these associations also were investigated. MEDLINE and EMBASE databases were
searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies
provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that
compared mortality between those with and without chronically reduced kidney function were included.
Studies were excluded from review when participants were followed for <1 yr or had ESRD. Two
reviewers independently extracted data on study setting, quality, participant and renal function
characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were
reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function
compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of
cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased
exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from
reduced kidney function, after adjusment for other estabilished risk factors. Although adjusted relative
hazards were consistently lower than adjusted relative risks (median reduction 17%), they remained
significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify
individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions
best offset this risk remains a health priority.
20. Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark.
Sorensen VR, Hansen PM, Heaf J et al.
Kidney Int.
2006 70 (1): 187-91.
Despite an improvement in diabetes care during the last 20 years, the number of diabetic patients
starting renal replacement therapy (RRT) has continued to increase in the Western world. The aim
was to study the incidence of patients starting RRT in Denmark from 1990 to 2004. Data were
obtained from The Danish National Registry; Report on Dialysis and Transplantation, where all
patients actively treated for end-stage renal disease have been registered since 1990. The incidence
of end-stage renal disease increased until 2001. Thereafter the incidence stabilized on 130 per million
people (pmp). The number of diabetic patients starting RRT increased steadily from 52 (number of
patients) in 1990, 113 in 1995, 150 in 2000, 168 in 2001, and 183 in 2002. However, during the years
2003 and 2004 this number was significantly reduced by 15% to 156 and 155, respectively. This was
mainly due to a 22% reduction in the number of non-insulin-treated (type II) diabetic patients (number
of patients): 98, 82, and 76 in 2002, 2003, and 2004, respectively. The mean age in the background
population, the mean age in diabetic patients starting RRT and the incidence of type I and type II
diabetes increased during the study period. The encouraging stabilization in the incidence of diabetic
patients referred for RRT observed in Denmark could be the result of implementation of a multifactoral
and more intensive renoprotective intervention in patients with diabetes and chronic progressive renal
disease.
21. Paulista registry of glomerulonephritis: 5-year data report.
Malafronte P, Mastroianni-Kirsztajn G, Betonico GN et al.
Nephrol Dial Transplant.
2006 Sep 12; [Epub ahead of print]
Background The Paulista Registry of Glomerulopathies was created in May 1999 and comprises
several centres of Sao Paulo, the most populous Brazilian State, that concentrates people from al
regions of the country who look for health care. Methods This report includes data from 2086 patients
from Brazil submitted to renal biopsy due to the presumed diagnosis of glomerular diseases,
registered prospectively since May 1999 until 2005. Data were collected by the integrants of the 11
centres involved, utilizing a standardized questionnaire. Results The mean age of the patients was
34.5 +/- 14.6 years. Primary glomerular diseases were more frequent in males (55.1%) than in
females; on the other hand, secondary glomerular disease were more frequent in females (71.8%).
The most common clinical presentation was nephrotic syndrome and the frequency of hypertension, at
this time, was 55.5%. There was a predominance of indication of biopsies in the third, fourth and fifth
decades of life. The most common primary glomerular diseases were focal and segmental
glomerulosclerosis (29.7%), followed by membranous nephropathy (20.7%), IgA nephropathy (17.8%),
minimal change disease (9.1%), membranoproliferative glomerulonephritis (7%), crescentic
glomerulonephritis (4.1%), advanced chronic glomerulopathy (4%), non-IgA mesangial
glomerulonephritis (3.8%), diffuse proliferative glomerulonephritis (2.5%), focal segmental proliferative
glomerulonephritis (1%) and others (0.3%). The most frequent secondary glomerular disease was
lupus nephritis, corresponding to 66.2% of the cases, followed by post-infectious glomerulonephritis
(12.5%), diabetic nephropathy (6.2%), diseases associated to paraproteinaemia (4.9%), hereditary
diseases (4.6%), vasculitis (3.2%), malignancies (0.9%), secondary focal segmental
glomerulosclerosis (0.6%) and others (0.9%). Conclusion Focal segmental glomerulosclerosis was
the most frequent primary glomerular disease, followed by membranous nephropathy and IgA
nephropathy. Lupus nephritis predominated over all the other secondary glomerular diseases.
22. A scoring system to predict renal outcome in IgA nephropathy: From a nationwide prospective
study.
Wakai K, Kawamura T, Endoh M et al.
Nephrol Dial Transplant.
2006 Jul 5; [Epub ahead of print]
Background Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis in
the world, and a substantial number of patients develop end-stage renal disease (ESRD). Although
there are several prognostic indicators, it remains difficult to predict the renal outcome in individual
patients. Methods A prospective cohort study was conducted in 97 clinical units in Japan from 1995 to
2002. We analysed the data from 2269 patients using proportional hazards models in order to
determine the predictors of ESRD in IgA nephropathy and to develop a scorring system to estimate
ESRD risk. Results During ther follow-up (median, 77 months), 207 patients developed ESRD.
Systolic hypertension, proteinuria, hypoproteinaemia, azotaemia and high histological grade at initial
renal biopsy were independently associated with the risk of ESRD. Mild haematuria predisposed
patients to ESRD more than severe haematuria. A scoring system was developed to estimate the 7year ESRD risk from eight clinical and pathological variables. Actually, this prognostic score accurately
classified patients by risk: patients with estimates of 0.0-0.9, 1.0-4.9, 5.0-19.9, 20.0-49.9, and 50.0100.0% had a 0.2, 2.4, 12.2, 40.2 and 80.8% of ESRD incidence over 7 years, respectively. The
corresponding area under the receiver operating characteristic curve was 0.939 [95% confidence
interval (CI), 0.921-0.958]. This score was verified in repetitions of the derivation-validation technique.
Conclusions Although the quality of some data collected by the mail survey is limited and influence of
therapy could not be considered, this scoring system serve as a useful prognostic tool for IgA
nephropathy in clinical practice.
23. Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk
cancer association.
Lefaucheur C, Stengel B, Nochy D et al.
Kidney Int.
2006 Aug 30; [Epub ahead of print]
The association between membranous nephropathy (MN) and cancer is often mentioned in textbooks
but poorly substantiated, and the characteristics of cancer-associated MN are unknown. To address
these questions, we studied a cohort of 240 patients with MN, among them 24 had malignancy at the
time of renal biopsy or within a year thereafter. Th incidence of cancer was significantly higher in these
patients than in the general population (standardized incidence ratio 9.8 [5.5-16.2] for men and 12.3
[4.5-26.9] for women). The frequency of malignancy increased with age. At the time of diagnosis,
clinical presentation did not differ between the patients with cancer-associated MN and those with
idiopathic MN, but smoking was more frequent among patients with cancer. Analysis of renal biopsies
revealed that the number of inflammatory cells infiltrating the glomeruli was significantly higher in
patients with cancer-associated MN (P=0.001). The best cutoff value for distinguishing malignancyrelated cases from controls was eight cells per glomerulus. Using this treshold led to a diagnosis of
cancer-associated MN with a specificity of 75% and a sensitivity of 92%. In patients with cancerassociated MN, there was a strong relationship between reduction of proteinuria and clinical remission
of cancer (P<0.001). In conclusion, our study provides epidemiologic evidence of an excess of cancer
risk in patients with MN. It also shows the age, smoking, and the presence of glomerular leukocytic
infiltrates strongly increase the likelihood of malignancy in MN patients.
24. Genetic kidney diseases in the pediatric population of southern Israel.
Finer G, Shalev H, Landau D.
Pediatr Nephrol.
2006 21 (7): 910-6.
Genetic kidney diseases (GKDs) are an important and well-known entity in pediatric nephrology. In the
past decade in genetic and molecular approaches have been enabled elucidation of the underlying
molecular defects in many of these disorders. Herein we summarize the progress that has been made
over the past decade in disclosing the molecular basis of several novel GKDs, which were
characterized in our area and include Bartter syndrome type IV, type II Bartter syndrome and transient
hyperkalemia, cystinuria and mental retardation, familial hypomagnesinemia with secondary
hypocalcemia, infantile nephronophthisis, familial hemolytic uremic syndrome with factor H deficiency,
and non-cystic autosomal dominant nephropathy. Retrospective analysis of our data reveals that
GKDs are over-represented among the pediatric population in southern Israel. GKDs are seen fourtimes more often than end-stage renal disease (ESRD) and comprise 38% of all cases of ESRD in our
area. This high rate of GKDs is mainly due to the high frequency of consanguineous marriages that
prevails in this area. Understanding of the genetic and molecular background of these diseases is a
result of a fruitful collaboration between the pediatric nephrologists and scientists, and has a direct
implication on the diagnosis and treatment of the affected families.
25. Spectrum of clinical features and type IV collagen {alpha}-chain distribution in Chinese patients
with Alport syndrome.
Wei G, Zhihong L, Huiping C et al.
Nephrol Dial Transplant.
2006 Aug 29; [Epub ahead of print]
Background Alport syndrome (AS) is a clinically and genetically heterogenous nephropathy. The goal
of the present study is to delineate clinical characteristics and the distribution of type IV collagen
chains in Chinese AS patients and to identify any alpha (IV)-chain expression and clinical phenotype
correlation. Methods A total of 126 biopsy-proven patients meeting immunofluorescence criteria for
the diagnosis of AS were investigated retrospectively. Results Microscope haematuria associated with
proteinuria was observed as the initial symptom in 77.8% of the patients; 59.8% showed hearing
impairment and 22.9% had ocular abnormalities. Renal biopsies from 118 patients revealed mesangial
proliferative glomerulonephritis (61.9%) and focal and segmental sclerosis glomerulonephritis (37.3%).
Ten different distribution patterns for the type IV collagen alpha-chains were found in the kidney; six of
these presented here for the first time. Based on renal immunofluorescence findings, 113 (89.7%)
were classified as X-linked dominant inherited AS (XLAS) and 13 (10.3%) as autosomal recessive AS
(ARAS). The XLAS group was divided into typical and non-typical subgroups according to the
expression patterns for the alpha3 (IV)-chain. Clinical phenotypes were more severe in XLAS patients
than in ARAS patients and the prognosis was poorer in typical XLAS patients than non-typical XLAS
patients. Conclusion In China, the incidence of XLAS is 89.7% and 10.3% for ARAS. Chinese
patients with AS have various distribution patterns of type IV collagen alpha-chains. The distribution
pattern of type IV collagen alpha-chains in the kidney may correspond to the severity of the clinical
phenotype.
26. Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: Another chain
of link?
Huang JF, Chuang WL, Dai CY et al.
J Intern Med.
2006 260 (3): 255-62.
Virus hepatitis may lead to nephropathy as one its multiple extrahepatic manifestations. Proteinuria by
dipstick, a simple test in practice, is a useful and cardinal sign of underlying renal abnormalities. The
aim of this study was to elucidate the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV)
infections on the occurence of proteinuria amongst adults. A prospective, cross-sectional, communitybased study was conducted in an HBV/HCV endemic area of southern Taiwan. Eligible subjects aged
40-65 years (n = 9934) underwent testing of hepatitis B surface antigen (HbsAg), HCV antibody (antiHCV) and other related biochemical profiles. Urinanalysis with repeated dipstick for proteinuria
detection was performed. Anti-HCV-positive rate amongst proteinuria subjects was significantly higher
than nonproteinuria subjects (9.6% vs. 6.2%, P < 0.001). By contrast, HbsAg-positive rate did not
differ between subjects with and without proteinuria (13.0% vs. 13.8%, P = 0.57). Prevalence of
proteinuria amongst anti-HCV-positive subjects (10.2%) was significantly higher than that in HbsAgpositive subjects (6.4%, P = 0.004) and in HbsAg-negative or anti-HCV-negative subjects (7.0%, P =
0.004). The difference persisted even after excluding diabetics. Multivariate logistic regression
analyses showed that diabetes was the most important significant factor associated with proteinuria,
followed by hypertension, anti-HCV seropositivity, body mass index, age and triglyceride levels. We
demonstrated the significant association between proteinuria and HCV, but not HBV, infection in this
HBV/HCV-endemic area.
27. Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for
renal disease and hypertension.
Hoy WE, Hughson MD, Singh GR et al.
Kidney Int.
2006 70 (1): 104-10.
Aborigines in remote areas of Australia have much higher rates of renal disease, as well as
hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney
function in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean
glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19
Abaorigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected
death in the Top End of Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines-202,000 fewer glomeruli per kidney , or an estimated 404,000 (P=0.036). Their mean glomerular
volume was 27% larger (P=0.016). Glomerular number was signifantly correlated with adult height,
inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than nonAboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than
those without--250,000 fewer per kidney (P=0.03), or 500,000 fewer per person, and their mean
glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is
compatible with their susceptibility to renal failure. The additional nephron deficit associated with
hypertension is compatible with other reports. Lower nephron numbers are probaly due to in part to
reduced nephron endowment, which is related to a suboptimal intrauterine environment.
Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total
filtering surface area, might be exacerbating nephron loss. Optimalization of fetal growth should
ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease.
28. Epidemiology and prognostic implications of contrast-induced nephropathy.
McCullough PA, Adam A, Becker CR et al; CIN Consensus Working Panel.
Am J Cardiol.
2006 98 (6 Suppl 1): 5-13.
Contrast-induced nephropathy (CIN), usually defined as an increase in serum creatinine of 0.5 mg/dL
(44.2 mumol/L), or a 25% increase from the baseline value 48 hours after the procedure, is a common
and potentially serious complication of the use of iodinated contrast media in patients at risk of acute
renal injury. It is an important cause of hospital-acquired renal failure, responsible for approximately
11% of cases. CIN may be to distinguish from cholesterol embolization, another cause of
postprocedure renal impairment. The reported incidence of CIN varies depending on the patient
population studied. The impact of postprocedural renal impairment on clinical outcomes has been
evaluated most extensively in patients undergoing percutaneous coronary intervention. CIN is
associated with increased mortality both in hospital and at 1 year. A higher incidence of in-hospital and
late cardiovascular events, as well as longer hospital stays, has been reported in patients developing
CIN. In a small proportion of patients, CIN is severe enough to require dialysis, and these patients
have a particularly poor prognosis. Many of the risk markers for CIN are also predictive of a worse
prognosis.
II.
ETIOPATHOGENESIS
1. Cis and trans regulatory elements in NPHS2 promoter: Implications in proteinuria and progression
of renal diseases.
Di Duca M, Oleggini R, Sanna-Cherchi S et al.
Kidney Int.
2006 Aug 9; [Epub ahead of print]
Podocin (NPHS2) expression in podocytes is associated with variable degrees of proteinuria and
progression to renal failure different glomerular diseases that suggest different expression profiles in
NPHS2 promoter. Three functional polymorphisms in NPHS2 promoter (-51T, -116T, and -535
insCTTTTTT (3)) were found determining strong downregulation (-73, -59, and -82%, respectively) of
the reporter gene expression when transfected in podocytes. Electrophoretic mobility shift assay
experiments showed that all wild-type variants (-51G, -116C, and -535 insCTTTTTT (2)) formed
specific DNA-protein complexes with podocyte nuclear extracts that were abolished by the presence of
the rare forms (-51T, -116T, and -535 insCTTTTTT (3)). In the case of -51G, upstream stimulatory
factor-1 (USF1) was identified as the specific trans element in accord to binding inhibition experiments
and USF1 RNA silencing. Haplotype analysis of 204 normal controls and 545 patients with renal
diseases (308 immunoglobulin (Ig)A nephropathy and 237 focal segmental glomerulosclerosis)
evidenced that -116/-51 and -535/P2OL formed two blocks in strong linkage disequilibrium in both
normal and pathological cohorts. The high NPHS2 promoter profile -116C/-51G haplotype was more
frequent in patients with IgA nephropathy (P-value = 0.005) and was associated with a better clinical
outcome in terms of proteinuria and creatinine levels. Overall our studies describes functional variants
of NPHS2 promoter and characterizes trans-acting elements that modulate podocin expression in the
kidney. High producer NPHS2 promoter haplotypes seem protective in patients with chronic
glomerular diseases.
2. Collapsing glomerulopathy.
Albaqumi M, Soos TJ, Barisoni L et al.
J Am Soc Nephrol.
2006 Aug 16; [Epub ahead of print]
Collapsing glomerulopathy (CG) has become an important cause of ESRD. First delineated from other
proteinuric glomerular lesions in the 1980s, CG is now recognized as a common, distinct pattern of
proliferative parenchymal injury, that portends a rapid loss of renal function and poor responses to
empiric therapy. Notwithstanding, the rise in disorders that are associated with CG, the identification of
the first susceptibility genes for CG, the remarkable increase in murine modeling of CG, and promising
preclinical testing of new therapeutic strategies suggest that the outlook for CG as a poorly understood
and therapeutically resistant renal disease is set to change in the future. This focused review
highlights recent advances in research into the pathogenesis and treatment of CG.
3. The molecular biology of thrombotic microangiopathy.
Tsai HM.
Kidney Int.
2006 70 (1): 16-23.
Thrombotic microangiopathy, which includes thrombotic thrombocytopenic purpura (TTP), shiga-toxinassociated hemolytic uremic syndrome (Stx-HUS) and atypical HUS, is characterized by the
development of hyalin thrombi in the microvasculature resulting in thromboctopenia, microangiopathic
hemolysis, and organ dysfunction. Renal failure is a predominant complication of both Stx-HUS and
atypical HUS, whereas neurological complications are more prominent in TTP. Other disorders such
as lupus or bone marrow transplantations may occasionally present with features of thrombotic
microangiopathy. Recent studies have found autoimmune inhibitors or genetic mutations of a von
Willebrand factor (VWF) cleaving metalloprotease ADAMTS13 in patients with TTP. In aproximatelly
30-50% of patients with atypical HUS, mutations have been detected in complement factor H,
membrane cofactor protein (CD46), or factor I. All three proteins are involved in the regulation of
complement activation. Additionally, autoantibodies of factor H have been described in patients
without genetic mutations. These advances illustrate that dysregulation of VWF homeostasis or
complement activation owing to genetic or autoimmune mechanisms may lead to the syndrome of
thrombotic microangiopathy.
4. Renal vascular sclerosis is associated with inherited thrombophilias.
Goforth RL, Rennke H, Sethi S.
Kidney Int.
2006 Jun 7; [Epub ahead of print]
Vascular sclerosis is often seen in renal biopsies. It is usually associated with diabetes mellitus,
hypertension, smoking, etc. However, whether inherited thrombophilc states such as factor V gene
mutation, protrombin gene mutation, and methhylenetetrahydrofolate reductase (MTHFR) gene
mutation are associated with vascular sclerosis is not known. Renal biopsies that showed vascular
disease were grouped into five groups: (1) diabetic patients, (2) hypertensive patients, (3) diabetic and
hypertensive patients, (4) smokers, (5) vascular sclerosis of unknown etiology (idiopathic renal
disease). Renal biopsies with no vascular sclerosis were used as controls. Frozen tissue was
analyzed for factor V Leiden mutation, protrombin G20210A mutation, and MTHFR C677T. Factor V
Leiden mutation and protrombin G20210A mutation was not seen in patients with diabetes,
hypertension, or smoking, whereas MTHFR C677T polymorphism in these group was not significant,
compared to the controls. In the idiopathic renal disease group, three of the 17 patients (17.6%) had
protrombin G20210A mutation, two of the 17 patients (11.8%) had the factor V Leiden mutation, and
five of the 17 (29.4%) were homozygous for the MTHFR C677T polymorphism. When the data were
evaluated as a whole, 10 mutations were found in 17 patients (P<0.0005 compared to controls) or
eight of the 17 patients (47%) were observed to have at least one of the three forms of inherited
thrombophilia (P<0.001 compared to controls). These findings indicate that renal vascular lesions, in
the absence of diabetes, hypertension, or smoking appears to be associated with inherited
thrombophilias.
5. Polycystic kidney disease: Cell division without a c(l)ue?
Simons M, Walz G.
Kidney Int.
2006 Jun 28; [Epub ahead of print]
Polycystic kidney disease are caused by an amazingly broad array of genetic mutations and
manipulations. The ciliary hypothesis has evolved as the unifying concenpt of cystogenesis: cilia, bend
by fluid flow, initiate a calcium influx that prevents cyst formation. The integrity of ciliary function has
been linked to the polycystic kidney disease gene products localizing to the cilium or the basal
body/centrosome. Until recently, the signals and cellular programs located downstream of the ciliarymediated calcium flux have remained elusive. Now, several reports point towards a role of the cilium
or the basal body/centrosome complex in planar cell polarity, a pathway that orients cell in the plane of
a tissue layer. First, Inversin, a protein mutated in nephronophthisis type II was found to act as a
switch between the canonical and the noncanonical Wnt cascade, suggesting that beta-catenin/TCFdependent gene transcription has to be curtailed to allow normal tubular differentiation. Second,
heterozygote deletions of Bardet-Biedl syndrome proteins affect neural tube closure and disrupt the
cochlear sterociliary bundles, two typical planar cell polarity defects. Third, tubular epithelial cells
undergo oriented cell division during tubular elongation, along the axis of the anterior-posterior axis of
the nephron. Thus, the cilium or the body/centrosome complex may provide the spatial cues to
position the centrosome and the mitotic spindle before the next cell division. Failure to communicate
this spatial information may condemn the tubular epithelial cells to proliferate and to form cysts.
6. Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome complex.
Guay-Woodford LM.
Pediatr Nephrol.
2006 Jul 6; [Epub ahead of print]
Inherited renal cystic diseases constitute an important set of single-gene disorders that frequently
progress to end stage renal disease (ESRD). Transmitted as autosomal dominant, autosomal
recessive, or X-linked traits, renal cystic disease are phenotypically diverse with respect to age at
onset, rate of disease progression, and association extra-renal manifestations. These disorders
involve defects in a set of gene products commonly referred to as cystoproteins that, while functionally
distinct, appear to co-localize, at least in part, with the cilia/centrosome complex. Therefore,
investigations are increasingly focused on the role of this complex in the pathogenesis of renal cystic
disease. Sorting out the functional relationship between these cystoproteins and the cilia/centrosome
complex will undoubtedly provide a better understanding of renal cystic disease pathogenesis and,
potentially, identify new targets for therapeutic intervention.
7. Understanding pathogenic mechanisms in polycystic kidney disease provides clues for therapy.
Harris PC, Torres VE.
Curr Opin Nephrol Hypertens.
2006 15 (4): 456-63.
Purpose of review Polycystic kidney diseases are a group of inherited disorders that result in tubular
dilatation and/or the development of fluid-filled cysts in the kidney. Identification and analysis of the
primary defective protein in many of these diseases are providing insights into a common
pathogenesis to polycystic kidney disease. This review explores this pathogenesis and determines the
role that this knowledge is playing in the development of potential therapies. Recent findings Study of
simple and syndromic forms of polycystic kidney disease has revealed that the defective proteins are
localized to the primary cilia/basal body and that the pleiotropic phenotypes are often associated with
defective ciliogenesis. Data indication that the polycystins are involved in ciliary mechanosensation,
and cellular changes in intracellular Ca and cAMP, have provided clues for possible therapeutic
approaches that have proved highly effective in pre-clinical trials. Summary Polycystic kidney
diseases are associated with defect to proteins involved in developing functional, sensory cilia in the
kidney. While the primary defects in these disorders cannot be corrected at present, downstream
cellular changes can be targeted. Potential therapeutic agents are being tested in patients, moving
polycystic kidney disease research into a new and exciting phase.
8. mRNA translation: Unexplored territory in renal science.
Kasinath BS, Mariappan MM, Sataranatarajan K et al.
J Am Soc Nephrol.
2006 Sep 7; [Epub ahead of print]
Ambient protein levels are under coordinated control transcription, mRNA translation, and degradation.
Whereas transcription and degradation mechanisms have been studied in depth in renal science, the
role of mRNA translation, the process by which peptide synthesis occurs according to the genetic code
that is present in the mRNA, has not received much attention. mRNA translation occurs in three
phases: Initiation, elongation, and termination. Each phase is controlled by unique eukaryotic factors.
In the initiation phase, mRNA and ribosomal subunits are brought together. During the elongation
phase, amino acids are added to the nascent peptide chain in accordance with codon sequences in
the mRNA. During the termination phase, the fully synthesized peptide is released from the ribosome
for posttranslational processing. Signaling pathways figure prominently in regulation of mRNA
translation, particularly the phosphatidylinositol 3 kinase-Akt-mammalian target of rapamycin pathway,
the AMP-activated protein kinase-tuberous sclerosis complex protein 1/tuberous sclerosis complex
protein 2-Rheb pathway, and the extracellular signal-regulated kinase 1/2 type mitogen-activated
protein kinase signaling pathway; there is significant cross-talk among these pathways. Regulation by
mRNA translation is suggested when changes in mRNA and protein levels do not correlate and in the
setting of rapid protein synthesis. Ongoing work suggest an important role for mRNA translation in
compensatory renal growth, hypertrophy and extracellular matrix synthesis in diabetic nephropathy,
growth factor synthesis by kidney cells, and glomerulonephritis. Considering that mRNA translation
plays an important role in cell growth, development, malignancy, apoptosis, and response to stress, its
study should provide novel insights in renal physiology and pathology.
9. Further insight into the role of angiotensin II in kidney development.
Lasaitiene D, Chen Y, Adams MA et al.
Clin Physiol Imaging.
2006 (26): 197-204.
Over the past decade, compelling studies have highlighted the fundamental role of the reninangiotensin system (RAS) in renal development and long-term control of renal function and arterial
pressure. The present review provides an update of the understanding of how the RAS controls
nephrogenesis and nephrovascular development. In addition, the investigators linking the perinatal
development of RAS inhibition-induced renal dysmorphology and establishment of adult blood
pressure are discussed.
10. Physiology of local renin-angiotensin systems.
Paul M, Poyan Mehr A, Kreutz R.
Physiol Rev.
2006 86 (3): 747-803.
Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system
(RAS) has been extensively studied. The current view of the system is characterized by an increased
complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In
recent years, the pathophysilogical implications of the system have been main focus of attention, and
inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG)
II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal
disease such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS
also plays an important role in mediating diverse physiological functions. These focus not only on the
classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular
homeostasis, but also on other functions. Recently, the research efforts studying these
noncardiovascular effects of the RAS have intensified, and a large body of data are now available to
support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II
has direct effects at the cellular level and can influence, for example, cell growth and differentiation,
but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions
may be important in many organ system and can mediate important physiological stimuli. Transgenic
overexpression and knock-out strategies of RAS genes in animals have also shown a central
functional role of the RAS in prenatal development. Taken together, these findings may become
increasingly important in the study of organ physiology but also for a fresh look at the implications of
these findings for organ pathophysiology.
11. The podocyte’s response to injury: Role in proteinuria and glomerulosclerosis.
Shankland SJ.
Kideny Int.
2006 69 (12): 2131-47.
The terminally differentiated podocyte, also called glomerular visceral epithelial cell, are highly
specialized cells. They function as a critical size and charge barrier to prevent proteinuria. Podocytes
are injured in diabetic and non-diabetic renal diseases. The clinical signature of podocyte injury is
proteinuria, with or without loss of renal function owing to glomerulosclerosis. There is an exciting and
expanding literature showing that hereditary, congential, or acquired abnormalities in the molecular
anatomy of podocytes leads to proteinuria, and at times, glomerulosclerosis. The change in podocyte
shape, called effacement, is not simply a passive process following injury, but is owing to a complex
interplay of proteins that comprise the molecular anatomy of the different protein domains of
podocytes. These will be discussed in this directly causes proteinuria and glomerulosclerosis. This
owing to several factors, including the relative inability for these cells to proliferate, detachment, and
apoptosis. The mechanisms of these events are being elucidated, and are discussed in this review. It
is the hope that by delineating the events following injury to podocytes, therapies might be developed
to reduce the burden of proteinuric renal diseases.
12. Erythropoietin and the cardiorenal syndrome: Cellular mechanisms on the cardiorenal connectors.
Jie KE, Verhaar M, Cramer MJ et al.
Am J Physiol Renal Physiol.
2006 Aug 1; [Epub ahead of print]
We have recently proposed the severe cardiorenal syndrome (SCRS), in which cardiac and renal
failure mutually amplifay progressive failure of both organs. This frequent pathophysiological condition
has an extremely bad prognosis. Positive feedback between inflammation, the renin-angiotensin
system, the balance between the nitric oxide and reactive oxygen species and the sympathetic
nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of the
severe cardiorenal syndrome. Absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo
in this syndrome both contribute to the development of anemia, which is more pronounced than renal
anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors
are present in the heart, kidney and vascular system, in which activation results in anti-apoptosis,
proliferation, and possibly anti-oxidation and anti-inflammation. Interestingly, Epo can improve cardiac
and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal
connectors. Indeed, there are indications that Epo can diminish inflammation, reduce reninangiotensin system activity and shift the nitric oxide and reactive oxygen species balance towards
nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis
underscores the relevance of further understanding of clinical and cellular mechanisms underlying
protective effects of Epo, since this will support a better treatment of the severe cardiorenal syndrome.
13. Common mechanisms in nephropathy induced by toxic metals.
Sabolic I.
Nephron Physiol.
2006 104 (3): p107-114.
Various metals of unknown function in the body (Cd, Cr, Hg, Pb, U) trace elements in excessive
concentrations (Co, Cu, Fe, Zn), or metals used in cancer therapy (Pt, V), accumulate in the
mammalian kidney, largely in the proximal tubule (PT) cells, and cause functional and structural
damage that results in reabsorptive secretory defects. The intracellular mechanisms of their toxicity in
the PT cells are not well known. Recent studies have indicated an oxidative stress with associated
lipid peroxidation, apoptosis, and necrosis as common phenomena in the course of nephrotoxicity of
these metals. However, a number of other phenomena, such as the selective inhibition and/or loss of
various membrane transporters, enhancement of ion conductances, increased cytoplasmic
concentration of calcium, deranged cytoskeleton and cell polarity, impaired endocytosis, swelling and
fragmentation of mitochondria, increased expression of metallothionein, heat-shock and multidrug
resistance proteins, loss of cell membrane integrity, as well as the damage of mitochondrial and
genomic DNAs have been fragmentarily demonstrated for the action of some toxic metals, but their
importance for the course of nephrotoxicity and the sequence of events in relation to oxidative stress,
apoptosis, and necrosis have not been clearly established. Recent studies of metal toxicity in various
tissues and cells of non-renal and renal origin enable us to estimate ’causes and consequences’ of
various phenomena in the metal-induced nephrotoxicity, and to assemble them in a possible common,
time-related sequence.
14. Meeting report: ISN forefronts in nephrology on endothelial biology and renal disease: From
bench to prevention.
Goligorsky MS, Rabelink T.
Kidney Int.
2006 70 (2): 258-64.
This ISN-sponsored Forefront in Nephrology meeting, which has brought together 120 scientis from 21
countries, has been concerned with various aspects of endothelial function and dysfunction and their
contribution to progression of chronic kidney disease and/or its cardiovascular complications. The
following themes were discussed in great depth: (1) phenotypical changes in the vascular endothelium
- permeability, senescence, and apoptosis; (2) regulation of endothelial nitric oxide (NO) synthase
function - caveolar and shear stress mechanisms, epigenetic regulation, S-nitrosylation, and Rhokinase regulation; (3) oxidative stress and hypoxia-induced changes; (4) organellar dysfunction lysosomes, mitochondria, and endoplasmic reticulum; (5) NO-independent mechanisms of vasomotion
- epoxides, heme oxygenase-1 and carbon monoxide, thromboxane, tumor necrosis factor-alpha, and
uric acid; (6) endothelial crosstalk with podocytes, monocytes, smooth muscle cells, and platelets; (7)
candidate clinical biomarkers of endothelial dysfunction - functional testing of macro- and microvascular functions, surrogate markers, circulating detached endothelial cells, and endothelial precusor
cells; and culminated in Round Table discussion on the diagnosis of endothelial dysfunction and its
treatment options. In conclusion, this meeting has focused on several key problems of endothelial cell
pathobiology relevant to chronic kidney disease.
15. Role of endothelin and endothelin receptor antagonists in renal disease.
Neuhofer W, Pittrow D.
Eur J Clin Invest.
2006 36 (Suppl 3): 78-88.
Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic
properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide
variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell
contraction, stimulation of extracellular matrix production, and inhibition of sodium and water
reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine
manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders.
These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial
fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In additon,
ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance,
including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal
syndrome and others. Furthermore, derangement of the ET system may be involved in conditions
associated with inappropriate sodium and water retention; for example, in congestive heart failure and
hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and
tested in animal models with promising results. As key events in progressive renal injury like
inflammation and fibrosis are mediated via both ET (A) and ET (B) receptors, while constrictor effects
are primarily transduced by ET (A) receptors, dual ET receptor blockade may be superior over
selective ET (A) antagonism. Several compounds have been developed with remarkable effects in
several models of acute and progressive renal injury. Thus, clinical studies are required to assess
whether these results can be confirmed in humans, hopefully leading to novel and effective
therapeutic options with few side effects.
16. Cross-talk between the kidney and the cardiovascular system.
Amann K, Wanner C, Ritz E.
J Am Soc Nephrol.
2006 17 (8): 2112-9.
In recent years, increasing evidence has been provided that even minor renal dysfunction is a
powerful cardiovascular risk factor that induces typical cardiovascular alterations and thus predisposes
to coronary heart disease as well as to noncoronary cardiovascular problems. This first had been
noted in patients with diabetes but now has been confirmed amply in patients without diabetes as well.
Numerous heterogenous abnormalities have been described in patients with early renal dysfunction
(e.g., microalbuminuria, reduced estimated GFR). One final common pathway seems to be endothelial
cell dysfunction. The link between albuminuria and generalized endothelial cell dysfunction (as
indicated by diminished flow-mediated vasodilation, markers of endothelial cell dysfunction, sloughed
off endothelial cells, and high transcapillary albumin escape rate) is unclear. In patients with early
renal dysfunction, a long list of classical and nonclassical cardiovascular risk factors have been
identified: Elevated asymmetric dimethyl-1-arginine concentrations, markers of microinflammation,
oxidative stress, features of metabolic syndrome, abnormal adipokine concentrations, dyslipidemia,
inappropriate activation of the renin-angiotensin system, and sympathetic overactivity. The
mechanisms that link dysfunction of the kidney and the cardiovascular system are being sought. The
most interesting unifying concept, however, is deranged fetal programming linking nephron
underdosing to the increased cardiovascular risk.
17. Heme oxygenase-1: A provenance for cytoprotective pathways in the kidney and other tissues.
Nath KA.
Kidney Int.
2006 70 (1): 432-43.
Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme, converting heme to
biliverdin, during which iron is released and carbon monoxide (CO) is emitted; biliverdin is
subsequently converted to bilirubin by biliverdin reductase. At least two isozymes possess HO activity:
HO-1 represents the isozyme induced by diverse stressors, including ischemia, nephrotoxins,
cytokines, endotoxin, oxidants, and vasoactive substances; HO-2 is the constitutive, glucocorticoidinducible isozyme. HO-1 is upregulated in the kidney in assorted conditions and diseases. Interest in
HO is driven by the capacity of this system to protect the kidney against injury, a capacity likely
reflecting, at least in part, the cytoprotective properties of its products: in relatively low concentrations,
CO exerts vasorelaxant, antiapoptotic, and anti-inflammatory effects while bile pigments are
antioxidant and anti-inflammatory metabolites. This article reviews the HO system and the extent to
which it influences the function of the healthy kidney; it summarizes conditions and stimuli that elicit
HO-1 in the kidney; and it explores the significance of renal expression of HO-1 as induced by
ischemia, nephrotoxins, nephritides, transplantation, angiotensin II, and experimental diabetes. This
review also points out the tissue specificity of the HO system, and the capacity of HO-1 to induce renal
injury in certain settings. Studies of HO in other tissues are discussed insofar as aid in elucidating the
physiologic and pathophysiologic significance of the HO system in the kidney.
18. Oxidants and iron in progressive kidney disease.
Shan SV.
J Ren Nutr.
2006 16 (3): 185-9.
Oxidants derived either from leukocytes in proliferative glomerulonephritis or from resident glomerular
cells in nonproliferative glomerulonephritis have been shown to have several biological effects relevant
to chronic kidney disease. These include the ability of oxidants to damage the glomerular basement
membrane and directly induce proteinuria, effects that would lead to a fall in the glomerular filtration
rate and account for the morphologic changes observed in chronic kidney disease. In experimental
models, the role of oxidants has been shown in both proliferative glomerulonephritis (eg,
antiglomerular basement antibody disease) as well as experimental models of minimal change
disease and membranous nephropathy. Oxidants have also been shown to be an important mediator
of various pathways that have been implicated in diabetic nephropathy. Antioxidants and iron
chelators have also been shown to retard functional and morphologic changes observed in
progressive kidney disease. Taken together, these experimental studies suggest an important role of
oxidants in chronic kidney disease.
19. The role of urotensin II in cardiovascular and renal physiology and diseases.
Zhu YC, Zhu YZ, Moore PK.
Br J Pharmacol.
2006 (148): 884-901.
Urotensin II (U-II) is a cyclic neuropeptide that was first isolated from teleost fish some 35 years ago.
Mammalian U-II is a powerful vasoconstrictor with a potency greater than that of endothelin-1.
Nevertheless, unlike endothelin-1, which constricts all or nearly all vascular beds, the vasoactive
effects of U-II are reported to be dependent both on the species and on the regional vascular bed
examined. Typical regional variability occurs in the rat in which vasoconstriction to U-II is most robust
in thoracic aorta proximal to the aortic arch and decreases gradually towards the distal peripheral
arteries. As small peripheral arteries but not larger arteries such as the aorta play a major role in
regulation peripheral resistance and consequent blood pressure as well as workload on the heart,
doubts have been raised concerning the importance of this peptide in cardiovascular physiology.
Moreover, an interaction between U-II and other endogenous vasoactive molecules may add a level of
complexity to the vascular actions of U-II. On the other hand, recent experimental and clinical studies
have related increased expression of U-II and urotensin receptor (UT receptor) in animals with
experimentally induced myocardial infarction, heart failure, and in patients with hypertension,
atherosclerosis, and diabetic nephropathy, which suggest a potential role for U-II in both
cardiovascular and renal diseases. A series of peptidic and nonpeptidic UT receptor ligands have
been shown to be effective in antagonizing the effects of U-II in the cardiorenal system. This article
aims to review recent advances in our understanding of the physiology and pathophysiology of U-II
with particular references to its role in cardiovascular health and disease.
20. Eicosanoids and renal vascular function in diseases.
Imig JD.
Clin Sci (Lond).
2006 111 (1): 21-34.
Arachidonic acid metabolites are vital for the proper control of renal haemodynamics and, when not
properly controlled, can contribute to renal vascular injury and end-stage renal disease. Three major
enzymatic pathways, COX (cyclo-oxygenase), CYP450 (cytochrome P450) and LOX (lipoxygenase),
are responsible for the metabolism of arachidonic acid metabolites to bioactive eicosanoids. These
eicosanoids can dilate or constrict the renal vasculature and maintain vascular resistance in the face
of changing vasoactive hormones. Renal vascular generation of eicosanoids is altered in
pathophysiological conditions such as hypertension, diabetes, metabolic syndrome and acute renal
failure. Experimental evidence supports the concept that altered eicosanoid metabolism contributes to
renal haemodynamic alterations and the development and progression of nephropathy. The possible
beneficail renal vascular actions of enzymatic inhibitors, eicosanoid analogues and receptor
antagonists have been examined in hypertension, diabetes and metabolic syndrome. This review
highlights the roles of renal vascular eicosanoids in the pathogenesis of nephropathy and therapeutic
targets for renal disease related to hypertension, diabetes, metabolic syndrome and acute renal
failure.
21. TGF-beta1 induces COX-2 expression and PGE (2) synthesis through MAPK and PI3K pathways
in human mesangial cells.
Rodrigez-Barbero A, Dorado F, Velasco S et al.
Kidney Int.
2006 Jul 5; [Epub ahead of print]
Transforming growth factor-beta1 (TGF-beta1) plays a fundamental role in the progressing of renal
diseases. Accumulating evidence has suggested that eicosanoids derived from cyclooxygenase-2
(COX-2) participate in a number of pathological processes in immune-mediated renal diseases.
Mesangial cells (MC) play a major role in physiological and pathophysiological renal processes. MC
express receptors for TGF-beta1, and COX-2 expression can be induced in MC. However, to date,
there are no published data on the possible role of TGF-beta1 in COX-2 expression in human
mesangial cells (HMC). We designed studies to determine (1) whether TGF-beta1 stimulates COX-2
expression in primary HMC, (2) whether mitogen-activated kinase (MAPK) and phosphatidylinositol 3kinase (PI3K) cascade are involved in TGF-beta1-induced COX-2 expression, and (3) whether
prostaglandin (PG) E (2) synthesis is affected by TGF-beta1 and MAP kinases and PI3K activation.
Studies were performed in primary cultures of HMC and in an immortalized line of HMC. TGF-beta1
induces COX-2 promoter activity and COX-2 mRNA and protein expression in HMC. COX-2 induction
is accompained by increased PGE (2) synthesis. Extracellular signal-regulated kinase (ERK) 1/2, p38
MAPK, and PI3K pathway inhibition blunted TGF-beta1-induced COX-2 overexpression. We
demonstrate that TGF-beta1 regulates COX-2 expression in HMC through the activation of ERK1/2,
p38 MAPK, and PI3K. These results can help to elucidate the molecular mechanisms underlying the
regulation of COX-2 and open up specific strategies for the treatment of glomerular disease.
22. Interferon-gamma enhances superoxide production in human mesangial cells via the JAK-STAT
pathway.
Moriwaki K, Kiyomoto H, Hitomi H et al.
Kidney Int.
2006 70 (4): 788-93.
Immune reactive cytokines, such as interferon (IFN)-gamma, have multiple effects in
glomerulonephritis. Superoxide anions (O (2) (-)), which are associated with the progression of
glomerulonephritis, are mainly generated by nicotinamide adenine dinucleotid phosphate (reduced
form) NAD (P) H oxidases. We determined the effects of IFN-gamma on O (2) (-) production,
phosphorylation of signal transducer and activator of transcription (STAT)-1alpha, and the mRNA and
protein expression of p22phox and Nox1, components of NAD (P) H oxidases, in human mesangial
cells (HMCs). Significant increases in O (2) (-) production with IFN-gamma were completely abolished
by the flavin containing enzyme inhibitor, diphenyleneiodonium (10 mumol/l), and the Janus-activated
kinase (JAK) 2 inhibitor, AG490 (100 mumol/l). Phosphorylated STAT-1alpha was detected after 5 min
of IFN-gamma stimulation using Western blot analysis, and binding to the gamma-activating site was
observed from 30 min to 4 h, thereafter by electrophoretic mobility shift assay (EMSA). Super-shift
analysis in EMSA revealed that the main transcription factor was STAT-1alpha. IFN-gamma
significantly increased the expression of p22phox mRNA and protein, although expression was
inhibited by AG490. These data suggest that IFN-gamma stimulates O (2) (-) production in HMCs via
the JAK-STAT pathway and NAD (P) H oxidase.
23. A critical look at growth factors and epithelial-to-mesenchymal transition in the adult kidney.
Interrelationships between growth factors that regulate EMT in the adult kidney.
Wahab NA, Mason RM.
Nephron Exp Nephrol.
2006 104 (4): e129-34.
In the adult kidney, the cellular phenotypes are maintained by a strict balance of growth factors.
Epithelial-to-mesenchymal transtion (EMT) is a program whereby injured epithelial cells that function
as ion and fluid transporters become matrix remodelling mesenchymal cells. This process requires
either transcriptional repression of genes that maintain the epithelial phenotype and transcriptional
activation, or relieved repression of genes needed for functional myofibroblasts. The transcriptional
regulators are controlled by several integrated signaling pathways which are triggered by growth
factors. Emerging evidence indicates that the growth factors TGFbeta/CTGF and BMP-7/HGF are the
main determinants that maintain the two cellular phenotypes. Both TGFbeta and BMP-7 counteract the
activity of each other by cross-inducing their respective inhibitory Smads. Both growth factors may
also induce the expression of other factors can change the cellular environment and enhance their
function. Chronic kidney disease (regardless of the aetiology of the disease) are associated with
increased TGFbeta and CTGF expression levels which, in turn, have an inverse effect on the activity
level of BMP-7 and HGF, leading to an EMT of injured tubular epithelial cells and progression of the
disease. A detailed understanding of the complex interrelationship between these growth factors may
lead to the development of novel drugs.
24. Consequences of intrauterine growth restriction for the kidney.
Schreuder M, Delemarre-van de Waal H, van Wijk A.
Kidney Blood Press Res.
2006 29 (2): 108-25.
Low birth weight du to intrauterine growth restriction is associated various diseases in adulthood, such
as hypertension, cardiovascular disease, insulin resistance and end-stage renal disease. The purpose
of this review is to describe the effects of intrauterine growth restriction on the kidney. Nephrogenesis
requires a fine balance of many factors that can be disturbed by intrauterine growth restriction, leading
to a low nephron endowment. The compensatory hyperfiltration in the remaining nephrons results in
glomerular and systematic hypertension. Hyperfiltration is attributed to several factors, including the
renin-angiotensin system (RAS), insulin-like growth factor (IGF-I) and nitric oxide. Data from human
and animal studies are presented, and suggest a faltering IGF-I and an inhibited RAS in intrauterine
growth restriction. Hyperfiltration makes the kidney more vulnerable during additional kidney disease,
and is associated with glomerular damage and kidney failure in the long run. Animal studies have
provided a possible therapy with blockade of the RAS at an early stage in order to prevent the
compensatory glomerular hyperfiltration, but this is far from being applicable to humans. Research is
needed to further unravel the effect of intrauterine growth restriction on the kidney.
25. Matrix metalloproteinase 2 and basement membrane integrity: A unifying mechanism for
progressive renal injury.
Cheng S, Pollock AS, Mahimkar R et al.
FASEB J.
2006 20 (11): 1898-900.
Chronic kidney disease (CKD) and failure are problems of increasing importance. Regardless of the
primary etiology, CKD is characterized by tubular atrophy, interstitial fibrosis, and glomerulosclerosis.
It has been assumed that diminished matrix metalloproteinase (MMP) activity is responsible for the
accumulation of the extracellular matrix (ECM) proteins and collagens that typify the fibrotic kidney.
Here we demonstrate that transgenic renal proximal tubular epithelial expression of a specific enzyme,
MMP-2, is sufficient to generate the entire spectrum of pathological and functional changes
characteristic of human CKD. At the earliest point, MMP-2 leads to structural alterations in the tubular
basement membrane, a process that triggers tubular epithelial-mesenchymal transition, with resultant
tubular atrophy, fibrosis and renal failure. Inhibition of MMP-2, specifically in the early, prefibrotic
stages of disease may offer an additional approach for treatment of these disabling disorders.
26. Mechanisms of development and progression of cyanotic nephropathy.
Inatomi J, Matsuoka K, Fujimaru R et al.
Pediatr Nephrol.
2006 Aug 11; [Epub ahed of print]
Cyanotic nephropathy (CN) is often accompained by congenital cyanotic heart diseases (CCHD) The
purpose of this study was to clarify the risk factors and the mechanisms of involved in the development
and progression of CN. Thirty patients with CCHD were examined. We analyzed the risk factors for the
development of CN on the basis of the clinical and laboratory findings. We also examined ten renal
biopsy specimens obtained from patients with CN. Patients with CN showed significantly higher
hematocrit levels than those without CN (P = 0.025), although was no difference between the two
groups in terms of oxygen saturation. The renal plasma flow (RPF) in patients both with and without
CN was low. However, filtration fraction (FF) was significantly lower in patients with CN than in those
without CN (P = 0.001). The glomeruli of biopsy specimens with significant proteinuria (n = 7) were
larger than those of biopsy specimens without significant proteinuria, and there were more capillaries
per glomerulus in the former than in the latter. (n = 3) and the control specimens (n = 6) (glomerular
size: P < 0.01; number of glomerular capillaries: P < 0.01). In conclusion, hyperviscosity by
polycythemia may be responsible for the development of CN. This pathological condition may induce
an angiogenic increase in the glomerular capillary beds, in turn leading glomerulomegaly. In additon,
the failure of a compensatory mechanism to respond to reduced RPF by hyperfiltration may be
accompained by the development and progression of CN.
27. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical
hemolytic uremic syndrome.
Fremeaux-Bacchi V, Moulton EA, Kavanagh D et al.
J Am Soc Nephrol.
2006 17 (7): 2017-25.
Hemolytic uremic syndrome (HUS) is characterized by triad of thrombocytopenia, microangiopathic
hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS
[aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma
complement regulators factor H and factor I and the widely expressed membrane cofactor protein
(MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120
patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine
pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with
factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS.
The majority of patients have a mutation that causes reduced MCP surface expression. A small
proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete
penetrance is shown, suggesting that MCP is predisposing factor rather than a direct causal factor.
The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed,
and the first MCP null individuals are descibed. This study confirms the association between MCP
deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically
cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
28. Microbal nucleic acids pay a toll in kidney disease.
Pawar RD, Patole PS, Wornle M et al.
Am J Physiol Renal Physiol.
2006 291 (3): F509-16.
Nucleic acids provide more than the genetic code that determines the morphological and functional
phenotype of microbes and eukaryotes. In fact, nucleic acids have immunomodulatory functions as
they are recognized by a set of pattern-recognition receptors that initiate and modulate immune
responses in the host. Toll-like receptor (TLR)-3 recognizes double-stranded RNA, TLR7 and TLR8
recognize single-stranded RNA, CpG-DNA is a ligand for TLR9, and all of these TLRs are expressed
in the nephtitic kidney. In this review, we summarize recent advances in this field and discuss new
hypotheses for the pathogenesis of kidney diseases that are triggered by infectious organisms.
29. Immunohistochemical expression of activated caspase-3 as a marker of apoptosis in glomeruli of
human lupus nephritis.
Jeruc J, Vizjak A, Rozman B et al.
Am J Kidney Dis.
2006 48 (3): 410-8.
Background The role of apoptosis in lupus nephritis (LN) is still controversial. One of the key events
in the process of apoptosis is activation of caspase-3. Studies of experimental models suggest that
activated caspase-3 is a reliable indicator of apoptotic rate, with a favorable comparison against
terminal transferase-mediated DNA nick-end labeling (TUNEL) assay. Our aim is to study apoptosis in
various forms of LN its relationship to histomorphological changes and selected laboratory findings by
using activated caspase-3 as a novel marker of apoptosis. Methods We investigated glomerular cell
apoptosis in 51 biopsy specimens from patients with LN classified according to the International
Society of Nephrology/Renal Pathology Society classification by using TUNEL method and
immunohistochemistry against activated caspase-3. In additon, activity and chronicity indices were
calculated and anti-Ki-67 antibody was used to estimate proliferative activity. Results Activated
caspase-3-positive cells were present in glomeruli of 88.2% of cases, observed in the glomerular tuft
and cellular fibrocellular crescents. In the glomerular tuft, they were found mainly in segments with
active inflammatory lesions. There was good correlation between apoptotic index assessed by using
activated caspase-3 immunolabeling and the TUNEL method (r = 0.72; P < 0.01). We observed a
significant positive correlation between apoptotic index and LN class (P < 0.001). Apoptotic index
correlated significantly with activity index, proliferation index, and daily protein excretion (P < 0.001),
but not chronicity index, creatinine concentration, or anti-DNA andibody-binding activity in serum.
Conclusion Apoptotic rate is greater in severe active glomerular lesions in human LN, suggesting that
apoptosis may be involved in augmenting inflammation in human LN.
30. Association of alpha-actinin-binding anti-double-stranded DNA antibodies with lupus nephritis.
Renaudineau Y, Croquefer S, Jousse S et al.
Arthritis Rheum.
2006 54 (8): 2523-32.
Objective Anti-double-stranded DNA (anti-dsDNA) antibodies may contribute to the pathogenesis of
glomerulonephritis (GN) by cross-reacting with alpha-actinin in murine models and in some patients
with systemic lupus erythematosus (SLE). We therefore sought to determine possible disease
associations with serologic and clinical features and to characterize this new auoantibody specificity.
Methods One hundred patients with SLE were recruited into this multicenter study, as well as 100
rheumatic disease controls and 2,100 healthy blood donors. Clinical disease was evaluated by the
SLE Disease Activity Index (SLEDAI; excluding the anti-DNA component). Anti-dsDNA antibodies
detected by conventional enzyme-linked immunosorbent assay (ELISA) and by a commercial enzyme
immunoassay (EIA). Anti-alpha-actinin antibodies were detected by ELISA, and their specificity was
confirmed by Western blotting and by indirect immunofluorescence using rat kidney sections and
mesangial cells as substrates. Highly positive sera were selected for absorption experiments and were
affinity-purified for cross-reactivity studies and measurement of antibody avidity. Results Sera from 62
of SLE patients had anti-dsDNA antibodies: 21 of these sera also had anti-alpha-actinin antibodies, as
compared with 1 of the 38 sera without anti-dsDNA antibodies. Of the 22 patients with anti-alphaactinine antibodies, 10 had GN, as compared with 14 of the 78 without anti-alpha-actinin antibodies (P
< 0.01). In patients with GN, anti-alpha-actinin, but not anti-dsDNA, antibodies correlated with the
SLEDAI score (minus the antiDNA component) and with treatment. The fraction of serum anti-dsDNA
antibodies that cross-reacted with alpha-actinin exhibited high avidity for dsDNA, as determined using
a commercial EIA for high-avidity anti-dsDNA antibodies and an in-house conventional ELISA.
Conclusion The alpha-actinin-binding antibodies are significantly associated with GN in SLE.
Whether such autoantibodies may anticipate the development of this complication of SLE remains to
be verified.
31. Characterization of the expanded T-cell populations in patients with Wegener’s granulomatosis.
Giscombe R, Wang XB, Kakoulidou M et al.
J Intern Med.
2006 260 (3): 224-30.
Wegener’s granulomatosis (WG) is a chronic inflammatory disease characterized by granulomatosis
inflammation, systemic vasculitis and glomerulonephritis. In patients, the peripheral T cells are
characterized by mono/oligoclonal CD4(+)/CD8(+) T-cell AV/BV receptor expansions, with aberrant
expression of activation markers. This study was designed to characterize the phenotypic differences
between the expanded and nonexpanded T-cell population. Expression of markers for activation,
costimulation and adhesion molecules was examined. As earlier studies have shown aberrant
expression of CD28/CD152, we also analysed the expression of another costimulatory system, the
tumour necrotic factor receptor (TNFR) superfamily proteins. Fluorocrome-conjugated monoclonal
antobodies and flow cytometry was used to analyse the expression of the different markers on the
surface of the expanded and nonexpanded subsets of T cells. The Karolinska Hospital and Karolinska
Institutet in Stockholm, Sweden. Nine patients with WG (six men and three women) had 16
TCRAV/BV CD4(+) / CD8(+) expanded populations that were characterized. The expanded TCRA/BV
CD4(+) and CD8(+) cells had lower percentages of cells expressing CD28 and higher of those
expressing CD152 (CTLA-4). The expanded CD4(+) population had more cells expressing HLA-DR,
CD57 and CCR5 (CD195), whilst the expression of CD25 was present on fewer of the expanded cells.
The expanded CD8 (+) population contained more cells expressing CD137 (4-1BB), CD137 (4-1BBL),
CD30 (Ki-1), CD40 and CD134 (OX40). There were marked differences in the phenotypes of
expanded and nonexpanded T-cell populations.
32. Persistent expansion of CD4 (+) effector memory T cells in Wegener’s granulomatosis.
Abdulahad WH, van der Geld YM, Stegeman CA et al.
Kidney Int.
2006 Jul 12; [Epub ahead of print]
In order to test the hypothesis that Wegener’s granulomatosis (WG) is associated with an ongoing
immune effector response, even in remission, we examined the distribution of periferal naive and
memory T-lymphocytes in this disease, and analyzed the function-related phenotypes of the memory
T-cell population. Peripheral blood mononuclear cells (PBMCs) were freshly isolated from WG-patients
in remission (R-WG, n=40), active WG-patients (A-WG, n=17), and age-matched healthy controls
(HCs, n=21). Expression of CD4, CD8, CD45RO, CCR7, interleukin (IL)-18Ralpha, ST2L, and FoxP3
were determined by four-color flow cytometric analysis. CD45RO and CCR7 were used for disctinction
between naive and memory T cells, IL-18Ralpha, ST2L, and FoxP3 for the assessment of Type1,
Type2, and regulatory T-cells, respectively. In R-WG, the CD4(+)CD45RO(+)CCR7(-) effector memory
T-cell subpopulation (T(EM)) was relatively increased, whereas the CD4(+)CD45RO(-)CCR7(+) naive
T-cell population (T (Naive)) was decreased as compared to HC. The distribution of naive and memory
CD8(+) T cells did not differ betwen R-WG, A-WG, and HC, nor did CD4(+)CD45RO(+)CCR7(+)
central memory T cells (T(CM)). In contrast to HC, the percentage of CD4(+)T(Naive) cells in R-WG
correlated negatively with age, whereas CD(+)T(EM) cells showed a positive correlation. In R-WG, a
skewing towards Type2 T cells was observed in CD4(+)T(EM) cells. No differences were detected in
FoxP3(+)CD4(+)T(EM) cells between R-WG and A-WG, whereas the FoxP3(-)CD4(+)T(EM) cells
were increased in R-WG and decreased in A-WG as compared to HC. Collectively, peripheral blood
homeostasis of CD4(+)T cells is disturbed in R-WG with the persistent expansion of non-regulatory
CD4(+)T(EM) cells. These cells might be involved in relapse and may constitute a target for therapy.
33. B lymphocyte maturation in Wegener’s granulomatosis: A comparative analysis of VH genes from
endonasal lesions.
Voswinkel J, Mueller A, Kraemer JA et al.
Ann Rheum Dis.
2006 65 (7): 859-64.
Background Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are
highly specific for Wegener’s granulomatosis (WG). Evidence for a pivotal role of PR3-ANCA in the
induction of vasculitis has been demonstrated. B cell clusters have been observed within endonasal
biopsy specimens. Objectives To determine whether B cell selection and maturation take place in
granulomatous lesions of WG. Methods Granulomatous lesions and the immunoglobulin (VH) gene
repertoire from nasal tissue of six WG patients-two active and two smouldering localised WG (ANCA
negative, resticted to respiratory tract), plus one active and one smouldering PR3-ANCA positive
generalised WG were characterised by immunohistochemistry, polymerase chain reaction, cloning,
DNA sequencing and database comparison. Results B lymphocyte-rich, follicle-like areas were
observed proximal to PR3 positive cells and plasma cells in granulomatous lesions; VH genes from
these granulomatous lesions were compared with 84 VH genes from peripheral blood of a healthy
donor. The mutational pattern of VH genes from active WG resembled memory B cells. Structural
homologies of VH genes from granulomatous lesions to PR3-ANCA encoding genes were detected.
Significantly more genes (55%, 45%, and 53%, respectively) from active WG compared with the
healthy repertoire carried mutations to negatively charged amino acids within the binding site coding
regions, favouring affinity to the positively charged PR3. Conclusions Selection and affinity
maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous
lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA
positive generalised WG.
34. Henoch-Schonlein purpura: Polymorphisms in thrombophilia genes.
Dagan E, Brik R, Broza Y et al.
Pediatr Nephrol.
2006 21 (8): 1117-21.
Henoch-Schonlein purpura (HSP) is a small-sized vasculitis affecting mainly children. Based on the
hypothesis that an inherited predilection to hypercoagulability may predispose to HSP or may mark
those who develop acute clinical manifestations, we evaluated the possible roles of
methylenetetrahydrofolate reductase (MTHFR) gene C677T, factor V (FV) gene G1691A (Leiden), and
prothrombin gene G20210A polymorphisms in patients with HSP. Fifty-two HSP patients (32 boys and
20 girls) from different ethnic groups (22 Jews and 30 arabs) and 104 ethnically matched controls
were studied for these three polymorphisms. The frequencies of these mutations for each group,
separetely and in combinations, are described. The mutation frequencies in the MTHFR, prothrombin
and FV genes in HSP patients did not differ from those in controls. In a small number of individuals
(n=5) homozygosity for the 677T thermolabile variant of MTHFR was associated with hematuria. To
summarise, hypercoagulability does not seem to play a role in HSP. Studies in larger cohorts and
possibly inclusion of additional factors may be needed to ascertain whether hozygoty for MTHFR 677T
polymorphism can influence disease severity.
35. Role of podocyte slit diaphragm as a filtration barrier.
Kawachi H, Miyauchi N, Suzuki K et al.
Nephrology (Carlton).
2006 11 (4): 274-81.
Although the role of glomerular basement membrane has been emphasized as the barrier for retaining
plasma proteins in the past three decades, some recent studies have demonstrated that the slit
diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the
glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnishtype congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome,
respectively. Nephrin is located at the outer leaflet of plasma membranes of the slit diaphragm.
Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of
inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit
diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change
nephrotic syndrome, which suggested that the altered expression of these molecules contributes to
the development of proteinuria also in acquired diseases. Some recent studies demonstrated that
CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression
is altered in membranous nephropathy. These observations suggest that alteration of the molecular
arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of
glomerular disease.
36. Tissue factor pathway inhibitor in childhood nephrotic syndrome.
Al-Mugeiren MM, Abdel Gader AG, Al-Rasheed SA et al.
Pediatr Nephrol.
2006 21 (6): 771-7.
It is now recognised that the extrinsic tissue factor pathway is the main trigger to the coagulation
system in vivo. Its main inhibitor, tissue factor pathway inhibitor (TFPI), has never been studied in
childhood nephrotic syndrome. The aim of the study was to monitor the level of TFPI in childhood
nephrotic syndrome. One hundred and thirty-nine nephrotic children were classified into the following
groups: group 1 (n=25), in relapse and receiving no treatment; group 2 (n=37), in relapse but receiving
steroid treatment; group 3 (n=45), in early remission and on steroids; group 4 (n=24), in estabilished
remission and receiving no steroids; group 5 (n=8), steroid-resistant. The controls (n=84) were healthy
and age-matched. There was significant elevation of total TFPI levels in groups 1 and 2 and 3; levels
were comparable to those of the healthy controls in group 4. The highest levels of toatl TFPI were
recorded in group 5. Like total TFPI, the levels of the free form of TFPI showed a statistically
significant increase in groups 1, 2, 3 and 4, when compared with levels of healthy controls. The
highest levels of free TFPI were recorded group 5. We concluded that the elevated levels of both the
total and free TFPI in various phases of nephrotic syndrome add another natural anticoagulant
mechanism, which will attenuate the hypercoagulability of childhood nephrotic syndrome.
37. Low protein Z levels in children with nephrotic syndrome.
Ozkaya O, Bek K, Fisgin T et al.
Pediatr Nephrol.
2006 21 (8): 1122-6.
Acquired deficiency of anticoagulant proteins, due to loss in the urine, has been proposed as one of
the major thrombogenic alterations in nephrotic syndrome (NS). Protein Z (PZ) is a single-chain
vitamin K-dependent glycoprotein. Low PZ levels are reported to be a risk factor for thrombosis. The
aim of this study was to investigate protein Z and other natural anticoagulant levels in children with
NS. Thirty children aged between 1.5 and 12 years with NS (Groups I and II) and 19 age-and-sexmatched healthy controls (Group III) were enrolled into the study. Patients were divided into two
groups: Group I (proteinuria > 40 mg/m(2)/hr) and Group II (patients in remission). Plasma PZ levels in
Group I were significantly lower than Group II (p=0.009) and Group III (p=0.018). Plasma levels of AT
III for Group I were significantly lower than for Groups II and III (p=0.009, p=0.005, respectively).
Protein C levels in Group I were higher than in Group II and Group III (p=0.002. p=0.000, respectively).
Protein Z levels positively correlated with serum total protein and albumin levels (p=0.003, p=0.003,
respectively) and negatively with the degree of proteinuria (p=0.000). Protein Z levels were positively
correlated with AT III (r=0.037, p=0.04). Along with the other coagulation abnormalities, decreased
protein Z may contribute to increased risk of thromboembolic complications in children with NS. The
negative correlation between proteinuria and PZ level suggest the possibility of renal PZ loss. Further
studies are need to investigate the mechanism and role of decreased PZ in NS.
38.
Nephrotic syndrome associated with chronic graft-versus-host disease after allogenic
hematopoietic stem cell transplantation.
Reddy P, Johnson K, Uberti JP et al.
Bone Marrow Transplant.
2006 38 (5): 351-7.
Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogenic
hematopoietic cell transplantation (HCT) causing significant morbidity and mortality. The kidneys are
not considered a target organ for cGVHD in humans, although animal models show renal damage.
Renal involvement in patients with cGVHD, presenting as nephrotic syndrome (NS), has rarely been
reported in patients who received allogenic transplantation. Herein we describe, by far, the largest
series of nine patients with NS associated with cGVHD, including two patients who received a
reduced-intensity regimen. Pathological features of membranous nephropathy were the most common
finding on renal biopsy. The clinical course of the NS was temporally associated with the classical
features of cGVHD in all but one of the nine cases. The clinicopathologic features of NS in our series
as well as reports in the literature demonstrate an immunopathologic process typical of antibodymediated damage consistent with cGVHD. Treatment directed against antibody-mediated damage,
such as anti-B-cell antibody may play an important role in ameliorating NS associated with cGVHD.
39. Renal corpuscle morphometry with increased reliability and high level of automation.
Caruntu ID, Covic A.
Pathol Res Pract.
2006 Sep 6; [Epub ahead of print]
The paper presents an original computerized histometric technique for renal biopsies that outlines the
role of quantitative information in the morphologic analysis of renal corpuscle (RC). We investigated 10
cases diagnosed as rapidly progressive glomerulonephritis (RPGN) by randomly selecting 10 RCs
from each case. Our technique is based on two algorithms (implemented in the Zeiss KS400) that
process digital color images for extracting the morphometric features at two levels: (1) of a single RC
and (2) of a whole case. The algorithm operating at level (1) includes instruments especially designed
for ensuring the accuracy in the identification of the regions occupied by the RC components; it
evaluates the areas of the RC components and their percentages relative to the total area of the RC.
The novelty of the instruments lies in the usage of intermediate recoloring for multifold thresholding
segmentation and in the mutual validation of the regions provided by red-green-blue (RGB) and huelightness-saturation (HLS) segmentation. The algorithm operating at level (2) averages the data
obtained from all the RCs considered in a case. The proposed technique offers a high level of
automation; it is reliable and repeatable. The basic principles of the presented technique can also be
adapted to the histometric approaches of other patholoy domains. Results illustrate the utilization of
the technique at both levels. The extraction of the RC morphometric features allows for estabilishing a
significant correlation between the quantitative and qualitative information. This may contribute to a
better understanding of the RPGN evolution and, implicity, to the refinement of the diagnosis.
40. Mechanisms of neutrophil transmigration across renal proximal HK-2 cells.
Bijuklic K, Sturn DH, Jenning P et al.
Cell Physiol Biochem.
2006 17 (5-6): 233-44.
Background Adhesion of intratubular leukocytes to proximal tubules in biopsies of patients with
rapidly progressive glomerulonephritis and the appearance of leukocytes in the urine in interstitial
nephritis suggest interactions between leukocytes and tubular epithelia in renal diseases. The aim of
this study was to investigate the effect of cytokines and endotoxin on leukocyte migration through
proximal tubular epithelial cells and also to determine the role of the transmembrane adhesion
molecules ICAM-1 and CD47 in this process. Methods Experimets determined transepithelial
migration (TEM) of PMN (polymorphonuclear) leukocytes throgh monolayers of HK-2. Expression of
ICAM-1 and CD47 was assessed via confocal immunoflurescence, FACS analysis and western
blotting. The effect of antibodies against ICAM-1 and CD47 on TEM was examined. Results
Preincubation of HK-2 cells with either TNFalpha or LPS resulted in stimulation of PMN migration
through monolayers of HK-2 cells. There was no preferred direction of transmigration. ICAM-1 was
expressed by HK-2 cells and expression was increased after 4 h stimulation TNFalpha or LPS.
Application of ICAM-1 antibodies inhibited TEM. CD47 was expressed in both HK-2 cells and PMN.
CD47 antibodies inhibited predominantly basolateral-to-apical TEM. HK-2 cell released IL-8 and IL-6
preferably into the apical compartment. Additionally, we showed that fMLP induced transmigration
through monolayers of HK-2 cells was associated with significant increased CD47 expression on PMN
cell surfaces. Conclusions Inflammatory mediators stimulate TEM of PMN through monolayers of HK2 cells without a clearly discernible preference of direction. Mechanisms involved in TEM stimulated by
cytokines or endotoxin appear to be mainly changes in surface receptor densites of HK-2 cells with
ICAM-1 and CD47 playing an essential role.
41. Loss of podocyte dysferlin expression is associated with minimal change nephropathy.
Izzedine H, Brocheriou I, Eymard B et al.
Am J Kidney Dis.
2006 48 (1): 143-50.
We report a case of limb-girdle muscular dystrophy type 2B (LGMD2B) associated with minimal
change disease. Immunohistochemical examination of quadriceps muscle showed a deficiency in
dysferlin in sarcolemma, and dysferlin gene analysis showed 3370 G missense mutation, leading us to
the diagnosis of LGMD2B. The patients also developed glomerular proteinuria. We also explored
urinary protein levels in 3 other patients with dysferlinopathy and found microalbuminura with albumine
excretion of 0.14 to 0.18 g/d in 2 patients. Renal abnormalities during LGMD2B and kidney dysferlin
expression have been never reported. Renal biopsy showed a lack of glomerular dysferlin expression
compared with a positive immunohistochemical marking in patients with idiopathic minimal change
nephropathy and healthy controls. We therefore suggest that dysferlin is present in glomeruli and may
be associated with glomerular permeability.
42.
Proliferating cells in HIV and pamidronate-associated
glomerulosclerosis are parietal epithelial cells.
collapsing
focal
segmental
Dijkman HB, Weening JJ, Smeets B et al.
Kidney Int.
2006 70 (2): 338-44.
Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by hyperplasia of glomerular
epithelial cells. In a mouse model of FSGS and in a patient with recurrent idiopathic FSGS, we
identified the proliferating cells as parietal epithelial cells (PECs). In the present study, we have
evaluated the origin of the proliferating cells in cFSGS associated with human immundeficiency virus
(HIV) and pamidronate. We performed a detailed study of glomerular lesions in biopsies of two
patients with HIV-associated cFSGS and a nephrectomy specimen of a patients with pamidronateassociated cFSGS. Glomeruli were studied by serial sectioning using light and electron microscopy
and immunohistochemistry to determine the epithelial cell phenotype. We used Synaptopodin,
vascular endothelial growth factor, and CD10 as podocyte markers, CK8 and PAX2 as PEC markers
and Ki-67 as marker of cell proliferation. The newly deposited extracellular matrix was characterized
using antiheparan sulfate single-chain antibodies. The proliferating cell were negative for the podocyte
markers, but stained positive for the PEC markers and the cell proliferation marker Ki-67. The
proliferating PAX-2 and CK-8 positive cells that covered the capillary tuft were always in continuity with
PAX-2/CK8 positive cells lining Bowman’s capsule. The matrix deposited by these proliferating cells
stained identically to Bowman’s capsule. Our study demonstrates that PEC prolferate in HIV and
pamidronate-associated cFSGS. Our data do not support the concept of the proliferating,
dedifferentiated podocyte.
43. Cell-cycle regulatory proteins in the podocyte in collapsing glomerulopathy in children.
Srivastava T, Garola RE, Singh HK.
Kidney Int.
2006 Jun 14; [Epub ahead of print]
Podocyte is a terminally comitted cell in G (1) arrest of cell cycle, and is unable to overcome G (1) /S
transition phase in children with minimal change disease (MCD) and classic focal segmental
glomerulosclerosis (FSGS), in contrast to dysregulated proliferative phenotype of idiopathic collapsing
glomerulopathy (CGN) in adults. Forty-two kidney biopsies, MCD (14), FSGS (12), CGN (4), and
normal (CON) (12), were evaluated by immunohistochemistry using dual staining for expression of
p27, p21, and p57, and cyclins D and A, in podocytes of children with CGN. On light microscopy, all
podocytes expressed p27, whereas p21 and p57 expression was seen in a portion of podocytes in
normal kidney biopsies. Cyclin D was expressed in a small percentage of podocytes. Cyclin A
expression was absent in normal biopsies. The staining for p27 decreased significantly, in order, from
normal (100%) to MCD (45.8%) to CGN (24.2%) to FSGS (16.6%). P21 staining was a signifcantly
decreased from normal (69.8%) to CGN (15.5%) to MCD (2.2%) to FSGS (0.6%), and the difference
between CGN and MCD and FSGS was also significant. There was no significant difference in
staining of p57. Cyclin D staining was significantly increased in CGN (26.8%) compared to normal
(7.2%), MCD (1.6%), and FSGS (0.0%), and the difference between CGN and MCD and FSGS was
also significant. De novo cyclin A staining was only observed in children with CGN. Thus, p27 and p21
but not p57 was decreased in CGN, as in FSGS when compared to normal. Both cyclins D and A
staining were increased in CGN. The staining pattern in CGN would suggest that podocyte is able
overcome G (1)/S transition phase, and has a proliferative phenotype. We propose, based on the
significant contrast observed in podocytes injury response between CGN (proliferative) and classic
FSGS (non-proliferative), that CGN not be considered as a morphological variant of FSGS.
44. Glomerular clusterin is associated with PKC-alpha/beta regulation and good outcome of
membranous glomerulonephritis in human.
Rastaldi MP, Candiano G, Musante L et al.
Kidney Int.
2006 Jun 14; [Epub ahead of print]
Mechanisms for human membranous glomerulonephritis (MGN) remain elusive. Most up-to-date
concepts still rely on the rat model of Passive Heyman Nephritis that derives from an autoimmune
response to glomerular megalin, with complement activation and membrane attack complex assembly.
Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been
clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies
against clusterin. C5b-9, and phosphorylated-protein kinase C (PKC) isoforms (pPKC). In vitro
experiments were performed to investigate the role of clusterin during podocyte damage by MGN
serum and define clusterin binding to human podocytes, where megalin is known to be absent.
Clusterin, C5b-9, and pPKC-alpha/beta showed highly variable glomerular staining, where high
clusterin profiles were inversely correlated to C5b-9 and PKC-alpha/beta expression (P=0.029), and
co-localized with low-density lipoprotein receptos (LDL-R). Glomerular clusterin emerged as the single
factor influencing proteinuria at multivariate analysis and was associated with a reduction of
proteinuria after a follow-up of 1.5 years (-88.1%), P=0.027). Incubation of podocytes with MGN sera
determined strong upregulation of pPKC-alpha/bet that was reverted by pre-incubation clusterin,
serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte
binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDLR antibodies and with specific ligands. These data suggest a central role of glomerular clusterin in
MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of
clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.
45. Study on hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B
virus-associated membranous nephropathy.
Kim SE, Park YH, Chung WY.
Pediatr Nephrol.
2006 21 (8): 1097-103.
This study aims to clarify the prevalence and significance of the emergence of hepatitis B virus (HBV)
pre-S/S mutations in children with hepatitis B virus-associated membranous nephropathy (HBVMN).
Direct sequencing of polymerase chain reaction products of renal tissue samples that were obtained
via percutaneous renal biopsy from seven children revealed the presence of HBV DNA. Seven adr
subtypes were analyzed. Deletions in the HBV pre-S region were observed once per seven patients.
The deletion were noted in both the pre-S1 (27 bp) and pre-S2 (60 bp) regions. Various point
mutations in the HBV pre-S region were detected in all seven patients and proved to be more frequent
in the pre-S1 region than in the S2 region. Point mutations in the HBV S region were detected in six
patients. Among these mutations, the mutation in the „a” determinant region was noted in five patients.
No deletion, however, was observed in the HBV S region. These observation suggested that deletions
and point mutations in the HBV pre-S1 and pre-S2 regions and point mutations in the HBV S region,
especially the „a” determinant region, are common frequent findings. These results also suggested
that HBV pre-S/S region mutation may be involved in the pathogenesis in children with HBVMN.
46. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are
associated with membranoproliferative glomerulonephritis type II (dense deposit disease).
Abrera-Abeleda MA, Nishimura C, Smith JL et al.
J Med Genet.
2006 43 (7): 582-9.
Introduction Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN
II/DDD) causes chronic renal dysfubnction that progressed to end stage renal disease in about half of
patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH)
gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the
alternative pathway of the complement cascade is important in disease pathophysiology. Subjects
Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and
CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was
compromised of 131 people in whom age related macular degeneration had been excluded. Results
Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were
significantly different between MPGN II/DDD patients and controls. Conclusion We have identified
specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype.
While our data can be interpretated to further implicate complement in the pathogenesis of MPGN
II/DDD, these associations could also be unrelated to disease pathophysiology.
47.
Mycoplasma pneumoniae detection with PCR in renal tissue of a patient with acute
glomerulonephritis.
Del Carmen Laso M, Cadario ME, Haymes L et al.
Pediatr Nephrol.
2006 Jul 4; [Epub ahead of print]
Renal disease concurrent with a Mycoplasma pneumoniae infection is uncommon. In this report we
describe the clinical outcome of a 6-year-old patient who presented with rapidly progressive
glomerulonephritis that required dialysis. A kidney biopsy was performed, and the results revealed
membranoprolierative glomerulonephritis. The IgM serology was positive, and M. pneumoniae DNA
was detected in a renal biopsy sample using a nested-PCR assay. The outcome was good.
48. Relationship between PAI-1 gene 4G/5G polymorphism and clinical profile of IgA nephropathy.
Ding R, Chen X, Liu S et al.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi.
2006 23 (4): 449-51.
Objective It is clear that PAI-1 is a very important factor inhibiting extracellular matrix (ECM)
degradation in the pathology process of IgA nephropathy (IgAN), so we design to investigate the
relationship between PAI-1 promoter 4G/5G polymorphism and IgAN pathogenesis and progression.
Methods Clinical baseline data such as blood pressure, urinary protein excretion, serum profile, and
extent of renal tissue damage at the time of renal biopsy were collected. The genotypes of PAI-1 were
profiled by PCR-RFLP. Results (1) The distribution of genotype 4G4G, 4G5G, 5G5G in PAI-1 gene
promoter showed no significant difference between the IgAN group (0.33, 0.19, 0.48) and control
group (0.3, 0.23, 0.47uchi-square = 1.63, P > 0.05); (2) There is an increasing frequency of 4G4G
homozygote in the IgAN group who had severe pathology change proved by biopsy (0.39 vs 0.28uchisquare = 7.86, P < 0.05); in the patients group, the ones who carried 4g4G genotype got lower Ccr
than 4G5G genotype cases did (P < 0.05). Conclusion The data here suggest that the 4G/5G
polymorphism of PAI-1 is not a risk factor in IgAN etiology, but may facilitate the process of IgAN to
end stage renal disease.
49. Impact of selectin gene polymorphisms on rapid progression to end-stage renal disease in
patients with IgA nephropathy.
Watanabe Y, Inoue T, Okada H et al.
Intern Med.
2006 45 (16): 947-51.
Objective It is evident that leukocyte infiltration plays an important role in the pathogenesis of IgA
nephropathy (IgAN). Selectin is one of the key adhesion molecules involved in leukocyte infiltration.
Recent studies demonstrated a significant association between the selectin gene polymorphisms and
susceptibility to IgAN. However, the impact of selectin gene polymorphisms on the progression to endstage renal disease (ESRD) has not been studied. Patients and Methods To evaluate the influence
of the selectin gene polymorphisms on the progression of IgAN, we designed specific primers for PCR
genotyping and analyzed the association of selectin gene polymorphisms with the declining rate in
renal function to its ESRD. Results A total of 61 hemodialysis patients were enrolled in the study. The
mean age at renal biopsy was 33.0 +/- 13.3 years old, and the mean age at the start of hemodialysis
was 41.2 +/- 13.8 years old. The mean interval between the time points of renal biopsy and the start of
hemodialysis was 8.2 +/- 6.5 years (ranging from 0 to 33 years). The interval was significantly longer
in IgAN patients with a homoallele of C in C1402T, C1402/C1402, of the E-selectin gene, or a
homoallele of C in C712T, C712/C712, of the L-selectin gene compared to others. The haplotype,
which is a combination of C1402/C1402 and C712/C712, is able to distinguish the group that is at
least a better prognosis than the severest prognostic one. Conclusion This study provides a possible
association between the selectin gene polymorphisms and the rapid progression to ESRD in IgAN
patients.
50. Association of uteroglobin G38A polymorphism with IgA nephropathy: A meta analysis.
Yong D, QingQing W, Hua L et al.
Am J Kidney Dis.
2006 48 (1): 1-7.
Both uteroglobin knockout and antisense transgenic mice develop pathological and clinical features
similar to immunoglobulin A (IgA) nephropathy. However, several association studies of uteroglobin
G38A polymorphism and IgA nephropathy showed controversial findings. We used meta-analysis to
assess the impact of the uteroglobin G38A polymorphism on susceptibility to and progression of IgA
nephropathy. Six studies involving uteroglobin G38A genotyping of 930 patients with IgA nephropathy
and 768 healthy controls were included. No significant publication bias was found (Egger’s linear
regression, P = 0.763; 95% confidence interval [CI], -0.610 to 0.476). All control samples were in
Hardy-Weinberg proportion. No association between the AA genotype and risk for IgA nephropathy
relative to both other genotypes (odds ratio [OR], 1.05; 95% CI, 0.71 to 1.54) or A allele and risk for
IgA nephropathy (OR, 0.96; 95%; CI, 0.84 to 1.11) were shown in the total meta-analysis. In both
Asian and European subgroups, the overall effect of the AA genotype and A allele also showed no
significant difference. There also was no significant association between uteroglobin AA genotype or A
allele and IgA nephropathy progression (OR, 3.62; 95% CI, 0.59 to 22.34; OR, 2.19, 95% CI, 0.37 to
13.14, respectively). We suggest that uteroglobin G38A polymorphism is not related to the
development and progression of IgA nephropathy.
51. Roles of TGF-beta1 and apoptosis in the progression of glomerulosclerosis in human IgA
nephropathy.
Chihara Y, Ono H, Ishimitsu T et al.
Clin Nephrol.
2006 65 (6): 385-92.
Apoptotic glomerular cells have been detected in the severely damaged glomeruli that are a
consequence of human IgA nephropathy. Transforming growth factor-(TGF) beta1 is known to induce
apoptosis in cultured mesangial cells. To clarify whether TGF-beta1 contribute to the progression of
IgA nephropathy by activating apoptosis in glomerular cells, we examined the expression of TGFbeta1 gene and apoptotic changes in kidney biopsy samples, and assessed those relations to the
severity of nephropathy. 32 patients with IgA nephropathy, showing proteinuria (> 1 g/day) and serum
creatinine less than 1.5 mg/dl were classified according to glomerular sclerosis index (GSI) into 3
groups (Group I: GSI < 0.3, Group II: 0.3 < or = GSI < 1.0, Group III: GSI > or = 1.0). Computer-aided
morphometry of glomeruli and arteries, and terminal deoxynucleotidyl transferase-mediated dUTP nick
end labeling of fragmented DNA (TUNEL) staining were performed. Expression of TGF-beta1 and
caspase-3 mRNAs in renal biopsy samples was analyzed by real-time PCR (Taq Man method).
Increased glomerular area, interstitial fibrosis, lymphocytic infiltration, and tubulointerstitial changes
were observed to accompany increased severity of GSI. TUNEL index was higher in Group III. The
levels of TG-beta1 and caspase-3 mRNAs were significantly increased in Group III (183 and 190%,
respectively). Furthermore, caspase-3 mRNA levels were tightly associated with TGF-beta1 mRNA
expression (r = 0.677, p < 0.0001). The present study suggest that the activation of TGF-beta1 plays a
role in the progression of IgA nephropathy even in the moderate degree of glomerular injury, in part via
activation of apoptosis of glomerular cells.
52. Histological differences in newly onset IgA nephropathy between children and adults.
Ikezumi Y, Suzuki T, Imai N et al.
Nephrol Dial Transplant.
2006 Aug 25; [Epub ahead of print]
Background It is suggested that IgA nephropathy (IgAN) manifest differently in children vs adults on
the basis of biopsy findings. However, this has been difficult to estabilish owing to the uncertainty of
the timing of disease onset in adult IgAN. We addressed this question by comparing both histology
and leukocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. Methods
Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of
age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in
mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and
interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of
macrophages, activated macrophages and T cells by immunohistochemistry. Results Glomerular
hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and
significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation
and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular
hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular
matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of
C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater
in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+
activated macrophages were identified in both paediatric and adult IgAN, being significantly greater
number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial
leukocyte infiltration correlated with interstitial damage in both groups. However, only the subset of
Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and
glomerular matrix. Conclusions This study has demonstrated significant differences in the early
glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are
implicated in the pathogenesis of IgAN in both patients groups. The prognostic significance of these
findings warrants further study.
53. 24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of
NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes.
Fava C, von Wowern F, Berglund G et al.
Kidney Int.
2006 Jun 21; [Epub ahead of print]
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood
pressure regulation. This locus harbors the neural precusor cell expressed developmentally
downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloridesensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single
nucleotide polymorphism markers located the NEDD4L gene) on chromosome 18 between 70-104 cM
and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found 24
h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population
sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by
alternative splicing leads to varying expression of a functional crucial C2 domain, was associated with
diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype
combination of the rs4149601and an intronic NEDD4L marker (rs2288774) was associated with
systolic blood pressure (SBP) (P=0.01), DBP (P=0.04) and progression of both SBP (P=0.03) and
DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the
rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In
conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by
genetic NEDD4L variation affecting cross-sectional and longitudinal blood presure, possibly as a
consequence of altered NEDD4L interaction with ENaC.
54. Research into the glomerular podocyte - is it relevant to diabetic nephropathy?
White KE.
Diabet Med.
2006 23 (7): 715-9.
The cause of proteinuria in renal disease is the subject of intensive research and, latterly, the
podocyte, a specialized epithelial cell of the kidney glomerulus, has been the focus of much of this
endeavour. It is a complex cell with functions and structural features that have an important role in the
development of proteinuria. This review explores some of the charcateristics of the podocyte and how
abnormalities of its structure and function may have particular relevance to the development and
progression of clinical diabetic nephropathy.
55. A disease hyplotype for advanced nephropathy in type 2 diabetes at the ACE locus.
Ng DP, Placha G, Choo S et al.
Diabetes.
2006 55 (9): 2660-3.
Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have
primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier
studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for
disease haplotype association. A case-control study design was used where case subjects were type
2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or
chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >
6 years of diabetes. None of the individual markers showed significant disease association when
considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of
the A.T.D risk haplotype in case subjects (0.136). compared with control subjects (0.075) (P = 0.009),
thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE
locus.
56. Impact of renin angiotensin system modulation on the hyperfiltration state in type 1 diabetes.
Sochett EB, Cherney DZ, Curtis JR et al.
J Am Soc Nephrol.
2006 17 (6): 1703-9.
The initial stage of diabetic nephropathy are characterized by glomerular hyperfiltration and
hypertension, processes that have been linked to initiation and progression of renal disease. Renin
angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay
progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting
heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in
adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the
presence of hyperfiltration. Baseline renal hemodynamic function was charaterized in 22 patients.
Eleven patients exhibited glomerular hyperfiltration (GFR >/= 135 ml/min), and in the remaining 11
patients, the GFR was <130 ml/min. Renal hemodynamic function was assesed in response to a
graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of
angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic
conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but
not the normofiltration group. After ACE inhbition, GFR fell but did not normalize in the hyperfiltration
group; the normofiltration group showed no change. These data show signifcant differences in renal
hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at
baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in
hyperfiltering patients suggest that vasodilation may complement RAS activation in causing the
hyperiltration state. The interaction between glomerular vasoconstrictors and vasodilators require
examination in future studies.
57. The relationship between genetic and haemodynamic factors in diabetic nephropathy (DN): Casecontrol study in type 1 diabetes mellitus (T1DM).
Shestakova MV, Vikulova OK, Gorashko NM et al.
Diabetes Res Clin Pract.
2006 Jul 24; [Epub ahead of print]
The development and progression of diabetic nephropathy shows the significant variation between
individuals and different ethnic groups and is known to have multiple risk factors. Chronic
hyperglycemia, glomerular and systemic hypertension, hyperlipidemia has been shown to play an
important roles as well as genetic factors. The relationship between genetically determined
polymorphic nature of metabolic and haemodynamic disorders and DN development have been
suggested. This case-control study was performed to evaluate gene polymorphisms effect on
development and progression of DN in T1DM. Using candidate gene approach we have studied
polymorphic markers in genes encoding the potential mediators of renal injury: I/D in ACE gene; A (1903G) in chymase gene (CMA1); M235T in angiotensinogen gene (AGT); A1166C in the angiotensin
II receptor, subtype 1 gene (AT2R1) and ecNOSa/4b in the endothelial NO-synthase gene (NOS3). To
reduce the probable masking effect of non-genetic factors the non-overlapping inclusion criteria for
group formation were used: 66 normoalbuminuric patients with long-standing T1DM >/= 20 years
(DN’’-”) 63 with overt DN and T1DM </= 15 years (DN’’+’’) and 96 healthy subjects. To clarify the
factors contributing to DN progression we have segreagetd DN’’+’’ patients into two subgroups: (1)
CRF’’-’’, n = 32 with stable renal function and (2) CRF’’+’’, n = 31 with progression to chronic renal
failure during the same period of T1DM duration. We observed significant difference in allele/genotype
frequencies between DN’’+’’and DN’’-’’ in gene NOS3: 4a/4b (76.2% versus 47.0%, OR = 3.61), 4b/4b
(22.2% versus 51.5%, OR = 0.27) and also in DN’’-’’compared to DN’’+’’ and healthy subjects in ACE
gene: II and DD genotype (36.4% verus 23.8% versus 13.5%, OR = 0.55 and 18.2% versus 20.6%
versus 41.7%, OR = 1.17, respectively). For CMA1, AGT and AT2R1 genes we have not found
significant differences in allele/genotype distribution. CRF””-’’and CRF’’+’’ patients were not differed in
alleles/genotypes frequencies as well as in sex distribution, age, aget at DM onset, DM duration,
HbA1c and serum lipids level. GFR decline (1.3 (ml/min)/1.73 (m(2)/yr) versus 11.2 (ml/min)/1.73
(m(2)/yr) ) was strongly associated with blood pressure (124/79 versus 145/93 and use of
antihypertensive agents (ACE inhibitors: 84.4% versus 55.2%; other agents: 9.4% versus 13.8%; 6.2%
versus 31.0% had no antihypertensive treatment). We conclude that gene polymorphisms involved in
production of angiotensin II and nitric oxide might contribute to the susceptibility to early DN onset,
while hypertension is the factor of rapid DN progression.
58. Connective tissue growth factor plays an important role in advanced glycation end product-induced
tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease.
Burns WC, Twigg SM, Forbes JM et al.
J Am Soc Nephrol.
2006 17 (9): 2484-94.
Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of
matrix protein that is associated with diabetic nephropathy. Both TGF-beta1 and advanced glycation
end products (AGE) are able to induce EMT in cell culture. This study examined the role of the
prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these
processes. EMT was assessed by the expression of alpha-smooth muscle actin, vimetin, E-cadherin,
and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an
adenovirus or as recombinant human CTGF (25 ng/ml), was shown to induce a partial EMT. This was
not blocked by neutralizing anti-TGF-beta1 antibodies, suggesting that this action was TGF-beta1
independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 muM) or TGFbeta1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and
protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated
phenotypic changes after treatment with AGE or TGF-beta1. These in vitro effects correlate with the in
vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular
epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF
expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF
represents an important independent mediator of tubular EMT, downstream of the actions of AGE or
TGF-beta1. This interaction is likely to play an important role in progressive diabetic nephropathy and
strengthens the rationale to consider CTGF as a potential target for treatment of diabetic nephropathy.
59. Aberrant heparan sulfate profile in the human diabetic kidney offers new clues for therapeutic
glycomimetics.
Wijnhoven TJ, Lensen JF, Rops AL et al.
Am J Kidney Dis.
2006 48 (2): 250-61.
Background Diabetic nephropathy poses an increasing health problem in the Western world, and
research to new leads for diagnosis and therapy is warranted. In this respect, heparan sulfates (HSs)
offer new possibilities because crude mixture of these polysaccharides are capable of ameliorating
proteinuria. The aim of this study is to immuno(histo)chemically profile HSs from microalbuminuric
kidneys from patients with type 1 diabetes and identify specific structural HS alterations associated
with early diabetic nephropathy. Methods Renal cryosections of control subjects and patients with
type 1 diabetes were analyzed immunohistochemically by using a set of 10 unique phage displayderived anti-HS antibodies. HS structures defined by relevant antibodies were characterized
chemically by means of enzyme-linked immunosorbent assay and probed for growth factor binding
and presence in HS/heparin-containing drugs. Results In all patients, HS structure defined by the
antibody LKIV69 consistently increased in basement membranes of proximal tubules. This structure
contained N- and 2-O-sulfates and was involved in fibroblast growth factor 2 binding. It was present in
HS/heparin-containing drugs shown to decrease albuminuria in patients with diabetes. The HS
structure defined by the antibody HS4C3 increased in the mesangium of some patients, especially
those who developed macroalbuminuria within 8 to 10 years. This structure contained N- and 6-Osulfates. For 8 other antibodies, no major differences were observed. Conclusion Specific structurasl
alterations in HSs are associated with early diabetic nephropathy and may offer new leads for early
diagnosis and the rational design of therapeutic glycomimetics.
60.
Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3-455T>C
polymorphisms on the susceptibility to diabetic nephropathy.
Ng M, Baum L, So WY et al.
Clin Genet.
2006 70 (1): 20-8.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride
(TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The
LPL S447X and apolipoprotein E (APOE) exon 4 polymorphisms affect TG levels, and the APOC3455T>C polymorphism affects LPL activity. Our aim was to examine the association of these
polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a casecontrol study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447Xcontaining genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio
(OR) = 0.66, p = 0.021], as were APOE3/3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In
addition, combination of genotypes [APOE3/3 and lPL 447+ (OR = 0.56), APOC3 CC and LPL 447+
(OR = 0.31), APOE3/3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most
common combination of the respective polymorphisms. Our findings suggest the importance of
interactions among lipid genes in modulating the risk of DN.
61. MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of
diabetic nephropathy in type 2 diabetes patients.
Mtiraoui N, Ezzidi I, Chaieb M et al.
Diabetes Res Clin Pract.
2006 Jul 4; [Epub ahead of print]
Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were
implicated in the pathogensis of diabetic nephropathy (DN) in many ethnic groups. This study
addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR
gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients,
267 patients with normoalbuminuria, and 400 control subjects. C677T and A1298C genotypes were
determined by PCR-RFLP analysis, and homocysteine levels were measured by ELISA. A1298C and
C677T were highly prevalent among T2DM patients, with allele frequencies of 0.26 and 0.36,
respectively. Higher mutant 677T allele and 677C/T and 677T/T SNP, not A1298C SNP, together with
677C/1298A, 677T/1298A haplotypes were seen in DN patients compared to normoalbuminuric
patients, (p<0.001). Plasma homocysteine was positively associated with MTHFR 677T/T genotype
among the tree groups, and was significantly elevated in double heterozygous DN patients but not in
normoalbuminuric patients and controls. Logistic regression analysis with DN as dependent variable
showed that homocysteine (OR, 1.153) and MTHFR 677T/T (OR, 9.799) were the only variables
associated with DN, after adjusting for possible confounding variables. C677T, but mot A1298C, SNP,
is a risk factor for DN, presumably acting by elevating homocysteine levels.
62. Redistribution of connexin 43 expression in glomerular podocytes predicts poor renal prognosis in
patients with type 2 diabetes and overt nephropathy.
Sawai K, Mukoyama M, Mori K et al.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
Background Significance of podocyte injury in the progression of diabetic nephropathy is not wellunderstood. In this study, we examined whether alteration of gap junction protein connexin43 (Cx43)
expression in podocyte is associated with the progression of overt diabetic nephropathy. Methods We
recruited 29 type 2 diabetic patients with overt nephropathy who underwent renal biopsy.
Nephrectomized kidney obtained from seven subjects with localized neoplasm and biopsy specimen
from five patients diagnosed as minor glomerular abnormalities were used as control. Cx43 staining on
pareffin-embedded kidney sections were studied by immunohistochemistry. Results In controls, Cx43
was expressed at podocytes in a linear pattern along the glomerular basement membrane. In contrast,
downregulation and loss of uniformly liner staining of Cx43 (Cx43 heterogeneity) in podocytes were
observed in diabetic nephropathy. Cx43 intensity correlated with current renal function (R = 0.647, P <
0.005), whereas the magnitude of Cx43 heterogeneity correlated well with degree of future decline in
renal function (R = 0.705, P < 0.001). Conclusions Alteration of Cx43 expression in podocytes was
closely associated with the progression of overt diabetic nephropathy. These results indicate taht
change in Cx43 expression at podocytes a progressive stage in overt diabetic nephropathy and that it
may be a convenient way to predict future decline in renal function.
63. ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease.
Caglar K, Yilmaz MI, Sonmez A et al.
Kidney Int.
2006 Jul 5; [Epub ahead of print]
The rationale of this study is based onthe fact that, both proteinuria and elevated asymmetric dimethyl
arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not
enough knowledge about any association between the levels of proteinuria and ADMA levels.
Seventy-eight non-diabetic patients (42 men, 36 women, mean age of 26.1 +/- 5.2 years) with
proteinuria having normal glomerular filtration rate enrolled along with 38 healthy subjects (20 men, 18
women, mean age 26.9 +/- 5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5
g/day in 38 patients. Both groups had similar age, gender, body mass index distribution. Serum
ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive
protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model
assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were
significantly higher in patients than in healthy control subjects. The above parameters were higher in
the nephrotic range proteinuria group when compared to patients having protein levels below 3.5
g/day. There were significant correlations between the levels of proteinuria and the above parameters.
According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of
serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly
associated with proteinuria. Further studies are recommended to find out whether elevated ADMA
levels are implicated in the high cardiovascular risk of proteinuric nephropathies.
64. Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and
senescent phenotypes in type 2 diabetes.
Sampson MJ, Hughes DA.
Diabetologia.
2006 49 (8): 1726-31.
Telomeres are the repeat DNA sequences at the end of chromosome necessary for succesful DNA
replication and chromosomal integrity. Telomeres shorten at cell division at a rate determined by
oxidative DNA damage, and cells are triggered into replicative senescence once telomeres shorten to
a critical lenght. Telomer-related chromosomal maintenace also has a role in carcinogenesis. Type 2
diabetes is charcaterised by increased oxidative stress, increased oxidative DNA damage, senescent
retinal and renal phenotypes, and increased risk of epithelial mailgnancy. We suggest that increased
oxidative DNA damage and telomere attrition in type 2 diabetes leads to: (1) carcinogenic telomeredependent chromosomal non-reciprocal translocations, genomic instability, and the development of
epithelial cancers; (2) senescent retinal and renal phenotypes (expressed diabetic retinopathy and
nephropathy); and (3) senescent vascular endothelial, monocyte-macrophage and vascular smooth
muscle cells (expressed as endothelial dysfunction and accelerated atherogenesis). An adverse
intrauterine environment leads to increased feto-maternal oxidative stress and feto-placental oxidative
DNA damage. We also suggest that intrauterine oxidative DNA damageand telomere shortening is
another point at which increased oxidative stress could contribute to a pre-programmed increased risk
of senescent phenotypes in adult offspring, charcaterised by type 2 diabetes and epithelial
malignancy. These suggestions can be used to understand early glucose intolerance in the young
children of type 1 diabetes pregnancies, poor cancer outcomes in type 2 diabetes, beta cell fatigue in
type 2 diabetes and the absence of increased epithelial cancer risk in type 1 diabetes.
65. Lipotoxicity.
Weinberg JM.
Kidney Int.
2006 Sep 6; [Epub ahead of print]
Excess fatty acids accompained by triglyceride accumulation in parenchymal cells of multiple tissues
including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic
cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many
manifestations of the ’metabolic syndrome’. Most data suggest that the triglycerides serve primarily a
storage function with toxicity deriving mainly from long-chain nonesterified fatty acids (NEFA) and their
products such as ceramides and diacylglycerols. In the kidney, filtered NEFA carried on albumin can
aggravate the chronic tubule damage and inflammatory phenotype that develop during proteinuric
states and lipid loading of both glomerular and tubular cells is a common response to renal injury that
contributes to progression of nephropathy. NEFA-induced mitochondrial dysfunction is the primary
mechanism for energetic failure of proximal tubules during hypoxia/reoxygenation and persistent
increase of tubule cell NEFA and triglycerides occur during acute renal failure in vivo in association
with downregulation of mitochondrial and peroxisomal enzymes of beta oxidation. In acute renal failure
models, peroxisome proliferator-activated receptor alpha ligand treatment can ameliorate the NEFA
and triglyceride accumulation and limits tissue injury likely via both direct tubule actions and antiinflammatory effects. Both acute and chronic kidney disease are associated with systemic
manifestations of the metabolic syndrome.
66.
Alterations of uromodulin biology: A common denominator of genetically heterogenous
FJHN/MCKD syndrome.
Vylet’al P, Kublova M, Kalbacova M et al.
Kidney Int.
2006 70 (6): 1155-69.
Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are
hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary
cystic kidney disease type 1 and type 2. In some families the disease is associated with mutations of
the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s)
leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant
biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin
gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical
and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease.
Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct
glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the
plasma membrane, which corresponded with the observations in the patient’s kidney tissue. We found
a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families.
This was associated with case-specific differences in the uromodulin immunohistochemical staining
patterns in kidney. Our results suggest that various genetic defect interfere with uromodulin biology,
which could lead to the development of the common disease phenotype. ’Uromodulin-associated
kidney disease’ may be thus a more appropriate term for this syndrome.
67. Update on HIV-associated nephropathy.
Shah SN, He CJ, Klotman P.
Curr Opin Nephrol Hypertens.
2006 15 (4): 450-5.
Purpose of review HIV-associated nephropaty is characterized by a constellation of pathologic
findings a collapsing glomerulopathy, tubular dialatation, and interstitial infiltration with leukocytes. This
review summarizes some of the recent advances in our understanding of the gene products and
signaling pathways that contribute to the pathogenesis of HIV-associated nephropathy. Recent
findings Podocytes infected with HIV-associated nephropathy exhibit podocyte proliferation and dediffrentiation. Restriction of HIV-1 transgene expression to the podocyte in a murine model supports
the belief that podocyte infection is pivotal to the development of the disease. Recent studies have
provided compelling in-vitro and in-vivo evidence that expression of the HIV-1 accessory gene nef is
critical in altering the phenotype of mature podocytes and causing injury to these cells. An in-vitro
study suggest that nef’s effects in the podocyte appear to be mediated through Scr kinase-dependent
activation of the signal transducer and activator of transcription 3 and mitogen-activated protein kinase
1,2 signaling pathways. Summary Recent evidence demonstrates that the viral protein nef plays a
critical role in the development of HIV-associated nephropathy and provides a foundation for
developing new therapeutic strategies for patients afflicted with this disease.
68. Quantitative imaging of basic functions in renal (patho)physiology.
Kang JJ, Toma I, Sipos A et al.
Am J Physiol Renal Physiol.
2006 291 (2): F495-502.
Multiphoton fluorescence microscopy offers the advantages of deep optical sectioning of living tissue
with minimal phototoxicity and high optical resolution. More importantly, dynamic process and multiple
functions of an intact organ can be visualized in real time using non-invasive methods, and quantified.
These studies aimed to extend existing methods of multiphoton fluorescence imaging to directly
observed and quantify basic physiological parameters of the kidney including glomerular filtration rate
(GFR) and permeability, blood flow, urinary concentration/dilution, renin content and release, as well
as more integrated and complex functions like the tubuloglomerular feedback (TGF)-mediated
oscillations in glomerular filtration and tubular flow. Streptozotocin-induced diabetes significantly
increased single-nephron GFR (SNGFR) from 32.4 +/- 0.4 to 59.5 +/- 2.5 nl/min and glomerular
permeability to a 70-kDa fluorophore approximately eightfold. The loop diuretic furosemide 2-fold
diluted and increased approximately 10-fold the volume distal tubular fluid, while also causing the
release of 20% of juxtraglomerular renin content. Significantly higher speeds of individual red blood
cells were measured in intraglomerular capillaries (16.7 +/- 0.4 mm/s) compared with peritubular
vessels (4.7 +/- 0.2 mm/s). regular periods of glomerular contraction-relaxation were observed,
resulting in oscillations of filtration and tubular flow rate. Oscillations in proximal and distal tubular flow
showed similar cycle times (approximately 45 s) to glomerular filtration, with a delay of approximately
5-10 and 25-30 s, respectively. These innovative technologies provide the most complex, immediate,
and dynamic portrayal of renal function, clearly depicting the components and mechanisms involved in
normal physiology and pathophysiology.
III.
CLINICAL PRESENTATION
1. Cardiovascular biomarkers in CKD: Pathophysiology and implications for clinical management of
cardiac disesase.
Roberts MA, Hare DL, Ratnaike S et al.
Am J Kidney Dis.
2006 48 (3): 341-60.
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with all forms
chronic kidney disease (CKD). The underlying pathological state is caused by a complex interplay of
traditional and nontraditional risk factors that results in atherosclerosis, and altered cardiac
morphological characteristics. This multifactoral disease introduces new challenges in predicting and
treating patients with CVD sufficiently early in the course of CKD to positively alter patients outcome.
Asymptomatic individuals with progressive CVD are a group of patients that deserve focused attention
because early detection and intervention may provide the best opportunity for improved outcome.
However, identifying CVD in asymptomatic patients with CKD or end-stage renal disease remains a
significant hurdle in the management of these patients. Recently, a number of cardiovascular
biomarkers were identified as predictors of patient outcome in individuals with CVD and, with
additional research, may be used to guide the early diagnosis of and therapy for CVD in patients with
CKD. This review examines the pathophysiological characteristics and potential clinical role of these
novel cardiovascular biomarkers in risk stratification, risk monitoring, and selection of preventing
therapies for patients with CKD.
2. Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress.
Schaufele TG, Schlaich MP, Delles C et al.
Kidney Int.
2006 Aug 2; [Epub ahead of print]
Endothelial dysfunction has been found to be linked to and predictive of cardiovascular events.
Whether endothelial function of the renal vasculature is impaired in patients with chronic kidney
disease and whether oxidative stress is of importance in this setting has not yet benn determined. In
this study, endothelial function of the renal vasculature was investigated in 25 patients with chronic
glomerular disease and 50 control subjects matched for age and blood pressure. Renal plasma flow
(RPF) and glomerular filtration rate were measured by constant infusion input clearence technique at
baseline and following infusions of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-Larginine (L-NMMA, 4.25 mg/kg), the substrate of NOS L-arginine (100 mg/kg) and the antioxidant
vitamin C (3 g co-infused with L-arginine 100 mg/kg). At baseline, RPF was similar in the two groups.
The reduction in RPF in response to L-NMMA was less pronounced in patients with chronic glomerular
disease compared to control subjects (-4.6 +/- 12 vs -9.8 +/- 9%; P = 0.040), indicating reduced basal
nitric oxide (NO) activity in chronic glomerular disease. Co-infusion of the antioxidant vitamin C on top
of L-arginine induced a more pronounced increase in RPF in patients with chronic glomerular disease
than in control subjects (21.7 +/- 17 vs 10.9 +/- 22%; P = 0.036). our findings suggest that basal NO
activity of the renal vasculature is reduced in patients with chronic glomerular disease compared to
age- and blood pressure-matched control subjects. This might be in part related to increased oxidative
stress.
3. Microalbuminuria as an early marker for cardiovascular disease.
de Zeeuw D, Parving HH, Henning RH.
J Am Soc Nephrol.
2006 17 (8): 2100-5.
Excretion of albumin in the urine is highly varible, ranging from nondetectable quantities to milligrams
of albumin and even grams of albumin. Microalbuminuria is defined as low levels of urinary albumin
excretion of 30 to 300 mg/day. Microalbuminuria is highly prevalent; in hypertensive and diabetic
populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found
frequently in seemingly healthy individuals (5 to 7%). The variable excretion of albumin in the urine is
related to the risk for the individual to develop cardiovascular (CV) disease: Absence or very low levels
of albuminuria is associated with low CV risk, whereas the CV risk increases markedly with increasing
amount of albumin in the urine (even within the now considered normal range). The predictive power
of urinary albumin levels for CV risk is independent of other CV risk factors and not only is present in
individuals with diabetes and/or hypertension but aslso in healthy individuals. Treatment that lower
albuminuria are associated with CV protection, as demonstrated in randomized, controlled trials of
patients with diabetes as well as in patients with hypertension. There is preliminary evidence that
albuminuria lowering is CV protective in healthy individuals with an elevated albumin excretion rate.
Differences between individuals in their level of albumin excretion are already observed at a very early
age (just after birth). In fact, the interindividual variability seems to be relatively constant in the first 5
decades of life, indicating that microalbuminuria is not necessarily a consequence of vascular damage
at later age. Higher levels of urinary albumin seem to reflect the ordinary intervidual variability in (renal
and systemic) endothelial function. Experimental data show that between strains and even within
strains, rats at young age show a remarkable difference in individual endothelial function, and this
strongly related to susceptibility of that rat to organ damage. In conclusion, albuminuria seems to be a
sensitive marker very early in life for the susceptibility of an individual to CV disease. It therefore may
be an ideal target for early primary prevention using CV-protective therapy regimens.
4. Macroalbuminuria is a better risk marker than low estimated GFR to identify individuals at risk for
accelerated GFR loss in population screening.
Halbesma N, Kuiken DS, Brantsma AH et al.
J Am Soc Nephrol.
2006 Aug 9; [Epub ahead of print]
Macroalbuminuria, erythrocyturia, and impaired renal function are strong predictors of poor renal
outcome in patients with known renal disease. However, the yield of mass screening for these
variables to identify individuals who are at risk for GFR loss is yet unknown in a Western population.
With the use of data from the Prevention of Renal and Vascular End-Stage Disease (PREVEND)
study, a prospective, population-based cohort study, the cardiovascular and renal prognosis was
investigated in patients with classical risk markers: Macroalbuminuria (>/= 300 mg albumin/24 h urine),
erythrocyturia (>/= 250/L, without leukocyturia), and impaired renal function (both 24-h creatinine
clearence and Modification of Diet in Renal Disease clearence below the fifth percentile of age- and
gender-matched control subjects). The 8592 patients who were included in this study were followed for
a 4-yr period. We identified 134 patients with macroalbuminuria, 128 with erythrocyturia, and 103 with
impaired renal function. There was only a little overlap among the three groups. The prevalence of
macroalbuminuria, erythrocyturia, and impaired renal function was calculated to be in the general
population 0.6, 1.3, and 0.9%, respectively. In all three groups, fewer than 30% of patients were
known to have this laboratory abnormality before screening. The incidence of cardiovascular disease
was high in the macrolabuminuria grouop (e.g., the age- and gender-adjusted hazard ratio for mortality
as a result of cardiovascular disease is 2.6 [1.1 to 6.0]) and for the impaired renal function group (3.4
[1.5 to 8.0]). After a mean follow-up of 4.2 yr, the macroalbuminuria group showed a -7.2 ml/min per
1.73 m(2) estimated GFR (eGFR) loss, compared with -2.3 ml/min per 1.73 m(2) in the control group
(difference P < 0.001), whereas the rate of eGFR loss in the impaired renal function group (-0.2 ml/min
per 1.73 m(2); P = 0.18), and the erythrocyturia group (-2.6 ml/min per 1.73 m(2)) was not different
from control group. Macroalbuminuria and impaired renal function both predict a worse prognosis with
respect to cardiovascular morbidity and mortality. However, macroalbuminuria is a better risk marker
than low eGFR or erythrocyturia to identify in population screening of individuals who are at risk for
accelerated GFR loss.
5. Adiponectin and mortality in patients with chronic kidney disease.
Menon V, Li L, Wang X et al.
J Am Soc Nephrol.
2006 Aug 2; [Epub ahead of print]
Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data
exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney
disease. The modification of Diet in Renal Disease study was randomized, controlled trial that was
conducted between 1989 and 1993. Adiponectin in frozen samples that were obtained at baseline (N =
820). Survival status and cause of death, up to Dcemeber 31, 2000, were obtained from the National
Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with allcause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular
filtration rate (GFR) was 33 +/- 12 ml/min per 1.73 m(2). Eighty-five percent of participants were white,
and 60% were male. Mean +/- SD adiponectin was 12.8 +/- microg/ml. Triglycerides, insulin
resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related
and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up
period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In
multivariable adjusted Cox models, a 1-microg/ml increase in adiponectin was associated with a 3%
(hazard ratio 1.03; 95% confidence interval 1.01 to 1.05, P = 0.02) increased risk for all-cause and 6%
(hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular
mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of
patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this
association and to elucidate the underlying mechanisms.
6. The urinary activity of angiotensin-converting enzyme in preterm, full-term newborns, and children.
Lopes Del Ben G, Redublo Quinto BM, Casarinin DE et al.
Pediatr Nephrol.
206 21 (8): 1138-43.
The urinary activity of the angiotensin-converting enzyme (U (ACE)) is not yet completely documented
in human neonates. We measured the U (ACE) in 36 premature neonates on the 1st, 2nd, 3rd, and
4th weeks of life, in 22 full-term neonates between the 1st and 2nd days, and in 30 nursing and
preschool children between 1 months and 6 years of age. The urinary excretion of sodium (U (Na) /
(Cr) ) and the potassium / sodium index (U (K) / (Na) ) were analyzed in the neonates. U (ACE) was
greater in premature than in full-term neonates and greater in both than in older children (p < 0.001).
In the premature neonates, U (ACE) peaked at 2nd week, U (Na) / U (Cr) index decreased, and the U
(K) / U (Na) index increased between the 1st day and 2nd week (p < 0.001). The U (Na) / U (Cr) index
on the 1st day and in the 1st and 2nd weeks was greater in premature than in full-term neonates (p <
0.001). There was no significant correletaion between the U (ACE) and U (Na) / U (Cr) index. In
conclusion, the U (ACE) profile was shown to be age dependent and related to postnatal renal
development. The increase in U (ACE) activity may reflect the high activity of the neonatal intrarenal
renin-angiotensin system (RAS).
7. Clinical characteristics of chronic kidney disease patients with and without diabetes: A subanalysis
of the PAERI study.
Lorber D, Reddan D.
Clin Nephrol.
2006 66 (1): 11-6.
Abstract. Aims Diabetes is the leading cause of chronic kidney disease (CKD) in the United States,
and cardiac disease is the primary cause of death in patients with CKD and diabetes. The Prevalence
in Early Renal Insufficiency (PAERI) study evaluated the prevalence of anemia associated
comorbidities in a community based sample of patients with CKD. The purpose of this post hoc
analysis was to identify differences, if any, in the prevalence and severity of anemia (hemoglobin < 12
g/dl (120 g/l)) and other clinical characteristics between CKD patients with diabetes and patients with
CKD who did not have diabetes. Materials and Methods The PAERI study was a prospective, crosssectional, multicenter survey. Eligible patients were > 18 years old with CKD, defined as serum
creatinine 1.5 – 6.0 mg/dl (132.6 – 530.4 umol/l) in females and 2.0 – 6.0 mg/dl (176.8 – 530.4 umol/l)
in males within 12 months before enrollment. Study duration for each patient was a single site visit.
Results Of the original 5,222 patients enrolled, 3,361 had diabetes and 1,861 did not. A family history
of diabetes was present in 72.7% of diabetic patients vs. 27.2% of nondiabetic patients (p < 0.0001).
Patients with diabetes had a significantly higher prevalence of anemia (52.7 vs 39.4%, p < 0.0001)
and cardiac disease (55.7 vs. 42.9%, p < 0.0001) The prevalence of hypertension was higher in both
groups (91.5 and 89.3%). Significantly more diabetic patients than nondiabetic patients received
angiotensin-converting enzyme inhibitors (60.4 vs 43.8%, p < 0.0001). Hyperlipidemia was more
common in patients with diabetes (73.9 vs. 55.4%, p < 0.0001). Patients with diabetes were
significantly younger and had a significantly higher mean body mass index and lower transferrin
saturation compared with nondiabetic patients. In diabetic and nondiabetic patients, more than 97%
had glomerular filtration rate < 60 ml/min/1.73 m^2 and more than 70% had serum creatinine < 2.5
mg/dl (221.0 umol/l). Conclusions These findings underscore the extent and severity of concurrent
illness in patients with both diabetes and CKD. In those patients, diabetes was associated with greater
prevalence of serious cardiac-related comorbidities than observed in nondiabetic patients.
8. Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: Epidemiology,
pathogenesis, and treatment.
Hingorani S.
J Am Soc Nephrol.
2006 17 (7): 1995-2005.
High-dose myeloablative hematopoietic cell transplantation is becoming an increasingly common
treatement modality for variety of disease. Patient survival may be limited by substantial treatmentrelated toxicities, including chronic kidney disease (CKD). Although the majority of CKD after
transplantation is idiopathic, thrombotic microangiopathic syndromes and nephrotic syndrome have
been described. Epidemiology, pathogenesis, and potential treatment options for the various clinical
syndromes that are associated with CKD in hematopoietic cell transplantation patients is reviewed. As
the indications for and the number of transplants that are performed worldwide increases so will the
burden of CKD. The nephrologists and oncologists will have to work together to identify patients who
are at risk for CKD early to prevent its development and progression to end-stage kidney disease.
9. Coeliac disease and risk of renal disease - - A general population cohort study.
Ludvigsson JF, Montgomery SM, Olen O et al.
Nephrol Dial Transpant.
2006 21 (7): 1809-15.
Background Coeliac disease (CD) may be a risk factor for renal disease. Methods We investigated
the risk of any form of glomerulonephritis (GN) (acute, chronic and non-specified), chronic
glomerulonephritis (CGN) and renal replacement therapy including dialysis and kidney transplantation
(KT) in patients with CD in ageneral population-based cohort study. We used Cox regression to
assess the rik of renal disease in 14 336 patients who had received a diagnosis CD (1964-2003) and
69 875 reference individuals matched for age, calendar year, sex and county. Patients were identified
using the Swedish Hospital Discharge Registry. Follow-up began 1 year after study entry. Results CD
was associated with an increased risk of any form of GN (hazard ratio (HR) = 1.64; 95% confidence
intervals (CI) = 1.02-2.66; P = 0.046; 89 events), CGN (HR = 2.65; 95% CI = 1.34-5.24; P = 0.005; 39
events), dialysis (HR = 3.48; 95% CI = 2.26-5.37; P < 0.001; 102 positive events) and KT (HR = 3.15;
95% CI = 1.29-7.71; P = 0.012; 22 events). Conclusion We suggest that immune characteristics
associated with CD increase the risk of chronic renal disease. Individuals with CD may also be et a
moderately increased risk of any form of GN.
10. WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and
renal phenotypes.
Aucella F, Bisceglia L, De Bonis P et al.
Pediatr Nephrol.
2006 Aug 15; [Epub ahead of print]
WT1 mutations have been considered a rare cause of nephrotic syndrome but recent reports
challenge this assumption. Exclusion of inherited forms is a basic point in any therapeutic strategy to
nephrotic syndrome since they not respond to drugs. We screened for WT1 mutations in 200 patients
with nephrotic syndrome: 114 with steroid resistance (SRNS) and 86 with steroid dependence (SDNS)
for whom other inherited forms of nephrotic syndrome (NPHS2, CD2AP) had been previously
excluded. Three girls out of 32 of the group with steroid resistance under 18 years presented classical
WT1 splice mutations (IVS9+5G>A, IVS9+4C>T) of Frasier syndrome. Another on presented a
mutation coding an amino acid change (D396N) at exon 9 that is typical of Denys-Drash syndrome. All
presented resistance to drugs and developed end stage renal failure within 15 years. Two girls the
Frasier group presneted a 46 XY karyoptype with streak gonads while one was XX and had normal
gonad morphology. In the two cases with IVS9+5G>A renal pathology was characterized by capillary
wall thickening with deposition of IgG and C3 in one that was interpreted as a membrane pathology.
Foam cells were diffuse in tubule-interstitial areas. In conclusion, WT1 splice mutations are not rare in
females under 18 years with SRNS. This occurs in absence of a clear renal pathology picture and
frequently in absence of phenotype change typical Frasier syndrome. In adults and children with
SDNS, screening analysis is of no clinical value. WT1 hot spot mutation analysis should be routinely
done in children with SRSN; if the molecular screening anticipate any further therapeutic approach it
may modify the long term therapeutic strategy.
11. Low protein Z levels in children with nephrotic syndrome.
Ozkaya O, Bek K, Fisgin T et al.
Pediatr Nephrol.
2006 21 (8): 1122-6.
Acquired deficiency of anticoagulant proteins, due to loss in the urine, has been proposed as one of
the major thrombogenic alterations in nephrotic syndrome (NS). Protein Z (PZ) is a single-chain
vitamin K-dependent glycoprotein. Low PZ levels are reported to be a risk factor for thrombosis. The
aim of this study was to investigate protein Z and other natural anticoagulant levels in children with
NS. Thirty children aged between 1.5 and 12 years with NS (Groups I and II) and 19 age-and-sexmatched healthy controls (Group III) were enrolled into the study. Patients were divided into two
groups: group I (proteinuria >40 mg/m(2)/hr) and Group II (patients in remission). Plasma PZ levels in
roup I were significantly lower than Group II (p = 0.009) and group III (p = 0.018). Plasma levels of AT
III for groups II and III (p = 0.009, p = .005, respectively). Protein C levels in Group I were higher than
in Group II and Group III (p = 0.002, p = 0.000, respectively). Protein Z levels positively correlated with
serum total protein and albumin levels (p = 0.003, p = 0.003, respectively) and negatively with the
degree of proteinuria (p = 0.000). Protein Z levels were positively correlated with AT III (R = 0.037, p =
0.04). Along with the other coagulation abnormalities, decreased protein Z may contribute to increased
risk of thromboembolic complications in children with NS. The negative correlation between proteinuria
and PZ level suggest the possibility of renal PZ loss. Further studies are needed to incvestigate the
mechanism and role of decreased PZ in NS.
12. Urine proteomic profiling of pediatric nephrotic syndrome.
Khurana M, Traum AZ, Aivado M et al.
Pediatr Nephrol.
2006 Jun 30; [Epub ahead of print]
The prognosis of pediatric nephrotic syndrome (NS) correlates with the responsiveness to
glucocorticoid therapy. Steroid-resistant NS (SRNS) patients progress to end-stage renal disease,
while steroid-sensitive NS (SSNS) and steroid-dependent (SDNS) patients not. We have performed
proteomic profiling of urine samples from a cross section of pediatric and adolescent subjects with
SSNS, SRNS, and orthostatic proteinuria (OP) to identify urinary biomarkers of steroid resistance. We
performed surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF
MS) on urine from 19 subjects with SSNS/SDNS in remission, 14 with SSNS/SDNS in relapse, 5 with
SRNS in relapse, and 6 with OP. genetic algorithm search of principal component space revealed a
group of five peaks distinguishing SRNS subjects, with mass/charge (m/z) values of 3,917.07,
4,155.53, 6,329.68, 7,036.96, and 11,117.4. Our analyses identified the peak at m/z 11,117.4 with an
accuracy of 95% for classifying SRNS. Multidimensional protein fractionation and mass spectrometric
analysis of SRNS urine samples combined with immunodepletion identified the 11,117.4 protein as
beta(2)-microglobulin (B2M). using an unbiased protein profiling approach, we have validated
previously reported findings of B2M as a biomarker associated with SRNS. Prospective studies are
warranted to estabilish additonal biomarkers that would be predictive of SRNS.
13. Urinary proteome of steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome in
childhood.
Woroniecki RP, Orlova TN, Mendelev N et al.
Am J Nephrol.
2006 26 (3): 258-67.
The response to steroid therapy is used to characterize the idiopathic nephrotic syndrome (INS) of
childhood as either steroid-sensitive (SSNS) or steroid-resistant (SRNS), a classification with a better
prognostic capability than renal biopsy. The majority (approximately 80%) of INS is due to minimal
change disease but the percentage of focal and segmental glomerulosclerosis is increasing. We
applied a new technological platform to examine the urine proteome to determine if different urinary
protein excretion profiles could differentiate patients with SSNS from those with SRNS. Twenty-five
patients with INS and 17 control patients were studied. Mid-stream urines were analyzed using surface
enhanced laser desorption and ionization mass spectrometry (SELDI-MS). Data were analyzed using
multiple bioinformatic techniques. Patient classification was performed using Biomarker Pattern
Software (TM) and a generalized form of Adaboost and predictive models were generated using a
supervised algorithm with cross-validation. Urinary proteomic data distinguished INS patients from
control patients, irrespective of steroid response, with a sensitivity of 92.3%, specificity of 93.7%,
positive predictive value of 96% and a negative predictive value of 88.2%. Classification of patients as
SSNS or SRNS was 100%. A protein of mass 4,144 daltons was identified as the single most
important classifier in distinguishing SSNS from SRNS. SELDI-MS combined with bioinformatics can
identify different proteomic patterns in INS. Characterization of the proteins of interest identified by this
proteomic approach with prospective clinical validation may yield a valuable clinical tool for the noninvasive prediction of treatment response and prognosis.
14. Expression of P-glycoprotein in lymphocytes from children with nephrotic syndrome, depending on
their steroid response.
Wasilewska A, Zoch-Zwierz W, Pietruczuk M et al.
Pediatr Nephrol.
2006 Jun 8; [Epub ahead of print]
The aim of this study was to examine the expression of P-glycoprotein (P-gp) in CD3 lymphocytes of
children with nephrotic syndrome (NS) in relation to their clinical response to glucocorticoid (GC)
treatment. The examinations were performed on two groups. The study group (I) consisted of 88
children aged 2.0-20.0 years with NS, divided according to their clinical response to GC: NFR-nonfrequent relapse NS; FR-frequent relapse NS; SD-steroid-dependent NS. The control group (II)
consisted of 18 healthy children never treated with GC. We measured P-gp expression on CD3
lymphocytes of patients with NS using a flow cytometric assay. The CD3/P-gp was significantly higher
than in controls. The difference was higher in SD (P=0.0001) and FR – (P=0.0002) group. The
difference in NFR was smaller. Mean CD3/P-gp (in percent was twice as high in SD children than in
NFR, and the difference, as between FR and NFR, was statistically significant (<0.01). Worse
response to GC or dependency may be due to overexpression of P-gp. Further examinations are
necessary to estabilish whether increased P-gp activity is a result of MDR-1 polymorphism and to
determine GC response, or to ascertain if such activity is only a result of GC therapy.
15. Nephrotic syndrome in a child after umbilical-cord-blood transplantation.
Lee JH, Kwon BS, Ha IS et al.
Pediatr Nephrol.
2006 Jun 22; [Epub ahead of print]
We report a 12-year-old girl who developed nephrotic syndrome 6 months umbilical-cord-blood
transplantation (UCBT) for acute lymphoblastic leukemia (L2). In addition to nephrotic syndrome, she
also showed autoimmune hemolytic anemia, thrombocytopenia and gastrointestinal symptoms. Since
these symptoms were manifested during the course of tapering immunosuppressive agents, a
diagnosis of chronic graft-versus-host disease (GVDH) was made. Findings from a kidney biopsy were
compatible with minimal-change disease (MCD), and focal glomerular capillary thrombosis and mild
tubular damage were also noted. She was treated with methylprednisolone pulse therapy followed by
oral prednisolone. Proteinuria disappeared in 14 days. Gastrointestinal symptoms, anemia and
thrombocytopenia were also corrected. This is a case report of nephrotic syndrome as a manifestation
of chronic GVHD developed after stem-cell transplantation. A review of the cases reported in the
literature is also made.
16. Steroid-responsive nephrotic syndrome in a patient with nail-patella sndrome.
Hari P, Mantan M, Dinda A et al.
Pediatr Nephrol.
2006 21 (8): 1197-9.
Nail-patella syndrome (NPS) is rare disorder with autosomal dominant mode of inheritance. We report
a child with NPS and steroid-responsive, frequently relapsing nephrotic syndrome. The child had
dystrophic nails, flexion contracture of both elbows and normal renal functions. X-rays of the knees
and pelvis showed hypoplastic patellae and iliac horns. Renal histology was unremarkable with mild
focal increase in mesangial cellularity compatible with minimal change disease. Ultrstructural features
of NPS including thickening of the glomerular basement membrane with electron-lucent areas were
not found.
17. The role of 99mTc DMSA renal scintigraphy in Joubert syndrome.
Kara Gedik G, Lay Ergun E, Fani Bozkurt M.
Rev Esp Med Nucl.
2006 25 (4): 258-62.
Joubert syndrome is a severe autosomal recessive disorder, which is characterized by hypotonia,
impaired psychomotor development, retinal dystrophy with abnormal ocular movements and cerebellar
vermis agenesis with dilatation of the fourth ventricle. Joubert syndrome type B is a developmental
disorder of the nephronophtisis complex with multiple organ involvement. Although this syndrome is
rare, since first described by Jourbert et al in 1969, there have been several cases about the
components and the chromosomal abnormalities related with it. Here we report 2 patients with Joubert
syndrome in whom renal involvement was demonstrated by ultrasonography as renal cystic disorders
which represented nephronophtisis. For each patient we performed renal cortical scintigraphy with
99mTc-DMSA (99mtechnetium-dimercaptosuccinic acid) which showed bilaterally decreased
radiopharmaceutical uptake in kidneys due to tubulointerstitial nephropathy. Scintigraphy may have a
great value in the diagnosis and evaluation of the presence and severity of renal involvement in
Joubert syndrome since it can evaluate kidney parenchyma and functioning renal tissue.
18. IgA nephropathy in two adolescent sisters heterozygous for Fabry disease.
Whybra C, Schwarting A, Kriegsmann J et al.
Pediatr Nephrol.
2006 Jul 13; [Epub ahead of print]
We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del124 of
the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry
disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine
analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant
glomerulonephritis. Light microscopy of kidney biopsy was characterized of IgA nephropathy (IgA
deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas
electron microscopy showed changes typical of Fabry disease (multiple osmophilic inclusions in the
subendothelial and mesangial areas). These two cases and similar reports in the literature suggest
that IgA nephropathy in FD is not merely coincidental.
19. Prognosis of lupus membranous nephropathy in children.
Nathanson S, Salomon R, Ranchin B et al.
Pediatr Nephrol.
2006 21 (8): 1113-6.
The occurence of membranous nephropathy in pediatric series of systemic lupus erythematosus has
been reported only rarely, probably due to a very low frequency. One hundred fifty-four children who
were seen in 100 French pediatric centers between January 2002 and April 2005 were included.
Fifteen (12 girls and three boys) out of the 81 (18.5%) children with renal involvement presented
histological features of membranous nephropathy.Their ages ranged from six to 15 years old
(mean=11.3) at the age of SLE diagnosis and 8/15 children were of African origin. Isolated
membranous nephropathy was observed in nine patients, of whom five patients displayed a complete
recovery following immunosuppressive treatment. Associated proliferative lesions were observed on
the first kidney specimen in two patients and in a further renal biopsy in four other patients, leading to
a less favorable course of lupus nephropathy.
20. Prognostic factors in lupus nephritis: Diagnostic and therapeutic delay increases the risk of
terminal failure.
Faurschou M, Starklint H, Halberg P et al.
J Rheumatol.
2006 33 (8): 1563-9.
Objective To evaluate the prognostic significance of clinical and renal biopsy findings in an
unselected cohort of patients with systemic lupus erythematosus (SLE) and nephritis. Methods
Ninety-one patients with lupus nephritis were included in the study. Renal biopsies were classified to
the WHO criteria and examined for the presence of active and chronic histological changes. Predictors
of endstage renal disease (ESRD) were identified by univariate and multivariate analyses. Results
The median followup time was 6.1 years (0.1-0.3 yrs). In all cases, immunosuppressive treatment was
initiated or intensified within one month following renal biopsy. The cummulative incidence of ESRD
after 1, 5, and 10 years was 3.5%, 15%, and 17%, respectively. A variety of clinical biopsy findings
including several histological markers of chronic renal damage were identified as univariate predictors
of ESRD. In multivariate regression analyses, duration of nephritis symptoms > 6 months prior to
biopsy, s-creatinine > 140 micromol/l, diffuse proliferative glomerulonephritis, and tubular atrophy
emerged as the strongest combination of independent risk factors (relative hazard ratios: 9.3, 5.6, 8.9,
and 3.1, respectively). Conclusion Our results confirm the negative prognostic impact of
hypercreatininemia, class IV histopathology, and tubular atrophy in lupus nephritis. Our data show that
delay between onset of nephritis and renal biopsy constitutes an important risk factor of ESRD.
Patients with SLE should have kidney biopsy as soon as clinical signs of nephritis are evident in order
to accelerate treatment decisions and minimize risk of inflammation-induced irreversible kidney
damage.
21. Lupus nephritis in Chinese children - A territory-wide cohort study in Hong Kong.
Wong SN, Tse KC, Lee TL et al.
Pediatr Nephrol.
2006 21 (8): 1104-12.
We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus
(SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or
casturia, were Chinese and younger than 19 years and had been diagnosis with SLE between
January 1990 and December 2003. Investigators in each center retrieved data on clinical features,
biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys,
120girls; mean age: 11.9 +/- 2.8 years). About 50% presented with multisystem illness and 40% with
nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients.
Renal biopsy revealed WHO Class II, III, IV, and V nephritis in 13 (10%), 22 (17%). 69 (54%) and 13
(10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal
biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean +/- SD: 5.76 +/- 3.61 years).
During the study five patients died (two from lupus flare, one from cardiomyopathy, two from
infections). Four patients had end-stage renal failure (ESRF) (one died during a lupus flare). All deaths
and end-stage renal failure occured in the Class IV nephritis group. Chronic organ damage was
infrequent in the survivors. The actuarial patient survival rates at 5, 10, and 15 years of age 95.3, 91.8,
and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and
15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of Chinese
SLE children in the present study are comparable to those of other published studies.
22. Full-house nephropathy in a patient with negative serology for lupus.
Baskin E, Agras PI, Menekse N et al.
Rheumatol Int.
2006 Sep 14; [Epub ahead of print]
A 10-year-old girl presented with a complaint of recurrent abdominal pain. Physical examination
findings were unremarkable. Laboratory investigations revealed BUN of 17 mg/dl and creatinine of 1
mg/dl, and complement levels were normal. She had neither hematuria nor proteinuria, and glomerular
filtration rate was 60.9 ml/min/1.73 m(2). ANA, anti-DNA, p-ANCA and c-ANCA were all negative.
Renal biopsy revealed findings of class III lupus nephritis in light, ’’full-house’’ nephropathy in immune
fluorescent and tubuloreticular inclusions in electron microscopic examinations. After 17 months of
treatment, her last creatinine is 2.5 mg/dl and GFR 17.9 ml/m,in/1.73 m(2) and ANA and anti-DNA
remain still negative. This case presents an example that decreased GFR can be the first presenting
symptom of full-house nephropathy. Those patients who have negative lupus serology and renal
biopsy findings of full-house nephropathy and tubuloreticular inclusions may behave and should be
treated as lupus nephritis.
23. Lupus nephropathy and cardiopulmonary and hepatic dysfunctions in a child.
Olowu WA.
Pediatr Nephrol.
2006 Jul 4; [Epub ahead of print]
Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune multi-systemic rheumatologic
disorder. An unusual case is reported of an 11.9-year-old Nigerian girl who was diagnosed after 2.8
years of non-specific symptoms and six episodes of recurrent haemolysis and pancytopenia
warranting blood transfusions. At diagnosis, she had hepatitis, polyarthritis, nephropathy, and
cardiopulmonary and bone-marrow dysfunctions. Lymphopaenia, thrombocytopaenia, and direct
antiglobulin-test positive haemolytic anaemia were present. Rapid resolution of disease activity
followed exchange blood transfusion after an initial poor response to corticosteroid and
cyclophosphamide therapy. Any child with recurrent haemolysis and pancytopaenia of unknown
aetiology should be invesgated for SLE.
24. Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid
syndrome.
Mora CS, Segami MI, Hidalgo JA.
Semin Arthritis Rheum.
2006 Aug 30; [Epub ahead of print]
Objective The Strongyloides stercoralis hyperinfection syndrome (SHS) may develop in individuals
with asymptomatic infection receiving immunosuppressive treatment. This report summarizes current
knowledge regarding SHS in patients with systemic lupus erythematosus (SLE) and associated
antiphospholipid syndrome (APS). Methods Two patients with active SLE and associated APS
presenting with SHS are reported. Additional cases of strongyloides in SLE were identified and
reviewed. Results Patient 1: A 34-year-old woman with SLE and APS characterized by active
glomerulonephritis, stroke, and several hospital-acquired infections presented with womiting and
diffuse abdominal pain. Intestinal vasculitis was suspected, and treatment with methylprednisolone
and cyclophosphamide was given. Response was partial. A gastric biopsy revealed S. stercoralis
larvae. She received ivermectin and eventually recovered. Patient 2: A 37-year-old man with active
glomerulonephritis and APS with recurrent thrombosis presented with digital necrosis. Necrotizing
vasculitis was suspected and treated with immunosuppressants. He suddenly developed respiratory
failure secondary to alveolar hemorrhage and bronchoalveolar lavage was performed. The patient
deveploped Gram-negative septic shock and died. The postmortem result of bronchoalveolar lavage
yielded Strongyloides larvae. Nine cases of strongyloidiasis and SHS in SLE patients reported in the
literature were identified and reviewed. Five of these patients died; none had associated APS.
Conclusions These cases suggest that the SHS can exacerbate SLE and APS, predisposing to
Gram-negative sepsis and death. Immunocompromised patients need an early diagnosis and specific
treatment of parasitic diseasea and their comlications. The SHS should be considered in the
differential diagnosis of lupus complications in patients from endemic areas.
25. Fanconi’s syndrome and distal (type 1) renal tubular acidosis in a patient with primary Sjogren’s
syndrome with monoclonal gammopathy of undetermined significance.
Kobayashi T, Muto S, Nemoto J et al.
Clin Nephrol.
2006 65 (6): 427-32.
Tubulointerstitial nephritis is a well-recognized complication in primary Sjogren’s syndrome. Fanconi’s
syndrome is a far less frequent complication compared with distal tubular dysfunction. We here
describe a 49-year-old woman with primary Sjogren’s syndrome. In 1997, she was diagnosed with
primary Sjogren’s syndrome with tubuointerstitial nephritis, and was then treated with oral
prednisolone for the tubulointerstitial nephritis. In 2002, she was referred to our hospital because of
progressive fatigue. At that time, biclonal spike on serum protein (IgG-kappa and IgA-kappa) and
Bence-Jones protein in urine found. Bone marrow aspiration showed 1.0% plasma cell infiltration.
Thus, a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was made. In
2004, she was again admitted to our hospital because of mild renal dysfunction and hypokalemia.
Laboratory evaluation showed inappropriate, alkaline urine in hyperchloremic metabolic acidosis and
positive urine anion gap, indicating the presence of distal (Type 1) renal tubular acidosis (RTA). The
urine concentration defect was also found. Further studies revealed proximal tubular dysfunction,
including renal glycosuria, generalized aminoaciduria, phosphaturia, uricosuria and proximal RTA. The
kidney biopsy represented diffuse and severe tubulointerstitial nephritis with dense infiltrates of
lymphocytes and IgA and K light chain-positive plasma cells. No findings of multiple myeloma or
malignat lymphoma were observed. In conclusion, our patients had Sjogren’s syndrome with MGUS
and exhibited dysfunction of both proximal tubule (Fanconi’s syndrome) and distal tubule, which may
be attributed to diffuse tubulointerstitial nephritis.
26. Myeloma renal disease: Presentation and outcome.
Chan DT, Craig K, Donovan K et al.
Nephron Clin Pract.
2006 104 (3): c126-31.
Background Renal disease can be the first presentation of multiple myeloma (MM) or develop during
the disease process. Aim To define the mode of presentation of MM to nephrologists and determine
the association with patient characteristics and outcome. Methods MM patients referred to a tertiary
renal unit were studied retrospectively. Group I presented to nephrologists prior to MM diagnosis (n =
36); group II was referred to nephrology after diagnosis (n = 27), and group III was known only to
haematlogy and never referred (n = 91). Age presentation, gender, paraprotein type, need for dialysis,
haematlogical and biochemical parameters, and survival were examined. Results Of the 154 MM
patients, 23.4% presented with renal impairment (group I), 17.5% were referred to nephrology after
MM diagnosis (group II) and 59.1% did not receive renal input (group III). On presentation, group I had
a median serum creatinine (sCr) of 700 (range 341-.1,023) mumol/l and 80% required dialysis.
Although the median sCr on presentation for group II was 131 (range 103-373) mumol/l, median sCr
on renal referral was 554 (range 181-807) mumol/l and 57% needed dialysis. In contrast, the median
sCr on presentation for group III was only 99 (range 85-117) mumol/l. Group I was more anaemic (p <
0.001) and had higher beta(2)-microglobulin levels (p<0.0001) on presentation compared to groups II
and III. For group I and II, the median survival after diagnosis (10.2 vs. 24.7 months, p = 0.11) and
renal referral (10.5 vs. 20.0 months, p = 0.68) was not significantly different. Conclusion Survival in
myeloma renal disease remains poor regardless of the mode of presentation to nephrologists.
27. Hyper-IgE syndrome and autoimmunity in Mexican children.
Yamazaki-Nakashimada M, Zaltzman-Girshevich S, Garcia de la Puente S et al.
Pediatr Nephrol.
2006 21 (8): 1200-5.
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent skin abscess,
recurrent pneumonia with pneumatocele formation, eczema, eosiniphilia, and elevated levels of serum
IgE. Patients with the autosomal recessive (AR) form of HIES appear to be prone to developing
autoimmune diseases. We present two cases of HIES with autoimmune complications; on case was a
product of a consanguineous marriage, the other one was a sporadic case. The first patient presented
with recurrent episodes of erythema nodosum, warts, bronchiolitis obliterans and thrombocytopenia.
The second patient developed glomerulonephritis resulting in endstage renal failure. She later
developed malar rash, oral ulcers, cerebral infarcts with vasculitis and positive ANA, anti-dsDNA, and
antiphospholipid antibodies. We discuss the dilema in treating patients who present both primary
immunodeficiency and autoimmunity.
28. Proliferative glomerulonephritis and primary antiphospholipid syndrome.
Abdalla AH, Kfoury HK, Al-Suleiman M et al.
Saudi Med J.
2006 27 (7): 1063-5.
Little is known regarding the association of primary antiphospholipid syndrome (APLS) and
proliferative glomerulonephritis (GN). We describe a biopsy-documented case with primary APLS and
proliferative GN with no evidence of thrombotic microangiopathy (TMA), and in the absence of other
manifestation of systemic lupus erythematosus SLE. She presented initially with left popliteal deep
venous thrombosis and nephrotic syndrome. Her first pregnancy at the age of 26 years resulted intrauterine fetal death at term. Two subsequent pregnancies ended up with miscarriages at 3 and 4
months of gestation. Urin analysis revealed glomerular red blood cells of 1.000.000/ml and granular
cast; proteinuria 13.4 grams/24 hours, wich was non-selective; hemoglobin 12 gm/dl, normal white
blood cell and platelets; serum albumin 2.6 gm/dl; anti-nuclear antibody (ANA) and anti DNA were
negative and complement levels normal. Lupus anticoagulant was positive leading to a diagnosis of
primary APLS. The biopsy finding were consistent with membranoproliferative GN. She continued to
have steroid-resistant proteinuria, but stable renal function after a 12-year follow up period. She had 2
pregnancy during this period and was delivered at term using caesarian section. She received heparin
during pregnancies. Later she developed hypertension easily controlled by atenolol. This case
provides evidence that primary APLS can be associated with proliferative GN due to immune deposits
and not only TMA as previously reported, and in the complete absence of SLE. Performing more renal
biopsies in this group of patients may disclose a greater prevalence of proliferative GN and may help
in devising a rationale for treatment.
29. Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A
prospective analysis of 100 patients with severe renal involvement.
de Lind van Wijngaarden RA, Hauer HA, Wolterbeek R et al.
J Am Soc Nephrol.
2006 17 (8): 2264-74.
This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients
with ANCA-associated vasculitis and severe renal involvement (serum creatinine > 500 micromol/L).
One hundred patients who were enrolled in an international, randomized, clinical trial to compare
plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed
prospetively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic
and nine clinical parameters were determined as candidate predictors of renal outcome. The end
points were renal function at the time of diagnosis (GFR0) and 12 mo after diagnosis (GFR12), dialysis
at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of
GFR0 were age (r = -0.4, P = 0.04), arteriosclerosis (r = -0.53, P = 0.01), segmental crescents (r =
0.35, P = 0.07), and eosinophilic infiltrate (r = -0.41, P = 0.04). Prognostic indicators for GRF12 were
age (r = -0.32, P = 0.01), normal glomeruli (r = 0.24, P = 0.04), tubular atrophy (r = -0.28, P = 0.02),
intraepithelial infiltrate (r = -0.26, P = 0.03), and GFR0 (r = 0.29. P = 0.01). Fibrous crescents (r = 0.22,
P = 0.03) were predictive of dialysis of entry. Normal glomeruli (r = -0.30, P = 0.01) and treatment arm
(r = -0.28, P = 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both
chronic and acute tubulointerstitial lesions predicted GFR12 in severe ANCA-associated
glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after
12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who
were dialysis dependent at presentatin were analyzed separately (r = -0.36, P = 0.01). Normal
glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo,
indicating that the unaffected part of the kidney is vital in determining renal outcome.
30. A new international classification of childhood vasculitis.
Dillon MJ, Ozen S.
Pediatr Nephrol.
2006 Jul 4; [Epub ahead of print]
There has been, for many years, a need for an accepteble classification of childhood vasculitis as well
as criteria for classifying specific sub-categories of vasculitic disease affecting the young. Hitherto,
there has been, with certain exceptions, much reliance on adult classification systems and criteria that
have not proved entirely satisfactory. A recent International Consensus Conference held in Vienna in
June 2005 attempted to rectify this state of affairs. It resulted in a new proposal for childhood vasculitis
classification and proposal of classification criteria for several important categories of chidlhhod
vasculits including Henoch-Schonlein purpura, Kawasaki disease, polyarteritis nodosa (with additional
definitions for cutaneous and microscopic polyarteritis), Wegener granulomatosis and Takayasu
arteritis. The process involved the Delphi technique to a gather a wide spectrum of opinion from
pediatric rheumatologists and nephrologists followed by the Consensus Conference attended by a
group of pediatricians with extensive vasculitis experience where nominal group techniques were
utilized to agree on a general classification and classification criteria for individual childhood
vasculitides. The consensus that was reached will hopefully provide pediatricians with a valuable tool
in the study of childhood vasculitides but will require appropriate validation using patients and control
groups.
31. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides.
Ozen S, Ruperto N, Dillon MJ et al.
Ann Rheum Dis.
2006 65 (7): 936-41.
Background There has been a lack of appropriate classification criteria for vasculitis in children.
Objective To develop a widely accepted general classification for the vasculitides observed in children
and specific and realistic classification criteria for common childhood vasculitides (Henoch-Schonlein
purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa (PAN), Wegener’s
granulomatosis (WG), and Takayasu arteritis (TA)). Methods The project was divided into two phases:
(1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric
rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was
held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at
least 80% of the participants was defined as consensus. Results Consensus was reached to base the
general working classification for childhood vasculitides on vessel size. The small vessel disease was
further subcategorised into „granulomatous” and „non-granulomatous”. Final criteria were developed to
classify a child as HSP, KD, childhood PAN , WG, or TA, with changes introduced based on paediatric
experience. Mandatory criteria were suggested for all disease except WG. Conclusions It is hoped
that the suggested criteria will be widely accepted around the world because of the reliable techniques
used and the international and multispecialist composition of the expert group involved.
32. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis in scleroderma - A
different kind of renal crisis.
Kamen DL, Wigley FM, Brown AN.
J Rheumatol.
2006 33 (9): 1886-8.
Objective Renal disease remains a major source of morbidity and mortality in patients with
scleroderma (systemic sclerosis, SSc). We describe the clinical course of 3 patients with diffuse
cutaneous SSc presenting with renal disease subsequently found to have antibodies to
myeloperoxidase (anti-MPO) and crescentic glomerulonephritis. The presence of antineutrophil
cytoplasmic antibodies (ANCA) and anti-MPO defines a subset of patients with SSc who are
susceptible to crescentic glomerulonephritis. These patients may present in a manner identical to
scleroderma renal crisis, yet treatment requirements differ significantly. We suggest that the presence
of ANCA be routinely evaluated when faced with renal failure in the setting of SSc.
33. Nephropathy, polyneuropathy, and gastroenteritis in child with Churg-Strauss syndrome.
Olowu WA.
Clin Rheumatol.
2006 Aug 2; [Epub ahead of print]
Churg-Strauss syndrome (CSS) is a serious but rare pauci-immune vasculitis of small- and mediumsized blood vessels. It is commonly seen in association with bronchial asthma and/or allergic
disorders. The syndrome is characterized by the presence of asthma, hypereosinophilia, and vasculitis
in any part of the body. Vasculitis is often associated with significant distortion of normal functions. A
rather severe case of CSS in an 8-year-old Nigerian girl with asthma and allergic rhinoconjunctivitis is
reported. She present with multiple morbidities, namely, vasculitic polyneuropathy and also nephriticnephrotic syndrome that eventuated in acute renal failure after onset of vasculitic gastroenteritis.
Routine screening of all asthmatic patients for CSS is advocated.
34. Microscopic polyangiitis associated with primary biliary cirrhosis: A causal or casual association?
Amezcua-Guerra LM, Prieto P, Bojalil R et al.
J Rheumatol.
2006 Sep 15; [Epub ahead of print]
Objective The association between microscopic polyangiitis (MPA) and primary biliary cirrhosis (PBC)
has seldom reported. We describe a patients with PBC and MPA who presented with polyarthritis and
pulmonary nodules followed by pauci-immune crescentic glomerulonephritis and liver dysfunction.
Detection of p-ANCA, antimyeloperoxidase, and antimitochondrial antibodies along with liver and renal
histopathology allowed a diagnosis of MPA and PBC. We also discuss 2 other cases that could be
unreciognized associations of both diseases. Further reports are necessary to clarify if the coexistence
between PBC and MPA is causal or casual.
35.
A case of Takayasu arteritis complicated with glomerulonephropathy
membranoproliferative glomerulonephritis: A case report and review of the literature.
Kuroda T, Ueno M, Sato H et al.
Rheumatol Int.
2006 Jul 8; [Epub ahead of print]
mimicking
In this report, we describe the case of a 50-year-old Japanese women with Takayasu arteritis who
developed severe proteinuria and renal dysfunction. Abdominal computed tomography did not
narrowing of both renal arteries. Although her levels of C-reactive protein were negative, plasma
vascular endothelial growth factor (VEGF) and serum interleukin (IL)-6 levels were elevated. Renal
biopsy showed glomerulonephropathy mimicking membranoproliferative glomerulonephritis (MPGN)
with glomerular capillary wall thickening (double contour). This was accompanied by mesangial cell
proliferation and moderate increase of mesangial matrix without deposits of C3. These findings are
quite different from MPGN as electron microscopy did not show subendothelial deposit and
circumferential mesangial interposition. Here, we present the case of Takayasu arteritis associated
with MPGN-like renal manifestation and elevated VEGF and IL-6. The presence of elevated VEGF and
IL-6 could be factors that might contribute to MPGN-like appearence.
36. PR3-ANCA-positive crescentic necrotizing glomerulonephritis accompained by isolated pulmonic
valve infective endocarditis, with reference to previous reports of renal pathology.
Fukuda M, Motokawa M, Usami T et al.
Clin Nephrol.
2006 66 (3): 202-9.
Abstract Patients with infective endocarditis (IE) often have renal complications which may include
infarcts, abscesses and glomerulonephritis (GN). Furthermore, it is generally accepted that there is an
association between IE and anti-neutrophil cytoplasmic antibody (ANCA). Here, we report the case of
a 24-year-old man who developed rapidly progressive GN in the course of IE due to infection with
alpha-streptococcus. The initial clinical manifestation of the condition was severe sacroiliitis without
fever. Sandwich ELISA showed that the patients was positive for PR3-ANCA at low titer, and the
classical complement pathway was also activated. Renal biopsy demonstrated several lesions: focal
embolic GN, GN with immune deposits and focal and segmental crescentic necrotizing GN. Treatment
with antibiotics and steroids led to eradication of the infection, and resolution of the renal disease was
accompained by immediate disappearance of PRS-ANCA and hypocomplementemia. During a 4-year
follow-up period, no recurrence was observed. Here have only been 7 case reports of GN associated
with IE and PR-ANCA in which the renal pathology has been described, and the current report is the
first to document renal pathology in a patient with isolated pulmonic valve IE and PR3-ANCA.
Moreover, this report is the first to show a change in renal biopsy findings in response to treatment. A
review of the 7 literature cases and that of our patient showed that none involved pauci-immune GN.
Hence, further studies are needed to clarify the prevalence of pauci-immune GN in ANCA-positive IE
patients.
37. Minimal change nephrotic syndrome and classical Hodgkin’s lymphoma: Report of 21 cases and
review of the literature.
Audard V, Larousserie F, Grimbert P et al.
Kidney Int.
2006 69 (12): 2251-60.
Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of
classical Hodgkin’s lymphoma (cHL). We reassessed the pathophysiological and clinical significance
of this association. A retrospective study was performed to evaluate a cohort of adult patients who
developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL
was associated with inflammatory and general symptoms in most cases. The morphological subtype
was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in
eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently
resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120months after
MCNS) and effective treatment of the hemopathy were associated with the disappearence of the
MCNS. cHL was diagnosed before MCNS in nine patients in nine patients (42.9%), and in this case,
glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two
diseases occured simultaneously. Extensive immunohistochemical study of lymph nodes was
performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with
cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained the cure of
lymphoma.
38. Minimal change disease following exposure to mercury-containing ligthening cream.
Tang HL, Chu KH, Mak YF et al.
Hong Kong Med J.
2006 12 (4): 316-8.
A 34-year-old woman developed nephrotic syndrome after using a skin lightening cream that
contained an extremely high level of mercury. Blood and urine mercury levels were elevated and a
renal biopsy revealed minimal change disease. Membranous nephropathy was excluded using
immunoflorescence and electron microscopy. Her proteinuria remitted 9 months after she stopped
using the cosmetic cream. This is the first reported case in the English literature of proven minimal
change disease secondary to mercury exposure. It is important that mercury poisoning due to to
cosmetic cream is considered in the differential diagnoses for any woman who presents with nephrotic
syndrome.
39. Predictive factors of chronic kidney disease in primary focal segmental glomerulosclerosis.
Abrantes MM, Cardoso LS, Lima EM et al.
Pediatr. Nephrol.
2006 21 (7): 1003-12.
Renal histological features of focal segmental glomerulosclerosis (FSGS) are found in 75% of pediatric
patients with steroid-resistant nephrotic syndrome. In order to evaluate the predictive factors of chronic
kidney disease (CKD), we retrospectively reviewed the records of 110 children with biopsy-proven
FSGS admitted between 1972 and 2004. Renal survival was analyzed by the Kaplan-Meier method
and Cox’s regression model. Two multivariate models were developed: (1) from the onset of
symptoms to the occurence of CKD and (2) the time of renal biopsy to CKD. Mean follow-up time was
10 years [standard deviation (SD) 5.5], and 24 patients (21.8%) progressed to CKD. At baseline, after
adjusment three variables remained as independent predictors of CKD: age >6.5 years (RR=3.3, 95%
CI=1.3-7.8), creatinine >1 mg/dl (RR=2.5, 95% CI=0.97-6.5), and non-response to steroids (RR=7.3,
95% CI=2.7-19.7). In a model with continuous variables only age and non-response to steroids were
associated with CKD. At the time of renal biopsy, after adjusment two variables remained as
independent predictors of CKD: hematuria (RR=3.0, 95% CI=1.2-7.3) and creatinine >0.8 mg/dl
(RR=4.3, 95% CI=1.7-10.6). In a model with continuous variables four factors predicted CKD: age,
creatinine, hematuria, and percentage of global sclerosis.
40. C1q nephropathy in association with Gitelman syndrome: A case report.
Hanevold C, Mian A, Dalton R.
Pediatr Nephrol.
2006 Sep 6; [Epub ahead of print]
There have been rare reports of glomerulopathies developing in patients with Bartter syndrome (BS)
and its milder variant, Gitelman syndrome (GS). We present the first case of C1q nephropathy (C1qN)
in an African American child with GS. This child was diagnosed with GS at 9 years of age and
subsequently developed nephrotic range proteinuria 3 years later. Renal biopsy revealed mesangial
hypercellularity and focal segmental glomerulosclerosis (FSGS). The segmental lesions were
generally located at the vascular pole. Dominant C1q (2+) staining along with IgG (1-2+) was
demonstrated in the mesangium, which correlated with scattered electron dense mesangial deposits
demonstrated by electron microscopy. Treatment with an angiotensin-converting enzyme inhibitor led
to an improvement in proteinuria to near-normal values (urine protein/creatinine ratio down to 0.5), but
the creatinine clearence declined to approximately 58 ml/min/1.73 m(2). This case highlights the
possible association between the milder hypokalemic tubulopathy, GS, and glomerular disease,
including C1qN. Prompt evaluation of proteinuria with renal biopsy in these patients is recommended
to detect significant glomerular pathology. Further research is needed to define risk factors for this
complication.
41. Idiopathic membranous nephropathy in children.
Lee BH, Cho HY, Kang HG et al.
Pediatr Nephrol.
2006 21 (11): 1707-15.
Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or
nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we
retrospectively reviewed 19 cases of idiopathic MN seen in our hospital a period of 28.5 years, i.e.,
from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All
eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given
to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid nonresponders, three achieved remissions with the addition of cyclosporine, and the five who were not
administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six
NS patients achieved remission remained free of proteinuria and had a normal renal function.
Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a
stable renal function. The remaining three steroid non-responders progressed into chronic renal
insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three
patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as
poor prognostic factors.
42. Acute renal failure due to IgM-lambda glomerular thrombi and MPGN-like lesions in a patient with
angioimmunoblastic T-cell lymphoma.
Miura N, Suzuki K, Yoshino M et al.
Am J Kidney Dis.
2006 48 (1): e3-9.
A 70-year-old man with angioimmunoblastic T-cell lymphoma developed acute renal failure.
Laboratory data showed decreased levels of serum C3, C4, and CH50, elevated immunoglobulin M
(IgM) levels, and the presence of cryoglobulinemia (IgM-lambda). Renal biopsy showed
membranoproliferative glomerulonephritis-like lesions with azan-red-stained thrombi in the glomerular
capillary lumen. Immunofluorescence showed that IgM-lambda stained strongly in the glomerular
capillary lumen. Equal to the azan-red-stained thrombi, whereas C3 and C4 staining was negative.
Electron microscopy showed electron-dense deposits in the subendothelial space and glomerular
thrombi lacking fine fibrillar structure. These findings suggest that cryoglobulin which consists of
monoclonal IgM-lambda, induced glomerular and acute renal failure in a patients with
angioimmunoblastic T-cell lymphoma.
43. Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense
deposit disease (MPGN II).
Licht C, Heinen S, Jozsi M et al.
Kidney Int.
2006 70 (1): 42-50.
We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II)
caused by a mutant factor H protein expressed in the plasma. Genetic analyses of two patients
revealed deletion of a single Lys residue (K224) located within the complement regulatory region in
domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified
from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well
as reduced binding to the central complement component C3b. However, cell-binding activity of the
mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of
consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic
factor, the mutant Factor H protein is considered relevant for unrestricted activation of the diseasecausing activation of the alternative complement pathway. Replacement of functional Factor H by
fresh frozen plasma (10-15 ml/kg days) was well tolerated, prevented so far disease progression in
both patients, and is in the long run expected to preserve kidney function.
44. Long-term outcome 19 years after childhood IgA nephritis: A retrospective cohort study.
Ronkainen J, Ala-Houhala M, Autio-Harmainen H et al.
Pediatr Nephrol.
2006 21 (9): 1266-73.
We evaluated the natural long-term outcome after childhood IgA nephritis. Altogether 55 patients with
biopsy-proven IgA nephritis were identified, 37 (67%) responded to the health questionnaire and 31
(56%) participated in the medical examination after a mean follow-up of 18.7 years (SD 6.2; range 8.529.8). The results of medical examination, onset data and the re-analysis of original biopsies of 31
participants were used when analyzing the predictive factors for persistent nephropathy, i.e. constant
proteinuria/hematuria or end-stage renal disease (ESRD) All patients’ medical history data were
obtained from regional hospitals and renal survival data from the national kideny register. Six (11%) of
the 55 identified patients had developed ESRD. Sixteen (52%) of the 31 participants were not
attending for regular follow-up visits after acute phase. Twenty-two (71%) had renal symptoms and 12
(39%) were receiving drugs for hypertension/proteinuria at their latest follow-up visit. The chronicity
index and total biopsy score in the first renal biopsy were higher in patients with persistent
nephropathy or ESRD than in those without (P=0.022 and p=0.014, respectively). Nine (69%) of the
13 subjects who had been over 16 years of age at diagnosis had persistent nephropathy or ESRD,
compared with 4 (22%) of the 18 subjects who had been under 16 years of age (relative risk 3.1, 95%
CI 1.2-8.0). Pregnancy complications were common: 12 (55%) of the 22 pregnancies had been
complicated by proteinuria and/or hypertension, and the prematurity rate was 30%. Long-term followup during adulthood is needed even after mild childhood IgA nephritis, espacially in women during and
after pregnancy.
45. A scoring system to predict renal outcome in IgA nephropathy: From a nationwide prospective
study.
Wakai K, Kawamura T Endoh M et al.
Nephrol Dial Transplant.
2006 Jul 5; [Epub ahead of print]
Background Immunoglobulin A (IgA) nephropathy is the most commom form of feature
glomerulonephritis in the world, and a substantial number of patients develop end-stage renal disease
(ESRD). Although there are several prognostic indicators, it remains difficult to predict the renal
outcome in individual patients. Methods A prospective cohort study was conducted in 97 clinical units
in Japan from 1995 to 2002. We analysed the data from 2269 patients using proportional hazards
models in order to determine the predictors of ESRD in IgA nephropathy and develop a scoring
system to estimate ESRD risk. Results During follow-up (median, 77 months), 207 patients developed
ESRD. Systolic hypertension, proteinuria, hypoproteinemia, azotemia and a high histological grade at
initial renal biopsy were independently associated with the risk of ESRD. Mild haematuria predisposed
patients to ESRD more than severe haematuria. A scoring system was developed to estimate the 7year ESRD risk from eight clinical and pathological variables. Actually, this prognostic score accurately
classified patients by risk: patients with estimates of 0.0-0.9, 1.0-4.9, 5.0-19.9, 20.0-49.9, and 50.0100.0% had a 0.2, 2.4, 12.2, 40.2 and 80.8% of ESRD incidence over 7 years, respectively. The
corresponding area under the reciver operating characteristic curve was 0.939 [95% confidence
interval (CI), 0.921-0.958]. This score was verified in repetions of the deriavtion-validation technique.
Conclusions Although the quality of some data collected by the mail survey is limited and the
influence of therapy could not be considered, this scoring system will serve as a useful prognostic tool
for IgA nephropathy in clinical practice.
46. IgA-containing immune complexes in the urine of IgA nephropathy patients.
Matousovic K, Novak J, Yanagihara T et al.
Nephrol Dial Transplant.
2006 21 (9): 2478-84.
Background Sera of IgA nephropathy (IgAN) patients contain high levels of circulating immune
complexes composed of IgA1 molecules with aberrantly glycosylated hinge-region O-linked
oligosaccharides and IgG or IgA1 antibodies with anti-glycan or anti-hinge-region peptide specificities.
Due to damaged sieving properties of the glomerular capillary wall in IgAN, these immune complexes
may appear in the urine. Methods We collected urine samples from 29 patients with biopsy-proven
IgAN (Group I), 27 proteinuric patients with non-IgA nephropathies (Group II) and 28 healthy
volunteers (Group III). The levels of urinary IgA and IgG and IgA-IgG-conataining immune complexes
were measured by ELISA and standardized for urinary creatinine concentrations. Results The urinary
IgA and IgG levels were significantly higher in Groups I and II than in Group III. Although the excretion
of IgA as a fraction of total urinary protein was not significantly greater in IgAN patients than in patients
with other renal diseases, the excretion of aberrantly glycosylated IgA1 was observed by western blot
in 68% of the IgAN patients but in none of healthy controls. The urinary levels of IgA-IgG immune
complexes were significantly higher in Group I than Groups II (P < 0.01) and III (P < 0.05). There was
no significant difference in the levels between Groups II and III. These immune complexes had a
molecular mass between 650-850 kDa, as shown by size-exclusion chromatography. Conclusion The
amounts of urinary IgA-IgG-conatining immune complexes were significantly higher in patients with
IgAN than in patients with non-IgA nephropathies or healthy controls.
47. Cholestatic jaundice and IgA nephropathy induced by OTC muscle building agent Superdrol.
Jasiurkowski B, Raj J, Wisinger D et al.
Am J Gastroenterol.
2006 Sep 4; [Epub ahead of print]
Over the counter (OTC) medicines are commonly used in the United States despite a lack of scientific
evidence for clinical utility and toxicity associated with their use. A case of jaundice and IgA
nephropathy as a consequence of use of a muscle enhancing OTC supplement that was advertised as
innocuous with no hormonal activity is described. IgA nephropathy has not been described previously
in association with the use of testosterone. The case highlights that, besides adulteration, the
misrepresentation of chemicals present in OTC medications and supplements can create confusion
and a false sense of security with their use.
48. The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy
and retinopathy in type 1 diabetic patients.
Lindholm E, Bakhtadze E, Sjogren M et al.
Diabetologia.
2006 Sep 13; [Epub ahead of print]
Aims/Hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signaltransducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune
diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE
(AGER) is associated with diabetes and presence of diabetic complications. Methods The AGER -374
T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patiens and
205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to
different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients
had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs
44.9%, p = 0.002) and control subjects (51.1 vs 47.6%, p = 0.0006). The RAGE -374 T/A
polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a
higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs
40.3%, p < 0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was
higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p = 0.006) and with sightthreatening retinopathy than without (56.1 vs 47.6%, p = 0.03). In type 2 diabetic patients with HbA(1c)
values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy
than without (54.3 vs 38.2%, p = 0.02). Conclusion/Interpretation Our results show an association
between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2
diabetes, in an HbA(1c)-dependent manner in latter group, and also with sight-threatening retinopathy
in type 1 diabetic patients.
49. Association between serum levels of soluble receptor for advanced glycation end products and
circulating advanced glycation end products in type 2 diabetes.
Tan KC, Shiu SW, Chow WS et al.
Diabetologia.
2006 Sep 13; [Epub ahead of print]
Aims/Hypothesis Activation of the the receptor for advanced glycation end products (RAGE, also
known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular
complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular
hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of
endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs
and the severity of nephropathy in type 2 diabetic patients. Materials/Methods We recruited 150
healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with
proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum
AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-Rnase. Results
Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1-1,423.0] interquartile range vs 1,002.6
[726.5-1,345.3], p < 0.05) and AGEs (4.07 +/- 1.13, SD, unit/ml vs 3.49 +/- 1.05, p < 0.01) than
controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between
the severity of nephropathy and sRAGE (p = 0.01). In diabetic subjects, serum log(sRAGE) correlated
with AGES (r = 0.27, p < 0.001), log(plasma creatinine) (r = 0.31, p < 0.001), log(urine AER) (r = 0.24,
p < 0.01) and log(triglycerides) (r = 0.15, p < 0.01). On stepwise linear regression analysis, AGEs and
creatinine levels were the main independent determinants of sRAGE concentration.
Conclusions/Interpretation Serum sRAGE levels and circulating AGEs associated with the severity
of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether
endogenous sRAGE potentially influences the development of diabetic vascular complications.
50. Urinary tumour necrosis factor-{alpha} excretion independently correlates with clinical markers of
glomerular and tubulointerstitial injury in type 2 diabetic patients.
Navarro JF, Mora C, Muros M et al.
Nephrol Dial Transplant.
2006 Aug 25; [Epub ahead of print]
Background Inflammation is a potential factor in the development and progression of diabetic
nephropathy. The aim of this study to analyse the relationship between the pro-inflammatory cytokine
tumour necrosis factor-alpha (TNFalpha) and clinical markers of glomerular and tubulointerstitial
damage [urinary albumin excretion (UEA) and urinary N-acetyl-beta-glucosaminidase (UNAG),
respectively] in a large group of type 2 diabetic patients. Methods A total of 160 diabetic patients and
32 healthy controls were included in the study. High-sensitive C-reactive protein (hs-CRP) as well as
serum and urinary levels of TNFalpha were measured. UAE and UNAG were determined by 24-h
urine collection. Results Serum hs-CRP and TNFalpha were significantly higher in diabetic than in
control subjects, as well as UAE and UNAG. Diabetic patients had increased urinary TNFalpha
compared to non-diabetics [14.5 (2-29) vs 4 (0.8-12), P < 0.001]. Serum hs-CRP and TNFalpha in
diabetics with increased UEA were elevated compared to diabetics having normoalbuminuria. Urinary
TNFalpha was also higher in diabetic subjects with micro- or macroalbuminuria than in patients with
normal UAE [10.5 (4-20) and 18 (2-18) pg/mg, P < 0.0001, respectively]. Multiple regression analysis
showed that urinary TNFalpha (P < 0.0001), hs-CRP (P < 0.0001) serum TNFalpha (P < 0.01) and
HbA1c (P < 0.05) were independent of and significantly associated with UAE, whereas duration of
diabetes (P < 0.001), urinary TNFalpha (P < 0.01), HbA1c (P = 0.01), hs-CRP (P < 0.05) and serum
creatinine (P < 0.05) were associated with UNAG. Conclusions In patients with type 2 diabetes,
urinary TNFalpha excretion is elevated and correlates with severity of renal disease in terms of both
glomerular and tubulointerstitial damage, suggesting a significant role for TNFalpha in the
pathogenesis and progression of renal injury in diabetes mellitus.
51. Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in
patients with type 2 diabetes and overt nephropathy.
Sawai K, Mukoyama M, Mori K et al.
Nephrol Dial Transplant.
2006 21 (9): 2472-7.
Background Significance of podocyte injury in the progression of diabetic nephropathy is not wellunderstood. In this study, we examined whether alteration of gap junction protein connexin43 (Cx43)
expression in podocytes is associated with the progression of overt diabetic nephropathy. Methods
We recruited 29 type 2 diabetic patients with overt nephropathy who underwent renal biopsy.
Nephrectomized kidney samples obtained from seven subjects with localized neoplasm and biopsy
specimens from five patients diagnosed as minor glomerular abnormalities were used as controls.
Cx43 staining on paraffin-embedded kidney sections were studied by immunohistochemistry. Results
In controls, Cx43 was expressed at podocytes in a linear pattern along the glomerular basement
membrane. In contrast, downregulation and loss of uniformly linear staining of Cx43 (Cx43
heterogeneity) in podocytes were observed in diabetic nephropathy. Cx43 intensity correlated with
current renal function (R = 0.647, P < 0.005), whereas the magnitude of Cx43 heterogeneity correlated
well with degree of future decline in renal function (R = -0.705, P < 0.001). Conclusions Alteration of
Cx43 expression in podocytes was closely associated with the progression of overt diabetic
nephropathy. These results indicate that change in Cx43 expression at podocytes represents a
progressive stage in overt diabetic nephropathy and that it may be a convenient way to predict future
decline in renal function.
52. Vascular defect beyond the endothelium in type II diabetic patients with overt nephropathy and
moderate renal insufficiency.
Chan WB, Chan NN, Lai CW et al.
Kidney Int.
2006 70 (4): 711-6.
There is a paucity of data on the effects of overt nephropathy and moderate renal impirment on
endothelial function in diabetic patients. A total of 26 type II diabetic (DM) patients with nephropathy
(DMN+) (mean +/- s.d. age: 63.7 +/- 6.3 years), 32 diabetic patients without nephropathy (MN-) (59.4
+/- 10.1 years), and 52 non-diabetic subjects (54.9 +/- 8.2 years) were recruited. High-resolution
ultrasound scan was used to measure carotid intima media thickness (IMT) and flow-mediated dilation
(FMD) of brachial artery. Endothelium dependent dilation was determined by maximal vascular dilation
after sublingual nitroglycerine (glycerol trinitrate (GTN-induced dilation). The mean carotid IMT
increased progressively from non-DM to MNN- to DMN+ groups (0.74 +/- 0.23 vs 0.80 +/- 0.25 vs 1.03
+/- 0.38 mm; P = 0.001 for trend) whereas FMD (4.3 +/- 2.5 vs 3.9 +/- 1.7 vs 1.9 +/- 2.0%, P < 0.001
for trend) and GTN-induced dilation (14.7 +/- 4.0 vs 14.5 +/- 3.9 vs 10.3 +/- 3.2%; P < 0.001 for trend)
declined in an opposite manner. On multivariate analysis, age (beta = 0.257, P = 0.009), glomerular
filtration rate (beta = -0.364, P < 0.001), and smokong (beta = 0.25, P = 0.013) were independently
associated with carotid IMT (F = 15.76, R(2) = 0.340, P < 0.001). After adjusment for baseline brachial
arterial diameter, history in smoking (beta = -0.039, P < 0.001), fasting plasma glucose (beta = -0.033,
P = 0.002) and total cholesterol (beta = -0.023, P = 0.024) were independently associated with vessel
diameter after FMD (F = 2446.5, R(2) = 0.992, P < 0.001); whereas age (beta = -0.069, P = 0.001) and
urinary albumin excretion (beta = -0.048, P = 0.018) were independently associated with vessel
diameter after GTN (F = 851.6, R(2) = 0.967, P < 0.001). Type II diabetic patients with overt
nephropathy and moderate renal impairment had both structural and functional vascular abnormalities
beyond endothelium.
53. Clinical characteristics of chronic kidney disease patients with and without diabetes: A subanalysis
of the PAERI study.
Lorber D, Reddan D.
Clin Nephrol.
2006 66 (1): 11-6.
Aims Diabetes is the leading cause of chronic kidney disease (CKD) in the United States, and cardiac
disease is the primary cause of death in patients with CKD and diabetes. The Prevalence of Anemia in
Early Renal Insufficiency (PAERI) study evaluated the prevalence of anemia and association
comorbidities in community-based sample of patients with CKD. The purpose of this post hoc analysis
was to identify differences, if any, in the prevalence and severity of anemia (hemoglobin < or = 12 g/dl
(120 g/l) and other clinical characteristics between CKD patients with diabetes and patients with CKD
who did not have diabetes. Material and Methods The PAERI study was a prospective, crosssectional, multicenter survey. Eligible patients were > or = 18 years old with CKD, defined as serum
creatinine 1.5 - 6.0 mg/dl (132.6 - 530.4 micromol/l) in females and 2.0 - 6.0 mg/dl (176.8 - 530.4
micromol/l) in males within 12 months before enrollment. Study duration for each patient was a single
site visit. Results Of the original 5,222 patients enrolled, 3,361 had diabetes and 1,861 did not. A
family history of diabetes was present in 72.7% of diabetic patients vs 27.2% of nondiabetic patients (p
< 0.0001). Patients with diabetes had a significantly higher prevalence of anemia (52.7 vs. 39.4%, p <
0.0001) and cardiac disease (55.7 vs. 42.9%, p < 0.0001). The prevalence of hypertension was high in
both groups (91.5 vs. 89.3%). Significantly more diabetic patients than nondiabetic patients received
angiotensin-converting enzyme inhibitors (60.4 vs. 43.8%, p < 0.0001). Hyperlipidemia was more
common in patients with diabetes (73.9 vs. 55.4%, p < 0.0001). Patients with diabetes were slightly
younger and had a significantly higher mean body mass index and lower transferrin saturation
compared with nondiabetic patients. In diabetic and nondiabetic patients, more than 97% had
glomerular filtration rate < 60 ml/min/1.73 m^2 and more than 70% had serum creatinine < 2.5 mg/dl
(221.0 micromol/l). Conclusions These findings underscore the extent and severity of concurrent
illness in patients with both diabetes and CKD. In those patients, diabetes was associated with a
greater prevalence of serious cardiac-related comorbidities than observed in nondiabetic patients.
54. Management of cardiovascular risk factors in advanced type 2 diabetic nephropathy: A
comparative analysis in nephrology, diabetology and primary care settings.
Minutolo R, Sasso FC, Chiodini P et al.
J Hypertens.
2006 24 (8): 1655-61.
Objectives Advanced diabetic nephropathy (DN) is characterized by a marked development of
cardiovascular and renal disease. These patients are frequently managed by different health
professionals with the consequence that the quality of care may differ substantially. To compare the
management of cardiovascular risk factors in patients with type 2 DN and an estimated glomerular
filtration rate (GFR) of 15-60 ml/min per 1.73 m (2) followed in nephrology, diabetology and primary
care. Methods This multicentre cross-sectional study verified the control of blood pressure (BP), total
cholesterol, triglycerides, glycosylated haemoglobin A1c (HbA1c) and haemoglobin in patients
exclusively followed in either nephrology (n = 266), diabetology (n = 246) or primary care (n = 195) of
the same metropolitan area for at least 1 year. Results Primary care patients were older and had a
greater prevalence of previous cardiovascular events. The GFR was lower in nephrology than in
diabetology and primary care (33 +/- 13 versus 47 +/- 9 and 40 +/- 12 ml/min/1.73 m(2), P < 0.0001).
the prevalence of BP target (<130/80 mmHg) was similary low in nephrology, diabetology and primary
care (14, 13 and 10%, P = 0.421) probaly because of insufficient prescription of diuretics and low-salt
diet. Whereas the prevalence of the triglycerides target was similar, that of total cholesterol (< 200
mg/dl) was larger in diabetology (63%) than nephrology and primary care (59 and 46%, P = 0.003)
because of greater statin prescription in hypercholesterolemic individuals (70, 50 and 41%,
respectively, P = 0.002). The attaiment of HbA1c less than 7% was less frequent in diabetology (32%)
than in nephrology and primary care (61 and 46%, P = 0.0003) despite a more frequent prescription of
insulin/oral agents in diabetology. The control of anemia was better in diabetology. Multivariate
analysis adjusted for the patient case-mix and physician-level clustering confirmed these differences
except of anemia. Conclusion Patients with advanced DN, despite the worst renal and cardiovascular
prognosis, are at high risk of being under-treated independently of the type of clinical setting.
55. Homocysteine and vitamin B (12) concentrations and mortality rates in type 2 diabetes.
Looker HC, Fagot-Campagna A, Gunter EW et al.
Diabetes Metab Res Rev.
2006 Jul 17; [Epub ahead of print]
Objective To assess the role of homocysteine as a risk factor for mortality in diabetic subjects.
Methods Homocysteine, vitamin B(12), and folate concentrations were measured in stored sera of
396 diabetic Pima Indians aged </=40 years when examined between 1982 and 1985. Vital status was
assessed through 2001. Results and Conclusions Over a median follow-up of 15.7 years, there were
221 deaths – 76 were due to cardiovascular disease (CVD), 36 to diabetes/nephropathy and 34 to
infections. Homocysteine was positively associated with mortality from all causes (hazard rate ratio
(HRR) for highest versus lowest tertile of homocysteine = 1.70, 95% confidence interval (CI) 1.182.46), from diabetes/nephropathy (HRR = 2.39, 95% CI 0.94-6.11) and from infectious diseases (HRR
= 3.39, 95% CI 1.19-9.70), but not from CVD (HHR = 1.16, 95% CI 0.62-2.17) after adjusment for age,
sex and diabetes duration. Homocysteine correlated with serum creatinine (r = 0.50), and the
relationships with mortality rates were not significant after adjusment for creatinine. Vitamin B(12) was
positively associated with all-cause mortality (HRR for 100 pg/mL difference adjusted for age, sex and
diabetes duration = 1.15, 95% CI 1.08-1.22) and death from diabetes/nephropathy (HRR = 1.27, 95%
CI 1.10-1.46). The association between homocysteine and mortality in type 2 diabetes is not causal,
but is confounded by renal disease in Pima Indians.
56. Possible relationship between adiponectin and renal tubular injury in diabetic nephropathy.
Fujita H, Morii T, Koshimura J et al.
Endocr J.
2006 Sep 12; [Epub ahead of print]
Adiponectin is an adipose-derived protein which has anti-inflammatory and anti-atherogenic properties
in addition to insulin-sensitizing effects. To date, the role of adiponectin in the pathogenesis of diabetic
nephropathy remains unclear. The aim of the present study was to explore the relationship between
adiponectin and renal tubular injury in diabetic nephropathy. We determined serum and urinary
adiponectin levels in type 2 diabetic patients with normoalbuminuria (n = 19), microalbuminuria (n =
18), and overt diabetic nephropathy (n = 16), and then analyzed the correlations between serum and
urinary adiponectin, urinary N-acetylglucosamidase (NAG) as a clinical marker of renal tubular injury,
urinary monocyte chemoattractant protein-1 (MCP-1) as an inflammatory marker in renal
tubulointerstitium, and clinical markers of renal disease. Notably, serum and urinary adiponectin levels
were significantly increased in patients with overt diabetic nephropathy compared to those with
normoalbuminuria and microalbuminuria. In univariate linear regression analysis, serum adiponectin
levels were positively correlated with serum creatinine (r = 0.648, P < 0.0001), urinary albumin (r =
0.583, P < 0.0001), urinary NAG (r = 0.406, P < 0,01), urinary MCP-1 (r = 0.514, P < 0.0001), and
urinary adiponectin (r = 0.691, P < 0.0001) levels in all diabetic patients. Urinary adiponectin levels
were also positively correlated with serum creatinine (r = 0.729, P < 0.0001), urinary albumin (r =
0.799, P < 0.0001), urinary NAG (r = 0.701, P < 0.0001), and urinary MCP-1 (r = 0.801, P < 0.0001)
levels in all diabetic patients. Multiple linear regression analysis showed that serum creatinine and
urinary adiponectin levels were independently associated with serum adiponectin levels (r(2) = 0.522),
and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponectin levels were
independent determinants of urinary adiponectin levels (r(2) = 0.851). These results collectively
indicate that renal insufficiency and tubular injury possibly play a contributory role in increases in
serum and urinary adiponectin levels in overt diabetic nephropathy. We presume that an increase in
circulating adiponectin in overt diabetic nephropathy might be a physiological response to mitigate
renal tubular injury and to prevent the further progression of diabetic nephropathy through its antiinflammatory and anti-atherogenic effects.
57. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic pupura and
related disorders.
Besbas N, Karpman D, Landau D et al.
Kidney Int.
2006 Jun 14; [Epub ahead of print]
The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura
(TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some
of the causes of the syndrome now permit many patients to be classified according to etiology. The
increased precision of a diagnosis based on causation is important for considering logical approaches
to treatment and prognosis. It is also essential for research. We propose a classification that
accomodated both a current understanding of causation (level 1) and clinical association in cases for
whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry
of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS
and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is
confirmed.
58. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: A novel marker of renal injury.
Trachtman H, Christen E, Cnaan A et al.; Investigators of HUS-SYNSORB Pk Multicenter Clinical
Trial.
Pediatr Nephrol.
2006 21 (7): 989-94.
Background Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure.
Neutrophil gelatinase-associated lipocalcin (NGAL) is an early indicator of kidney injury. Objective To
determine if urinary NGAL excretion is a biomarker of severe renal injury and predicts the need for
dialysis in D+HUS. Methods Patients were randomly selected from among participants in the
SYNSORB Pk trial. Urine samples were collected daily if available during the first week of
hospitalization. NGAL levels were determined by ELISA. Results 34 children, age 5.9 +/- 3.9 yr, were
studied; ten (29%) required dialysis. Patients were categorized on urinary NGAL concentration within
five days of hospitalization - <200 ng/ml and >/=200 ng/ml. Twenty patients (58%) had increased
urinary NGAL excretion. The severity of D+HUS at enrollment was similar in the two groups. However,
children with increased urinary NGAL levels had higher peak BUN and creatinine concentrations
(P<0.01) and required dialysis more often, 9/20 versus 1/14 (P=0.024) compared to children with
normal excretion. Conclusion The majority of patients with D+HUD have renal tubular epithelial injury,
as evidence by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five
days of hospitalization may be an adjunctive marker that defines less severe renal involvement.
59. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical
correlates of progressive renal failure.
Guasch A, Navarrete J, Nass K et al.
J Am Soc Npehrol.
2006 17 (8): 2228-35.
Patients with sickle cell anemia (SCA) may develop a glomerulopathy with proteinuria and progressive
renal insufficiency, leading to ESRD. Albuminuria is a sensitive marker of glomerular damage in this
population and precedes the development of renal insufficiency. For determination of the prevalence
of glomerular damage in SCA and the clinical correlates of renal insufficiency, 300 adult patients with
SCA were studied (hemoglobin SS = 184; and 116 with other sickling hemoglobinopathies: SC, SD,
and S-beta thalassemia); albumin excretion rates (AER) and renal function (Cockroft-Gault formula)
were determined, and clinical and hematologic evaluations were conducted. In hemglobin SS disease,
increased AER (micro- and macroalbuminuria) occured in 68% of adult patients, and
macroalbuminuria occured in 26%. In other sickling disorders, increased AER occurs in 32% of adults,
and macroalbuminuria occurs in 10%. The development of graded albuminuria was age dependent, so
at 40 yr, 40% of patients with SS disease had macroalbuminuria. There were no difference in
hematologic parameters, (hemoglobin levels, white blood cell count, percentage of reticulocytes,
platelet counts, or lactate dehydrogenase levels) between patients with normoalbuminuria and those
with micro- or macroalbuminuria. By multivariate analysis, albuminuria correlated with age and serum
creatinine in SS disease but not with BP or hemoglobin levels. In other sickling disorders, albuminuria
tended to be associated with age but not with hemoglobin or BP levels. The diastolic BP was lower in
patients with SCA than in African American control subjects, and the development of renal
insufficiency, which was present in 21% of adult with SS disease, was not accompained by significant
hypertension. It is concluded that glomerular damage in adults with SCA is very common, and a
majority of patients with SS disease are at risk for the development of progressive renal failure. The
development of micro- and macroalbuminuria is not related to degree of anemia, suggesting that sickle
cell glomerulopathy is not solely related to hemodynamic adaptations to chronic anemia. In contrast to
other glomerulopathies, the development of systemic hypertension is uncommon in SS disease with
renal insufficiency.
60. Autosomal dominant Alport’s syndrome: Study of a large Tunisian family.
Kharrat M, Makni S, Makni K et al.
Saudi J Kidney Dis Transpl.
2006 17 (3): 320-5.
Alport’s syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in early
adult life. It is a clinically and genetically heterogenous nephropathy. Alport’s syndrome is often
associated with sensorineural deafness and/or ocular abnormalities. In contrast with the weel-known
X-linked phenotype, very little is known about the autosomal dominant form caused by mutations in
COL4A3 and COL4A4 in the chromosome region 2q35-q37. We describe a Tunisian family with
autosomal dominant Alport’s syndrome in which male and females were equally affected. Two
members reached ESRD at age 40 and 53 years, respectively. Three members experienced isolated
microhematuria and one members experienced sensorineural deafness. No eye abnormalities were
observed. Immunohistochemical studies showed a normal distribution of the alpha5 (type IV collagen)
chain in the epidermal basement membrane. Genetic analysis demonstrated that a common haplotype
co-segregated with the disease in the heterozygous state in all affected patients, thereby, confirming
an autosomal dominant mode of inheritance. The same haplotype was observed in two asymptomatic
children. We conclude that autosomal dominant Alport’s syndrome, follows a rare mode of inheritance
and exhibits a milder phenotype than usually observed in classic X-linked Alport’s syndrome. The
frequency of this mode of inheritence should be confirmed by a larger study.
61. Hereditary periodic fever with systemic amyloidosis: Is hyper-IgD sydrome really a benign
disease?
Siewert R, Ferber J, Horstmann RD et al.
Am J Kidney Dis.
2006 48 (3): e41-5.
We report a case of amyloidosis in associatation with hyperimmunoglobulinemia D syndrome (HIDS).
The patients showed typical clinical features of HIDS. He had crescentic glomerulonephritis
progressing to end-stage renal disease at age 13 years. Eight years later, he developed an AA-type
amyloidosis with extensive involvement of the intestine, respiratory tract, and thyroid gland. These
unusual complications of HIDS seriously challenge the assumption that the disease associated with a
good prognosis.
62. A case of Weber-Christian disease with collapsing glomerulopathy.
Nahar N, Pardo V, Sadhu S et al.
Am J Kidney Dis.
2006 48 (3): 484-8.
We report a case of Weber-Christian disease confirmed by skin biopsy in a patients who presented
with collapsing glomerulopathy and lipophagic interstitial nephritis. On renal biopsy, glomerular
visceral epithelial cells, tubular cells, and interstitial macrophages were loaded with inclusion that were
morphologically consistent with oxidized lipoproteins, suggesting that lipids derived from the
panniculitis may have an etiopathogenic role.
63. Mesangial proliferative glomerulonephritis after autologous stem cell transplantation.
Forslund T, Anttinen J, Hallman H et al.
Am J Kidney Dis.
2006 48 (2): 314-20.
Although glomerulonephritis and renal failure have been observed after allogenic stem cell
transplantation, only a few such reports were published about patients undergoing autologous stem
cell transplantation. We report a case of mesangial proliferative glomerulonephritis developing 4 month
after autologous stem cell transplantation for chronic lymphatic leukemia. Serological test results,
together with histological, immunohistochemical, and electronic microscopic findings of kidney biopsy
specimen, confirmed the diagnosis of mesangial proliferative glomerulonephritis in our patient.
Complement and immunoglobulin A were not present in the kidney biopsy specimen. An abnormal
clone, not previously reported, with the translocation t (5;11) (q31;q13) in blood and bone marrow was
observed. The reason for and whether progenitor cells in stem cell transplantations could contribute to
the devvelopment of glomerulonephritis remain open questions. Kidney biopsy should be performed in
patients with microscopic hematuria and/or proteinuria after autologous stem cell transplantation.
64. Polyclonal IgG4 hypergammaglobulinemia associated with plasmatic lymphadenopathy, anemia
and nephropathy.
Boulanger E, Fuentes V, Meignin V et al.
Ann Hematol.
2006 Jul 27; [Epub ahead of print]
Marked polyclonal immunoglobulin (Ig) G4 hypergammaglobulinemia has exceptionally been reported.
Here we report on two Algerian patients who presented a syndrome characterized by anemia,
plasmacytic lymphadenopathy, renal manifestations, and a marked polyclonal IgG4
hypergammaglobulinemia leading to a hyperviscosity syndrome in one case. The IgG4-expressing cell
percentage was significantly increased in the peripheral blood lymphocytes collected from the two
patients upon diagnosis. Moreover, in contrast with normal sera, both patients’ sera significantly
increased the percentage of IgG4-expressing cells when incubated with CD40-stimulated normal B
lymphocytes. Similar effects were obtained with the culture supernatans of the patients’ activated T
cells. Anti-interleukin (IL) 4 and/or anti-IL-13 antibodies were unable to anatgonize the IgG4
production. IL-4 and IL13 serum concentration were found to be normal in the two patients. The
increased IgG4 production was found to be mediated by soluble factor(s), most probably secreted by
activated T cells, which did not require the signal transducer and activator of transcription 6 signaling
pathway.
65. Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis.
Miettinen MH, Makela SM, Ala-Houhala IO et al.
Kidney Int.
2006 69 (11): 2043-8.
Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome caused by Puumala
hantavirus. Its long-term prognosis is considered favorable. There are, however, some reports about
subsequent hypertension, glomerular hyperfiltration, and proteinuria after previous hantavirus
infection. Therefore, we studied 36 patients 5 and 10 years after acute NE, with 29 seronegative
controls. Office blodd pressure, ambulatory 24-h blood pressure (ABP), glomerular filtration rate
(GFR), and proteinuria were examined. Hypertensive subjects were defined as those patients having
increased ambulatory or office blood pressure, or receiving antihypertensive therapy. Office blood
pressure was used to define hypertension only if ABP was not determined. At 5 years, the prevalence
of hypertension was higher among NE patients than in controls (50vs 21%, P=0.020). At 10 years, the
difference between the groups was no more significant (39 vs 17%, P=0.098). Five years after NE,
patients showed higher GFR (121 +/- 19 vs 109 +/- 16 ml/min/1.73 m(2), P=0.012) and urinary protein
excretion (0.19 g/day, range 0.12-0.38 vs 0.14 g/day, range 0.09-0.24, P P=<0.001) than controls. At
10 years, there were no more differnece in GFR or protein excretion between the groups (GFR: 113
+/- 20 vs 108 +/- 17 ml/min/1.73 m(2), P=0.370; proteinuria: 0.14 g/day, range 0.07-0.24 vs 0.13
g/day, range 0.06-0.31, P=0.610). In conclusion, the 10-year prognosis of NE is favorable, as
glomerular hyperfiltration and slight proteinuria detected at 5 years disappeared during the longer
follow-up. However, the possibility exsist that NE may predispose some patients to the development of
hypertension.
66. Symmetric dimethylarginine (SDMA) as endogenous marker of renal function - - A meta-analysis.
Kielstein JT, Salpeter SR, Bode-Boeger SM et al.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
Background Dosing of the most drugs must be adapated in renal insufficiency, making accurate
assessment of renal function essential in clinical medicine. Furthermore, even modest impairment of
renal function has been recognized as a cardiovascular risk factor. The purpose of this analysis was to
identify the role of symmetric dimethylarginine (SDMA), the structural isomer of the cardiovascular risk
marker asymmetric diethylarginine (ADMA), as an endogenous marker of renal function. Methods
Comprehensive searches of Medline and the Cochrane Library from 1970 to February 2006 were
performed to identify studies that evaluated the correlation between SDMA and renal function. The
search was augmented by scanning references of identified articles and reviews. The correlation
coefficients (R) were recorded from each study for the values of 1/SDMA and clearence estimates and
for SDMA and creatinine levels. The summary correlation coefficients with 95% confidence intervals
(CIs) were pooled using the random-effects method. Results In 18 studies involving 2136 patients
systemic SDMA concentrations correlated highly with inulin clearence [R = 0.85 (CI 0.76-0.91, P <
0.0001)], as well as with various clearence estimates combined [R = 0.77 (CI 0.65-0.85, P < 0.0001)]
and serum creatinine [R = 0.75 (CI 0.46-0.89, P < 0.0001)]. Conclusions SDMA exhibits some
properties of a reliable marker of renal function. Future studies have to clarify whether SDMA is indeed
suited to impove diagnosis and eventually optimize care of patients.
67. Cystatin C, kidney function and cardiovascular disease.
Bokenkamp A, Herget-Rosenthal S, Bokenkamp R.
Pediatr Nephrol.
2006 Jul 13; [Epub ahead of print]
Cystatin C, an endogenous low-molecular-weight marker of glomerular filtration rate, has recently
been shown to be associated with future cardiovascular disease in healthy elderly populations and
patients with documented atherosclerosis in a dose-dependent manner that possibly reflects a very
early stage of chronic renal dysfunction. At the time, local cystatin C deficiency has been
demonstrated in atherosclerotic and aneurismal lesions, suggesting a protective role of cystatin C in
the vessel wall, possibly in concert with TGF-beta1. Although cystatin C is not acute phase reactant,
large epidemilogical studies have documented a highly significant association between serum cystatin
C and mildly increased C-reactive protein (CRP) levels, the hallmark of the chronic inflammatory state
associated with atherosclerosis and chronic renal failure. Since cystatin C is produced by all nucleated
cells, it is unlikely that local in cystatin C synthesis in diseased arteries - rather than global cystatin C
production and renal elimination - should determine its serum concentration. Consequently, the
present review proposes microinflammation as the unifying for both lines of evidence.
68. GFR is better estimated by considering both serum cystatin C and creatinine levels.
Bouvet Y, Bouissou F, Coulais Y et al.
Pediatr Nephrol.
2006 Jun 22; [Epub ahead of print]
Serum cystatin C (cysC) is a potential marker of the glomerular filtration rate (GFR) that has generated
conflicting reports in children. A prospective study was conducted to assess the benefit of considering
cysC together with serum creatinine (SCr) and demographic and morphologic characteristics to better
estimate the (51) Cr-ethylenediaminetetraacetate (EDTA) clearence (CL), i.e. the GFR. Plasma (51)
Cr-EDTA data from 100 children or young adults (range: 1.4-22.8 years old) were analyzed according
to the population pharmacokinetic approach by using the nonlinear mixed effects model (NONMEM)
program. The actual CL was compared to the CL predicted according to different covariate equations.
The best covariate equation (+/-95% confidence interval) was: GFR (ml/min)=63.2 (+/- 3.4) . [(SCr
(muM/96) (-0.35 (+/- 0.20) ) ] . [(cysC (mg/l) / 1.2) (-0.56 (+/- 0.19) ) ] . [(body weight (kg) / 45) (0.30
(+/- 0.17) ) ] . [age (years / 14) (0.40 (+/- 0.16) ) ]. This equation was associated with a less biased and
more precise estimation than Schwartz equation. CysC improves the estimation of the GFR in children
if considered with other covariates within the mathematical formula.
69. Outpatient versus inpatient renal biopsy: A retrospective study.
Lin WC, Yang Y, Wen YK et al.
Clin Nephrol.
2006 66 (1): 17-24.
Abstract. Objective and Methods There are is a growing interest in the safety and efficacy of
percutaneous kidney biopsy for outpatientsin Taiwan. We conducted a retrospective study for patients
receiving the biopsy in 2002 and 2003. Complication and mortality associated with the biopsy were
compared between 147 inpatients and 183 outpatients who had been judged to need no
hospitalization. All biopsies were performed the ultrasound guidance and an automated spring-loaded
biopsy device. Results There were no death and no significant in complication rates between the two
groups. No delayed gross hematuria, delayed pain, fever or biopsy site bleeding developed in
outpatients, who were followed-up by telephone contacts for 1 – 5 days after they had been
discharged. Both outpatients and inpatients with hematoma were younger than those without (p <
0.05). Template bleeding time was longer for inpatients with hematuria compared with inpatients
without (12.0 vs. 5.8 minutes in average, p = 0.036), but not for outpatients (4.5 vs. 6.0 minutes in
average, p = 0.282). There were moderate differences in platelet count between outpatients with
hematuria and those without (p = 0.057), and in serum creatinine between inpatients with hematuria
and those without (p = 0.069). Conclusion The outpatient renal biopsy appears to be equally as safe
and efficent as the inpatient biopsy. However, we suggest checking template bleeding time and
platelet count before biopsy for patients with clinical bleedeng tendency, such as patients with a serum
creatinine level over 4 mg/dl (approaching CKD stages IV, V) due to a higher risk of prolonged
bleeding time. Outpatient biopsy with a 6-hour inpatient observation can be considered as a medically
adequate procedure.
70. Mortality after acute renal failure: Models for prognostic stratification and risk adjusment.
Chertow GM, Soroko SH, Paganini EP et al.
Kidney Int.
2006 Jul 19; [Epub ahead of print]
To adjust adequately for comorbidity and severity of illness in quality improvement efforts and
prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately
identified. Most epidemiological studies of AFR in the critically ill have been based at single centers, or
have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality).
We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multicenter observatinal study of ARF. We determined correlates of mortality in 618 patients with ARF in
intensive care units using three distinct analytic approaches. The predictive power of models using
information obtained on the day of ARF diagnosis was extremely low. At the time of consultation,
advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were
associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory
failure, sepsis and thrombocytopenia were associated with mortality; higher blood urea nitrogen and
lower serum creatinine were also associated with mortality in logistic regression models. Models
incorporating time-varying covariates enhanced predictive power by reducing misclassification and
incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis
during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill
patients, we developed several predictive models for prognostic stratification and risk-adjusment. By
incorporating exposures over time, the discriminatory power of predictive modles in ARF can be
significantly improved.
71. Comparison of 2 acute renal failure severity scores to general scoring systems in the critically ill.
Ahlstrom A, Kuitunen A, Peltonen S et al.
Am J Kidney Dis.
2006 48 (2): 262-8.
Background Several proposed definitions for acute renal failure (AFR) exist, but little is known of their
significance in clinical practice. We evaluated the ability to predict hospital mortality in 2 ARF-specific
severity-of-illnes scoring methods, the Risk, Injury, Failure, Loss End-Stage Renal Disease (RIFLE)
score and the score presented by Bellomo et al in 2001. Methods The study included 668 consecutive
patients with 694 treatment episodes treated in 2 intensive care units (ICUs) in university hospital
within 11 months. ARF prevalence was classified according to the RIFLE and Bellomo scores. As
references, we evaluated 2 general severity-of-illness scoring systems, the admission Acute
Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment
(SOFA) scores. Results Admission SOFA scores and maximum RIFLE scores for the first days in the
ICU were independent predictors of hospital mortality by means of forward conditional logistic
regression. In receiver operating characteristic analysis, SOFA and APACHE II scores performed
better than ARF-specific scores, and discriminative powers for hospital mortality were only moderate
for the RIFLE and Bellomo scores: areas under the curve were 0.653 (95% confidence interval, 0.588
to 0.719) and 0.587 (95% confidence interval, 0.514 to 0.660) respectively. Conclusion Neither of the
ARF-specific scoring methods presented good discriminative power regarding hospital mortality.
However, maximum RIFLE score for the first 3 days in the ICU was found to be an independent
predictor of hospital mortality, along with admission SOFA score.
72. Validity of International Classification of Diseases, Ninth Revision, Clinical Modification Codes for
Acute Renal Failure.
Waikar SS, Wald R, Chertow GM et al.
J Am Soc Nephrol.
2006 17 (6): 1688-94.
Administrative and claims databases may be useful for the study of acute renal failure (ARF) and ARF
that requires dialysis (ARF-D), but the validity of the corresponding diagnosis and procedure codes is
unknown. The performance characteristics of International Classification of Diseases, Ninth Revision,
Clinical Modification (ICD-9-CM) codes for ARF were assessed against serum creatinine-based
definition of ARF in 97,705 adult discharges fro three Boston hospitals in 2004. For ARF-AD, ICD-9CM codes were compared with review of medical records in 150 patients with ARF-D and 150 control
patients. As compared with a diagnostic standard of a 100% change in serum creatinine, ICD-9-CM
codes for ARF had a sensitivity of 35.4%, specificity of 97.7%, positive predictive value of 47.9%, and
negative predictive value of 96.1%. As compared with review of medical records, ICD-9-CM codes for
ARF-D had positive predictive value of 94.0% and negative predictive value of 90.0%. It is concluded
that administrative databases may be a powerful tool for the study of ARF, although the low sensitivity
of ARF codes is an important caveat. The excellent performance characteristics of ICD-9-CM codes
for ARF-D suggest that administrative data sets may be particularly well suited for research endeavors
that involve patients with ARF-D.
73. Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand.
Vachvanichsanong P, Dissaneewate P, Lim A et al.
Pediatrics.
2006 Aug 7; [Epub ahead of print]
Objectives The objectives of this study were to review the prevalence, cause, and morbidity and
mortality rates of acute renal failure in a large tertiary care institution in southhern Thailand, to
examine any differences in acute renal failure cases diagnosing during a 22-year period, and to
determine the risk factors indicating death. Methods The case records for children 1 months to 17
years of age who were diagnosed as having acute renal failure between February 1982 and
December 2004, in the department of Pediatrics, Songklanagarind Hospital, in southern Thailand,
were reviewed. Results A total of 331 children with 318 episodes of acute renal failure were included,
that is 177 boys (55.7%) and 141 girls (44.3%), 1 month to 16.7 years of age (mean gae: 7.6 +/- 5.1
years; median age: 7.8 years). The causes of acute renal failure in each age group were significantly
different. Overall, sepsis was the major cause of acute renal failure, accounting for 68 episodes
(21.4%), followed by hypovolemia, poststreptococcal glomerulonephritis, systemic lupus
erythematosus, and infectious diseases. Renal replacement therapy was performed in 55 cases
(17.3%). The overall mortality rate was 41.5%. Logistic regression analysis showed that disease
groups and creatinine levels were significant independent predictors of outcomes. Conclusions The
incidence of acute renal failure in Songklanagarind Hospital was 0.5 to 9.9 cases per 1000 pediatric
patients, with a mortality rate of 41.5%. sepsis was a major cause of acute renal failure and death.
Causes of acute renal failure and serum creatinine levels were significant independent predictors of
death.
74. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary
interventions.
Bachorzewska-Gajewska H, Malyszko J, Sitniewska E et al.
Am J Nephrol.
2006 26 (3): 287-92.
Background/Aims The value of neutrophil-gelatinase-associated lipocalin (NGAL), a novel biomarker
in the detection of acute renal failure in children after cardiac surgery, has been highlighted in previous
studies. The incidence of percutaneous coronary intervention (PCI) increases, which may possibly
result in increased incidences of contrast nephropathy, is potentially serious complication. Therefore,
the aim of our study was to assess prospectively NGAL in patients undergoing elective PCI in relation
to serum creatinine. Methods NGAL was assessed in the serum and urine using commercially
available kits. Results We mesured urinary and serum NGAL before, and 2, 4, 12, 24 and 48 h after
PCI. We found a significant rise in serum NGAL 2 and 4 h after PCI, and a rise urinary NGAL 4 and 12
h after PCI. Before PCI, serum NGAL was significantly associated with serum creatinine, urea, urinary
NGAL, hemoglobin, hematocrit, albumin, age and presence of diabetes. In multivariate analysis,
serum creatinine was the only predictor of serum NGAL. Serum NGAL 2 h after PCI correlated with
serum creatinine, duration of PCI, HbA1c, hematocrit, hemoglobin and urinary NGAL. In multivariate
analysis, the only predictors of serum NGAL 2 h after PCI were serum creatinine, time of PCI and
HbA1c. Serum NGAL before PCI was significantly higher in diabetics than in non-diabetics.
Conclusions NGAL may represent a sensitive early biomarker of renal impairment after PCI. Serum
creatinine, duration of PCI, but not type and amount of contrast agent, and appropriate treatment of
diabetes, reflected by HbA1c, predict a rise in serum NGAL and kidney function following PCI.
75. Acute renal failure with acyclovir in a 42-year-old patient without previous renal dysfunction.
De Deyne S, De la Gastine B, Gras G et al.
Rev Med Interne.
2006 Jun 27; [Epub ahead of print]
Introduction Herpetic meningoencephalitis is treated with acyclovir (15 mg/kg/8 h). This higher
dosage enhance the risk of acute renal failure. Case report We report the case of a previously healthy
42 years old man treated by intravenous acyclovir 1g/8 h for a herpetic meningoencephalitis. He
presented an acute renal failure and an acute confusional state at the end of the treatment. Renal
function and neurologic status improved rapidly with increased hydration and stop of antiviral therapy.
Conclusion If acyclovir is usually well tolerated, there is also a risk of acute nephropathy, especially
dose-dependent. We point out the need to monitor renal function when high dosage of acyclovir is
indicated.
IV.
TREATMENT
1. Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome.
Yi Z, Li Z, Wu XC et al.
Pediatr Nephrol.
2006 21 (7): 967-72.
We aimed to test if fosinopril reduces urinary protein excretion and alleviates renal tubular damage in
normotensive children with steroid-resistant idiopathic nephrotic syndrome (SRINS). We also aimed to
evaluate whether there are changes in steady-state blood pressure and serum concentrations of
serum angiotensin-converting enzyme (ACE) and plasma renin activity or angiotensin II (AT-II) in
children under this treatment. Forty-five normotensive patients with SRINS were randomly divided into
two groups. Group I was treated with fosinipril and prednisone for 12 weeks, while group II was treated
with prednisone alone for the same duration. The values of 24-h urinary protein excretion were 1.25+/0.64 vs 2.52+/-0.56 g/24 h (P<0.05), 1.16+/-0.45 vs 2.42+/-0.24 g/24 h (P<0.05), and 1.10+/-0.41 vs
2.05+/-0.46 g/24 h (P<0.05) in group I and group II patients, respectively, at 4, 8, and 12 weeks.
Patients in group I showed lower serum concentrations of urinary retinol-binding protein and beta(2)microglobulin (P<0.01) at the end of the study, but the patients’ blood pressure and components of the
renin-angotensin system (RAS) had no change during treatment. The result suggested that fosinopril
significantly reduced proteinuria and alleviated renal tubular damage, but did not influence blood
pressure and components of systemic RAS in normotensive children with SRINS.
2. Mesangial hypercellularity predicts antiproteinuric response to dual blockade of RAS in primary
glomerulonephritis.
Minutolo R, Balletta MM, Catapano F et al.
Kidney Int.
2006 70 (6): 1170-6.
The greater antiproteinuric efficacy of converting enzyme inhibitor and angiotensin II receptor blocker
combination (CEI+ARB), versus monotherapy with either drug, is not a consistent finding. We
evaluated the clinicopathologic predictors of response to CEI+ARB in 43 patients with primary
glomerulonephritis (GN), never treated with immunosuppressive drugs, and with persistent proteinuria
after CEI alone. Main histological lesions were analyzed by obtaining on 557 glomeruli and 165
arteries formal score of mesangial cellularity, glomerulosclerosis, tubulointerstitial damage,
mononuclear cell infiltration, arteriosclerosis, and arteriolar hyalinosis. Duration of CEI and CEI+ARB
therapy was similar (4.7 +/- 2.4 and 5.0 +/- 1.5 months). Proteinuria (g/day) decreased from 3.5 +/- 2.9
to 2.4 +/- 2.3 after CEI, and to 1.5 +/- 1.3 after CEI+ARB (P < 0.0001). Reduction of proteinuria after
CEI+ARB was greater in proliferative versus non-proliferative GN (-63.3 +/- 23.4 versus 42.4 +/23.7%, respectively; P = 0.006). When patients were categorized in responders and non-responders
to CEI+ARB, no difference between the two groups was detected in any demographic or clinical
variable, whereas histology showed in responders a greater prevalence of proliferative GN (71.4
versus 31.8%, P = 0.009) and higher score of mesangial cellularity (1,76 +/- 0.53 versus 1.20 +/- 0.22,
P < 0.0001). AT multiple regression analysis (r (2) = 0.476, P = 0.001), response to CEI+ARB resulted
independently related only to mesangial cellularity ( P < 0.0001). In conclusion, the best independent
predictor of antiproteinuric efficacy of CEI-ARB in patients with primary GN is the degree of mesangial
cellularity. This finding supports the experimental evidence that high angiotensin II contributes to
proliferation of mesangial cells.
3. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal
disease: A systematic review of the efficacy and safety data.
MacKinnon M, Shurraw S, Akbari A et al.
Am J Kidney Dis.
2006 48 (1): 8-20.
Blockade of the renin-angiotensin system either an angiotensin-converting enzyme (ACE) inhibitor or
an angiotensin receptor blocker (ARB) was shown to decrease urinary protein excretion and slow the
progression of both diabetic and nondiabetic proteinuric renal disease. The safety and efficacy of
combined ACE inhibitor and ARB therapy is not well estabilished. We conducted a systematic review
and meta-analysis of randomized trials evaluating the combination of an ACE inhibitor and an ARB in
patients with chronic proteinuric renal disease. Twenty-one randomized controlled studies (n = 654
patients) were identified using MEDLINE, EMBASE, and Cochrane Central databases. Five trials had
a parallel-group design and 16 trials used a crossover design. Combination therapy with an ACE
inhibitor and an ARB resulted in a small, but significant, increase in serum potassium levels (weighted
mean difference, 0.11 mEq/L [0.11 mmol/L]; 95% confidence interval [CI], 0.05 to 0.17) and a
nonsignificant decrease in glomerular filtration rate (weighted mean difference, 1.4 mL/min [0.02 mLs];
95% CI, –2.6 to 0.2). Additional of an ARB resulted in a further decrease in proteinuria (weighted
mean difference, 440 mg/d; 95% CI, 289 to 591) compared with an ACE inhibitor alone. This effect
was observed in patients with diabetic (210 mg/d; 95% CI, 84 to 336) and nondiabetic (582 mg/d; 95%
CI, 371- to 793) renal disease. In conclusion, the combination of ACE-inhibitor and ARB therapy in
patients with chronic proteinuric renal disease is safe, without clinically meaningfull changes in serum
potassium levels or glomerular filtration rates. Combination therapy also was associated with a
significant decrease in proteinuria, at least in the short term. Additional trials with longer follow-up are
needed to determine whether the decrease in proteinuria will result in significant preservation of renal
function.
4. Rationale and design of a study to evaluate management of proteinuria in patients high risk for
vascular events: The IMPROVE trial.
Bakris GL, Ruilope L, Locatelli F et al.
J Hum Hypertens.
2006 20 (9): 693-700.
Declining kidney function predicts increasing cardiovascular risk in people with hypertension.
Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block
the renin-angiotensin system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure
and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination
of an ACE and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression
of nephropathy independently of blood pressure lowering to a greater degree than can be achieved
using maximum approved doses of either agent alone. However, the emerging therapeutic potential of
ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further
characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular
Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and
an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin
excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or
microalbuminuria.
5. Add-on therapy with angiotensin II receptor 1 blocker in children with chronic kidney disease
already treated with angiotensin-converting enzyme inhibitors.
Litwin M, Grenda R, Sladowska J et al.
Pediatr Nephrol.
2006 Aug 15; [Epub ahead of print]
The standard renoprotection is based on the inhibition of the renin-angiotensin system (RAS) by
angiotensin convertase inhibitors (ACEi) or angiotensin II receptor 1 blockers (AT1B). The aim was to
analyze the effects of the addition of AT1B to ACEi-based renoprotection with chronic kidney disease.
We examined 11 children with a mean age of 10.5 years (range, 0.5-18 years) with a mean glomerular
filtration rate (GFR) of 61 +/- ml/min/1.73 m (2). In four patients, with primary renal disease was
hemolytic uremic syndrome, in three congenital nephrotic syndrome (CNS), in two reflux nephropathy,
prune-belly syndrome in one and acute cortical necrosis in one. All patients were treated with complex
hypotensive ACEi-based therapy. AT1B losartan was added in a mean dose of 0.9 mg/kg/day. The
change in GFR, proteinuria and blood pressure at two 12-month intervals before and after adding
AT1B was compared. The results showed that during the 12 months preceding AT1B therapy, there
was no change in blood pressure and proteinuria, but the GFR declined in 7 of 11 patients. After the
12th month of add-on therapy with AT1B, there was a significant decrease in both absolute and
indexed blood pressure values. Proteinuria decreased in eight patients, did not change in one and
increased in two, including one with CNS. The GFR stabilized or increased in eight patients and
decreased in three patients with CNS. In 7 of 11 patients, there was a significant, but not threatening
increase in serum potassium. In conclusion, add-on renoprotection with AT1B added to ACEi is safe
and signficantly improves the renoprotective effects of ACEi treatment in children with progressive
nephropathies, including patients with advanced CKD.
6. Antiproteinuric effects of losartan in non-diabetic renal disease is not dependent on ACE
insertion/deletion polymorphism.
Park HC, Choi HY, Kim BS et al.
Kidney Blood Press Res.
2006 29 (4): 216-24.
Background The antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors appears to
vary depending on the ACE insertion (I) / deletion (D) genotype in non-diabetic nephropathy. This
interaction may be overcome by using an angiotensin II receptor blocker. We evaluated the short-term
antiproteinuric effect of losartan according to the ACE I/D genotype in patients with non-diabetic
proteinuric renal diseases. Methods Ninety-nine (II/ID/DD: 36/52/11) non-diabetic patients with overt
proteinuria were enrolled. The patients received losartan 50 mg daily follwed by 100 mg in two
treatment periods each lasting 12 weeks. Clinical parameters including proteinuria were measured at
baseline and at the end of each period. Results At baseline each genotype (II/ID/DD) had comparable
mean arterial blood pressure (mean +/- SD) 103.2 +/- 11.1/102.7 +/- 10.6/104.1 +/- 15.3; proteinuria
(geometric mean, 95% CI, mg/day) 1,839 (1,518-2.227) / 1,998 (1,683-2.372) / 1,613 (1,072-2,427),
and creatinine clearence (ml/min/1.73 m(2)) 65.7 +/- 28.4/63.2 +/- 27.8/68.8 +/- 25.3, respectively.
Both doses of losartan significantly lowered blood pressure and proteinuria (p < 0.05 vs. baseline),
and losartan 100 mg was more efective than 50 mg in reducing proteinuria (52.5 +/- 29.0 vs. 40.5 +/30.8%, respectively, p = 0.001). No differences in the antiproteinuric effect of losartan was observed
among the ACE I/D genotype. Losartan 100 mg demonstrated a comparable degree of mean arterial
pressure (mean +/- SD), %) (II/ID/DD, 13.3 +6- 7.6/10.8 +/- 9.8/13.0 +/- 11.6, respectively, p = NS)
and proteinuric reduction (mean, 95% CI) among the three genotypes (51.4% (40.3-62.5%) / 53.4%
(45.5-61.4%) / 51.4% (40.0-63.8%), respectively, p = NS). Conclusion Our data suggest that losartan
provides a similar short-term antiproteinuric response for all three genotypes of ACE I/D genotype in
non-diabetic proteinuric chronic renal disease.
7. Gender differences in the renal response to renin-angiotensin system blockade.
Miller JA, Cherney DZ, Duncan JA et al.
J Am Soc Nephrol.
2006 Aug 16; [Epub ahead of print]
Evidence suggest that gender differences exist in renin-angiotensin system (RAS) function. It was
hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral
hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of
angiotensin II (Ang II) insensitivity achieved during 8 wk were examined in men and women.
Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age
28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral,
renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4
wk) was assessed, as was the pressor response to Ang II (3 ng/kg per min), at 2 wk interwals. Ang II
type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time
PCR protocol. Men and women both exhibited significant declines in BP. Women achieved
significantly reduced Ang II sensitivity compared with men at lower dosages, showing no pressor
response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk
of 150mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was
significantly decreased in women and unchanged in men. Our findings indicate that men may require
larger dosages of angiotensin receptor blocker than do women and that th BP response cannot be
used as a surrogate marker for adequate RAS blockade of the renal microvasculature.
8. Candesartan cilexetil in children with hypertension or proteinuria: Preliminary data.
Child Project; Simonetti GD, von Vigier RO, Konrad M et al.
Pediatr Nephrol.
2006 Jun 27; [Epub ahead of print]
The angiotensin II receptor blockers irbesartan and losartan effectively reduce blood pressure and
proteinuria in childhood. We were impressed by the neutral taste and the small size of the candesartan
cilexetil tablets. This angiotensin II receptor blockers was used during 4 months in 17 pediatric patients
(aged 0.5-16, median 4.5 years) with chronic arterial hypertension (n=6), overt proteinuria (n=2), or
both (n=9). The initial candesartan dose of 0.23 (0.16-0.28) mg/kg body weight once daily (median
and interquartile ranged) was doubled in ten patients [final dose 0.35 (0.22-0.47) mg/kg body weight].
No adverse clinical experiences were noted on candesartan. Candesartan increased plasma
potassium by 0.3 (0.0-0.8) mmol/l (P<0.01). In children with arterial hypertension, blood pressure
decreased by (3-13) / 9 (3-18) mmHg (P<0.01); in those with overt proteinuria the urinary
albumin/creatinine ratio decreased by 279 (33-652) mg/mmol (P<0.05). In conclusion, in children
candesartan reduces blood pressure and proteinuria with an excellent short-term tolerability profile.
9. Comparison between valsartan and valsartan plus cilnidipine in type II diabetics with normo- and
microalbuminuria.
Katayama K, Nomura S, Ishikawa H et al.
Kidney Int.
2006 70 (1): 151-6.
Cilnidipine, an L-/N-type calcium channel blocker, dilates the different glomerular arterioles in an
experimental model and shows a renoprotective effect, but its clinical benefits and safety have not yet
been assessed in type II diabetics with albuminuria. The objective of this trial was to evaluate the
effect of reducing albuminuria in type II diabetic patients with a combination therapy consisting of
valsartan plus cilnidipine versus monotherapy with valsartan. An open-label, randomized controlled
trial was conducted fro April 2002 to October 2003 in 87 Japanese patients aged 31-90 years with
type II diabetes showing albuminuria (urinary albumin/creatinine ratio: 10-300 mg/g). The patients
were randomized to receive either valsartan (n=41) or valsartan plus cilnidipine (n=46) once daily for 1
year. The primary end point was the percent change in the albumin/creatinine ratio. The secondary
end point were the progression/regression of albuminuria, blood pressure (BP), renal function, and
safety. After 1 year, the albumin/creatinine ratio was found to have decreased more markedly in the
valsartan plus cilnidipine group than in the valsartan group (reduction rate -44 +/- 11% (s.e.) versus -9/
+/- 7% (s.e.); P=0.014 by analysis of covariance). Although a significant reduction was observed in the
systolic and diastolic BP of both groups from baseline to 1 year (P<0.0001, respectively), there no
significant difference in the change in the BP between the two groups (systolic BP, P=0.066; diastolic
BP, P=0.391). There were also no significant differences in the side effects between the two groups.
Cilnidipine was thus found to show an additive effect with valsartan and thereby caused a reduction in
albuminuria in type II diabetics.
10. Role of endothelin and endothelin receptor antagonists in renal disease.
Neuhofer W, Pittrow D.
Eur J Clin Invest.
2006 36 (Suppl 3): 78-88.
Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic
properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide
variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell
contraction, stimulation of cellular matrix production, and inhbition of sodium and water reabsorption
along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner.
Increasing evidence indicates that the ET system is involved in an array of renal disorders. These
comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial
fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition,
ET-1 causally linked to renal disorders characterized by increased renal vascular resistance, including
acute ischemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and
others. Furthermore, derangement of the ET system may be involved in conditions associated with
inappropriate sodium and water retention; for example, in congestive heart failure and hepatic
cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in
animal models with promising results. As key events in progressive renal injury like inflammation and
fibrosis are mediated via both ET (A) and ET (B) receptors, while constrictor effects are primarily
transduced by ET (A) receptors, dual ET receptor blockade may be superior over selective ET (A)
antagonism. Several compounds have been developed with remarkable effects in several models of
acute and progressive renal injury. Thus, clinical studies are required to assess whether these results
can be confirmed in humans, hopefully leading to novel effective therapeutic options with few side
effects.
11. Statins for diabetic cardiovascular complications.
Ludwig S, Shen GX.
Curr Vasc Pharmacol.
2006 4 (3): 245-51.
The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in
industrialized and many developing countries. The predominant cause of death in diabetic patients is
vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol
synthesis. Landmark clinical trial indicated that statins effectively reduced cardiac death and events in
patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular
events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only
prevent atherosclerotic macrovascular complications, but also postpone the development of
microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol
lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and
clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet
aggregation, and improve insulin resistance, fibrinolysis and endothelial function and help to prevent
thrombosis, restenosis or organ transplantation rejection. Statins may effect the intracellular
prenylation of proteins which modulate the activity of small-GTP binding proteins. This may be an
underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile
and seldom cause adverse effects. Increasing evidence suggest that statins are the current of choice
to prevent vascular complications in diabetic patients with hypercholesterolemia.
12. Simvastatin maintains steady patterns of GFR and improves AER and expression of slit
diaphragm proteins in type II diabetes.
Tonolo G, Velussi M, Brocco E et al.
Kidney Int.
2006 70 (1): 177-86.
The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate
(AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric,
hypertensive, type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were
studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random
double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2)
per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73
m(2). Both Group 1 and 2 showed a significant decrease of low-density liporpotein cholesterol levels
after simvastatin and cholestyramine treatment. (P<0.01). No change from baseline values was
observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not
change fro baseline with simvastatin, whereas a decrease was observed with cholestyramine
treatment (simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/1.73 m(2), P<0.01). AER decreased in
Group 1 (P<0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of
mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney
biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not
cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and
expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.
13. Protection of the kidney by thiazolidinediones: An assessment from bench to bedside.
Sarafidis PA, Bakris GL.
Kidney Int.
2006 Aug 2; [Epub ahead of print]
The global epidemic of diabetes mellitus has led to a continous increase in the prevalence of diabetic
nephropathy over the past years. Thus, diabetic nephropathy is currently the number one cause of
end-stage renal disease in the Western world. It represents a major public health problem for which
more effective prevention and treatment strategies are needed. Thiazolidinediones (TZDs) are a class
of agents that lower blood glucose through reduction of insulin resistance in patients with type 2
diabetes. Growing evidence support the concept that TZDs have several beneficial effects on the
cardiovascular system beyond their effects on glycemic control. These benefits include: blood
pressure lowering, triglyceride reduction, high-density lipoprotein-cholesterol elevation, and reduction
in subclinical vascular inflammation. Moreover, data from several animal and human studies support
the notion that TZDs reduce urine albumin excretion and may prevent development of renal injury. The
relative lack of evidence, however, demonstrating the effects of TZDs on hard renal outcomes
mandates the need for well-designed trials with this particular objective. This paper summarizes all the
from clinical and experimental studies relevant to a possible renoprotective effect of TZDs and
discusses actions of these compounds that may contribute toward this effect.
14. Effect of pioglitazone on urinary liver-type fatty acid-binding protein concentrations in diabetes
patients with microalbuminuria.
Nakamura T, Sugaya T, Kawagoe Y et al.
Diabetes Metab Res Rew.
2006 22 (5): 385-9.
Background Urinary liver-type fatty acid-binding protein (L-FABP) is a useful marker for renal
tubulointerstitial injury. Pioglitazone is reported to be effective in early diabetic nephropathy. The aim
of the present study was to determine whether pioglitazone affects urinary L-FABP levels in diabetic
nephropathy patients with microalbuminuria. Methods Sixty-eight patients with type 2 diabetes and
microalbuminuria were randomized to a 12-month treatment with pioglitazone (30 mg/d, n = 17),
glibencamide (5 mg/d, n = 18), voglibose (0.6 mg/d, n =17), or nateglinide (27 mg/d, n = 16). Pre- and
posttreatment urinary albumin excretion (UAE) and urinary L-FABP concentrations were compared
between the four treatment groups and 40 age-matched healthy subjects. Results Pretreatment UAE
and urinary L-FABP levels differed little between the four groups. UAE and urinary L-FABP levels were
significantly greater in the diabetes patients than in the healthy subjects (UAE: p < 0.001; L-FABP: p <
0.01). After 6 and 12 months, UAE and urinary L-FABP were significantly lower in the pioglitazone
treatment group than in the other treatment groups (UAE: 6 months, p < 0.01 and 12 months, p <
0.001; 6 months, p < 0.05 and 12 months, p < 0.01). Conclusions Pioglitazone, but not glibencamide,
voglibose, or nateglinide, appears to be effective in reducing UAE and the urinary L-FABP level,
suggesting that pioglitazone has a specific role in ameliorating both glomerular and tubulointerstitial
lesions associated with early diabetic nephropathy.
15. Effect of 15d-PGJ (2) on the expression of CD40 and RANTES induced by IFN-gamma and TNFalpha on renal tubular epithelial cells (HK-2).
Zhang YJ, Yang X, Kong QY et al.
Am J Nephrol.
2006 26 (4): 356-62.
Background/Aims Recent evidence shows that peroxisome proliferator-activated receptor-gamma
(PPAR-gamma) ameliorates a variety of inflammatory conditions. CD40 is a co-stimulatory molecule
and its ligation induces production of different proinflammatory cytokines including RANTES (regulated
upon activation, normal T cell expressed), which are considered as important factor in the initiation
and maintenance of inflammatory response. The aim of this study was to investigate the effect of
PPAR-gamma on CD40 and RANTES production on cultured human renal proximal tubular epithelial
(HK-2) cells. Methods HK-2 cells were maintained under defined in vitro conditions and treated with
either PPAR-gamma agonist 15-deoxy-12, 14-prostaglandin J (2) (15d-PGJ (2)) or 15d-PGJ (2) +
PPAR-gamma antagonist GW9662, and then stimulated with a combination of tumor necrosis factoralpha (TNF-alpha) and interferon-gamma (IFN-gamma). The CD40 and RANTES levels were
investigated. Results HK-2 cells expressed low levels of CD40 and RANTES. Activation of HK-2 cell
by combined treatment of TNF-alpha and IFN-gamma results in strong synergistic effects on the
expression of CD40 and the secretion of RANTES. 15d-PGJ (2) significantly CD40 and RANTES
expression and GW9662 partly abrogated the inhibition of 15d-PGJ (2) on CD40 and RANTES.
Conclusion 15d-PGJ (2) significantly decreased CD40 and RANTES expression in HK-2 cells, which
were partially mediated by PPAR-gamma-dependent pathways. These results point to PPAR-gamma
as a remarkable new target in the prevention of tubular inflammatory injury associated with renal
disease.
16. Long-term treatment with EPO increases serum levels of high-density lipoprotein in patients with
CKD.
Siamopoulos KC, Gouva C, Katopodis KP et al.
Am J Kidney Dis.
2006 48 (2): 242-9.
Background Among lipid abnormalities observed in patients with chronic kidney disease (CKD) is a
significant decrease in serum high-density lipoprotein cholesterol (HDL-C) levels. In a previously
published randomized control trial, we showed that early erythropoietin (EPO) administered in a
predialysis population slowed the progression of CKD. In the present nested substudy, we examine
whether EPO has an influence on serum HDL-C levels in comparison to other lipid parameters in this
population. Methods Eighty-eight patients with CKD stages 3 and 4 were enrolled in the study. Fortyfive patients (group 1) were treated with EPO (50 U/kg/wk), targeting to increase hemoglobin levels to
13 g/dL or greater (> or = 130 g/L). The other patients (group 2) remained without treatment until
hemoglobin levels decreased to less than 9 g/dL (< 90 g/L). The duration of the study was 12 months.
Results At the end of the study, we observed a statistically significant decrease in serum levels of
total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides in both groups.
However, serum HDL-C levels significantly increased in only group 1 (from 42.5 +/- 10.4 to 55.9 +/- 8.1
mg/dL [1.10 +/- 0.27 to 1.45 +/- 0.21 mmol/L]; P < 0.001), wheras they were unchanged in group 2. In
additon, a significant decrease in atherogenic LDL-C/HDL-C ratio was observed in only group 1.
Importantly, the increase in serum HDL-C levels correlated positively with the increase in hemoglobin
values in EPO-treated patients. Conclusion Our resutls show that EPO treatment of predialysis
patients with CKD significantly increases serum HDL-C levels, which may represent an important
antiatherogenic effect of this hormone.
17. Modulating the progression in IgA nephropathy.
Chan JC, Trachtman H.
Nephron Clin Pract.
2006 104 (1): c61-8.
IgA nephropathy affects almost 1% of the population and yet the diagnosis is often missed. This
significant kidney disease is often progressive with 25% of the patients going on to end-stage kidney
disease over the course of 25 years. This minireview describe the clinical presentations in children and
young adults. Therapeutic options are discussed including angiotensin-converting enzyme blockade,
steroids, cytotoxics, tonsillectomy, fish oil, vitamine E, singly or in combination, in order to modulate
the rate of progression.
18. Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in
macroalbuminuric, diabetic patients.
Sidharta PN, Wagner FD, Bohnemeier H et al.
Clin Pharmacol Ther.
2006 80 (3): 246-56.
Objective In patients with renal disease increased urotensin II plasma levels have been observed. We
have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin
II receptor, has effects in patients who are prone to the development of renal disease. Methods
Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125
mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting
enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was
determined twice at baseline and after 13.5 days of treatment. Plasma concentration of palosuran
were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured
before and after 12.5 days of treatment. Tolerability and safety parameters were monitored. Results
An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to
15.0) in the 24-hour urinary albumin excretion rate was observed (P = 0.014). No effect was observed
on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma
concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean)
(95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated. Conclusions The good tolerability
profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients
with renal failure with regard to their disease progression. Larger placebo-controlled trials in this
patient population are need to investigate whether urotensin II receptor antagonists, given as
monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.
19. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with
microproteinuria: A double-blind, placebo-controlled randomized trial.
Rodríguez-Morán M, González-González G, Bermúdez-Barba MV et al.
Clin Nephrol.
2006 66 (1): 3-10.
Abstract. Aims The purpose of this study was identify the effect of pentoxifylline on the urinary protein
excretion profile in type 2 diabetic patients. Methods 40 type 2 nonhypertensive diabetic patients were
randomly allocated to receive either pentoxifylline 400 mg t.i.d. or placebo daily for 16 weeks. Eligible
subjects were those with urinary albumin excretion between 20 and 200 ug/min. Subject receiving
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium
antagonists, and diuretics as well as those with reduced renal function, pregnancy, urinary tract
infection, and smoking were not included. A 6-month pretreatment stabilization phase aimed to reduce
and stabilize fasting serum glucose levels was carried out. Urinary proteins were identified by
electrophoresis, and immunodetection was identified by western blot. Electrophoretic analysis was
performed using molecular weight markers of 150, 132, 77, and 66 kAd to identify high-weight
proteins, and 54, 41, 36, 27, 21, 14.3, and 12 kDa to identify low-weight proteins. Results At baseline,
subjects in both groups who showed a glomerular tubular pattern did not differ in their urinary
excretion profile. The urinary proteins identified were immunoglobulin G, ceruloplasmin, transferrin,
and albumin (glomerular pattern) as well as alpha1-antitrypsin, alpha1-acid glycoprotein, collagenase
inhibitor, alpha1-microglobulin, trypsin inhibitor, lysozyme, and ß2-microglobulin (tubular pattern).
Subjects who recived pentoxifylline had reduced urinary excretion of high- and low-molecular weight
proteins. Conclusions Urinary protein excretion in type 2 diabetic subjects shows a mixed, glomerular
and tubular, pattern. Pentoxifylline reduces the excretion of both high and low molecular-weight urinary
proteins.
20. Enzyme replacement therapy and renal function in 201 patients with Fabry disease.
Schwarting A, Dehout F, Feriozzi S et al. on behalf of the European FOS Investigators.
Clin Nephrol.
2006 66 (2): 77-84.
Abstract. Aim Fabry disease is a rare lysosomal storage disorder caused by deficient activity of
alpha-galactosidase A, resulting in progressive cellular accumulation of glycolipids, which may
ultimately result in end-stage renal disease. We examined the effects of enzyme replacement therapy
(ERT) with Agalsidase-alpha on renal function using data from a large international database, the
Fabry Outcome Survey (FOS). Methods This analysis was based on 1,040 serum creatinine
measurements in 201 patients with Fabry disease, aged 20-60 years, with serum creatinine
concentrations of less than 2 mg/dl and duration of ERT of up to 4.7 years. Both pretreatment and
treatment data were used to examine independent predictors of changes in serum creatinine. In a
second approach longitudinal serum creatinine measurements from 1 year before treatment, at
baseline and 1 and 2 years after the start of treatment were analyzed in 20 patients with chronic
kidney disease (CKD) Stage 2 and 3. Results We found an independent negative association
between serum creatinine and time on Agalsidase-alpha treatment (p < 0.05). renal function declined
significantly (p < 0.05) in the year before treatment. After 1 year of treatment, however, the decline in
estimated glomerular filtration rate had been halted, and renal function was preserved for up to 2
years. Conclusions In conclusion, ERT with Agalsidase-alpha is associated with decrease of serum
creatinine and may prevent the deterioration of renal function in patients with Fabry disease.
21. Iloprost for prevention of contrast-mediated nephropathy in high-risk patients undergoing a
coronary procedure. Results of a randomized pilot study.
Spargias K, Andreanides E, Giamouzis G et al.
Eur J Clin Pharmacol.
2006 62 (8): 589-95.
Objective The prevention of contrast-mediated nephropathy (CMN), which accounts for considerable
morbidity and mortality, remains a vexing problem. Contrast induced renal vasoconstriction is belived
to play a pivotal role in the CMN mechanism. The aim of this study was to examine the safety and
efficacy of two doses of the prostacyclin analogue iloprost in preventing CMN in high-risk patients
undergoing a coronary procedure. Methods Forty-five patients undergoing coronary angiography
and/or intervention who had a serum creatinine concentration >/= 1.4 mg/dL were randomized to
receive iloprost at or 2 ng/kg/min or placebo, beginning 30-90 minutes before and terminating 4 hours
after procedure. CMN was defined by an absolute increase of serum creatinine >/= 0.5 mg/dL or a
relative increase of >/= 25% measured 2 to 5 days after the procedure. Study drug infusion was
discontinued in 2 patients in the low-dose iloprost group due to flush/nausea and in 5 patients in the
high-dose group due to severe hypotension. Results The mean creatinine concentration change in
the placebo group (0.02 mg/dL) was unfavorable compared to that in the low-dose iloprost group (0.11 mg/dL; p = 0.08) and high-dose iloprost group (-0.23 mg/dL; p = 0.048). The difference between
the absolte changes in creatinine clearence was favorable compared to placebo for both the low
(mean difference 6.1 mL/min, 95% CI –0.5 to 12.8 mL/min, p = 0.07) and the high-dose iloprost group
(11.8 mL/min, 95% CI 4.7 to 18.8 mL/min, p = 0.002). Three cases of CMN were recorded; all in the
placebo group (p = 0.032). Conclusions The results of this pilot study suggest that prophylactic
administration of iloprost may effectively prevent CMN, but higher dosages are connected with
substantial tolerability issues.
22. Role of carbon monoxide and biliverdin in renal ischemia/reperfusion injury.
Li Volti G, Rodella LF, Di Giacomo C et al.
Nephron Exp Nephrol.
2006 104 (4): e135-9.
Heme oxygenase (HO) isoforms the conversion of heme to carbon monoxide (CO) and
biliverdin/bilirubin with a concurrent release of iron. There is strong evidence that HO activity and
products play a major role in renoprotection, however the exact molecular mechanisms underlying the
beneficial effects exerted by this pathway are not fully undrestood. This review is aimed at illustrating
the possible mechanism/s by which HO is renoprotective in the context of ischemia/reperfusion. We
will first analyze the effects of exogenous administration of bilirubin/bliverdin and CO and then
describe their biological activities once generated endogenously following stimulation of the HO
pathway by either pharmacological means or gene targeting-mediated approaches.
23. Update on the treatment of lupus nephritis.
Waldman M, Appel GB.
Kidney Int.
2006 Aug 23; [Epub ahead of print]
Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus
erythematosus. Although the use of aggressive immunosuppression has improved both patients and
renal survival over the past several decades, the optimal treatment of LN remains challenging.
Improved outcomes have come at the expense of significant adverse effects owing to therapy.
Moreover with long-term survival, the chronic adverse effects of effective therapies including risk of
malignancy, atherosclerosis, infertility, and bone disease all become more important. Finally, some
patients fail to achieve remission with standard cytotoxic therapy and others relapse when therapy is
reduced. For these reasons, recent clinical trials have attempted to define alternate treatment
protocols that apper to be efficacious in achieving and maintaining remission, but with less toxicity
than standard regimens. This paper discusses estabilished and newer treatment options for patients
with proliferative and membranous LN, with an emphasis on the results of these recent clinical trials.
We also review the experimental and human data regarding some of the novel targeted forms of
therapy that are under investigation and in different phases of clinical trials.
24. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A
randomized controlled trial.
Grootscholten C, Ligtenberg G, Hagen EC et al.
Kidney Int.
2006 70 (4): 732-42.
Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard
therapy for proliferaive lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to
be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we
randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in
2 years) combined with oral prednisone, (CY) or to azathioprine (2 mg/kg/day in 2 years) combined
with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA).
After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine
was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with
95% confidence interval (95% CI): 0.8-20.4. Relapses occured more often in the AZA group (RR: 8.8,
95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment
arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment.
During the first 2 years, the frequency of remission was not diffferent, but infections, especially herpes
zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function
did not between the two groups. In conlcusion, in this open-label randomized controlled trial,
cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At least followup, there were no difference in serum creatinine or proteinuria between the two groups. However,
since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.
25. Long-term mizoribine intermittent pulse therapy for young patients with flare of lupus nephritis.
Tanaka H, Tsugawa K, Suzuki K et al.
Pediatr Nephrol.
2006 21 (7): 962-6.
Mizoribine (MZR) is a novel purine synthesis inhibitor that was developed in Japan. We previously
reported the efficacy and safety of oral MZR intermittent pulse therapy, which is associated with
elevated peak serum MZR levels, in selected patients with lupus nephritis. However, the efficacy and
safety of long-term MZR intermittent pulse therapy (administered for over 24 months) in lupus nephritis
patients at high risk for relapse has not yet been reported. Our study included five patients with a long
history of systemic lupus erythematosus (SLE), icluding four patients with proliferative lupus nephritis
(WHO class IV) and one patient with WHO class II lupus nephritis, in whom remission had been
achieved through treatment with high-dose corticosteroids combined with cytotoxic agents. For the
most recent flares, all patients were treated with MZR intermittent pulse therapy without increase in the
dose of corticosteroids. MZR was administered at 5-10 mg/kg per day (up to 500 mg) as a daily dose
on two days of the week (Monday and Thursday) for over 24 months. Concomitantly administered
corticosteroid dose was gradually or continued unchanged. At presentation, the urinary protein
excretion, serum complement hemolytic activity (CH50) and serum anti-dsDNA antibody titer were
1.7+/-1.0 g/day, 16.6+/-3.8 U/ml (normal 23-46 U/ml) and 143.7+/-151.1 IU/mL (normal, < 12.0 IU/mL),
respectively. At the latest observation point, after a mean interval of 31 months (24-34 months) after
the initiation of MZR pulse therapy, the urinary protein excretion and serum anti.dsDNA antibody titer
were significantly decreased (0.3+/-0.2 d/day and 18.5+/-19-1 IU/mL, respectively; P<0.05), and the
serum CH50 value had returned to within normal range (33.6+/-7.8 U/mL, P<0.05). Despite the
reduced minimum dose of prednisolone required to maintain clinical remission at the time of the posttreatment evaluation after MZR pulse therapy as compared with that at the time of pretreatment
evaluation (9.0+/-4.5 vs. 17.5+/-7.9 mg/day; P=0.0656), the calculated flare rate was significantly
decreased (0.15+/-0.2 vs. 0.6+/-0.11 times per year, P<0.05). The serum creatinine level remained
within normal range in all study participants. Furthermore, the platelet count increased following the
MZR pulse therapy in two patients who had suffered from chronic thrombocytopenia. No serious
adverse effects observed. From the view point of the balance between suppression of disease activity
and the adverse effects of treatment, we believe that long-term MZR pulse therapy may be the
treatment of choice in selected patients with lupus nephritis at high risk for relapse. However, this was
only a pilot study conducted on a small number of subjects, without a control group. Further studies to
confirm the long-term efficacy and safety of oral MZR intermittent pulse therapy in larger numbers of
patients are needed.
26. Pathogenesis and treatment of systemic lupus erythematosus nephritis.
Davidson A, Aranow C.
Curr Opin Rheumatol.
2006 18 (5): 468-75.
Purpose of review Glomerulonephritis is a challenging complications of systemic lupus
erythematosus that still results in kidney loss in up to 30% of patients. In this review we highlight the
development of integrated efforts to link pathogenesis with disease definition and new therapeutics.
Recent findings Immune complex deposition in the kidney initiates an inflammatory cascade that
causes glomerular disease but there are many modulating factors including genetic predisposition,
products of the innate immune system, cytokines, complement and activated cells (both renal and
immune). Animal models can help dissect potential disease mechanisms but the study of multiple
models will be required since there are multiple subsets of human disease. Recent therapeutic studies
in humans address the distinction between therapies for remission induction and remission
maintenance. Multiple studies confirm the therapeutic equivalence of mycophenolate mofetil and
cyclophosphamide in induction of remission but results are still far from ideal. The next few years
should see the testing of new biologic reagents in humans. Another area of interest is the search for
noninvasive measures of disease and disease response. Summary Although there has been
remarkable progress in our understanding of the immunology and phenotype of lupus nephritis current
therapies have insufficient efficacy. As new therapies emerge, improved clinical design coupled with
mechanistic studies will be needed to identify agents that may be effective only in some patients
subpopulations.
27. Direct effects of dexamethasone on human podocytes.
Xing CY, Saleem MA, Coward RJ et al.
Kdney Int.
2006 Jul 12; [Epub ahead of print]
Glucocorticoids are widely used in the treatment of human glomerular diseases, but their mode of
action is poorly understood particularly in steroid-sensitive nephrotic syndrome, which is most common
in childhood and is characterized by a lack of inflammation in the kidney. The podocyte is a key cell in
the glomerulus in healthy and disease: until recently, human pdocytes have been difficult to study in
vitro. We have developed a conditionally immortalized human podocyte cell line transfected with a
temperature-sensitive simian virus 40 transgene: when transgene is inactivated in vitro, these cells
adopt the phenotype of differentiated podocytes. We have used these cells to evaluate, using
immunocytochemistry, reverse transcriptase-polymerase chain reaction, and Western blotting, direct
effects of the glucocorticoid dexamethasone at concentrations designed to mimic in vivo therapeutic
corticosteroids levels. Dexamethasone upregulated expression of nephrin and tubulin-alpha, and
downregulated vascular endothelial growth factor. Effects on cell cycle were complex with
downregulation of cyclin kinase inhibitor p21 and augmentation of podocyte survival, without any effect
on apoptosis. We report cytokine production by human podocytes, espacially interleukin (IL)-6 and -8;
IL-6 expression was suppressed by dexamethasone. These potent direct effects on podocytes
illustrate a novel mode action of glucocorticoids and suggest potential new therapeutic strategies for
glomerular disease.
28. Complete remission of minimal-change nephrotic syndrome induced by apheresis monotherapy.
Kobayashi T, Ando Y, Umino T et al.
Clin Nephrol.
2006 65 (6): 423-6.
We report a case of a 17-year-old male with relapse of minimal-change nephrotic syndrome (MCNS),
in whom apheresis monotherapy without steroids or immunosuppressants resulted in complete
remission. The patients initially developed nephrotic syndrome in February 1998. The first renal biopsy
confirmed the diagnosis of MCNS. The patients was also found to be a carrier of hepatitis B virus.
Steroid therapy was started with oral prednisolone 60 mg/day. Complete remission was achieved in 3
months, and the steroid treatment was tapered off in May 2001. During the steroid tapering, temporal
exacerbation of liver function was noted. In July 2002, the patient was admitted to our hospital again
due to relapse of nephrotic syndrome. Second biopsy reconfirmed the diagnosis of MCNS. Since the
serum titer of HBV was elevated, apheresis monotherapy was selected to avoid the risk of steroidinduced fulminant hepatitis. Four sessions of low-density lipoprotein apheresis (LDL-A) and 5 sessions
of double-filtration plasmapheresis (DFPP) reduced the proteinuria from 9.2 g/day to 0.2 d/day over 38
days without any additional medications. Proteinuria remaine suppressed below 0.2 g/day for more
than 12 months and no exacerbation of liver function was observed up to the final follow-up in
September 2003. The present case suggested the potential of apheresis monotherapy to induce and
maintain complete remission of MCNS and an important role of circulating factors in the pathogenesis
of MCNS.
29. Immunosuppressive treatment of idiopathic focal segmental glomerulosclerosis: A five-year followup study.
Goumenos DS, Tsagalis G, El Nahas AM et al.
Nephron Clin Pract.
2006 104 (2): c75-82.
Background/Aims Focal segmental glomerulosclerosis (FSGS) is a common type of glomerular
disease that can lead to chronic renal failure. Various therapeutic regimens have been used in
nephrotic FSGS patients. The effect of treatment with prednisolone alone or its combination with
azathioprine and cyclosporin and parameters related to a poor outcome are studied. Methods Fityone patients with idiopathic FSGS and a follow-up of 5 years were included. Twenty-five were treated
with prednisolone alone (1 mg/kg BW/day) or combination of prednisolone (0.5 mg/kg BW/day) with
azathioprine (2 mg/kg BW/day) or cyclosporine (3 mg/kg BW/day) in gradually reduced doses whereas
26 patients received no immunosuppressive drugs. Lower prednisolone dose regimens were used as
initial treatment in obese, boderline diabetics or patients with bone disease. The clinical course was
estimated using the end-points of 50% or doubling of baseline serum creatinine and/or end-stage
renal failure. The contribution of clinical and hstological parameters in the clinical outcome was
estimated by univariate and mutivariate analyses. Results Increase of baseline serum creatinine by
50% during the follow-up was observed in 2 treated and 9 untreated patients (8% vs. 35%, p = 0.03)
whereas doubling of serum creatinine in 2 and 5 patients respectively (8% vs. 19%, p= NS). End-stage
renal failure developed in 4 of 51 patients (8%), 2 treated and 2 untreated (p = NS). Parameters
related to a poor outcome were baseline serum creatinine and severity of glomerulosclerosis
(multivariate analysis OR = 1.08, p = 0.01). Most of patients (68%) who reached end-points had
persistent nephrotic syndrome during the follow-up. Remission of nephrotic syndrome was observed
more frequently among treated (75 vs. 30.7%, p = 0.05). Prednisolone alone was follwed by remission
of nephrotic syndrome in 62.5% whereas combination of lower prednisolne dose with azathioprine and
cyclosporine in 80 and 85.7% of patients. No serios side-effects were observed. Conclusion This and
previous studies suggest that steroid and/or immunosuppressive therapy have a role in studies
suggest that steroid and/or immunosuppressive therapy have a role in amelioration of the clinical
course and remission of nephrotic syndrome in patients with FSGS. A combination of low prednisolone
dose with cyclosporine could be used as initial treatment in patients with higher risk for side-effects
from the usual prednisolone dose.
30. Cyclosporin-A in the treatment of nephrotic syndrome: The importance of monitoring C0 (trough)
and C2 (two hours after its administration) blood levels.
Goumenos DS, Kalliakmani P, Tsakas S et al.
Med Chem.
2006 2 (4): 391-3.
Cyclosporin-A (CsA) is often used in treatment of nephrotic syndrome. The effectiveness of CsA and
the value of C2 blood levels in the treatment of nephrotic syndrome, due to various glomerular
diseases, were studied. Forty-two nephrotic patients (M/F 21/21), with well-preserved renal function
(creatinine clearence 87+/-20 ml/min) were included in the study. The original diagnoses were minimal
change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN),
IgA nephropathy (IgAN), and lupus nephritis (LN). All patients were treated with prednisolone and CsA
for 24 months. Cyclosporin-A C0 and C2 blood levels determined at regular intervals. Remission of the
nephrotic syndrome was observed in all patients with MCD, IgAN, and LN, in 75% with FSGS and
83% with with MN. Relapses were observed in some patients with MCD (25%) and MN (36%). The C0
levels were 93+/-15 ng/ml and the corresponding C2 levels were 498+/-110 ng/ml. However,
significantly lower (340+/-83 ng/ml) or higher (660+/-127 ng/ml) to the average C2 levels were found in
6 patients (14%). No relation of C0and C2 levels with the remission and relapse rate of the nephrotic
syndrome and with renal function impairmnet was observed. Small doses of CsA with prednisolone
are effective in the treatment of nephrotic syndrome. Although an individual variation of C2 was
observed for the same target C0 levels, no relation of C2 levels was found with the remission or
relapse rate of the nephrotic syndrome.
31. Induction and long-term treatment with cyclosporine in membranous nephropathy with the
nephrotic syndrome.
Alexopoulos E, Papagianni A, Tsamelashvili M et al.
Nephrol Dial Transplant.
2006 Sep 12; [Epub ahead of print]
Background Cyclosporine A (CyA) has been shown to be effective in membranous nephropathy
(MN). However, the optimal dose and the duration of treatment remain controversial issues. We
evaluated the efficacy of low-dose CyA alone or combined with corticosteroids as inductinon and longterm treatment for nephrotic patients with MN. Methods In the first part of the study, 51 nephrotic
patients with MN were treated either CyA and prednisolone (n = 31) or CyA alone (n = 20) for 12
months. Patients who responded with complete remission (CR) or partial remission (PR) placed on
long-term treatment with lower doses of CyA and prednisolone or CyA alone. The mean follow-up of
the second part of the study was 26 +/- 16 months and 18 +/- 7 months. Results After 12 months
treatment, 26 patients in the combination group and 17 patients in the monotherapy group had a CR
or PR of proteinuria (P = NS). Renal function was unchanged in the two groups. During long-term
treatment relapses were more frequent in the monotherapy group (47 vs 15%, P < 0.05). Daily CyA
dose was higher in non-relapses in both groups (combination 1.4 +/- 0.5 vs 1.0 1.0 +/- 0.3 mg/kg, P <
0.001, monotherapy 1.5 +/- 0.4 vs 1.1 +/- 0.2 mg/kg, P < 0.003). Relapser in both groups had lower
CyA trough levels (72 +/- 48 ng/ml) compared with non-relapsers (194 +/- 80 ng/ml) (P < 0.03). Renal
function and proteinuria remained stable durng the follow-up. Conclusion This study suggest that 12month therapy with CyA (+/- prednisolone) is effectively in inducing remission in most nephrotic
patients with MN and well preserved renal function. Longer treatment with lower doses is a useful
approach to maintain remission. Relapses occur more frequently in the monotherapy group usually are
associated with CyA trough levels < 100 ng/ml.
32. Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic
syndrome.
Fujinaga S, Kaneko K, Muto T et al.
Arch Dis Child.
2006 91 (8): 666-70.
Background Cyclosporine A (CsA) has been widely used in children with steroid dependent and
steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from
systemic side effects of steroids. However, its long term use is controversial, since chronic CsA
induced nephropathy (CsAN) may develop in a considerable number of patients. Aims and Methods
In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children
with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for
more than six months, managed at a single centre, were retrospectively amalysed. Results Thirteen
of 30 children (24 boys and 6 girls) taking (mean duration 43 months, range 6-144) had CsAN defined
as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The
multivariate analyses revealed that CsA treatment for more than 36 months an age than 5 years at the
start of CsA treatment were independent risk factors for the development of CsAN. The univariate
analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than
those without CsAN. Conclusion An alternative treatment should be seriously considered a 36 month
administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children
younger than 5 years should be avoided if possible.
33. Steroid pulse therapy impaired endothelial function while increasing plasma high molecule
adiponectin concentration in patients with IgA nephropathy.
Uchida HA, Nakamura Y, Kaihara M et al.
Nephrol Dial Transplant.
2006 Sep 2; [Epub ahed of print]
Background Decreased plasma adiponectin is associated with impaired endothelial function and,
thereby, increased risk for cardiovascular events. Glucocorticoid (GC) affects vascular endothelial
cells either favourably or harmfully depending upon the dosages and duration. We examined the effect
of GC pulse therapy on vascular endothelial function. Methods Forteen young patients with IgA
nephropathy were evaluated for flow-mediated vasodilation (FMD), plasma levels of adiponectin both
in high molecular weight (HMW adiponectin) form and in single molecular form (total adiponectin),
hepatocyte growth factor (HGF), asymmetric dimethylarginine (ADMA), and high-sensitive C-reactive
protein, before and after a course of GC pulse therapy. Results GC pulse therapy significantly
decreased FMD (from 7.2 +/- 2.6 to 5.7 +/- 2.5%, P < 0.01). Meanwhile, plasma adiponectin levels
were significant augmented (total adiponectin: from 10.2 +/- 4.0 to 12.1 +/- 6.3 microg/ml, P < 0.05;
HMW: from 6.5 +/- 3.2 to 7.7 +/- 3.3 microg/ml, P < 0.05). In parallel, elevated concentrations of serum
HGF (from 0.28 +/- 0.12 to 0.63 +/- 0.38 ng/ml, P < 0.01) and plasma ADMA (from 0.45 +/- 0.07 to
0.53 +/- 0.04 nmol/ml, P < 0.05) were observed. Conclusions GC pulse therapy impaired endothelial
function while increasing plasma adiponectin levels, which may in turn restore the endothelial function
in patients with IgA nephropathy.
34. Succesfull therapeutic use of rituximab in refractory membranous glomerulonephritis.
Cobo M, Hernández D, Rodriguez C et al.
Clin Nephrol.
2006 66 (1): 54-57.
Abstract We present the case of a 57-year-old man with nephrotic syndrome secondary to idiopathic
membranous glomerulonephritis unsuccesfully treated with angiotensin-converting enzyme inhibitor
(ACEI), angiotensin II receptor antagonist (ARA), prednisone and chlorambucil. After treatment with
rituximab, we observed a progressive decrease of proteinuria and normalization of serum albumin. 18
months after treatment, he remained remission. No adverse reactions to rituximab were noted
throughout follow-up.
35. Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome.
Westhoff TH, Schmidt S, Zidek W et al.
Clin Nephrol.
2006 65 (6): 393-400.
Background Steroid resistance and steroid dependence constitute a major problem in the treatment
of minimal-change disease and focal segmental glomeruosclerosis (FSGS). Cyclophosphamide and
cyclosporine are well-estabilished alternative immunomodulating agents, whereas data on FK 506
(tacrolimus) are rare. Methods The present work provides data from 10 patients of an open,
monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change
nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with
steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid
dependence, prednisolone was tapered of in presence of tacrolimus within one month. Results Within
6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients
(40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroidrefractory minimal-change), another patients becam secondarily resistant to tacrolimus after initial
remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/1.4 – 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 – 64.6 +/- 1.9 g/l
(p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 – 5.1 +/- mmol/l),
systolic blood pressure (131.4 +/- 7.1 – 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 – 1003.2 +/15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4
of them (80%). Relapse occured at tacrolimus levels between 2.6 and 6.9 ng/ml. Conclusions Our
data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant
and steroid-dependent nephrotic syndrome.
36. Meta-analysis: Anti-viral therapy of hepatitis B virus-associated glomerulonephritis.
Fabrizi F, Dixit V, Martin P.
Aliment Pharmacol Ther.
2006 24 (5): 781-8.
Hepatitis B virus-associated glomerulonephritis is an infrequent complication of chronic hepatitis B
virus (HBV) with significant morbidity. A causal association between hepatitis B virus infection and the
development of glomerulonephritis remains controversial. Also, the optimal therapy is undefined
although several approaches have been made. To evaluate the efficacy and safety of anti-viral
therapy (interferon or lamivudine) in HBV-associated glomerulonephritis by a systemic review and
meta-analysis of clinical trial. The primary outcome was clinical response (as a measure of efficacy);
the secondary outcome were drop-out rate (as measure of tolerability), and virological response. We
used the random effects model of DerSimonian and Laird, with heterogeneity, sensitivity and metaregression analyses. We identified six clinical trials (84 unique patients); three had controlled design.
The overall estimate for proteinuria remission was 65.2% (95% confidence intervals: 52.7-75.9%), Qtest for heterogeneity = 7.731, P = 0.172, I (2) = 35.327. The overall estimate for hepatitis B e antigen
clearence was 62.0% (95% confidence intervals: 50.5-72.2%). The overall estimate for drop-out rate
was 12.7% (95% confidence intervals: 6.4-23.6%). Meta-regression analysis showed a significant link
between hepatitis B e antigen clearence and logit rate of proteinuria remission after interferon therapy
[coefficient -2.585 (S.E. 1.089), P = 0.017]. Remission of the nephrotic syndrome is accompained by
clearence of HBV replication, supporting the role of the virus in the pathogenesis of the disease.
37. Nephrotoxicity as a complication of antiretroviral therapy.
Valle R, Haragsim L.
Adv Chronic Kidney Dis.
2006 13 (3): 314-9.
Since 1984, human immunodeficiency virus-associated nephropathy has been estabilished as a
clinical entity that presents with nephrotic syndrome and progressive kidney failure. The pathological
description is usually consistent with a collapsing form of focal segmental glomerulosclerosis.
Podocytes and renal tubular cells have been proposed as a reservoir for the human immunodeficiency
virus. This nephropathy is the third leading cause of end-stage renal disease in the population of
African descent. It is documented that highly active retroviral therapy (HAART) successfully reverses
or at least controls nephropathy in HIV-positive patients. The success of the treatment of HIV
nephropathy now poses 2 problems to nephrologists: (1) an increased population of HIV-positive
patients with chronic kidney disease not yet on dialysis and (2) potential nephrotoxicity of antiretroviral
medications as well as medications used to treat opportunistic infections. HAART is defined by the
combination of 2 reverse-transcriptase inhibitors with a protease inhibitor or 3 reverse-transcriptase
inhibitors. Many of these antiretroviral have well-defined nephrotoxic effects. The objective of this text
is to review data pertaining to some of the most common antiretrovirals (ARTs) and include
information regarding nephrotoxicity of the medications frequently used to combat opportunistic
infections. ARTs included in the review are (1) nucleoside reverse-transcriptase inhibitors (zidovudine
and didanosine), (2) nucleotide reverse-transcriptase inhibitors (adefovir and tenofovir), (3) the
protease inhibitors (indinavir and saquinavir), and (4) the HIV fusion inhibitors.
38. HIV-associated nephropathy.
Khan S, Haragsim L, Laszik ZG.
Adv Chronic Kidney Dis.
2006 13 (3): 307-13.
Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is one of the most important
causes of progressive kidney failure in HIV-1-seropositive patients. Since the 1980s, much has been
published regarding the epidemiology, pathogenesis, and treatment of HIVAN. Our knowledge of the
clinical features, pathologic manifestations, course, and potential outcome of HIVAN has increased
considerably. The use of highly effective antiretroviral therapy has shown significant improvement in
the outcome of human immunodeficiency virus infection and is found to be effective in preventing endstage renal disease. The purpose of this review is to summarize the data about the clinical
manifestations, pathogenesis and pathophysiologic mechanisms of HIVAN with particular attention on
treatment including pharmaceutical and renal replacement options.
39. Antiretroviral therapy in the treatment of HIV-associated nephropathy.
Atta MG, Gallant JE, Hafizur Rahman M et al.
Nephrol Dial Transplant.
2006 Jul 24; [Epub ahead of print]
Background The effect of antiretroviral therapy (ART) on the clinical course of patients with human
immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is not well-estabilished. This study
was undertaken to further elucidate the potential benefit of ART in HIV-infected patients with
documented HIVAN. Methods A cohort of 263 consecutive HIV-infected patients referred to the Johns
Hopkins renal clinic from 1995 to 2004 was examined. Patients were included if they had biopsyproven HIVAN and did not require dialysis within 1 month of their kidney biopsy. The cummulative
probability of renal survival was calculated using the Kaplan-Meier method. Multivariate analysis was
performed using the Cox regression methods. Results Fifty-three patients among 152 biopsied had
HIVAN. Among 36 patients who met the inclusion criteria, 26 were treated with ART (group I) and 10
patients were not (group II). Except for age, baseline demographics and clinical characteristics were
similar in the two groups. Renal survival was a significantly better in the group receiving ART by both
univariate (P = 0.025) and multivariate analysis (overall adjusted hazard ratio = 0.30; 95% confidence
interval 0.09-0.98; P < 0.05) for ART compared with no treatment. Conclusions patients with biopsyproven HIVAN treated with ART had better renal survival compared with patients who did not receive
ART. HIVAN should be considered as an indication to initiate ART.
40. FK506 in treatment of children with nephrotic syndrome of different pathological types.
Xia Z, Liu G, Gao Y et al.
Clin Nephrol.
2006 66 (2): 85-8.
Abstract. Objective To evaluate the efficacy of FK506 in the treatment of children with nephrotic
syndrome of different underlying pathology. Methods 12 patients were treated with FK506 with a
dosage of 0.1-0.15 mg/kg/d while corticosteroid dose was tapered stepwise. This therapeutic course
lasted 3-6 months during which the plasma concentration of FK506 was monitored. Results 12
children with different pathological types nephrotic syndrome were treated with FK506, including 4
cases of MCN, 6 cases of MsPGN, and 1 case MPGN and 1 case of FSGS. After 2-month duration, 8
patients got complete remission including 4 cases of MCN an 4 cases of MsPGN and 3 children
including 1 case MsPGN, 1 case MPGN, and 1 case of FSGS got partial remission. Only 1 child with
MsPGN was considered to be a treatment failure. The overall response rate was 91.67% with the
plasma concentration of FK506 maintained at 5~12 ng/ml, and the response time was 10-38 days.
After 1-month duration, all patients except one experienced a reduction in proteinuria to normal levels
or a partial response (50% reduction in protein excretion), significant increase in serum albumin,
decrease in serum cholesterol and triglyceride and disappearance of edeme. 2 months later, in 11
patients, blood biochemiocal values had returned to normal levels. The drug was generally welltolerated. 3 patients had anorexia, nausea, vomiting. 2 patients experienced transient elevated serum
creatinine which was reversible after the adjusment of dosage. 3 patients had minor changes in urine
NAG. Only 2 of all patients relapsed. Conclusion FK506 is one of the effective immunosuppressants.
In this study, FK506 in combination with a small doses of steroid while decreasing FK506 dosage
plays a role in consolidating the curative effect and preventing relapse. In conclusion, FK506 may be
effective in the treatment of nephrotic syndrome.
41. Modulator of bone morphogenetic protein activity in the progression of kidney diseases.
Yanagita M.
Kidney Int.
2006 70 (6): 989-93.
Tubular damage and interstitial fibrosis is a final common pathway leading to end-stage renal disease,
and once tubular damage is estabilished, it cannot be reversed by currently available treatment. The
administration of bone morphogenetic protein-7 (BMP-7) in pharmacological doses repairs
estabilished tubular damage and improves renal function in several kidney disease models; however,
pathophysiological role of endogenous BMP-7 and regulatory mechanisms of its activities remain
elusive. The activity of BMP is precisely regulated by certain classes of molecules termed BMP
agonist/antagonist. In this review, roles of BMP agonist/antagonists possibly modulating the activity of
BMP in kidney diseases are discussed. Our group demonstrated that uterine sensitization-associated
gene-1 (USAG-1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative
regulator of BMP-7 in the kidney, and that mice lacking USAG-1 (USAG-1 (-/-) mice) are resistant to
kidney injuries. USAG-1 (-/-) mice exhibited markedly prolonged survival and preserved renal function
in acute and chronic renal injuries. Renal BMP signaling, assessed by phosphrylation of Smad
proteins, is a significantly enhanced in USAG-1 (-/-) mice during renal injury, indicating that the
preservation of renal function is attributed to enhancement of endogenous BMP-7 signaling.
Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in
USAG-1 (-/-) mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective
action of BMP, and that inhibition of USAG-1 will be promising means of development of novel
treatment for kidney disease.
42. Effect of tranilast in early-stage diabetic nephropathy.
Soma J, Sato K, Saito H et al.
Nephrol Dial Transplant.
2006 Jul 4; [Epub ahead of print]
Background Tranilast is an antifibrotic drug known to suppress collagen synthesis by fibroblasts by
interfering with the effects of TGF-beta. We recently reported that it slowed the progression rate of
advanced diabetic nephropathy (DN) by reducing the accumulation of collagens in renal tissue. The
present study was undertaken to examine the effect of tranilast on early-stage DN. Methods Among
out-patients with diabetes mellitus, we selected patients with (i) urinary albumin excretion of 30-1000
mg/g creatinine (/gCr) in the first morning urine, (ii) serum creatinine (SCr) </=1.2 mg/dl and no
haematuria and (iii) currently taking an angiotensin-converting enzyme inhibitor or angiotensin
receptor blocker. Twenty patients fulfilled the criteria, of whom 10 were selected at random and
commenced on tranilast [100 mg, 3 times daily; T (+) group]. The remaining 10 patients comprised the
T (-) group. Excretion of both urinary type IV collagen (U-IV) and albumin (U-A) in the first morning
urine was measured every 3 months. The follow-up period was 1 years. Results At baseline, no
significant differences were observed in SCr, HbA1c, blood pressure and U-A excretion between the T
(+) and T(-) groups, but U-IV excretion in the T (+) group was higher than in the T(-) group (6.4 +/0.66 vs 3.7 +/- 0.36 microg/gCr, mean mean +/- SEM, P < 0.01). At 1 year, SCr was not different from
the baseline in either group. In the T (+), however, excretion rates of both U-IV and U-A tended to
decrease with the time, and after 1 year, were significantly compared with excretion at baseline (U-A:
279 +/- 78 to 191 +/- 62; P = 0.049, U-IV: 6.4 +/- 0.66 to 4.4 +/- 0.99 microg/gCr; P = 0.02). In contrast,
in the T (-) group, excretion of both U-A and U-IV tended to increase with the time. The changes of
both U-A and U-IV excretions in the two groups took staistically different trends through tranilast
treatment (P = 0.01 and P = 0.04, respectively). Conclusions Our results suggest that tranilast could
be therapeutically beneficial in early-stage DN.
43. The management of tumor lysis syndrome.
Rampello E, Fricia T, Malaguarnera M.
Nat Clin Pract Oncol.
2006 3 (8): 438-47.
The manifestation of tumor lysis syndrome (TLS) occurs when the destruction of tumor cells releases
breakdown products that overhelm the excretory mechanisms of the body. A cardinal sign is
hyperuricemia, leading to uric acid nephropathy. Other signs are hyperkalemia, hyperphosphatemia
and secondary hypocalcemia. Conventional management of TLS consist of aggressive intravenous
hydration, diuretic therapy, urinary alkalization, and inhibition of urate production by high-dose
allopurinol. Urate oxidase has been used in the management of patients at risk for TLS and recently
the recombinant urate oxidase rasburicase was developed. Several data indicate that rasburicase is
effective and well tolerated in the prevention and treatment of chemotherapy-induced hyperuricemia.
Treatment options of hyperkalemia include sodium polystyrene sulfonate, hypertonic glycose and
insulin, loop diuretics, and bicarbonate. Treatment of hyperphosphatemia reduces dietary phosphate
intake and includes phosphate binders such as aluminium hydroxide and aluminium carbonate. When
recurrent hypocalcemia is present, a continous intravenous infusion of calcium gluconate can be
initiated. Hemodialysis should be considered for every patients with excessively elevated uric acid,
phosphate and/or potassium and in those patients with acute renal failure to control urinary volume
and manage uremia.
44. Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult
human kidneys.
Sagrinati C, Netti GS, Mazzinghi B et al.
J Am Soc Nephrol.
2006 Aug 2; [Epub ahead of print]
Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification
of renal adult multipotent progenitor cells has remains elusive. It is demonstrated that in human adult
kidneys, a subset of parietal epithelial cells (PEC) in the Bowman’s capsule exhibit coexpression of the
stem cell markers CD24 and CD133 and of the stem cell-specific transcription factors Oct-4 and BmI1, in the absence of lineage-specific markers. This CD24 (+) CD133 (+) PEC population, which could
be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning
efficiency. Under approprite culture conditions, individual clones of CD24 (+) CD133 (+) PEC could be
induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal
tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of
neuronal cells. The injection of CD24 (+) CD133 (+) PEC but not of CD24 (-) CD133 (-) renal cells into
SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different
portions of the nephron. More important, treatment of acute renal failure with CD24 (+) CD133 (+) PEC
significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the
existence and provides the characterization of a population of resident multipotent progenitor cells in
adult human glomeruli, potentially opening new avenues for the development of regenerative medicine
in patients who have renal diseases.
45. Regrow or repair: Potential regenerative therapies for the kidney.
Little MH.
J Am Soc Nephrol.
2006 Jul 26; [Epub ahead of print]
Rgenerative medicine is being heralded in a similar way as gene therapy was gene therapy was some
15 yr ago. It is an area of intense excitement and potential, as well as myth and disinformation.
However, the increasing rate of end-stage renal failure and limited alternatives for its treatment, we
must begin to investigate seriously potential regenerative approaches for the kidney. This review
defines wich regenerative options there might bo for renal disease, summarize the progress that has
been made to date, and investigates some of the unique obstacles to such treatments that the kidney
presents. The options discussed include in situ organ repair via bone marrow recruitment or
differentiation; ex vivo stem cell therapies, including both autologous and nonautologous options; and
bioengineering approaches for the creation of a replacement organ.
46. Secondary failure of plasma therapy in factor H deficiency.
Nathanson S, Ulinski T, Fremeaux-Bacchi V et al.
Pediatr Nephrol.
2006 Aug 15; [Epub ahead of print]
We report a patients with homozygous factor H deficiency leading to permanent complement
activation and early onset of the hemolytic uremic syndrome. He was successfully treated with weekly
infusion of fresh frozen plasma over 4 years, displaying normal blood pressure while only treated with
an angiotensin converting enzyme (ACE) inhibitor, a steady level of haptoglobin, low-range proteinuria
and normal creatinine clearence. By the end of the fourth year of treatment, he dramatically developed
a relapse of hemolytic and uremic syndrome, displaying undectable haptoglobin, nephrotic range
proteinuria and progressive renal failure. Despite a ten-fold increase in the dosage of plasma infusion
through daily plasma exchange, haptoglobin remained undetectable while circulating antigenic factor
H levels reached 22-24% (normal value 65-140%). Three months following the biological onset of the
relapse, a bilateral nephrectomy was performed owing to uncontrolled hypertension and rapidly
progressive renal failure. The molecular mechanism of plasma resistance remaind unclear while
antifactor H antibodies were not detected in the plasma. We suggest that protracted adminstration of
exogenous factor H might not be a long-term strategy in homozygous factor H deficiency.
47. Neutrophil gelatinase-associated lipocalin-mediated iron traffic in kidney epithelia.
Schmidt-Ott KM, Mori K, Kalandadze A et al.
Curr Opin Nephrol Hypertens.
2006 15 (4): 442-9.
Purpose of review Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin
superfamily of carrier proteins. NGAL is the first known mammalian protein which specifically binds
organic molecules called siderophores, which are high-affinity iron chelators. Here, we review the
expression, siderophore-dependent biological activities and clinical significance of NGAL in epithelial
development and kidney disease. Recent findings NGAL expression is rapidly induced in the
nephron in response to renal epithelial injury. This has led to the estabilishment of NGAL assays that
detect renal damage in the human. Additionally, only when complexed with siderophore and iron as a
trimer, NGAL induces mesenchymal-epithelial transition (or nephron formation) in embryonic kidney in
vitro and protects adult kidney from ischemia-reperfusion injury in vivo. While the structure of NGAL:
siderophore: iron complex has thus far only been solved for bacterially synthesized siderophores, new
evidence suggest the presence of mammalian siderophore-like molecules. Summary NGAL is rapidly
and massively induced in renal epithelial injury and NGAL: siderophore: iron complexes may comprise
a physiological renoprotective mechanism. The data have implications for the diagnosis and treatment
of acute renal injury.
V.
TRANSPLANTATION
1. Subclinical rejection impairs glomerular adaptation after renal transplantation.
Ibernon M, Goma M, Moreso F et al.
Kidney Int.
2006 70 (3): 557-61.
After transplantation, glomerular volumes increases and large glomerular volume at 4 months is
associated with better renal function. The aim is to characterize glomerular adaptation after the fourth
month in two serial protocol biopsies and its relationship with subclinical rejection and chronic allograft
nephropathy (CAN). Mean glomerular volume (Vg) was estimated according to the Weibel and Gomez
method in a 4-month and 1-year serial biopsies in 61 stable grafts. Glomerular enlargement (deltaVg)
was calculated as the Vg difference between both biopsies. Banff schema was used to evaluate renal
biopsies. Vg increased from 4.4+/-2.4 to 5.7+/-2.6 x 10 (6) microm3 (P<0.001). Mean deltaVg was 1.0
x 10 (6) microm3. Patients with deltaVg<1 were considered as patients with impaired glomerular
enlargement (n=29). Impaired glomerular enlargement was associated with increased acute index
score in the 4-month (1.83+/-1.56 vs 1.06+/-1.48; P<0.05) and 1-year protocol biopsies (1.52+/-1.59 vs
0.26+/-1.07; P<0.05). Impaired glomerular enlargement was also associated with increased
progression of chronic lesions between the 4-month and 1-year biopsy in the glomerular (0.17+/-0.38
vs 0.55+/-0.63; P<0.01), tubular (0.38+/-0.56 vs 0.83+/-0.85; P<0.01), and interstitial compartment
(0.41+/-0.57 vs 0.90+/-0.86; P<0.01). The proportion of sclerotic glomeruli between both biopsies
increased in patients with impaired glomerular enlargement (1.5+/-3.9 to 5.3+/-10.1; p<0.05) while did
not modify in patients with glomerular enlargement (2.1+/-7.3 vs 2.6+/-4.5; P=NS). During the first
year, glomeruli enlarge but this adaptation mechanism is impaired in patients with subclinical rejection.
Moreover, impaired glomerular enlargement is associated with progression of CAN.
2. Experience with an organ procurement organization-based non-directed living kidney donation
programme.
Mark PJ, Baker K, Aguayo C et al.
Clin Transplant.
2006 20 (4): 427-37.
The organ procurement organization (OPO)-based non-directed living kidney donation programme
was developed to decrease wait times for kidney transplants, and to meet the community’s desire for
altruistic living donation. Community awareness was encouraged through information about nondirected living kidney donation on the state donor registry Web site, and through the media. The OPO
received all inquiries and responded with phone calls, e-mails, printed information, medical/social
history questionnaires, interviews, and referrals to the transplant centres. Kidney were allocated
according to the United Network for Organ Sharing (UNOS) wait list for the evaluating transplant
centre. Between March 2002 and 23 September 2005, there were 608 inquiries to the OPO about
non-directed living kidney donation. In 41 months, 20 transplants occured with kidneys from nondirected donors. The donor registry and OPO-sponsored publicity led to 578 of the 608 inquiries and
15 of the 20 transplants. OPO screening saved transplant centre resources by ruling out 523 inquiries,
referring 76 to transplant centres for complete evaluations. Optional donor/recipient meetings
appeared to be beneficial to those participating. OPO-based non-directed living donor programmes
can be effective and efficient. Standardization of evaluation, allocation, and follow-up will allow for
better data collection and more widespread implementation.
3. Kidney transplantation without prior dialysis in children: The eurotransplant experience.
Cransberg K, Smits JM, Offner G et al.
Am J Transplant.
2006 6 (8): 1858-64.
Kidney transplantation without prior dialysis may prevent dialysis-associated morbidity. We analyzed
the outcome of 1113 first kidney transplants in children performed between 1990 and 2000 in the
Eurotransplant community. Enlistment for a decreased donor kidney before start of dialysis (127/895,
14%) made dialysis redundant in 55% of cases. Mean residual creatinine clearence at transplantation
of these patients was 8 mL/min/1.73 m(2). Pre-emptive transplantations of deceased donor kidneys
showed less acute rejections (52% vs. 37%) rejection-free at 3 years, p = 0.039), compared to
transplantations following dialysis. The difference in graft survival between non-dialyzed and dialyzed
patients (82% vs. 69% at 6 year) did not reach statistical significance (p = 0.055). No differences were
noted after living donor transplantation. Multivariate analysis showed that the period of transplantation
was the strongest predictor of graft survival (p < 0.001). Congenital abnormalities such as primary
kidney disease predominated in nondialyzed patients as compared to dialyzed patients (p < 0.001);
this factor did not influence graft survival. Based on our conclusion that pre-emptive transplantation is
at least as good as post-dialysis transplantation, as well as on quality of life arguments, we
recommend to consider pre-emptive transplantation in children with end-stage renal failure.
4. Reflux nephropathy in kidney transplants, demonstrated by dimercaptosuccinic acid scanning.
Coulthard MG, Keir MJ.
Transplantation.
2006 82 (2): 205-10.
Background This study determines why kidney transplant develop new focal defects. Methods Thirty
children at a U.K. pediatric nephrology department receiving kidney transplants had early and late
dimercaptosuccinic acid (DMSA) scans to detect aquired focal defects, and their presence correlated
with possible risk factors. Association between clinical events and focal DMSA lesions appearing in
grafts were measured. Results Of the 30 early DMSA scans (within 2 weeks of function), one child
with a thrombosed polar artery had a focal defect. On scanning later, 11 (37%) had aquired segmental
defects; five were multiple, and their glomerular filtration rate were 20 ml/min/1.73 m (2) lower (95% CI
7-34). Histology in one case showed pyelonephritic scarring. Reflux into the transplant ureter occured
in 19/27 (70%) of children tested (by radilogical or indirect radionuclide cystography). Nine of 13
children (69%) who had a combination of reflux and a urine infection had aquired scars, whereas only
1/14 (7%) did without this combination (P = 0.001). Scarring was not associated with the age or sex of
the donor or recipient, rejection episodes, renal biopsy, or drug-induced nephrotoxicity. Conclusion
Kidney transplants are at high risk of developing segmental pyelonephritic scars if infected urine
refluxes into the graft, either early through a transanastomotic stent or later from vesicoureteric reflux.
These scars may reduce the renal function and are readily seen on DMSA, but not ultrasound scans.
Consideration should be given to more effective antireflux surgery for transplants, with subsequent
testing for reflux, urinary antibiotic prophylaxis, and prompt treatment of urine infections.
5. Pediatric live-donor kidney transplantation in Mansoura Urology & Nephrology Center: A 28-year
perspective.
El-Husseinin AA, Foda MA, Bakr MA et al.
Pediatr Nephrol.
2006 Jun 22; [Epub ahead of print]
Our objective was to evaluate our overall experience in pediatric renal transplantation. Between March
1976 and March 2004, 1,600 live-donor kidney transplantations were carried out in our center; 216 of
the patients were 18 years old or younger (mean age 12.9). There were male patients and 80 female
patients. The commonest causes of end-stage renal disease (ESRD) were renal dysplasia (22%),
nephrotic syndrome (20%), hereditary nephritis (16%), and obstructive uropathy (16%). Of the donors,
94% were one-haplotype matched and the rest were identical. Pre-emptive transplantation was
performed in 51 (23%) patients. Triple-therapy immunosuppression (prednisone + cyclosporine +
azathioprine) was used in 78.2% of transplants. Rejection-free recipients constituted 47.7%.
hypertension (62%) was the commonest complication. A substantial proportion of patients (48%) were
short, with heght standard deviation score (SDS) less than -1.88. The overall infection rate was high,
and the majority (53%) of infections were bacterial. The graft survival at 1 year, 5 years and 10 years
were 93.4%, 73.3% and 48.2%, respectively, while the patient’s survival at 1, 5 and 10 years were
97.6%, 87.8% and 75.3%, respectively. Despite long-term success results of pediatric renal
transplantation in a developing country, there is a risk of significant morbidity.
6. The advantage of allocating kidneys from old cadaveric donors to old recipients: A single-center
experience.
Bodingbauer M, Pakrah B, Steininger R et al.
Clin Transplant.
2006 20 (4): 471-5.
Background In January 1999 a new kidney allocation program was launched by the Eurotransplant
Foundation, the ’ Eurotransplant Senior Program ’ (ESP). Cadaveric donors above the age of 65 yr are
allocated to kidney transplant recipients of the same age group. Methods Using a single-center
database, 91 patients who underwent first renal transplantation at the age of 65 yr older in the years
1999-2002 were identified. Fifty-six patients were transplanted through ESP allocation (study group)
and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS)
procedure. Results Age, sex and comorbid conditions did not differ by group. The rate of acute
rejection episodes, primary non-function, delayed graft function, perioperative mortality did not differ by
group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p = 0.015)
from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS
group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group,
cumulative patient survival according to the Kaplan-Meier estimation was not statistically different at
five yr. Conclusions We did not find a relevant differences in the outcome between young and old
kidney transplants in old recipients after this long observation period.
7. Early posttransplant serum osteoprotegerin levels predict long-term (8-year) patient survival and
cardiovascular death in renal transplant patients.
Hjelmesaeth J, Ueland T, Flyvbjerg A et al.
J Am Soc Nephrol.
2006 17 (6): 1746-54.
The primary objectives of this analysis were to examine of early posttransplantation (10 wk) serum
levels of osteoprotegerin (OPG), mannose-binding lectin (MBL), and MBL-associated serine proteases
(MASP; MASP-2 and MASP-3) on long-term (8-year) patient survival, graft survival, and
cardiovascular (CV) death. During a period of 16 mo (1995 to 1996), a to total of 173 consecutive
renal transplant recipients without diabetes before transplantation were included in a prospective study
that designed to adress the impact of metabolic CV risk factors on survival and CV end points.
Baseline sera from 172 patients were available for analysis. Follow-up data until January 1, 2004,
were obtained from a national renal registry. Patients with high (fourth quartile) serum levels of OPG
had significantly higher all-cause mortality (hazard ratio [HR] 6.3; 95% confidence interval [CI] 3.3 to
11.8; P < 0.001) and CV death (HR 10.8; 95% CI 3.8 to 30.4; P < 0.001) than patients with lower OPG
concentrations. After multiple Cox regression analysis, high serum levels of OPG remained an
independent predictor of all-cause mortality (HR 6.0; 95% CI 3.1 to 11.6; P < 0.001) and CV death (HR
8.2; 95% CI 2.5 to 26.4; P < 0.001). Multiple linear regression analysis revealed that age, creatinine
clearence, and high-sentivity C-reactive protein all were independently associated with OPG (R(2) =
0.42). No significant association between OPG and death-censored graft loss was revealed. Serum
levels of MBL, MASP-2, and MASP-3 were not significantly associated with patient survival, CV death,
or graft loss. Early measured posttransplantation serum OPG is a highly significant independent
predictor of death any cause or CV death in white renal transplant recipients.
8. Color Doppler ultrasonograpy in the diagnostic evaluation of renal allografts.
Schwenger V, Hinkel UP, Nahm AM et al.
Nephron Clin Pract.
2006 104 (3): c107-12.
Color Doppler ultrasonography of large allograft vessels and renal parenchyma is estabilished firmly in
the diagnosis of renal allograft perfusion. While conventional color Doppler ultrasonography has
proven itself to be an indispensable, rapid, highly valid and practicable method, e.g. in the diagnosis of
allograft artery stenosis or allograft vein thrombosis, the diagnostic usefulness of this method with
regard to allograft perfusion is considerably limited. With contrast-enhanced sonography, a simple and
readily implementable method that enables the early diagnosis of chronic allograft nephropathy is now
available. The timely diagnosis of vascular damage prior to a rise in S-creatinine offers the possibility
of early therapeutic intervention and thus at least the potential for the improvement of allograft survival.
9. Agreement of immunesuppression regimens described in Medicare pharmacy claims with the
Organ Procurement and Transplantation Network Survey.
Stirnemann PM, Takemoto SK, Schnitzler MA et al.
J Am Soc Nephrol.
2006 Jul 6; [Epub ahead of print]
The Organ Procurement and Transplantation Network (OPTN) collects intermittent survey data on
immunosuppressive mediaction use that are studied frequently as research measures. Pharmacy
billing claims may provides an accurate measure of immunosuppression use over time. Herein is
characterized the agreement of Medicare pharmacy claims for immunosuppressive mediactions with
(OPTN) reports. Data were drawn from the United States Renal Data System. Participants received a
kidney transplant in 2000 to 2001 and had an OPTN record and a Medicare pharmacy claim for an
immunosuppressive drug at transplant discharge and 6 mo and 1 yr after transplantation. The
concordance (kappa) of the OPTN and claims (+/- d of survey) for indicated medication use was
compared, and sensitivity, specificity, and predictive values for claims were computed, assuming
OPTN as a ’’gold standard’’. Clinical trial participation and regimen changes were examined as
explanations for discordance. A total o 4357 eligible subjects were identified. Concordance over
observation ranged from excellent for calcineurin inhibitors (kappa > 0.86) to generally very good for
adjunctive agents (kappa = 0.49 to 0.75) to poor for corticosteroids (kappa < 0.15). Claims
demonstrated high positive predictive values (>/=97%) but low negative predictive values (</=13%) for
OPTN-reported corticosteroid use. Regimen changes (28 to 75%) but not clinical trial participation
(</=21%) were identified frequently among cases with discordant indications of nonsteroid medication
use. Close agreement of Medicare billing claims and the OPTN for indicated use of nonsteroid
immunosuppressive mediactions supports both as useful measures of drug exposure. Low detection
rates of OPTN-indicated corticosteroid use within claims require further examination.
10. Effect of induction therapy protocols on transplant outcomes in crossmatch positive renal allograft
recipients desensitized with IVIG.
Vo AA, Toyoda M, Peng A et al.
Am J Transplant.
2006 Jul 25; [Epub ahead of print]
Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax ((R))
or Thymoglobulin ((R)) in patients with positive complement-dependent cytotoxicity crossmatches
(CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March
2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living
donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was
obtained. Patients were divided into two groups: 1. IVIG + Zenapax ((R)) (n = 58), 2. IVIG +
Thymoglobulin ((R)) (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2
years of follow up. Patient and graft survival was 96%/84% in group 1 and 100%/90% in Group 2, p =
NS. The nuber and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as
was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs.
21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. 1.5
+/- 0.7 mg/dL). Induction therapy with Zenepax ((R)) or Thymoglobulin ((R)) results in excellent
patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or
malignancies with either agent. Neither agent was effcetive in reducing the incidence of AMR.
11. Living donor renal transplantation using alemtuzumab induction and tacrolimus monotherapy.
Tan HP, Kaczorowsky DJ, Basu A et al.
Am J Transplant.
2006 Aug 4; [Epub ahead of print]
Alemtuzumab was used as an induction agent in 205 renal transplant recipients undergoing 207 living
donor renal transplants. All donor kidneys were recovered laparoscopically. Postoperatively, patients
were treated with tacrolimus monotherapy, and immunosuppression was weaned when possible. Firtyseven recipients of living donor renal transplant prior to the induction era who received conventional
triple drug immunosuppression without antibody induction served as historic controls. The mean
follow-up was 493 days in the alemtuzumab group and 2101 days in the historic control group.
Actuarial 1-year patient and graft survival were 98.6% and 98.1% in the alemtuzumab group,
compared to 93.6% and 91.5% in the control group, respectively. The incidence of acute cellular
rejection (ACR) at 1 year was 6.8% in the alemtuzumab group and 17.0% (p < 0.05) in the historic
control group. Most (81.3%) episodes of ACR in the alemtuzumab group were Banff 1 (a or b ) and
were sensitive to steroid pulses for the treatment of rejection. There was no cytomegalovirus disease
or infection. The incidence of delayed graft function was 0%, and the incidence of posttransplant
insulin-dependent diabetes mellitus was 0.5%. This study represents the largest series to date of live
donor renal transplant recipients undergoing alemtuzumab induction, and confirm the short-term safety
and efficacy of this approach.
12. Pharmacodynamics of rituximab in kidney allotransplantation.
Genberg H, Hansson A, Wernerson A et al.
Am J Transplant.
2006 Aug 21; [Epub ahead of print]
The anti-CD20 antibody rituximab has recently gained interest as a B-cell depleting agent in renal
transplantation. However, little is known about the pharmacodynamics of rituximab in renal transplant
recipients. We have therefore studied the effect of single-dose rituximab in combination with
conventional triple immunosuppressive therapy on the B-cell population in peripheral blood as well as
in tissue. A total of 49 renal transplant recipients received single-dose rituximab, as induction therapy
(n = 36) or as antirejection therapy (n = 13). We conducted B cells in peripheral blood and performed
immunohistochemical staining on lymph nodes and kidney transplant tissue samples to assess the
prevalence of B cells. In all but 6 patients (88%) complete depletion of B cells in peripheral blood was
achieved. In adults, 15 months after treatment the CD19+ and CD20+ cell counts still below 5
cells/muL in the majority of patients (78%). The immunohistochemical staining showed a complete
elimination of B cells in kidney tissue and reduction of B cells in lymph nodes. In conclusion, singledose rituximab in kidney transplant recipients evokes a long-term elimination of B cells in peripheral
blood as well as within the kidney transplant. The effect seems to extend beyond the expected 3-12
months observed in lymphoma patients.
13. Late corticosteroid withdrawal can be safely performed for kidney recipients with stable graft
function under pathological confirmation.
Harada H, Miura M, Ogawa Y et al.
Clin Transplant.
2006 20 (Suppl 15): 26-32.
Corticosteroid withdrawal (CSWD) protocols to minimize the risk of cardiovascular events after kidney
transplantation have been reported. However, most of them were within one year post-transplant, and
the pathological survey after CSWD was poorly done. We conducted the present retrospective study
to elucidate the usefulness and safety of late-steroid withdrawal more than one year after
transplantation in kidney recipients with pathological evaluation. Twenty kidney recipients with stable
graft function more than one year post-transplant, and whose corticosteroid (CS) was withdrawn were
enrolled in this study. The change in their clinical parameters of graft function (sCr and uP/Cr),
metabolic profiles, and histological graft status (Banff 97 scoring system) were studied pre- and postCSWD, and compared with a control cohort taking continous CS. The dose of CS was tapered
gradually and has been maintained with the minimal dose of CS (1.25 mg of prednisone) by three
months after transplant. CS was furthermore reduced thereafter, if graft function had been stable more
than on year and a patient wanted CS to withdrawn, then a graft biopsy was undertaken. CSWD was
accomplished between 16 and 195 (median 41.5) months post-transplant, if there was no significant
histological graft damage or on-going acute rejection. A repeat biopsy was carried out two to 21
months after CSWD. In contrast, the observation point of the control cohort was 24 to 49 (median
36.5) months after transplant, and the second biopsy was done five to 30 months after the initial
biopsy. The control cohort took 2.5 to 5 (median 2.5) mg of prednisone daily. There were no significant
alterations of graft function between pre- and post-CSWD (sCr: 1.14 +/- 0.1 and 1.17 +/- 0.1 mg/dL,
respectively, p = 0.3299, uP/Cr: +/- 0.12 +/- 0.01 and 0.21 +/- 0.06, respectively, p = 0.0574). The
hypertension rate between both groups was not different between double biopsy point. In addition the
rates of glucose intolerance and hyperlipidemia were comparable between two points in both cohorts.
There were no significant change in the acute/active lesion scoring (2 t1 and 3 i1 were only positive
factors before CSWD and they all returned to t0and i0 after CSWD). Moreover, chronic/sclerosing
allograft nephropathy scorings were minimal and similar between pre- and post-CSWD compared with
the control. CSWD for more than one year is safe for patients whose graft functions are stable with
pathological confirmation; however, a longer follow-up study is warranted.
14. Steroid-free immunosuppression after renal transplantation - - long-term experience from a single
centre.
El-Faramawi M, Rohr N, Jespersen B.
Nephrol Dial Transplant.
2006 21 (7): 1966-73.
Background A steroid-free immunosuppressive protocol may improve the general well-being of
patients, but long-term renal graft survival has been a concern. Methods In a retrospective clinical
study, 329 consecutive transplantations with renal grafts at our centre during period 1995-204, were
followed for up to 9.3 years. Patients mainly received steroid-free immunosuppression with an initial
induction with antithymocyte globulin or basiliximab and maintenance therapy with cyclosporine and
mycophenolate mofetil (MMF). Steroids were given after rejection, or if the physician judged it
necessary, for instance because of primary kidney disease or when calcineurin inhibitor toxicity was
suspected. Results About 71% of the patients did not take steroids at all. Nevertheless, graft survival
rates at 1, 5 and 7 years were 95, 77 and 72% for all grafts, including 27% living donor transplants and
27% second or subsequent grafts. Ten patients (3.2%) died with functioning grafts. Within the first
year of transplantation there were 69 acute rejections in 63 patients (19%). Four cases (1.3%) of posttransplant lymphoproliferative disorder (PTLD) occured with one graft loss and no deaths. Owing to a
high PTLD rate in a previous patient cohort, total immunosuppression was lessened after 1998.
Conclusions Steroid avoidance is possible with good results with respect to acute rejection and longterm graft survival. After introducing MMF, largely avoiding muromonab-CD3 mouse raised
monoclonal antibody against CD (OKT3), had reducing doses of calcineurin inhibitor, the rates of
PTLD did not differ from what is usually found. For the present, induction and use of MMF, together
with a calcineurin inhibitor, is probably to be preferred.
15. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation.
Harmon W, Meyers K, Ingelfinger J et al.
J Am Soc Nephrol.
2006 17 (6): 1735-45.
Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor
kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone,
mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr
of follow-up. One enrolled patients did not receive the transplant because of a donor problem, eight
terminated because of one or more rejection episodes, four terminated because of adverse events,
and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other
as result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo
acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of
the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend
to a mean of 70 ml/min therafter. Early surveillance graft biopsies frequently showed focal interstitial
mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared
without treatment. Ant-HLA class I and II antibodies were detected in three patients before
transplantation, and all three had acute rejections, including the two patients who lost their grafts. De
nove anti-HLA Ab production occured in only one patients after transplantation. There were two
episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which
developed after the patient had been terminated from the study. It is concluded that calcineurin
inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal
transplantation. However, further modifications that are designed to lessen early rejection rates and
decrease complications should be tested before this approach is used routinely.
16. Long-term safety and efficacy after conversion of maintenance renal transplant recipients from
mycophenolate mofetil (MMF) to enteric coated mycophenolate sodium (EC-MPS, myfortic®)
Budde K, Knoll G, Curtis J et al. on behalf of the ERL B302 Study Group.
Clin Nephrol.
2006 66 (2): 103-11.
Abstract. Aim A 12-month multicenter, double-blind trial in which maintenance renal transplant
patients were randomized to remain on mycophenolate mofetil (MMF) or convert to enteric-coated
mycophenolate sodium (EC-MPS, myfortic®) has demonstrated that conversion from MMF to ECMPS is safe. Patients completing the study were invited to enter an open-label extension. Upon entry
to the extension, patients who had received MMF during the randomized phase were converted to ECMPS (’’newly-exposed EC-MPS’’ group) and were monitored separately from those who had been
randomized to EC-MPS (’’long-term EC-MPS’’ group). The aim of the extension study was to collect
long-term safety and efficacy data on EC-MPS, and to confirm the safety of conversion from MMF to
EC-MPS in a larger patient population. Methods All patients received EC-MPS 720 mg b.i.d. with
cyclosporine microemulsion and corticosteroids per local practice. Data derived from the analysis of
the first 24 months of the extension phase are presented. Results Of the 297 patients who completed
the core study, 260 (88%) entered the extension; 195 (75%) completed the 24-month extension visit.
For on-treatment patients > 95% of the planned daily dose of EC-MPS was administered, and < 13%
of patients in both groups had discontinued EC-MPS due to adverse events by 24 months. The overall
incidence of adverse events during the extension phase, including infections and hematological
abnormalities, was comparable to that seen in the core study, with a similar safety profile in the newlyexposed and long-term EC-MPS groups. There were 3 deaths during the first 24 months of the
extension, and 2 graft failures in both the ’’newly-exposed’’ and ’’long-term’’ EC-MPS groups.
Conclusions These data demonstrate that long-term use of EC-MPS is effective and has an
acceptable tolerability profile in renal transplant patients, and confirm that conversion of maintenance
renal transplant patients from MMF to EC-MPS is a safe therapeutic option.
17. Tacrolimus and quality of life after kidney transplantation - - A multicenter study.
Bohlke M, Rocha M, Gomes RH et al.
Clin Transplant.
2006 20 (4): 504-8.
Kidney transplantation is currently the treatment of choice for end-stage renal disease. Although new
immunosuppressive drugs have been introduced into clinical practice, the effect of such medication on
quality of life (QoL) in transplant recipients is still unclear. The present study analyzes the impact of
tacrolimus-based immunosuppression on QoL in a representative sample of adult kidney transplant
recipients from Rio Grande do Sul, a Brazilian southern state. This was a cross-sectional multicenter
study which used the SF-36 Health Survey for measuring QoL. The effect of tacrolimus on QoL was
adjusted for possible confounders using multiple linear regression. A total of 272 patients (from 11
different centers) were evaluated, 48 of them were treated with tacrolimus. Transplant patients in use
of tacrolimus presented significant higher scores in the physical component summary of SF-36 than
non-users (49.1 +/- 8.3 vs. 46.1 +/- 8.7, p = 0.03), and such differences was noted in the physical
functioning and general health subscales (81.5 +/- 17.1 and 74.7 +/- 21.8; 74.6 +/- 22.3 and 67.1 +/22.3 for users and non-users of tacrolimus, respectively, p < 0.05). The effect of tacrolimus remained
significant after adjusment for age, gender, skin color and time since transplantation. (coeff.: 2.83,
95% CI: 0.05-5.6, p = 0.045). The association betwen tacrolimus-based immunosuppression and
better perception of physical functioning and general health for renal transplant patients represents a
significant finding as it may influence therapeutical decisions and contribute to maximize kidney
transplantation benefits.
18. A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without
basiliximab in pediatric renal transplantation.
Grenda R, Watson A, Vondrak K et al.
Am J Transplant.
2006 6 (7): 1666-72.
In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the
efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal
transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or
tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20
ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups.
Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of
reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4%
(TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively.
Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of
adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were
significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02;
respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and
91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (ml/min/1.73 m2),
respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does
not improve clinical efficacy.
19. Ketoconazole-tacrolimus coadministration in kidney transplant recipients: Two-year results of a
prospective randomized study.
El-Dahshan KF, Bakr MA, Donia AF et al.
Am J Nephrol.
2006 26 (3): 293-8.
Background/Aims In development countries, kidney transplantation is greatly hindered by financial
problems, espacially due to costly newer immunosuppressive medications. Ketoconazole increases
blood levels of tacrolimus and cyclosporine through inhibition of cytochrome P450 microsomal
enzymes. We previously reported on the 6-month safety and the outstanding impact on treatment
costs of the ketoconazole-tacrolimus combination in kidney transplant recipients. Data of this
combination are still lacking in the literature. We hereby report on the 2-year results of our trial.
Methods This prospective, randomized study included 70 live-donor kidney transplant recipients
receiving tacrolimus (age 16-45 years, 54 males and 16 females). Patients were randomized into
equal groups: group 1, where ketoconazole 100 mg/day was added, ang group 2 (control group).
Results After 2 years, group 1 (ketoconazole) patients still showed a highly significant reduction of the
tacrolimus dose (by 53.3%) and cost (by 52.9%) compared with the control group (p < 0.001) and a
significant improvement in graft function in comparison to their own initial graft function ( p = 0.002).
Throughout the 2 years, no side effects of ketokonazole were noted. Conclusion We concluded that
the long-term keoconazole-tacrolimus combination therapy in kidney transplant recipients during the 2
years is safe, has an outstanding impact on treatment costs and improves graft outcome.
20. Everolimus in clinical practice - - renal transplantation.
Pascual J.
Nephrol Dial Transplant.
2006 21 (Suppl 3): iii18-23.
Everolimus is a proliferatin signal inhibitor (PSI) / mammalian target of rapamycin inhibitor that is
structurally similar to sirolimus, but with a number of pharmacokinetic differences, including a shorter
half-life and time to steady state. In clinical trials, the efficacy of everolimus 1.5 mg/day and 3.0
mg/day combined with ciclosporin (CsA) and steroids in de novo renal transplant recipients is similar
to that mycophenolate mofetil, with one study showing a significantly lower risk of antibody-treated
acute rejection with everolimus. When combined with reduced-dose CsA, everolimus is associated
with improved renal function compared with full-dose CsA, with no decrease in efficacy. Thus,
everolimus may play an important role in calcineurin inhibitor (CNI)-sparing regimens for renal
transplant recipients. Studies with sirolimus have shown that CNI withdrawal is associated with a
significant improvement in renal function, although there may be an increase in the risk of acute
rejecion, however, patients and graft survival are not adversely affected by CNI withdrawal. Notably,
proteinuria <800 mg/day before conversion is a strong predictoe of successful response to sirolimus
treatment, and hypertensive therapy and serum lactate dehydrogenase levels may also predict
response. Adverse event commonly associated with PSIs include dyslipidemia, proteinuria and
anaemia, although thes can usually be managed without difficulty. Data are also available to suggest
that the PSIs are associated with a lower risk of malignancy than other immunosuppressive agents. In
conclusion, everolimus may permit reduced exposure to CINs in renal transplant recipients, with the
potential to improve tolerabilty and renal function.
21. Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients.
Andres V, Castro C, Campistol JM.
Nephrol Dial Transplant.
2006 21 (Suppl 3): iii14-17.
Over the last decade, there has been a decrease in acute graft rejection rates following renal
transplantation; however, has not corresponded with an improvement in long-term outcomes of
transplantation. One of the major problem causes of long-term morbidity and mortality in renal
transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those
including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk
factors. The proliferation signal inhibitors (PSIs) / mammalian target of rapamycin (mTOR) inhibitors
sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal
transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia
(hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and
associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from
atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the
results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on
the benefical and adverse effects that these drugs exert on the cardiovascular system, and the
underlying molecular mechanisms.
22. Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: A randomized,
double-blind, placebo-controlled, crosover trial.
Sharma RK, Prasad N, Gupta A et al.
Am J Kidney Dis.
2006 48 (1): 128-33.
Background Erectile dysfunction (ED) is observed frequently in patients with end-stage renal disease,
hemodyalisis patients, and renal allograft recipients. There are few studies of sildenafil use in renal
allograft recipients. Methods The study is designed as a randomized, double-blind, placebocontrolled, crossover trial. Efficacy was assessed by using the self-administered International Index of
Erectile Function (IIEF), a 15-question validated measure of ED, and a global efficacy question (Did
the treatment improve your erection?). Results Thirty-two eligible renal transplant recipients were
included in this study. After treatment with sildenafil citrate, patients had significantly better scores in
13 of 15 questions, except for questions 11 (desire frequency; P = 0.39) and 12 (desire level; P =
0.61). Treatment efficacy assesed through question 3 (penetration ability; P < 0.001) and 4
(maintenance frequency; P < 0.001) was significantly better after sildenafil therapy. There were no
significant differences between baseline and post-placebo treatment scores, except for question 13
(relationship satisfication). Patients treated with sildenafil had significantly better scores in 4 domains
compared with baseline, but a difference was not observed in the sexual desire domain (P = 0.32).
There were no significant differences in scores between placebo and baseline in any domain. On the
global efficacy question, 81.3% of patients showed improvement compared with 18.7% with placebo.
There were no differences in areas under the curve and maximum cyclosporine concentrations before
and after sildenafil therapy. No patient discontinued the drug because of side effects except for 1
patients with visual hallucination. Conclusion Treatment with sildenafil in renal transplant recipients is
a valid option with an effective response.
23. Soluble CD30 concentrations in ESRD patients with and without panel reactive HLA antibodies.
Vaidya S, Partlow D, Barnes T et al.
Clin Transplant.
2006 20 (4): 461-4.
Background In this retrospective study we compared accuracy of panel reactive antibodies (PRA)
with serum soluble CD30 (sCD30) contents in predicting acute rejection crisis post-renal transplant.
Methods Pre-transplant sera from 115 patients were evaluated for their PRA and sCD30
concentrations. All patients received calcineurin inhibitor-based immunosuppressive therapy.
Objective measurements for rejection were biopsy-proven acute rejection (AR) episodes within first six
months of the transplant. Post-transplant sera of patients with AR were tested for the presence of
donor-specific HLA antibodies (DSA). Results Overall AR rate was 16% (18/115). Patients positive for
PRA and sCD30 tests were at significantly higher risk for AR compared with those patients negative
for both the tests (36% vs 5%, p = 0.01). Among negative PRA patients risk for AR was significantly
elevated if they were also tested positive for sCD30 concentrations (21% vs. 5%, p = 0.04). Of the 18
patients with AR, 14 were positive for sCD30, and 13 of them (93%) developed DSA post-transplant (p
= 0.001). Conclusion These data showed that patients positive for sCD30 contents are at high risk for
the development of DSA and AR post-transplant regardless of their pre-transplant PRA.
24. Late and early C4d-positive acute rejection: Different clinico-histopathological subentities in renal
transplantation.
Sun Q, Liu ZH, Ji S et al.
Kidney Int.
2006 70 (2): 377-83.
This study was performed to investigate the clinical and pathologic features of C4d-positive steroidresistant acute rejection (AR) at different phases after renal transplantation. Fifty-six allograft
recipients with C4d-positive AR were divided into thre groups, very early rejection (VER, occuring
</=14 days following transplantation, n=28), early rejection (ER, occuring 15-180days following
transplantation, n=5), and late rejection (LR, occuring >180 days following transplantation, n=23).
Clinical and pathological features were evaluated. Significantly more patients in the ER and LR groups
were associated with a reduction or withdrawal of immunosuppressants. More patients in the ER and
LR groups experienced a significant (>3 g/l) decrease serum albumin (80% ER, 91.3% LR, 7.1% VER,
P<0.001) and decrease in hemoglobin (>1 d/dl) (80, 100vs 17.9%, P<0.001). Most VER patients
reported a fever and had vary rapid graft dysfunction requiring dialysis. Significantly more patients
(87%) had interstitial fibrosis and tubular atrophy in the LR group compared with the other groups and
13% had transplant glomerulopathy. Most cases of VER were reversed with tacrolimus and
mycophenolate mofetil treatment, with or without immunoadsorption, with a 21-year survival rate of
96.4%, compared with only 60 and 52.2% in the ER and LR groups. In conclusion, C4d-positive
steroid resistant AR at different time points is associated with unique clinico-histopathological
manifestations requiring distinct treatment strategies. Late episodes are usually associated with
significantly reduced serum albumin and hemoglobin levels and a poorer outcome. A more specialized
treatment protocol should be estabilished for these patients.
25. Association of high pretransplant sIL-6R plasma levels with acute tubular necrosis in kidney graft
recipients.
Sadeghi M, Daniel V, Naujokat C et al.
Transplantation.
2006 81 (12): 1716-24.
Background Delayed graft function is primarily caused by acute tubular necrosis (ATN). We studied in
renal transplant graft biopsy whether an up-regulated immune system in the recipient immediately
before transplantation affects the risk of developing ATN and might be relevant for the pathogenesis of
ATN. Methods In a retrospective study, we analyzed pretransplant and early posttransplant soluble
interleukin (sIL)-1RA, interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6R, IL-10, tumor necrosis factor (TNF)alpha, transforming growth factor (TGF)-beta2, interferon (IFN)-gamma, and neopterin plasma levels
in patients with ATN (n=26). Matced patients with acute rejection (AR) (n=26) or normal posttransplant
biopsy (n=26) served as controls. Results Pretransplant sIL-6R was higher (P=0.0004) and
pretransplant TGF-beta2 lower (P=0.002) in patients with ATN than in patients with normal biopsy.
ROC curves showed that pretransplant sIL-6R has a high sensitivity (77%) and high specificity (64%)
for ATN (P=0.002). Posttransplant plasma sIL-6R continued to be higher in ATN patients than in
patients with normal biopsy (P=0.001). Patients with acute rejection showed pre- and posttransplant
sIL-6R and TGF-beta2 plasma levels similar to those of patients with normal biopsy (P=NS).
Conclusion High pretransplant sIL-6R plasma levels are associated with an increase risk of ATN and
might cintribute to the development of ATN early posttransplant. Our data suggest that preactivation of
the recipient’s immune system increase the risk of ATN.
26. Noninvasive immune monitoring assessed by flow cytometry and real time RT-PCR in urine of
renal transplantation recipients.
Galante NZ, Camara NO, Kallas EG et al.
Transpl Immunol.
2006 16 (2): 73-80.
Background Monitoring recipient’s alloreactivity has shown to be critical for limiting
overimmunosuppression besides allowing preemptive treatment of acute rejection (AR). Methods
Flow cytometry and real time RT-PCR were performed in urine of kidney transplant recipients with AR
(n = 13) and compared with pyelonephritis (n = 10), chronic allograft nephropathy (n = 13), acute
tubular necrosis (n = 13) and stable graft function (n = 11). Expression of CD3, CD4, CD8, HLA-DR,
Fas-L, ICAM-1 and CD25 were assessed using flow cytometry. mRNA of perforin, granzyme B and
Fas-L were quantified by real time PR-PCR. Results Frequencies of CD3+, HLA-DR+, Fas-L+, ICAM1+ and CD25+ cells were significantly higher in AR group (p < 0.05). ROC curves showed sensitivity
from 70% to 91% and specificity from 30% to 100%, whereas the highest sensitivity and specificity
was 91% and 100% respectively, for Fas-L+ cells. Levels of mRNA of perforin, granzyme B and Fas-L
were significantly augmented in AR, while the sensitivity and specificity ranged from 85% to 88% and
from 55% to 100%, respectively. Conclusions Analyses of immune activation markers by flow
cytometry and real time RT-PCR are equally useful for noninvasive monitoring kidney allografts.
27. Upregulation of ADAM19 in chronic allograft nephropathy.
Melenhorst WB, van den Heuvel MC, Stegeman CA et al.
Am J Transplant.
2006 6 (7): 1673-81.
ADAM19 (a disintegrin and metalloproteinase 19) is involved in cell-cell and cell-matrix interaction and
tumor necrosis factor (TNF)-alpha shedding. We studied ADAM19 in chronic allograft nephropathy
(CAN) nephrectomies and in normal human kidney. Reverse transcriptase (RT) PCR revealed an
upregulation of ADAM19 mRNA in CAN when compared with control kidneys (p = 0.002). Using RNA
in situ hybridization (ISH), we detected moderate ADAM19 mRNA expression in vascular smooth
muscle cells (SMCs) and distal tubuli of control kidneys. In CAN, massive ADAM19 expresion was
detected in SMCs, distal tubuli, glomerular lesions and inflammatory CD4+ cells. To determine
whether ADAM19 is specifically related to CAN, we studied transplant biopsies with and without CAN,
acute rejection and non-transplant-related kidney diseases: interstitial fibrosis (IF), interstitial atrophy,
glomerular fibrosis and interstitial inflammation. In various renal structures, ADAM19 mRNA was
significantly higher in CAN when compared with renal allografts without CAN or acute rejection.
ADAM19 expression in renal endothelium was significantly higher in acute rejection when compared
with renal allografts without CAN. When compared to CAN, ADAM19 was expressed to a similar
extent in non-transplant-related interstitial and glomerular fibrosis, interstitial atrophy and inflammation.
Although these observational data do not estabilish a cause and effect relationship, ADAM19 may
have a modulatory role in the dysfunctional renal allograft state.
28. Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: Impact of
different immunosuppressive regimens.
Weimer R, Susal C, Yildiz S et al.
Am J Transplant.
2006 6 (8): 1865-74.
Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We
assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4
helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year followup. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect
of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejection did
not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p
= 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p
= 0.005 at 2 years), Tacr versus CsA treatment proved to be an independent variable associated with
downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01,
respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated
with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and
evidence of CAN (p < 0.0005) High 1-year could not be attributed to enhanced Th2-type responses
and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and
neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and
might be of advantage in patients with elevated sCD30 or neopterin.
29. Post-transplant anti-HLA class II antibodies as risk factor for for late kidney allograft failure.
Campos EF, Tedesco-Silva H, Machado PG et al.
Am J Transplant.
2006 Aug 21; [Epub ahead of print]
The purpose of this study was to prospectively analyze the relationship between the post-transplant
anti-HLA class I and/or class II panel reactive antibodies and graft failure due to chronic allograft
nephropathy (CAN). We studied 512 first kidney recipients transplanted at a single center, with a graft
functioning for at least 3 years. A single blood sample was collected from each patients for antibody
evaluation. The median posttransplant time after blood collection was 4.4 years and did not differ
between patients with (n = 91) or without anti-HLA antibodies (n = 421). Female gender, pregnancies
and blood transfusions were associated with the presence of anti-HLA class I antibodies. Graft
function deterioration was associated with anti-HLA class II antibodies. Multivariate analysis showed
independent association for creatinine levels (RR = 7.5), acute rejection (RR = 2.6), recipient male
gender (RR = 3.6) and anti-HLA class II antibodies (RR = 2.9) and CAN-associated graft loss. In
conclusion, the presence of anti-HLA class II antibodies conferred a risk for graft loss before a decline
in renal function and increased the risk of graft failure in patients who already had a decline in graft
function. Thus, anti-HLA class II antibody monitoring is a useful toll for the management of long-term
kidney recipients.
30. Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched renal
allografts from chronic rejection.
Benigni A, Tomasoni S, Turka LA et al.
J Am Soc Nephrol.
2006 17 (6): 1665-72.
Short-term results of renal transplantation have improved considerably in the past 20 yr; similar
improvements in long-term outcome have not been achived. The primary cause of late graft loss is
chronic rejection that might be treated by gene therapeutic approaches. Ideally, one wold like to impair
locally the contact between transplant antigen and host immune system without compromising the
generalizated immune competence of the recipient. This can be achieved by local expression of the
therapeutic protein in the site of interest using gene therapy. Here it is shown that chronic allograft
rejection can be prevented effectively by local delivery of recombinant adeno-associated virus (AAV)
vectors that encode the CTLA4Ig immunosuppressant protein to the donor kidney in a fully MHCmismatched rat strain combination. AAV CTLA4Ig prevented progressive proteinuria and protected
transplant kidneys from renal structural injury. A population of anergic T cells with regulatory activity,
which eventually were responsible for the induction of tolerance, were found in recipient lymph nodes
and in the graft as long as 120d after transplantation. These data indicate that AAV-mediated CTLA4Ig
gene transfer to donor graft represents a promising tool to prevent the onset of chronic rejection and
circumvent the unwanted systemic adverse effects of the administration of immunmodulatory protein.
31. Hepatocyte growth factor: New arsenal in the fights against renal fibrosis?
Liu Y, Yang J.
Kidney Int.
2006 70 (2): 238-40.
Hepatocyte growth factor (HGF) has emerged as a potent, endogenous antifibrotic factor that shows
an impressive efficacy in ameliorating tissue fibrosis in a wide variety of animal models. Herrero-
Fresneda et al. provide new evidence demonstrating that intramuscular injection of HGF gene reduces
mortality, inflammation, and renal fibrosis in chronic allograft nephropathy.
32. HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatoryinduced mechanisms.
Herrero-Fresneda I, Torras J, Franquesa M et al.
Kidney Int.
2006 70 (2): 265-74.
Inflammatory processes and tissue scarring are characteristic features of chronic allograft
nephropathy. Hepatocyte growth factor (HGF) has beneficial effects on renal fibrosis and it also
ameliorates renal interstitial inflammation as it has been recently descibed. Contrarily to protein
administration, intramuscular gene electrotransfer allows sustained release of HGF. So, here we
hypothesized that gene therapy with human HGF would diminish the characteristic scarring of chronic
allograft nephropathy either by anatagonized tissue fibrosis mechanisms or by reducing inflammation.
Lewis rats transplanted with cold preserved Fischer kidneys received vehicle (NoHGF) or
intramuscular plasmid DNA encoding HGF plus electroporation either before transplantation (IniHGF,
early post-transplant cytoprotection of tubular cells) or 8/10 weeks after transplantation (DelHGF),
delayed prevention of chronic mechanisms). Serum creatinine and proteinuria were measured every 4
weeks for 24 weeks. Grafts at 12 or 24 weeks were evaluated for glomerulosclerosis, fibrosis,
inflammatory cells and mediators, cell regeneration and tubulo-interstitial damage. Nontreated animals
developed renal insufficiency, progressive proteinuria and fibrosis among other characteristic
histological features of chronic allograft nephropathy. Treatment with human HGF, especially when
delayed until the onset of fibrotic mechanisms, reduced renal failure and mortality, diminished tubulointerstitial damage, induced cell regeneration, decreased inflammation, NF-kappaB activation, and
profibrotic markers at 12 weeks and prevented late interstitial fibrosis and glomerulosclerosis. The
effectiveness of HGF-gene therapy in the prevention of renal allograft scarring is related with halt of
profibrotic inflammatory-induced mechanisms.
33. Reccurent glomerulonephritis after kidney transplantation.
Choy BY, Chan TM, Lai KN.
Am J Transplant.
2006 Aug 19; [Epub ahead of print]
Thirty to fifty percent of kidney transplant recipients have glomerular diseases as the underlying
causes of end-stage renal failure. While recurrence of glomerulonephritis is an important cause of late
renal allograft failure, the risk factors for recurrence are largely unknown or imprecise and prediction
remains difficult. Recurrent disease usually presents with similar manifestations as the native disease.
With regard to treatment of recurrent glomerular disease in the renal allograft, plasma ecchange may
be effective in reducing proteinuria in patients with early recurrence of focal and segmental
glomerulosclerosis, but immunosuppressive therapy is generally ineffective in the prevention or
treatment of recurrent disease. General supportive measures including strict blood pressure control
and inhibition or blockade of the renin-angiotensin pathway are helpful in retarding the rate of
deterioration in renal allograft function. Despite the risk of recurrence, kidney transplantation following
primary glomerulonephritides enjoys graft and patient survival rates comparable to other causes of
end-stage renal failure. With a few exceptions, living related renal transplantation is not
contraindicated in view of the favorable outcome and the donor shortage. This review discusses
commonly encountered recurrent glomerulonepritidies, with special emphasis on the influence of posttransplant prophylactic immunosuppression and emerging treatments.
34. Secondary focal segmental glomerulosclerosis following kidney transplantation in a patients with
type I diabetes mellitus.
Yamamoto I, Yamamoto H, Mitome J et al.
Clin Transplant.
2006 20 (Suppl 15): 7-10.
Although recurrent diabetic nephropathy is common in patients with type I diabetes after kidney
transplantation, the development of focal segmental glomerulosclerosis (FGS) is rare, and its
development generally takes several years. We report here a case of type I diabetes mellitus with
secondary FGS accompained by proteinuria 10 months following kidney transplantation. Episode
biopsy showed secondary FGS, evidenced by glomerular capillary collapse and large epithelial cells
with ballooning degeneration. Exudative dense deposition of IgM in a diffuse global mesangial pattern
and enlarged glomerular diameters were observed, suggestive of glomerular hyperfiltration which can
lead to secondary FGS. An imbalance in body size between donor and recipient and/or uncontrolled
diabetes are potential causes of glomerular hyperfiltration. We administered angiotensin-converting
enzyme inhibitor and angiotensin II receptor blocker to reduce hyperfiltration-induced renal damage;
the combination therapy reduced proteinuria from 2346 to 258 mg/d. Secondary FGS should be a
consideration after kidney transplantation in patients with typeI diabetes mellitus.
35. IL-6 promoter polymorphism –174 is associated with new-onset diabetes after transplantation.
Bamoulid J, Courivaud C, Deschamps M et al.
J Am Soc Nephrol.
2006 Jul 12; [Epub ahead of print]
New-onset diabetes after transplantation (NODAT) is a serious complications of transplantation. This
study tested whether IL-6 production capacity may influence the development of NODAT in two
different groups of patients. The occurence of NODAT was analyzed with respect to IL-6 gene
promoter polymorphism at position –174 (G- ->C) and other relevant risk factors retrospectively in 217
renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09)
and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC
genotype was observed. In the multivariate model, the CC genotype was associated with a decreased
risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment
for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers
(2.15 +/- 0 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene
promoter polymorphism on the development of NODAT was restricted mostly to overweight patients.
These results highly suggest that IL-6 production capacity influences the development of NODAT and
that diabetes-inducing drug administration should be limited in overweight patients who carry the GG
genotype.
36. Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine
nephrotoxicity.
Perez-Rojas J, Blanco JA, Cruz C et al.
Am J Physiol Renal Physiol.
2006 Jul 11; [Epub ahead of print]
Recent studies from our laboratory have shown that the mineralocorticoid receptor blockade with
spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chronic
(CsA) nephrotoxicity. This study was design to evaluate if Sp administration reduces functional and
structural renal damage associated with existing chronic CsA nephrotoxicity. Twenty eight male Wistar
rats were fed a low sodium diet. Fourten received vehicle (V) and others were treated with CsA (15
mg/K sc). After 18 days one half of each received Sp (20 mg/K p.o.) for the subsequent 18 days.
Creatinine clearence, arteriolopathy, tubulo-interstitial fibrosis, arteriolar thickening, glomerular
diameter, apoptosis index and TGF-beta, procaspase-3 and kidney injury molecule 1 (Kim-1) mRNA
levels, as well as Kim-1 shedding in urine were evaluated. Spironolactone reduced the progression of
renal dysfucntion and tubulo-interstitial fibrosis in preexisting chronic CsA nephrotoxicity. There was a
significant reduction of arteriolar thickening in the CsA+Sp group that was associated with greater
glomerular diameter and reduction of apoptosis index. These renoprotective effects were associated
with reduction of TGF-beta, procaspase-3 and Kim-1 mRNA levels as well as Kim-1 shedding into the
urine. In conclusion mineralocorticoid receptor (MR) blockade with spironolactone prevented the
progression of renal injury in preexisting chronic CsA nephropathy. These results suggest that
spironolactone may reduce CsA-induced estabilished nephrotoxicity in patients.
37. Infectious complications after kidney transplantation: Current epidemiology and associated risk
factors.
Alangaden GJ, Thyagarajan R, Gruber SA et al.
Clin Transplant.
2006 20 (4): 401-9.
The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of
infectious complications following kidney transplantation has not been well studied. This is an
observational study in 127 adult recipients transplanted from 2001 to 2004. Patients received
thymoglobulin (ATG) (50%) or basiliximab (50%) for induction and were maintained on mycophenolate
mofetil, either tacrolimus (73%) or sirolimus (SRL) (27%), and prednisone (79%). Antimicrobal
prophylaxis included perioperative cefazolin, trimethorprim/sulfamethaxazole for six months,
valganciclovir for three months and nystatin for two months. Regression models were used to examine
the association of various factors with infections. We observed 127 infections in 65 patients, consisting
of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%) and surgical wound
infection (7%). UTI was the most common infection in all post-transplant periods. Enterococcus spp.
(33%) and Escherichia coli (21%) were the most prevalent uropathogens. Of six patients with
cytomegalovirus infection, none had tissue-invasive disease. There was no cases of pneumocystis
pneumonia or BK nephropathy. Six patients developed fungal infections. Two deaths due to
disseminated Rhizopus and Candida albicans accounted for a 1.5% infection-related mortality.
Retransplantation and ureteral stents were independently associated with UTI (OR = 4.5 and 2.9, p =
0.06 and 0.03, respectively), as were ATG and SRL with bacterial infections (OR = 3.3 and 2.5, p =
0.009 and 0.047, respectively). This study suggest the use of newer immunosuppressive agents in
recent years is associated with some changes in the epidemiology of post-transplant infections.
Enterococci have become the predominant uropathogen. Invasive fungal infections, although rare, are
often fatal.
38. The prevalence of BK viremia and urinary viral shedding in a pediatric renal transplant population:
A single-center retrospective analysis.
Alexander RT, Langlois V, Tellier R et al.
Pediatr Transplant.
2006 10 (5): 586-92.
Polyomavirus-induced nephropathy has emerged as an important cause of renal graft dysfunction.
Limited pediatric data are available for this disease. We therefore reviewed the results of the first year
of polyomavirus screening in our pediatric renal transplant recipients to determine the prevalence of
polyomavirus viremia and urinary shedding. Screening inclused detection of polyomavirus in plasma
by polymerase chain reaction (PCR) and urine by electron microscopy (EM). In patients with a positive
screening test, an assessment of graft dysfunction was made. Fifty-two patients met the inclusion
criteria. Urinary EM was performed in 205 samples and polyomavirus was detected in 10 patients,
representing 19% of the study population. PCR was performed on 222 samples and was positive for
the BK virusin plasma from seven patients or 13.4% of the study population. Eight patients had a
positive test and increased creatinine. All these patients underwent renal transplant biopsy. This
revealed evidence of polyomavirus nephropathy in four patients. Our findings reveal a high prevalence
of polyomavirus in both urine and plasma that is frequently associated with graft dysfunction. These
findings support the routine screening of pediatric post-renal transplant for polyomavirus replication.
39. Clinical utility of histological features of polyomavirus allograft nephropathy.
Gaber LW, Egidi MF, Stratta RJ et al.
Transplantation.
2006 82 (2): 196-204.
Background The purpose of this study was to determine if histological features of polyomavirus
allograft nephropathy (PVAN) are associated with the clinical presentation and outcomes of PVAN.
Methods We examined the histological features of initial and follow-up biopsies of 20 kidney and
kidney-pancreas transplant recipients with PVAN during a time prior to routine surveillance. The
subjects’ demographics, clinical characteristics, and outcomes were compared based upon
classification of histological features of PVAN in initial biopsy. Results Diabetes mellitus (45%) and a
history of tacrolimus-induced nephrotoxicity (35%) appeared to be prevalent in subjects with PVAN.
Although histological severity of PVAN did not predict or correlate with the clinical course of PVAN,
subjects with pattern C on inittial PVAN biopsy presented later posttransplant, had higher serum
creatinine level at presentation, and had significant allograft deterioration at follow-up than subjects
with either pattern A or B on initial biopsy. Resolution of PVAN was noted in 60% of follow-up biopsies
and occured more frequently in subjects with pattern B on initial biopsy. Most subjects developed
chronic allograft nephropathy after PVAN and viral clearence did not abrogate the progression to
chronic allograft nephropathy. Conclusions These data indicate that histologic patterns of PVAN may
have clinical correlation to disease presentation and prognosis.
40. De novo gastrointestinal tumours after renal transplantation: Role of CMV and EBV viruses.
Adani GL, Baccarani U, Lorenzin D et al.
Clin Transplant.
2006 20 (4): 457-60.
The development of new and more effective immunosuppressive agents has provided long-term
survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic
immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin
cancer has been shown to have an increased incidence in long-term surviving solid organ transplant
recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients
(5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 nonskin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one
gastric cancer). Immediately after tumour’s diagnosis, immunosuppressive therapy was reduced; all
patients were shifted from cyclosporine to rapamicine within 30 d. The tumour was surgically resected
with curative intent in three cases, while one patient had only palliative surgery because of metastatic
disease. The post-operative course was uneventful. All patients maintained normal graft function.
However, three out of four patients (75%) died of progression of the neoplasm, within a median time
from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI
cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV)
reactivation, episodes of rejection, and blood transfusion. All cases with GI de novo cancers reported
in this paper developed CMV and EBV reactivation within three months after transplantation.
Thereafter we suggest a closer follow-up for the de novo GI cancer in renal transplant with early CMV
and EBV reactivation in order to avoid delayed diagnosis.
41. Reduction of chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.
Wada T, Azuma H, Furuichi K et al.
Am J Nephrol.
2006 26 (4): 319-25.
Background Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is
therefore a key target for therapy. Methods The impact of p38 mitogen-activated protein kinase
(MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of
p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in
an estabilished experimental rat transplantation model. Results Transplanted rats develop
glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are
characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38
MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal
function and prolonged survival. The FR167653-treated rats had fewer phosphorylated p38 MAPKpositive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein1/CCL2 and transfoming factor-beta (1) was markedly reduced. Conclusion These results suggest
that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38
MAPK is a novel, appealing therapeutic target for combating CAN.