1. Role of recurrent disease for late allograft loss Fernando G. Cosio Mayo Clinic, Rochester MN 10 th Banff conference on allograft pathology

2. Issues to be addressed Relevance of recurrent disease to the overall outcomes of kidney transplantation. Relevance of recurrent disease to the overall outcomes of kidney transplantation. Role of protocol biopsies in improving our understanding of recurrent glomerular diseases. Role of protocol biopsies in improving our understanding of recurrent glomerular diseases. Role of protocol biopsies in improving our understanding of glomerulonephritis Role of protocol biopsies in improving our understanding of glomerulonephritis

3. Causes of Graft Loss in 1317 conventional recipients transplanted between 1996-2006 Cause GroupNumber of cases Percent of all transplants Total33025% Primary non-function 392.9% Death with function 13810.4% Graft loss (death censored) 15311.6% (Ziad El-Zoghby, Cosio AJT 9:527-535, 2009) F/u months: 50 ± 33 (0-138)

4. Mechanisms of death-censored kidney graft loss (1996-2006) Cell-mediated Antibody-mediated 1317 transplants 153 losses 1317 transplants 153 losses (Ziad El-Zoghby, Cosio et al AJT 9:527-535, 2009)

5. Recurrent glomerular diseases (rGD) Recipient’s original kidney disease NLosses due to rGD FSGS104 12 (12%) IGA nephropathy 84 4 (5%) Membranous nephropathy 29 3 (11%) 3 (11%) MPGN24 4 (17%) 4 (17%)

6. Recurrent non-glomerular diseases Graft losses due to recurrent non-GN disease: Graft losses due to recurrent non-GN disease: 7/153 (5%) Oxalosis 2 Oxalosis 2 Sickle cell anemia 1 Sickle cell anemia 1 Light chain DD 1 Light chain DD 1 HUS/TTP 1 HUS/TTP 1 Scleroderma 2 Scleroderma 2

7. Causes of renal failure in transplant recipients: Mayo versus USA Cause of ESRDMayo Clinic Rochester UNOS 2006 Glomerular disease 35.6%21.2% Diabetes16%27.8% PKD13%6.8% HTN/vascular11.5%25% Other15.9%17.2% Unknown6%2%

8. Mayo Clinic experience with recurrent GN: Preliminary analyses 1317 kidney recipients transplanted from 1996-2006. 1317 kidney recipients transplanted from 1996-2006. Subpopulations: Subpopulations: Controls: 172 patients with ADPKD Controls: 172 patients with ADPKD Patients with GN (FSGS, MN, MPGN) Patients with GN (FSGS, MN, MPGN) End points: End points: Death-censored graft survival Death-censored graft survival Disease recurrence (protocol Bx) Disease recurrence (protocol Bx) General observations (vignettes) General observations (vignettes)

9. Kidney transplantation in focal segmental glomerulosclerosis (FSGS) PKD, N=172 FSGS, N=103 p=0.0048 Compared to PKD, recipients with FSGS have reduced death-censored graft survival. Compared to PKD, recipients with FSGS have reduced death-censored graft survival. Only patients with FSGS and recurrence have reduced graft survival. Only patients with FSGS and recurrence have reduced graft survival. PKD FSGS + recurrence FSGS - recurrence p<0.0001 71% 58%

10. Kidney transplantation in FSGS 103 patients with FSGS (unselected) (8% of recipients) 103 patients with FSGS (unselected) (8% of recipients) 35% recurrence (clinical and/or histologic) 35% recurrence (clinical and/or histologic) Median time to recurrence: 6.9 months (0.01-116) Median time to recurrence: 6.9 months (0.01-116) 44%16% 41% Often subclinical with minor proteinuria and FSGS on protocol bx Present with higher grade proteinuria but no FSGS lesions

11. Kidney transplantation in membranoproliferative GN (MPGN) PKD (N=172) p=0.048 MPGN (N=25) 25 patients with MPGN (excluding type II, fibrillary and secondary forms). 25 patients with MPGN (excluding type II, fibrillary and secondary forms). 2% of recipients. 2% of recipients. Reduced graft survival compared to PKD. Reduced graft survival compared to PKD. 17% of grafts lost due to recurrence 17% of grafts lost due to recurrence

12. Kidney transplantation in MPGN 41% recurrence at 3.7 months (0.36- 17.9) post-Tx. 41% recurrence at 3.7 months (0.36- 17.9) post-Tx. Higher likelihood of recurrence: Higher likelihood of recurrence: Low C3 or C4 Low C3 or C4 Living donors Living donors Monoclonal proteins Monoclonal proteins p=0.020 Low C3 and /or C4 Nl C3 and C4

13. Kidney transplantation in membranous nephropathy (MN) PKD (N=172) MN (N=31) 31 patients with MN. 31 patients with MN. 2% of recipients. 2% of recipients. 42% recurrence at 2.5 months (4-64) 42% recurrence at 2.5 months (4-64) Histologic recurrence is often subclinical for several months Histologic recurrence is often subclinical for several months 11% of grafts lost due to recurrent MN 11% of grafts lost due to recurrent MN p=0.284

14. Protocol biopsies and recurrent disease: Postulates 1.Protocol biopsies may allow early diagnosis of recurrent GN before it is clinically apparent. 2.The earliest histologic changes of GN may give us clues about the pathogenesis of these diseases. 3.Early histologic diagnosis may allow more effective treatment.

15. Course and management of GNs in native kidneys: current status Disease starts Clinical diagnosis Histologic diagnosis Progressive disease justifies treatment ? Waiting period due to the following issues: Disease may go away? Disease may go away? Treatments are toxic and partially effective Treatments are toxic and partially effective Deployment of appropriate treatment is difficult Deployment of appropriate treatment is difficult

16. Protocol biopsies suggest several interesting questions / possibilities Disease starts Clinical diagnosis Histologic diagnosis Progressive disease justifies treatment How do these diseases look like when they start? How do these diseases look like when they start? Does the histologic Dx precede clinical manifestations? Does the histologic Dx precede clinical manifestations? Are there variables that relate to this transition? Are there variables that relate to this transition? Should we treat based on histology? Can we thus achieve better results? Improve kidney prognosis?

17. A familiar challenge: diagnosis of recurrent FSGS without FSGS 4 month protocol Bx. Urine protein 420 mg/day. EM: focal FPF Original Dx: FSGS 5 month clinical Bx. Urine protein 6030 mg/day. LM: normal. EM: diffuse FPF 12 month protocol Bx. Urine protein 1030 mg/day. LM: FSGS, finally!

18. Diagnostic challenges are also pathogenic lessons 51 yo recipient of a kidney transplant in 1/2008. Original disease MN. 51 yo recipient of a kidney transplant in 1/2008. Original disease MN. One month post-Tx surgery is done for lymphocele (  creatinine). A biopsy done during Sx. Urine protein 179 mg/day. One month post-Tx surgery is done for lymphocele (  creatinine). A biopsy done during Sx. Urine protein 179 mg/day. Light microscopy: Normal, no “spikes” no deposits. C4d done… Light microscopy: Normal, no “spikes” no deposits. C4d done…

19. C4d C3 IgG

20. Electron microscopy

21. Protocol biopsies and diagnosis of recurrent GN Protocol biopsies can make pre- clinical diagnoses of some GN. Protocol biopsies can make pre- clinical diagnoses of some GN. Current diagnostic criteria for GN are invalid: Current diagnostic criteria for GN are invalid: FSGS without F, S, G or S FSGS without F, S, G or S MN without C3 or EM deposits MN without C3 or EM deposits MPGN without MP MPGN without MP

22. Next question: Does a pre-clinical diagnosis lead to clinical disease? 19 patients with MN diagnosed by protocol biopsy and followed, untreated for at least one year: 19 patients with MN diagnosed by protocol biopsy and followed, untreated for at least one year: 2 (10.5%) have maintained low levels of proteinuria. 2 (10.5%) have maintained low levels of proteinuria. 17 (89.5%) have had progressive proteinuria 17 (89.5%) have had progressive proteinuria Repeat biopsies: MN in all (no spontaneous histologic remissions) Repeat biopsies: MN in all (no spontaneous histologic remissions)

23. Protocol biopsies  early diagnosis or over-diagnosis? Tx year: ‘00-’07 Dx: protocol Bx (N=30) Recurrence: 42% Median months to recurrence: 4 (2-61) Tx year: ‘90-’99 Dx: clinical with Bx confirmation (N=20) Recurrrence: 55% Median months to recurrence: 83 (6-149)

24. Postulated benefits of protocol biopsies in recurrent GN 1.Early, pre-clinical diagnosis 2.Pathogenic clues 3.Early histologic diagnosis may allow more effective treatment (preliminary studies suggest that we can/should start to explore this question)

25. Interesting initial observations treating recurrent MN Diagnosis(4 mo post-Tx) 1y after Rituximab (no proteinuria) 2 y after Rituximab (no proteinuria) Rituximab treatment of recurrent MN: (1y) 75% complete or partial clinical remission (1y) 75% complete or partial clinical remission (2y) Evidence of DD resorption in 6/7 (2y) Evidence of DD resorption in 6/7 (2y) Negative IgG (4/7) and negative C3 (3/7) (2y) Negative IgG (4/7) and negative C3 (3/7) Rituximab treatment of recurrent MN: (1y) 75% complete or partial clinical remission (1y) 75% complete or partial clinical remission (2y) Evidence of DD resorption in 6/7 (2y) Evidence of DD resorption in 6/7 (2y) Negative IgG (4/7) and negative C3 (3/7) (2y) Negative IgG (4/7) and negative C3 (3/7)

26. 45 yo female with SLE. LRD kidney transplant 2/2007… Parameters4 mo. post-Tx 12 mo. post-Tx 24 mo. post-Tx Creatinine (GFR) 1.1 (57) 1.0 (63) U. Protein (mg/day) 13290165 Histology: Mesangial proliferation Mesangial proliferation C1q (IF) IGG (IF) Deposits (EM) NoneTraceNegativeNoMild2+3+ Not done Moderate3+3+ Mesangial paramesangi al What do we do now? - Current approach: do not treat unless the disease is clinically apparent… - Should we explore alternative approaches? What do we do now? - Current approach: do not treat unless the disease is clinically apparent… - Should we explore alternative approaches?

27. Recurrent disease 20% of death-censored graft losses are due to recurrent disease (15% rGN). 20% of death-censored graft losses are due to recurrent disease (15% rGN). Studies using protocol biopsies suggest: Studies using protocol biopsies suggest: Need diagnostic criteria for early dis. Need diagnostic criteria for early dis. Need multicenter studies based on protocol biopsies to determine: Need multicenter studies based on protocol biopsies to determine: Histologic diagnosis  clinical? Histologic diagnosis  clinical? Effectiveness early Rx? Effectiveness early Rx? We finally have good questions and reasonable tools to try to answer them! We finally have good questions and reasonable tools to try to answer them!

29. If we knew what we were doing it would not be called research A. Einstein If we knew what we were doing it would not be called research A. Einstein Recurrent disease after kidney transplantation-- it is time to unite to address this problem! A. Matas

30. If we knew what we were doing it would not be called research A. Einstein If we knew what we were doing it would not be called research A. Einstein In addition,

31. Graft loss by cause in 1317 transplants recipients (1996 to 2006) Death Graft failure (Ziad El-Zoghby, Cosio AJT 9:527-535, 2009)

32. Impact of recurrent glomerular diseases on death-censored graft survival (Ziad El-Zoghby, Cosio AJT 9:527-535, 2009)