Renal Complications in
Hemoglobinopathies
Miguel R. Abboud M.D.
Department of Pediatrics and Adolescent
Medicine
American University of Beirut Medical Center
Sickle Cell Disease: Overview
• Sickle cell disease (SCD) is one of the most common
severe monogenic disorders in the world.
• Despite a simple molecular etiology, SCD is a
multisystem disease, associated with episodes of
acute illness and progressive organ damage.
Sickle Nephropathy
• Renal involvement in SCD includes a variety of
glomerular and tubular disorders and is associated
with increased mortality if left untreated.
• Kidneys can be affected in both patients with sickle
cell disease and even in sickle cell trait.
• Kidney disease begins in childhood and progresses
into adulthood in patients with SCD.
Abbott KC, Hypolite IO, Agodoa LY. Sickle cell nephropathy at end-stage renal disease in the United
States: patient characteristics and survival. Clin Nephrol. 2002; 58: 9-15.
Overview
Improved care
and therapies
for SCD
Longer lifespan
Increased endorgan damage
including CKD
Not all renal disease or renal failure in SCD is due to SCN. Other
medical conditions like lupus nephritis, HCV, HIV nephropathy and
others must be ruled-out.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
SC Kidney Disease
Adults with SCA
40%
microalbuminuria
20-30% proteinuria
The mean survival
after developing ESRD
is 4 years, and 40% of
SCA patients will die
within 20 months of
starting dialysis.
4-18% ESRD needing
dialysis or transplant
Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study
of 1056 patients. Med Baltim. 2005; 84:363–376.
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and
mortality. Ann Intern Med. 1991; 115:614–620.
The microvasculature of the nephron.
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Distal nephron
(hyposthenuria,
impaired
acidification)
Proximal
tubule (B2MG,
Po4, uric acid,
creatinine
secretion)
Hematuria and
papillary
necrosis
Hemodynamic
changes (GFR,
RBF)
Renal
abnormalities
in SCD
Glomerulus
(proteinuria,
NS, CRF)
Modified hemolysis-endothelial dysfunction phenotype and proposed renal pathophysiology
in human SCD. Hemolysis in human SCD leads to NO scavenging by plasma hemoglobin
(HbSS) and increased amounts of heme because of the instability of sickle hemoglobin.
Nath K A , Katusic Z S JASN 2012;23:781-784
©2012 by American Society of Nephrology
Classification Based on Phenotypes
Cortex: hemolysis-endothelial dysfunction phenotype
Hyperfiltration
Glomerular hypertrophy
Glomerulopathy
Hypermetabolism
CKD
Hematuria
Papillary necrosis
Impaired concentrating ability
Impaired potassium excretion
Tubular acidosis
Nath KA, Katusic ZS. Vasculature and kidney complications in sickle cell disease. J Am Soc Nephrol. 2012; 23: 781784.
Classification Based on Phenotypes
• Microalbuminuria and hyperfiltration are more associated
with hemolytic phenotype of SCD spectrum.
Haymann JP, Stankovic K, Levy P, et al. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis
associated feature. Clin J Am Soc Nephrol. 2010; 5: 756–761.
• In the hemolysis-endolthelial dysfunction type, in addition to
the intermittent, localized microvascular occlusion, kidney
pathology is also caused by multi-organ vasculopathy related
to the chronic nitric oxide depletion from the ongoing
hemolysis
Kato GJ, Wang Z, Machado RF, Blackwelder WC, Taylor JG 6th, Hazen SL. Endogenous nitric oxide synthase
inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation,
haemolysis, organ dysfunction and death. Br J Haematol. 2009; 145(4): 506-13.
Urine concentration abnormalities
• Following overnight water deprivation, urine osmolality is
significantly lower in subjects with SCA compared to normal
controls.
RBC Sickling
Medullary
congestion and
fibrosis
Loss of gradient
Impaired Na
reabsorption by
collecting ducts
Scheinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol. 2009; 5:78–88.
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
Urine concentration abnormalities
• The inability to concentrate urine to its maximum
(hyposthenuria) as a response to water deprivation is an early
finding in sickle cell nephropathy.
• It has been observed in infants at 6–12 months of age.
• Hyposthenuria is the most common tubular dysfunction in
SCD and can be found in patients with sickle cell trait.
• Severity is associated with HbS levels.
• Patients with higher levels of HbF have a greater ability to
concentrate urine.
Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol. 2002; 63:205–211.
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Urine concentration abnormalities
• Symptoms
– May be asymptomatic in absence of water
deprivation
– Polyuria secondary to polydipsia
– Nocturnal enuresis, reported in 28% to 37% of
children with SCD
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Bruno D, Wigfall DR, Zimmerman SA, Rosoff PM, Wiener JS. Genitourinary complications of sickle cell
disease. J Urol 2001;166: 803–811.
Urinary Acidification Deficit
Medullary ischemia in SCD
Impaired urinary acidification (energy-dependent
process that necessitates a high proton gradient)
Incomplete form of RTA type IV with
hyperchloremic hyperkalemic metabolic acidosis
•
•
Less frequent than the concentration deficit
More problematic in patients with worsening renal fuction
Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol. 2002; 63:205–211.
Batlle, D., Itsarayoungyuen, K., Arruda, J.A. & Kurtzman, N.A. Hyperkalemic hyperchloremic metabolic
acidosis in sickle cell hemoglobinopathies. American Journal of Medicine. 1982; 72, 188–192.
Increased Proximal Tubule Function
• The increase in sodium and water loss from the collecting
ducts leads to a reactive increase in sodium and water
reabsorption by the proximal tubule.
• Sodium reabsorption is the driving force for the reabsorption
of other solutes:
–
–
–
–
β2-microglobulin
Phosphate  hyperphosphatemia
Uric acid
Creatinine
• Up to 30% of the total creatinine excretion can arise from
tubular secretion, so creatinine-based measurements of GFR
can significantly overestimate renal function.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Hyperfiltration
• An increase in renal blood flow and glomerular filtration is
frequently observed in SCD, becoming apparent around 1 year
after birth and tending to decrease with aging. It is involved in
the pathogenesis of glomerular disease and kidney failure in
SCD.
• BABY HUG Trial:
– At a mean age of 13 months, the mean serum creatinine and serum
cystatin in patients with SCD were similar to published age norms.
– However, isotope-derived measurement of GFR showed that these
patients had significantly elevated GFR compared with the age norm
at 1 year of age. These results were statistically significant (P-value
<0.001).
Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function results from the multi-center
placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012; 59(4): 668-74.
Hyperfiltration
Aygun B, Mortier NA, Smeltzer MP, Hankins JS, Ware RE. Glomerular hyperfiltration and albuminuria in
children with sickle cell anemia. Pediatr Nephrol. 2011; 26(8):1285–1290.
Hyperfiltration
Current theory
Medullary ischemia
and vasa recta
destruction
Production of
vasodilating
substances (PGs,
NO)
Increased renal
blood flow
Increased
glomerular size, and
glomerulosclerosis
later
Increased GFR
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
Glomerular Hypertrophy
Wesson DE. The initiation and progression of sickle cell nephropathy. Kidney Int. 2002; 61:2277–2286.
Hyperfiltration
• The renal kinin-kallikrein system also seems to be
involved in hyperfiltration, as the production of
bradykinins can contribute to vasodilation and
glomerular blood flow increase.
• Bergmann et al(2006): The urinary excretion of
kallikrein showed a significant correlation with
albuminuria.
• Further studies are needed.
Bergmann S, Zheng D, Barredo J, Abboud MR, Jaffa AA. Renal kallikrein: a risk marker for nephropathy in
children with sickle cell disease. J Pediatr Hematol Oncol. 2006; 28(3):147-53.
Hyperfiltration
• Haem oxygenase-1 (HO-1) has been shown to be
upregulated in injured tissues including the kidneys
in response to the ongoing hemolysis in SCD.
• HO-1 is responsible for the conversion of heme to
biliverdin with the subsequent release of carbon
monoxide (CO). Both biliverdin and CO are potent
antioxidants and the CO acts locally as a vasorelaxant
thus increasing renal blood flow and GFR.
Nath KA. Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues.
Kidney International. 2006; 70, 432– 443.
Microalbuminuria and Proteinuria
• Increased urine albumin levels is an early manifestation of
SCN.
• It may start in late childhood and tends to increase with age
as the kidney sustains more damage over time.
• Data by Sharpe & Thein:
SCD Patients Age Group
Proportion with urinary
albumin:creatinine ≥ 4.5 mg/mmol
15-23 years
30%
23-35 years
40%
>35 years
60%
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Microalbuminuria and Proteinuria
• Risk factors:
– Advanced age (shown in almost all studies)
– Low hemoglobin (shown in some studies)
• No significant association between proteinuria and other SCD
complications like ACS, VOCs, ASS, etc.
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
• No difference in WBC, platelet count, reticulocyte count, LDH
levels in patients with microalbuminuria vs.
normoalbuminuria
Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell
hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006;
17: 2228–2235.
Microalbuminuria and Proteinuria
• Nephrotic syndrome is rare  poor renal prognosis
• Hypothesis of 5 clinical stages (further longitudinal studies
needed):
Normoalbuminuria
Microalbuminuria
Macroalbuminuria with
preserved GFR
Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in
adults with sickle cell hemoglobinopathies: prevalence and clinical
correlates of progressive renal failure. J Am Soc Nephrol. 2006; 17:
2228–2235.
Macroalbuminuria
with progressive
renal insufficiency
ESRD
Microalbuminuria and Proteinuria
• A rare reported cause of acute nephrotic syndrome in SCD is
human parvovirus B19 infection.
• HPV B19 infection often causes aplastic crisis in SCD, and in
some reports this acute infection was followed by acute
nephrotic syndrome within 2–3 months.
• Older SCD patients with acute HPV B19 infection may be more
susceptible to complications, including the development of
nephrotic syndrome and progressive renal fibrosis.
Quek L, Sharpe C, Dutt N, et al. Acute human parvovirus B19 infection and nephrotic syndrome in patients with
sickle cell disease. Br J Haematol. 2010; 149(2): 289-91.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Hematuria
• One of the most frequent complications of sickle cell
nephropathy
• It is usually macroscopic and painless, but can also be
microscopic and/or painful
• Most frequent renal abnormality in patients with sickle cell
trait
• Hematuria can originate in one or both kidneys as a result of
papillary necrosis or microthrombosis in peritubular
capillaries, and it is also associated with infections or late
transfusion reactions
Schneinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol. 2009; 5:78–88.
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Hematuria
• It is usually self-limited and managed by good hydration,
pain medications and antibiotics when needed
• The etiology of renal papillary necrosis (RPN) includes
diabetes, analgesic abuse or overuse, sickle cell disease,
pyelonephritis, renal vein thrombosis, tuberculosis, and
obstructive uropathy. RPN can be found incidentally on
imaging in asymptomatic patients.
• More severe causes of hematuria should be investigated
like renal stones, or carcinomas in older populations.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Acute Renal Failure
• ARF is less common than CKD in patients with SCD
• Most commonly due to dehydration, as a result of urinary
concentration deficit after water deprivation
• Complete recovery of renal function occurs with adequate
treatment
• Can also result from sepsis, heart failure, renal vein
thrombosis, rhabdomyolysis, hepato-renal syndrome,
multiple-organ failure
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Chronic Kidney Disease
• Some patients with proteinuria progress to CKD
• 25-year prospective cohort study including 725
patients with SCD (HbSS):
– 4.2% developed chronic renal failure (RF)
– RF was preceded by ineffective erythropoiesis with
decreasing Hb, proteinuria, nephrotic syndrome,
hypertension and microscopic hematuria
– Chronic restrictive lung disease, leg ulcers and stroke were
3 times more common in these patients
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course,
and mortality. Ann Intern Med. 1991; 115:614–620.
Chronic Kidney Disease
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course,
and mortality. Ann Intern Med. 1991; 115:614–620.
Chronic Kidney Disease
• Generally diagnosed between 30 and 40 years of age
• Guasch et al:
Hb SS disease
Other sickling
hemoglobinopathies
Renal insufficiency
(GFR < 90ml/min)
21%
27%
Advanced CKD
stage III
29%
6%
Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell
hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006;
17: 2228–2235.
Chronic Kidney Disease
• Based on the results of a 4-decade observational
study by Powars et al:
SCD Subtype
Median age of onset of renal failure
Hb SS
23-37 years
Hb SC
50 years
Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study
of 1056 patients. Med Baltim. 2005; 84:363–376.
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and
mortality. Ann Intern Med. 1991; 115:614–620.
Other GU Abnormalities
• Cases of testicular infarction described in
patients with SCD or even sickle cell trait.
• Renal medullary carcinoma, a rare aggressive
tumor of the kidney, has been reported in
patients with sickle cell trait, and rarely SCD.
Davir CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy.
Am J Surg Pathol. 1995; 19: 1–11.
Renal medullary carcinoma in 11-year-old boy with known sickle cell trait who presented with
2-week history of fever, malaise, and weight loss.
Dyer R et al. Radiology 2008;247:331-343
©2008 by Radiological Society of North America
Renal medullary carcinoma in 11-year-old boy with known sickle cell trait who presented with
2-week history of fever, malaise, and weight loss.
Dyer R et al. Radiology 2008;247:331-343
©2008 by Radiological Society of North America
Urinary Tract Infections
• Higher risk of UTI than the general population.
• Renal papillary necrosis is a risk factor for UTI.
• Most frequent pathogens are Escherichia coli,
Klebsiella and Enterobacter sp.
• Patients are at risk of sepsis, need for
prolonged antibiotic treatment.
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Diagnosis
• The laboratory findings SCN may include: lower density urine,
proteinuria, hematuria, micro- and macroalbuminuria and
increased creatinine clearance.
• Hyponatremia, hyperkalemia and hypoalbuminemia can be also
found.
• Serum creatinine levels are low in SCD due to increased urinary
excretion, and levels only rise when renal damage is extensive.
• Similarly, GFR only decreases in the late stages of SCN.
• Creatinine clearance is not a good test to evaluate renal function in
SCD as it may overestimate GFR.
Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early
detection of sickle nephropathy. Am J Hematol 86:559–566
Diagnosis
• Study by Sundaram et al. comparing characteristics of SCA
patients with normoalbuminuria, microalbuminuria and
macroalbuminuria
• No significant differences in:
• Hemoglobin, reticulocyte count and bilirubin (as markers of
hemolysis)
• WBC counts (inflammation marker)
• BP, Cr, BUN, specific gravity
• Routine renal indicators do not predict the onset of SCN
Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early
detection of sickle nephropathy. Am J Hematol 86:559–566
Diagnosis
• Cystatin C: endogenously produced molecule that is freely
filtered in the glomeruli, completely absorbed and broken
down by proximal tubular cells.
• The plasma concentration increases with reduction in GFR,
even in patients with normal creatinine levels.
• Estimations of GFR based on serum cystatin C correlate well
with isotopically-measured GFR and with the degree of
proteinuria.
• It is a more accurate surrogate marker of renal function in
both adults and children with SCD and can detect early
decline in renal function.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Diagnosis
• Other early biomarkers:
– Urinary endothelin-1 (ET-1)
– Urine kidney injury molecule-1 (KIM-1)
– Urinary N-acetyl-b-D-glucosaminidase (NAG)
• More studies are required to establish the best
method for renal function evaluation.
• Combination of more than one biomarker improves
diagnostic accuracy.
Diagnosis
• Imaging examinations may show caliceal cysts, papillary necrosis,
and cortical sclerosis.
• Images are usually normal in children.
• Increased kidney size can be found in young adults with SCD,
whereas among adults older than 40 years, kidney size can be
diminished or even atrophic.
• Doppler ultrasound changes can be used as early markers.
• Renal biopsy should be considered in cases of significant
proteinuria, when glomerular diseases are suspected and in the
cases of rapid or unexplained renal function loss.
• In the cases of isolated hematuria in SCD, renal biopsy is not
indicated.
De Jong PE, Statius van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 1985;
27: 711–717.
Treatment
• There are no established guidelines for treatment of
sickle cell nephropathy.
• Data from case series and extrapolation from renal
disease due to other causes such as diabetic
nephropathy.
Treatment
Transfusions
• Alvarez et al (2006): Chronic transfusions started
before the age of 9 years may protect against
microalbuminuria.
• Becton et al (2010): no correlation between
microalbuminuria and transfusions.
• No sufficient evidence for use of transfusions for
prevention or treatment of SCN.
lvarez O, Montane B, Lopez G, Wilkinson J, Miller T. Early blood transfusions protect against
microalbuminuria in children with sickle cell disease. Pediatr Blood Cancer. 2006; 47(1): 71–76.
Becton LJ, Kalpatthi RV, Rackoff E, et al. Prevalence and clinical correlates of microalbuminuria in children
with sickle cell disease. Pediatr Nephrol. 2010; 25, 1505–1511.
Treatment
Hydroxyurea
• Data from the BABY HUG trial
• Children who received hydroxyurea had:
– Better urine concentrating capacity than children on
placebo
– Smaller kidney volumes on ultrasound than those on
placebo
• However, hydroxyurea had no effect on GFR.
Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function results from the multi-center
placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012; 59(4): 668-74.
Treatment
HSCT
• Most studies exclude SCD patients with established renal
disease from receiving HSCT.
• Study by Hsieh et al (2009):
– HCT in 10 adults with SCD included 3 patients with renal dysfunction
– After an average of 30 months of follow up: the decline in renal
function post-procedure did not exceed the slope before the
transplantation.
• Some reports describe HCT as a safe procedure in adults with
ESRD, suggesting that the presence of advanced SCN should
not exclude patients from receiving this treatment if available.
Hsieh MM, Kang EM. Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell
disease. N Engl J Med. 2009; 361(24): 2309–2317.
Treatment
ACE Inhibitors
• ACE inhibitors have been used in small studies and
showed decrease in proteinuria and hyperfiltration.
• Risk of developing hyperkalemia.
• No data on the use of ACEI in children with SCN.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Treatment
Advanced CKD
• Patients with ESRD secondary to SCN have poor
prognosis.
• Better survival after renal transplantation has been
shown in some studies.
• More data is needed.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287-297.
Renal disease in thalassemia
Overview
• Thalassemia patients suffer from end-organ damage;
however, little is known about the mechanisms and treatment
of kidney involvement.
• Most studies available are cross-sectional and involve a small
number of patients.
• Proper assessment of renal function abnormalities in
thalassaemia can be challenging because of the increased use
of iron chelators, which themselves can also affect renal
function.
Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta
thalassaemia. Blood Rev. 2010; 24:239–244.
Mechanisms of renal disease in
β-thalassaemia intermedia
Glomerular filtration rate (GFR)
Chronic anaemia/hypoxia
Iron overload
Iron chelation
?
●
●
●
●
●
●
●
●
●
Vascular resistance
Renal plasma flow
GFR
●
●
●
Endothelial and epithelial
damage
Transudation of
macromolecules
Mesangial dysfunction
GFR
●
●
Tubular cell damage
Epithelial-mesenchymal
transdifferentiation
Tubulointerstitial injury
Glomerular sclerosis
GFR
●
●
Relative iron depletion
Abnormal mitochondrial
function and arachidonic acid
cascade
Tubuloglomerular feedback
and haemodynamic change
GFR
Tubular cells
Chronic anaemia/hypoxia
●
●
●
Iron overload
Oxidative stress
Lipid peroxidation
Cellular damage
Iron chelation
●
Nephrotoxicity
Musallam KM, Taher AT. J Am Soc Nephrol. 2012. In press.
Renal impairment in
β-thalassaemia intermedia
● 50 β-TI patients
● eGFR
– median 142.3 ml/min/1.73 m2
– glomerular hyperfiltration in 24 (48%)
– negative correlation between eGFR
and age
● UPr/UCr ratio
– median 213.3 mg/g
– proteinuria (UPr/UCr ratio
> 500 mg/g) in 7 (14%)
– proteinuria associated with
elevated LIC (> 7 mg Fe/g dry wt),
NTBI levels, and nucleated RBC
counts
eGFR = estimated glomerular filtration rate; NTBI = non-transferrin-bound
iron; UPr/UCr = urinary protein to creatinine.
eGFR (mL/min/1.73 m2)
– median age 28 years
300
200
180
160
140
120
100
80
60
40
20
0
R2: 0.413; p < 0.001
Beta: −1.60 (95% CI: −2.15 to −1.05)
Constant: 189.59 (95% CI: 1730.07 to 206.12)
0
10
20
30
40
50
60
70
Age (years)
Ziaydef F Mussalam KM, et al Kid Int in lress .
Tubular Abnormalities
• Study on 94 patients with TM:
Koliakos G, Papachristou F, Koussi A, et al. Urine biochemical markers of early renal dysfunction are
associated with iron overload in beta-thalassaemia. Clin Lab Haematol. 2003; 25:105–9.
Tubular Abnormalities
Study by Sumboonnanonda et
al. on 104 TM patients:
– Aminoaciduria in onethird of the patients
– Low molecular weight
proteinuria in all
patients
Study of 166 TM patients:
Finding
%
Hypercalciuria
12.9
Hyperphosphaturia
9.2
Hypermagnesuria
8.6
Hyperuricosuria
36
Increased β2
microglobulin excretion
13.5
Sadeghi-Bojd S, Hashemi M, Karimi M. Renal tubular function in patients with beta-thalassaemia major in
Zahedan, southeast Iran. Singapore Med J. 2008; 49: 410–2.
Sumboonnanonda A, Malasit P, Tanphaichitr VS, Ong-ajyooth S, Sunthornchart S, Pattanakitsakul S, et al.
Renal tubular function in beta-thalassemia. Pediatr Nephrol 1998;12:280–3.
Tubular Abnormalities
In patients with TM and TI, direct correlation of renal function disturbance to total
amount of transfused iron, but not to the actual ferritin level.
Smolkin V, Halevy R, Levin C, et al. Renal function in children with beta-thalassemia major and
thalassemia intermedia. Pediatr Nephrol. 2008; 23:1847–51.
Tubular Abnormalities
• Toxicity of iron overload
•
•
•
•
Hemosiderin deposits on autopsy in patients with TM
Correlation between ferritin levels and markers of kidney injury
Oxidative stress and lipid peroxidation in renal tubules
Reversal of tubular defects after starting iron chelation
• Toxicity of anemia
• Oxidative stress and lipid peroxidation
• Damage secondary to hypoxia
Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta
thalassaemia. Blood Rev. 2010; 24:239–244.
Parameters After HSCT
Sumboonnanonda A, Sanpakit K, Piyaphanee N. Renal tubule function in betathalassemia after
hematopoietic stem cell transplantation. Pediatr Nephrol. 2009; 24:183–7.
GFR Abnormalities
Among regularly transfused patients, creatinine clearance was lower in adults than children.
Decrease in Cr clearance with blood transfusions may be related to alleviation from anemia.
Quinn CT, Johnson VL, Kim HY, et al. Renal dysfunction in patients with thalassaemia. Br J Haematol.
2011; 153: 111-117.
GFR Abnormalities
Anemia
Injury and
transudation of
molecules
Mesangial
overload and
dysfunction
Decreased SVR
Stretching of the
glomerular
capillary wall
Progressive
decline in GFR,
worsened by iron
overload
Hyperdynamic
circulation
Increased RBF and
hyperfiltration
Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta
thalassaemia. Blood Rev. 2010; 24:239–244.
The microvasculature of the nephron.
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology
Multiple mechanisms of chronic hypoxia in the kidney.
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology
GFR Abnormalities
• Study by Ali et al. (Iran)
TM (50 patients)
TI (50 patients)
Mean Hb (g/dL)
9.11 ± 0.83
9.81 ± 1.13
Mean ferritin
level (mcg/L)
3533 ± 201
871 ± 82
Mean serum
creatinine
(mcmol/L)
78.7 ± 17.7
52.2 ± 32.7
Ali D, Mehran K, Moghaddam AG. Comparative evaluation of renal findings in Beta-thalassemia major
and intermedia. Saudi J Kidney Dis Transpl. 2008; 19: 206–9.
Iron Chelators
• Cases of acute renal failure (ARF) attributed to deferoxamine
overdose have been reported.
• Damage was reversible, and renal biopsy in one patient
showed renal tubular necrosis.
• ARF also described in patients on oral deferasirox (Exjade)
who had:
– Advanced age
– High-risk myelodysplastic syndromes
– Underlying renal/hepatic problems
Musallam KM, Taher AT. Mechanisms of renal disease in β-thalassemia. J Am Soc Nephrol. 2012; 23(8):
1299-302.
Iron Chelators
• Mild dose-dependent increases in creatinine were reported in
patients on deferoxamine or deferasirox.
• Transient changes, not exceeding twice the upper limit of
normal. Some spontaneously normalized, others required
dose-reduction.
• Creatinine increases were not progressive over a 5-year
follow-up.
• Increases in serum creatinine were more often observed in
patients with lower ferritin levels, less frequent blood
transfusions, and lower LIC.
Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron
chelator, in patients with beta-thalassemia. Blood. 2006; 107:3455–62.
Iron Chelators
Current theory
Relative iron depletion
1. Damage to mitochondrial function in tubular
cells.
2. Interference with arachidonic acid cascade
1. Tubuloglomerular feedback, decrease in GFR
2. Imbalance in prostaglandins, decrease in GFR
Musallam KM, Taher AT. Mechanisms of renal disease in β-thalassemia. J Am Soc Nephrol. 2012; 23(8):
1299-302.
Nephropathy in Thalassemias
• Data is still lacking.
• More long-term studies involving a larger number of
patients with thalassemia major and intermedia are
needed.
• Questions
De Jong PE, Statius van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 1985;
27: 711–717.
Urine concentration abnormalities
• Unrelated to ADH production
• Study by Tharaux et al:
– Endothelin-1 (ET-1) counters the effects of ADH on tubular
functions
– SCD patients at steady state have marked increase in
urinary ET-1 excretion, which is likely to favor diabetes
insipidus and subsequent dehydration
Tharaux PL, Hagege I, Placier S, et al. Urinary endothelin-1 as a marker of renal damage in sickle cell
disease. Nephrol Dial Transplant. 2005; 20:2408– 2413
Hyperfiltration
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
Hyperfiltration
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
Age and the prevalence of albuminuria in adults with sickle cell hemoglobinopathies. □,
normoalbuminuria; □, microalbuminuria; ▪, macroalbuminuria.
Guasch A et al. JASN 2006;17:2228-2235
©2006 by American Society of Nephrology
Microalbuminuria and Proteinuria
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
Figure 1. Intrarenal arterial anatomy.
Jung D C et al. Radiographics 2006;26:1827-1836
©2006 by Radiological Society of North America
Diagnosis
Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early
detection of sickle nephropathy. Am J Hematol 86:559–566
Diagnosis
Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early
detection of sickle nephropathy. Am J Hematol 86:559–566
Plasma concentration of endothelin-1 on day 0 and day 1, after overnight water deprivation, in
17 sickle cell patients at steady state and 17 matched controls.
Tharaux P et al. Nephrol. Dial. Transplant. 2005;20:24082413
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Distribution of ET-1 urinary output for three hours on day 1 (x) and urinary albumin output
normalized against creatinine (y) in the study sample of SCD patients, and the corresponding
estimated linear regression equation (P<0.01, Spearman's non-parametric correlation test).
Tharaux P et al. Nephrol. Dial. Transplant. 2005;20:24082413
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
NAG
KIM-1
Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early
detection of sickle nephropathy. Am J Hematol 86:559–566
Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical
manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371-1379.
Mechanisms of renal disease in patients with β-thalassemia.
Musallam K M , Taher A T JASN 2012;23:1299-1302
©2012 by American Society of Nephrology
Current Model of SCN
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.