Tuesday Case Conference
May 2009
Biopsy finding
•
LM
– Glomeruli
• are normal in size to mildly enlarged
• Mild enlargement of the mesangial areas with occasional nodular appearance
– Tubulointerstitial
• Interstitial fibrosis and tubular atrophy, involving approximately 50%
– Artery
• Severe intimal fibrosis of arcuate artery
• Sever cirucumferential hyalinosis of arterioles
•
IF
– Negative for C4D, BKV, and CMV
•
EM
– Podocyte effacement invovling ~40% of the surface area
•
Diagnosis:
– Early Diabetic Nephropathy
– IFTA related to CNI
Objectives
• What are different causes of allograft failure?
– What is Interstitial Fibrosis and Tubular
Atrophy - Chronic Allograft Nephropathy?
• A new biomarker for IFTA?
Transplantation
The preferred prescription for ESRD patients
Mortality on Dialysis
Annual Death Rate
N
All dialysis patients
16 per 100 patient years
~300,000
Patients on list
6 per 100 patient years
~50,000
Cadaver transplant
patients
3 per 100 patient years
~25,000
Graft survival increases with less time
on dialysis
Goldfarb-Rumyantzev A, et al. Nephrol Dial Transplant 2005;20:167–175
Risk of Death with Transplantation
OJO, A. O. et al. J Am Soc Nephrol 2001;12:589-597
Renal Transplantation
• Transplant is preferred prescription of
choice for ESRD patients
– Sooner the better
• Dramatic improvement, since 1980s, 1-year
allograft survival rates: 90-95%
• Long-term outcomes have changed little
– Death with a functioning graft
– Chronic allograft nephropathy
Recurrent glomerulonephritis and other
causes of graft failure
2002_NEJM_Briganti-Chadban_risk of renal allograft loss from recurrent glomerulonephritis
The most common cause of
graft failure, after the first year
What is CAN – IFTA?
• Incompletely understood clincopathological entity
– chronic rejection, transplant nephropathy, chronic renal
allograft dysfunction, trnasplant glomerulopathy, or
chronic allograft nephropathy
• Chronic Allograft Nephropathy
– Banff 1991
• used interchangeably with ‘chronic rejection’
– Banff 1997
• term to be used when it is impossible to precisely define the
etiology of chronic allograft damage
– Banff 2005
• “interstitial fibrosis and tubular atrophy, without evidence of
any specific etiology”
IF/TA (CAN)
Interstitial
fibrosis
Fibrointimal
proliferation
Nankivell at ASN
Electron microscopic appearances in
chronic allograft nephropathy
Some possible immune and nonimmune mechanisms of
injury leading to chronic allograft nephropathy
IF/TA score
Nankivell at ASN
Onset of IFTA
• Very common
• Progressive
• Associated with
– Proteinuria
– Decreased
GFR
– hypertension
2003_NEJM_Nankivell-Chapman_antural history of chronic allograft nephropathy
Nankivell at ASN
Nankivell at ASN
Clinical Risk Factors for long-term
allograft failure
• IF/TA is a major cause of late allograft loss
• Challenge is to dissect the identifiable
causes and to develop cause-specific
treatment
• Existing risk factors/markers
– Increased serum creatinine
– Proteinuria
– HTN
An innovative biomarker for
IFTA?
Background
• In kidney, interstitial fibrosis has been
considered a common mechanism of
disease progression
– No effective treatment to revert established
fibrosis and diagnosis is often late in the
disease course
– Fibroblasts are the pivotal effector cells in
fibrogenesis
– Studies looking to identify activated fibroblast
found abnormal expression of mesenchymal
markers (fibroblast) by tubular epithelial cells
• Epithelial phenotypic changes (EPC)
Background
• Epithelial-mesenchymal transformation
(EMT)
– where cell shifting between epithelial and
mesenchymal phenotype is well recognized
process that characterizes the embryonal
plasticity
– Key element in metastasis of tumors
– Observed in the process of wound healing and
fibrotic remodeling after inflammatory injury
Four key events during EMT
2006_ArthritisResTx_Zvaifler_Relevance of the stroma and epithelial mesenchymal transition_REV
• Examined whether EPC of tubular cells
predict the progression of fibrosis in the
allograft
– Cytoplasmic translocation of β-catenin
– Expression of Vimentin
– intermediate filament typically expressed by mesenchymal
cells
• 83 kidney tranplant with protocol graft
biopsy at both 3 and 12 mo
2008_JASN_Hertig-Dubois_Early epithelial phenotypic changs predict graft fibrosis
Role of the Cadherins in Establishing
Molecular Links between Adjacent Cells
NEJM, 1996
Immunohistochemical staining
epithelial phenotypic change
β-catenin
Vimentin
2008_JASN_Hertig-Dubois_Early epithelial phenotypic changs predict graft fibrosis
IF/TA score and EPC status
2008_JASN_Hertig-Dubois_Early epithelial phenotypic changs predict graft fibrosis
Change in Serum Creatinine by EPC
status
2008_JASN_Hertig-Dubois_Early epithelial phenotypic changs predict graft fibrosis
Conclusion
• EPC (+)
– an early and independent marker to predict the
progression of IF/TA lesions between 3 and 12
mo after transplantation
– Associated with poorer graft function from the
time point of 18 mo and thereafter
• Risk factors for renal graft fibrosis
– 3-mo EPC score and 12-mo t scores were
significantly higher in progressors as compared
with nonprogressors
Treatment
Strategies to prevent and treat IFTA
Reference
• Goldfarb-Rumyantzev A, et al. Nephrol Dial
Transplant 2005;20:167–175
• OJO, A. O. et al. J Am Soc Nephrol 2001;12:589597
• Briganti EM, Russ GR, McNeil J, et al: Risk of
renal allograft loss from recurrent
glomerulonephritis. N Engl J Med 2002;347:103–
109
• Nankivell-Chapman, Natural history of chronic
allograft nephropathy, NEJM, 2003
• Briganti-Chadban, Risk of renal allograft loss
from recurrent glomerulonephritis, NEJM, 2003