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Understanding Recurrent Glomerulonephritis in Renal Transplants: 50 Years of Progress

Understanding Recurrent Glomerulonephritis in Renal Transplants: 50 Years of Progress. Richard J. Glassock, MD Geffen School of Medicine at UCLA Terasaki Festschrift January 25, 2014.

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Understanding Recurrent Glomerulonephritis in Renal Transplants: 50 Years of Progress

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  1. Understanding Recurrent Glomerulonephritis in Renal Transplants:50 Years of Progress Richard J. Glassock, MD Geffen School of Medicine at UCLA Terasaki Festschrift January 25, 2014

  2. Recurrent Glomerulonephritis:The Beginning(Advances in Transplantation. Edited by J. Dausset, J. Hamburger,G. Mathe. 1967; pp. 361-363 ; ibid- Medicine (Baltimore) 1968; 47:411-454)

  3. Recurrent Glomerulonephritis (GN) in Renal Iso-grafts: Some Salient Points • Described 22recipients of renal iso-grafts (monozygotic twins) performed since 1954 –average follow-up 5 years • 11 of 17 (65%) with biopsy-proven (GN) developed recurrent biopsy proven GN in the iso-graft (1 d to 6 years post-transplantation) • 6 of 17 patients had crescentic GN and 4 of these developed crescentic GN in the iso-grafts • 6 of 7 deaths were due to progressive renal failure • 0 of 3 patients given “prophylactic immunosuppression” developed recurrent GN.

  4. Recurrent Glomerulonephritis in Renal Iso-grafts(average FU = 5 years)

  5. Main Conclusions • A recurrence of the original disease, glomerulonephritis, represents a significant impediment for the long-term benefits of renal transplantation in the absence of a histo-compatibility barrier to organ acceptance • A short duration of disease before transplantation and the presence of crescentic disease magnifies the risk of recurrence • Systemic factors likely determine recurrence risk • Approaches to prevention of recurrence are uncertain (? prophylactic immunosuppression)

  6. FAST FORWARD to 2014

  7. Recurrent GN in 2014 • Risk of recurrent GN now known for specific disease entities • Factors predicting risk of recurrence partially understood. Pathogenetic mechanisms of recurrent GN now established for several disease entities • Strategies to prevent and/or treat recurrent GN are emerging. Little differences in recurrence rates observed among currently used post-transplant immunosuppressive regimens • Recurrent GN remains as a potential threat to long-term allograft graft survival, even if immunological barriers to organ acceptance are overcome

  8. Risk of Recurrent GN:Specific Diseases(from Ponticelli C and Glassock R. CJASN 2010; 5:2363-2372 and 2011; 6: 1214-1221) • Anti-GBM disease--~ 10% • IgA Nephropathy– ~ 33% (50%after 10 years) • Focal Segmental Glomerulosclerosis- 30-40%(90% for second transplants after failure from initial recurrent FSGS) • Dense Deposit Disease/C3GN (CfH deficient)- ~ 80% • Membranous Nephropathy--- 30-45% • Lupus Nephritis--- <10% (Higher in some reports) • ANCA+ Vasculitis-- <10% • Fibrillary GN- 30-40% • Henoch-Shoenlein Purpura- 50-75% • Systemic Amyloidosis- Variable depending on type • Monoclonal Immunoglobulin Deposition Disease– Variable depending on type

  9. Risk of Allo-graft Loss from Recurrent GN(Briganti EM, et al NEJM. 2002; 347: 103-109)

  10. Recurrent GN in HLA-Identical Living Donor Allo-Transplants(Andresdotir M, et al Transplantation 1999; 68:623-627) • 60 HLA-identical renal allografts; 33 with “primary” GN and 27 with non-glomerular disease • No difference in patient survival at 5, 10 20 years • Functional Graft Survival (death censored) 88%, 70% and 63% at 5, 10 and 20 years in GN vs 100% at 5, 10 and 20 years in non-GN • 45% GN recurrence rate at 12 years

  11. Prediction of Recurrent GN • Anti-GBM- high titer anti COLIVa3 IgG ab • IgA N- IgA deposits in donor Ky, no ALG, crescents, ?anti gdIgA1 ab • FSGS- young age, rapid course, mesangial proliferation, ?high suPAR levels • DDD/C3GN- CfH deficiency, crescents • Membranous nephropathy- intra-familial donor, ?high titer anti-PLA2R Ab • MIDD/Amyloid- high serum Free Light Chains; alpha Fibrinogen type of hereditary disease

  12. Avoidance/Treatment of Recurrent GN • Anti-GBM/ANCA+ Vasculitis- Cyclophosphamide/Steroids/Rituximab/ PLEX/Delay grafting until clinically quiescent • IgA N- ?Avoid donor with IgA, ? ALG, ?reduce anti-gdIgA1ab • FSGS- PLEX/Rituximab/ ?suPAR immunoadsorption • DDD/C3GN- Plasma infusion/PLEX/Eculizumab/Liver Tx (CfH deficiency) • Membranous Nephropathy- ?Avoid intra-familial donors/?treat anti-PLA2R • MIDD/AL Amyloid- Chemotherapy for hematologic remission (FLC assay) • Hereditary Amyloid- combined Liver/Kidney Tx

  13. Recurrent GN in Renal Iso-grafts Back to the Future

  14. Recurrent GN in Renal Iso-grafts:2014 Perspective • The pathogenesis for GN was largely unknown in 1954-1967- sub-categorization of GN was rudimentary • In retrospect, one case of Recurrent GN was almost certainly IgA N and one case of Vasculitis • No cases of Anti-GBM, LN, MN, DDD or FSGS

  15. Recurrent GN:Going Forward • As control of acute/chronic allograft rejection improves (including its elimination by acquired tolerance/chimerism) the importanceof avoidance/treatment of recurrent GN will increase • Present day immunosuppression is not fully adequate for avoidance of recurrence in many cases (IgA N, FSGS, MN) • Identification of underlying patho-mechanisms offers best promise for control of recurrent GN.

  16. Sa Yo Ga Uma- (Every Cloud Has a Silver Lining)

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