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A clinician’s view of Vascular Rejection

This article discusses the increasing frequency of vascular rejections in transplantation, highlighting the importance of new detection and cross-match techniques, as well as the role of C4d. It also examines the prognostic significance of vascular rejections and various treatment options.

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A clinician’s view of Vascular Rejection

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  1. A clinician’s view of Vascular Rejection D. Glotz, D. Nochy 2005

  2. Vascular Rejections Seem more and more frequent.... • 10 à 20% historically • Close to 30% or more today....

  3. Rejections St S Rej St S Rej 1970 1980 1990 2000 A changing picture… 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

  4. Vascular Rejections A much better understanding.. • New Antibodies detection techniques • New Cross-match techniques • C4d

  5. Vascular Rejections Histological Définition • Banff: score V (IIb, III) • CCTT: individualisation

  6. Vascular Rejections Types Types • Arteriolar, glomerular, capillaries • Arteries

  7. 6 months Survival 5 years Survival Normal 20% 95% 78% Borderline 34% ACR 18% IIa 6% IIb et III 15% 78% 61% Vascular Rejections Pronostic Importance 293 Bx (J2-J35) of 382 pts Tx 1985 - 1989 Bates NDT 1999

  8. Vascular Rejections Pronostic Importance • 177 Bx of 134 transplants 1994-1996 • 31% failures if vascular rejection (58) p<0,05 • 15% failures if interstitial rejection (65) Mc Donald NDT 1999

  9. Vascular Rejections Pronostic Importance 245 Tx 1995-2002 Loucaidou Transpl 2003

  10. AHR (DSA,C4d+) ACR (DSA,C4d-) Mild AR n=18 n=30 n=30 - - + Steroid Sensitivity Antibody Sensitivity 33% 97% Graft Surv. 6 mo 77,80% 96,70% 96,70% Vascular Rejection Treatment OKT3 OKT3 232 Tx 1995-1999 Mauiyyedi JASN 2002

  11. ･ 65% men ･ Time on dialysis: 3,8 years (0,5/14) ･ Patients with PRA>0: 30% (36%) ･ Thymoglobulin, Aza, Sandimmune, steroids RENALTRANSPLANTS RENALTRANSPLANTS BROUSSAIS 1989-1993 BROUSSAIS 1987-1992 240 transplantations ･ Mean age: 42,3 years (18/64)

  12. RENALTRANSPLANTS RENALTRANSPLANTS BROUSSAIS 1989-1993 BROUSSAIS 1987-1992 Patient and Graft survival Patient and Graft survival 1 5 10 years Patient 97% 91% 82% Graft 92% 77% 58%

  13. RENAL TRANSPLANTS RENAL TRANSPLANTS BROUSSAIS 1989-1993 BROUSSAIS 1987-1992 Rejections Rejections ･ < 1% during Thymo administration ･ 22% at 6 months ･ 29% at 12 months ･ of which 81% were Steroid-sensitive ･ 10% of recurrent rejections

  14. Vascular Rejections 17 Vascular rejections • 7,1% of all patients • 76% steroid-resistant • 4 treated with OKT3 as first-line TT • 28% of all rejections

  15. Vascular Rejections Histology • 38% G3, only 24% G0 • 71% I1 • 59% T1 or T0 • 38% V3, 63% V2-V3

  16. Vascular Rejections 17 Vascular rejections • 47% sensitized patients • 82% first episode of rejection • Delay Tx-rejection: 89 days (53% 35 days, 47% >6 months) • Creatinin at rejection: 408 µM/l • Reversal: 75% All treated with Steroid pulses and OKT3

  17. Vascular Rejections 100% 90% 80% 70% 60% PATIENT 50% GRAFT 40% 30% 20% 10% 0% 0 1 2 3 4

  18. Vascular Rejections Repeat biopsies (67% of patients) • 100% reversal • No recurrent rejections • Extensive fibrosis

  19. Vascular Rejections 100% 90% 80% 70% 60% PATIENT 50% GRAFT 40% 30% 20% 10% 0% 0 10 20 30 40

  20. Vascular Rejections A much better understanding.. • New Antibodies detection techniques • New Cross-match techniques • C4d

  21. Our series 76% Glomerulitis 46% 10% 0,01 59% T0-T1 50% 5% 0,02 41% T2-T3 50% 95% 0,02 37% V0-V1 42% 90% 0,01 63% V2-V3 58% 10% 0,01 Graft loss 12 (50%) 3 (15%) 0,025 Antibody associated Rejections Histology Abs + (n=24) Abs - (n=20) p 44/459 Tx 1987-1994 Trpkov Transpl 1996

  22. C4d associated to the existence of DSA • Unselected biopsies • Specificity: 93% • Sensitivity: 31% • P. Positive Value : 87% Bohmig JASN 2002

  23. C4d associated to humoral rejection with DSA • 232 pts Tx 1995 - 1999 • 67 pts with rejet<3 months, IF and sérum • 30% C4d + (20/67) • 30% AHR, 45% AHR+ACR • 96% with DSA Mauiyyedi JASN 2002

  24. C V 58 35 C4d+ 31% 46% C4d- 69% 54% C V Graft loss 58 35 C4d+ 38% 33% 44% C4d- 7% 5% 11% p<0,0001 p<0,001 p<0,05 C4d positive Rejections Pronostic Importance Hertzenberg JASN 2002

  25. Humoral Rejection Définition Définition • Histological Lesions • NTA • CPT, glom, thromboses • Arteritis • C4d positive • Donor specific Antibodies

  26. Humoral Rejection The Pompidou experience 1999-2004 • 237 transplants • 25% immunized/re-transplant patients • Thymoglobulin, Neoral, Cellcept, steroids • 14,6% Rejections • 9,7% Humoral Rejections

  27. Humoral Rejection The Pompidou experience 1999-2004 • 23 patients, 56 Biopsies of A.H.R. • 78% in immunized patients • Delay Tx-A.H.R. 16 days in 87% of cases • Creatinin at rejection 290 µM/l

  28. Humoral Rejection C4d and D.S.A. at 1st Biopsy • C4d +, D.S.A. + 52,2% • C4d +, D.S.A. - 30,5% • C4d ?, D.S.A. + 8,7% • C4d -, D.S.A. - 8,7%

  29. Humoral Rejection Histological findings at 1st biopsy • Glomerular neutrophils 78,6% • PTC dilatation 83,9% • PTC neutrophils 39,1% • Acute Tubular damage 65,2% • Glomerular TMA 30,4% • G1-3 94,6% • V1-2 56,5%

  30. Abs + (n=24) Abs - (n=20) Trpkov Transpl 1996 Peak PRA 36,50% 24,50% NS Pre-Tx PRA 11,30% 14,70% NS Re-Tx 50% 10% p<0,01 AHR (DSA,C4d+) ACR (DSA,C4d-) Mild AR Crespo, Transpl 2001 n=18 n=30 n=30 Peak pre-Tx PRA 56,50% 3% 3% Re-Tx 38,90% 6,70% 6,70% Who’s at risk of Humoral Rejection?

  31. Who’s at risk of Humoral Rejection? The Pompidou experience 1999-2004 • 30% A.H.R. in immunized vs 3% in non immunized patients • D.S.A. pre-Tx (ELISA): 65,2% • Historical positive crossmatch: 43,5%

  32. Humoral Rejection Treatment • IVIg • IVIg/Plasmapheresis

  33. Humoral Rejection Treatment IVIg Treatment • 7 patients • 6 resistant to anti-lymphocyte antibodies • 7 short term success (<6months) Jordan, Transpl 1998

  34. Humoral Rejection Treatment IVIg Treatment • 17 patients • 13 rejections StR, 4 AbR • Patient Survival 18 months: 94% • Graft Survival 18 months: 71% Luke, Transpl 2001

  35. Humoral Rejection Treatment IVIg/PP treatment • 3 patients • AHR with DSA • 100% success Montgomery, Transpl 2000

  36. Humoral Rejection Treatment IVIg/PP treatment • 16 patients • 100% StR, 50% AbR • Graft survival 1 year: 81% (84%) Rocha, Transpl 2003

  37. Humoral Rejection The Pompidou experience 1999-2004 • Treatment with IVIg high dose and Steroid pulses • 75% success, no deaths • Mean Follow-up 36 ± 21 months • Last creatinin 193 µM/l

  38. Period 1989-1993 1999-2004 Type of rejection "Vascular" "Humoral" % immunised patients 30% 25% % rejection 29% 14,30% % V/AHR 7,10% 9,70% % V/AHR in rejections 25% 68% % Immunized pats/rej 47% 78% Delay Tx-rejection 35 days 16 days Creatinin at rejection 406 µM/l 290µM/l Treatment OKT3 IVIg Success rate short term 75% 75% And the same success rate…. 2 periods in time, 2 definitions of rejection, 2 treatments…

  39. Humoral Rejection D.S.A. IVIg/PP Vascular Rejection « Cellular » Ab Anti-Lymphocytes Vascular Rejections Rejets Vasculaires

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