Dix ans de transplantation rénale Fonds Boussard

Transcription

1 Dix ans de transplantation rénale Fonds Boussard Groupe Spiesser A.T.N. Christophe Legendre, Hôpital Necker & Université Paris Descartes, Paris Fondation Day-Solvay Actualités Néphrologiques Jean Hamburger Paris, avril 2018

2 Activité de transplantation rénale DSA 100 TR Donneur RC décédé TR Donneur DV vivant 50 0 Data from Hôpital Necker

3 Day 22 post-rt Complement was normal, and the gamma-globulin fraction was elevated. It is therefore possible to hypothesize that this increase was due to antibodies against the transplant itself = DSA!! Pr Jean Hamburger, 1953! L Michon et al, La Presse Médicale 1953 H Kreis et al, Am J Transplant 2013

4 The index case Mr RAZ, IgA nephropathy, TR#1 on 6/4/89, back to HD on 1/3/98, Anti-HLA abs including anti-a11, TR#2 on 7/4/05 with a graft from an A11 DD, Historical X-match negative but current X-match IgM positive, Anti-A11abs detected with Elisa.

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6 Necker: initial experience with DSA+ recipients D Anglicheau et al, Am J Transplant 2007

7 Necker: initial experience with DSA+ recipients D Anglicheau et al, Am J Transplant 2007

8 Necker: initial experience with DSA+ recipients D Anglicheau et al, Am J Transplant 2007

9 JM Gloor et al, Am J Transplant 2006 M Haas et al, Am J Transplant 2007

10 A Loupy et al, Am J Transplant 2009

11 A Loupy et al, Am J Transplant 2009 Acute lesions of AMR

12 A Loupy et al, Am J Transplant 2009 G Hill et al, J Am Soc Nephrol 2011 Chronic lesions of AMR

13 SAMR: outcome: M3 Glomérulite Capillarite Oedème Creatinine 82 µmol/l A Loupy et al, Am J Transplant 2009

14 SAMR: outcome: Y1 Glomérulite Capillarite * FIAT Creatinine 124 µmol/l A Loupy et al, Am J Transplant 2009

15 SAMR: outcome: Y3 Glomérulite Capillarite FIAT TG Creatinine 168 µmol/l A Loupy et al, Am J Transplant 2009

16 Graft survival according to Y1 screening biopsy A Loupy et al, J Am Soc Nephrol 2014

17 Anti-HLA donor-specific antibodies

18 Acute ABMR Chronic ABMR Subclinical ABMR Electron microscopy Endothelial-associated transcripts A Loupy et al, Clin J Am Soc Nephrol 2011

19 The presence of pre-transplant donorspecific antibodies (DSAs) is deleterious Risk of acute AMR Risk of graft failure S Mohan et al, J Am Soc Nephrol 12

20 The presence of de novo post-transplant donorspecific antibodies (DSAs) is deleterious C Wiebe et al, Am J Transplant 2012

21 ABMR: the first cause of graft dysfunction J Sellares et al, Am J Transplant 2011

22 Perte du greffon Design de l étude Cohorte : Necker, Saint-Louis, Foch et Toulouse : 4783 patients 732 pertes de greffon 9959 biopsies rénales Caractéristiques de la greffe Caractéristiques donneur receveur DSA Évaluation annuelle clinique + biologique: Immunosuppresseurs DFG et protéinurie DSA DSA Mars 2015 Profil immunologique: Ac anti HLA (DSA) J0 Biopsie de dépistage M3 (n=2383) Biopsie de dépistage A1 (n = 2193) Biopsie pour cause (n = 5387) C Lohéac et al, ANJH 2018 Diagnostic histologique (BANFF) : Rejet humoral, Rejet cellulaire Récurrence Néphropathie virale Toxicité anticalcineurines

23 Phénotype histologique : biopsies pour cause C Lohéac et al, ANJH 2018

24 Causes spécifiques de perte du greffon après exclusion des causes vasculaires C Lohéac et al, ANJH 2018

25 Distribution des causes de perte du greffon C Lohéac et al, ANJH 2018

26 The 10 ways to avoid DSAs! No DSA DSA

27 1. Perfect HLA matching No immunosuppression No DSA!

28 2. Wait for a kidney without DSA V Van Gogh, La méridienne, Orsay 1889

29 3. Acceptable mismatches or KPE programs FHJ Claas et al, Transplantation 2004 FHJ Claas et al, Transplantation 2009

30 4. Improve HLA-Ag matching C Süsal et al, Curr Opin Organ Transplant 2013

31 5. Improve HLA-epitope matching C Wiebe et al, Am J Transplant 2013

32 6. Risks of reduced-immunosuppression: role of patients non compliance. C Wiebe et al, Am J Transplant 12

33 7. Risk of reduced-immunosuppression: role of doctors. L Liefeldt et al, Am J Transplant 2012

34 P Gatault et al, Am J Transplantation 2017 Basiliximab + TAC + MMF + Ste Group A: 4.1±2.2mg/day, Group B: 6.4±3.7mg/day, p< Dose Group A: 4.3±2.7mg/day, Group B: 6.0±3.7mg/day, p= Group A: 5.3±1.7µg/L, Group B: 8.4±2.1µg/l, p< Trough Group A: 5.6±2.0 µg/l, Group B: 7.4±2.0µg/L, p<0.0001

35 Adverse events

36 TCMR more severe after tacrolimus reduction P Gatault et al, Am J Transplantation 2017 DSA = 6 out 87 patients in groupe A DSA = 0 in group B

37 Risks of reducing immunosuppression early (6m) D Hricik et al, J Am Soc Nephrol 2015

38 Risks of reducing immunosuppression late (5 years)

39 8. Prevention of acute TCMR Post-TCMR de novo DSAs Post-TCMR de novo DSAs and acute rejection JM Chemouny et al, Transplantation 2015

40 9.To avoid post-kt blood transfusions I Ferrandiz et al, Am J Transplant 2016 ATC 2017

41 10.The choice of immunosuppression Cumulative incidence of de novo DSA is way lower under belatacept at 7 years post-tx F Vincenti et al, N Engl J Med 2016

42 How to transplant immunized patients? DSA

43 1. Wait for «the few» non-incompatible donors! Vincent Van Gogh, La méridienne ou la sieste Jules Bastien Lepage, Les foins

44 2. Acceptable mismatch or KPE programs FHJ Claas et al, Transplantation 2004 FHJ Claas et al, Transplantation 2009

45 3. Live with DSA = desensitization Transplantation LD DD Early pre-transplant desensitization Immediate pre-transplant desensitization (Vienna) Post-transplant desensitization (Necker) CDC or Fl X-match negativation Negative CDC X-match

46 MR Clatworthy, Am J Transplant 11

47 Early pretransplant desensitization = SOC IVIg and anti-cd20 IVIg : 2g/kg at day 0 and 30 Anti-CD20: 1g at day 7 and 22 AA Vo et al, N Engl J Med 2008

48 Early pretransplant desensitization = SOC Plasma exchanges + IVIg (0.1mg/kg per session RA Montgomery et al, N Engl J Med 2011

49 Immediately postransplant desensitization Necker protocol L Amrouche et al, Transplantation 2017

50 HLA-incompatibility = acceptable risk (USA)? Patient survival (%) RA Montgomery et al, N Engl J Med 2011

51 HLA-incompatibility = acceptable risk (USA)? Graft survival (%) BJ Orandi et al, N Engl J Med 2016

52 HLA-incompatibility = acceptable risk (UK)? Graft survival (%) M Manook et al, Lancet 2016

53 Patient survival (%) L Amrouche et al, Transplantation 2017

54 Graft survival (%) L Amrouche et al, Transplantation 2017

55 DSAs : risk stratification

56 L Amrouche et al, Transplantation 2017 Chronic ABMR No chronic ABMR Need for a better stratification of «patients at risk for graft loss».

57 Luminex : our worst nightmare! Semi-quantitative Single Screening DTT pre-treatment Heat pre-treatment Denatured antigens HC Sullivan, Am Transplant 2017

58 Complement binding anti-hla Antibodies and graft phenotype 1016 allograft biopsies A Loupy et al, N Engl J Med 2013

59 A Loupy et al, N Engl J Med 2013

60 A Loupy et al, N Engl J Med 2013 C1q+ DSAs

61 A Loupy et al, N Engl J Med 2013

62 C Lefaucheur et al, J Am Soc Nephrol 2015

63 IgG1 IgG2 IgG3 IgG4 C Lefaucheur et al, J Am Soc Nephrol 2015

64 D Viglietti et al, (submitted) Risk stratification according to DSAs

65 A Bouquegneau et al, PLOS One 2018

66 Acute antibody-mediated rejection (ABMR) 1. Renal dysfunction (screat, Pu, HTA) 2. Histologic features: Glomerulitis and peritubular capillaritis Arterial v3 (III) Double contours and multilayering BM Fibrous arterial intimal thickening IF/TA C4d+ 3. Donor specific antibodies K Solez et al, Am J Transplantation 2007 Subclinical antibodymediated rejection Vascular lesions as severity index C4d negative antibodymediated rejection C4d positivity as severity index Ant-HLA C DSAs Anti-HLA DSAs of UO Non anti-hla DSAs

67 Courtesy of A Loupy

68 M Haas et al, Am J Transplant 2018

69 M Haas et al, Am J Transplant 2018

70 Urinary biomarkers and ABMR

71 Chemokines as diagnostic biomarkers of ABMR Urinary CXCL9 is a strong diagnostic biomarker of T cell mediated rejection Urinary CXCL10 is a strong diagnostic biomarker of antibody mediated rejection Urinary CXCL10 is a prognostic biomarker after ABMR Early urinary CXCL10 is a prognostic biomarker of acute rejection JASN 2015 AJT 2016

72 Chemokines as prognostic biomarkers of ABMR Urinary CXCL10 independently improves the noninvasive diagnosis of antibody mediated kidney allograft rejection Rabant M et al. JASN 2015

73 Therapeutic options

74 MD Stegall et al, Am J Transplant 2011

75 Purified C1-esterase inhibitor: Berinert

76 Anti-IL6-Receptor: Tocilizumab Serum Cell Mb Cell

77 SC Jordan et al, N Engl J Med 17 Bacterial IgG-degrading enzyme

78 M Mengel et al, Kidney Int 2017

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80 Thank you for your attention! Christophe Legendre Université Paris Descartes & Hôpital Necker, Paris.