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Strategies to improve long-term outcomes after kidney transplantation Miha Arnol 5 th Congres of Nephrology in BIH, Tuzla, October 18, 2019 Kidney transplant medicine A story of success A story of barriers A story of how modern

  1. Strategies to improve long-term outcomes after kidney transplantation Miha Arnol 5 th Congres of Nephrology in BIH, Tuzla, October 18, 2019

  2. Kidney transplant medicine A story of success… A story of barriers… A story of how modern scientific medicine overcame several barriers

  3. Long-term survival of ESKD patients Kidney Tx vs. Dialysis vs. General population EU cohort: 2012-2016 ERA-EDTA Registry Annual Report 2016, Amsterdam 2018

  4. Challenges in transplant medicine

  5. Challenges in transplant medicine ◼ Lack of (appropriate) donors and organs ◼ Adverse events of immunosuppression - metabolic, cardiovascular, infections, cancer ◼ Monitoring of patients/grafts is inaccurate ◼ No effective treatments for (chronic) rejection ◼ Immune tolerance not a near-future reality ◼ Long-term outcomes are suboptimal

  6. Challenges in kidney transplant medicine Kidney graft survival: Europe ◼ short-term vs. long-term survival Gondos A et al. Transplantation 2013; 95: 267; Kramer A et al. Clin Kidney J 2016; 9: 457

  7. Challenges in kidney transplant medicine Number of patients returning to dialysis USA USRDS: Annual Data Report 2010

  8. Challenges in kidney transplant medicine Number of patients returning to dialysis SLO Buturović -Ponikvar J et al. Slovenian RRT Registry; ET period: 2000-2014

  9. Causes of kidney graft failure / loss

  10. A model of kidney graft loss Comorbidities Patient Adverse events: metabolic, CV, infectious, malignant Immunosuppression death (CNI toxicity) Donor Brain IF / TA DGF death IR injury Graft TCMR • failure clinical • Rejection HLA MM subclinical (class II) de-novo DSA ABMR CG • clinical • subclinical IR , ischemia-reperfusion; DGF , delayed graft function; DSA, donor-specific antibodies; TCMR , T-cell mediated rejection; ABMR , antibody-mediated rejection; CG , chronic glomerulopathy; IF/TA , interstital fibrosis/tubular atrophy

  11. A model to improve outcomes

  12. #1 quality of donor kidneys

  13. Deceased donors in Eurotransplant Donor age statistics.eurotransplant.org/1086P_kidney

  14. Deceased donors in Eurotransplant Donor age categories > 50% statistics.eurotransplant.org/1229P_Slovenia_kidney

  15. Deceased donors in Slovenia Donor type standard criteria expanded criteria statistics.eurotransplant.org/1086P_Slovenia_kidney

  16. Kidney graft survival Donor relationship www.ctstransplant.org

  17. Kidney transplants in Slovenia Donor relationship Since 2016: Living-Donor Kidney Program - 6 Tx (parents to children) Arnol M et al. Ther Apher Dial 2016; 20: 229

  18. #2: ischemia-reperfusion (IR) injury and delayed graft function (DGF)

  19. Comorbidities Patient Adverse events: metabolic, CV, infectious, malignant Immunosuppression death (CNI toxicity) Donor Brain IR injury IF / TA DGF (Circ.) death Graft TCMR • failure clinical • Rejection subclinical HLA MM (class II) de-novo DSA ABMR CG • clinical • subclinical IR , ischemia-reperfusion; DGF , delayed graft function; DSA, donor-specific antibodies; TCMR , T-cell mediated rejection; ABMR , antibody-mediated rejection

  20. Kidney graft survival Cold ischemia time SLO (2000-2017) CIT > 12h: 90 % pts CIT > 24h: 21 % pts www.ctstransplant.org

  21. Hypothermic machine perfusion LifePort Kidney Transporter 1. Decreases the risk for DGF 2. Attenuates impact of DGF 3. Improves graft survival

  22. Hypothermic machine perfusion LifePort Kidney Transporter All donors ECD donors SCS, static cold storage; MP, machine perfusion Moers C et al. N Engl J Med 2009; 360: 7; Treckman J et al. Transplant Int 2011; 24: 548

  23. Hypothermic machine perfusion LifePort Kidney Transporter - UMC Ljubljana September 19, 2018 Arnol M et al. UMCL Research Grant 2017-2019

  24. Machine perfusion Current perspectives: oxygenation POMP trial : ECD COMPARE trial: DCD ◼ oxygenated HMP improves 1-year graft function ◼ mediated via reduction in acute rejection Jochman I et al. ATC 2019 Congress

  25. #3: HLA matching

  26. Comorbidities Patient Adverse events: metabolic, CV, infectious, malignant Immunosuppression death (CNI toxicity) Donor IR injury Brain IF / TA DGF death Graft TCMR • failure clinical • Rejection subclinical HLA MM (class II) de-novo DSA ABMR CG • clinical • subclinical HLA MM, human leukocyte antigen mismatch; DSA, donor-specific antibodies; TCMR , T-cell mediated rejection; ABMR , antibody-mediated rejection

  27. HLA matching Graft survival www.ctstransplant.org

  28. HLA matching Towards epitope matching An HLA antigen has a unique epitope set - individual epitopes can also be present on other HLA antigens Tambur AR & Claas FHJ. Am J Transplant 2015; 15: 1148

  29. HLA matching Towards epitope matching Wiebe C et al. J Am Soc Nephrol 2017; 28: 3353

  30. HLA matching Towards epitope matching ◼ NGS methodology: expensive / time consuming Wiebe C et al. Am J Transplant 2019; 19: 1708

  31. #4: immunosuppression discontinuation / minimization

  32. Comorbidities Patient Adverse events: metabolic, CV, infectious, malignant Immunosuppression death (CNI toxicity) Donor Brain IF / TA DGF death IR injury Graft TCMR • failure clinical • Rejection subclinical HLA MM (class II) de-novo DSA ABMR CG • clinical • subclinical underimmunosuppression DSA, donor-specific antibodies; TCMR , T-cell mediated rejection; ABMR , antibody-mediated rejection

  33. Immunosuppression minimization De-novo donor-specific antibodies (DSA) Wiebe C et al. Am J Transplant 2012; 12: 1157

  34. Immunosuppression minimization Patient non-adherence and DSA De-novo DSA (%) Wiebe C et al. Am J Transplant 2015; 15: 2921

  35. Immunosuppression minimization Steroid withdrawal: rapid SW at day 5 All patients Rapid SW No rapid SW P (N = 91) (n = 55) (n = 36) Subclinical rejection at 1 year Incidence 26 (29) 12 (22) 14 (39) 0,127 T-cell mediated 22 (24) 10 (18) 12 (33) 0,099 Antibody-mediated 4 (4) 2 (4) 2 (6) 0,647 Banff classification T-cell mediated Banff 3 8 (9) 4 (7) 4 (11) 0,708 Banff 4/IA,B 8 (9) 3 (6) 5 (14) 0,256 Banff 4/IIA,B 6 (7) 3 (6) 3 (8) 0,678 Antibody-mediated Acute 4 (4) 2 (4) 2 (6) 0,647 Chronic 0 0 0 / Silent de-novo DSA at 1 year Incidence 13 (14) 9 (16) 4 (11) 0,554 Specificity HLA class I 4 (4) 2 (4) 2 (6) 0,530 HLA class II 9 (10) 7 (13) 2 (6) 0,530 2600 9100 2600 MFI values 0,604 (1980 – 4855) (1825 – 17445) (2020 – 3620) Visočnik N, Arnol M et al. ESOT 2019

  36. Immunosuppression minimization Steroid withdrawal: rapid SW at day 5 All patients Rapid SW No rapid SW Adverse event (N = 91) (n = 55) (n = 36) Metabolic post-transplant diabetes 12 (13%) 1 (2%) 11 (31%) hyperlipidemia 18 (20%) 10 (19%) 8 (22%) osteopenia/osteoporosis 8 (9%) 2 (4%) 6 (17%) Infections CMV 17 (19%) 9 (16%) 8 (22%) Polioma BK 12 (13%) 4 (7%) 8 (22%) respiratory 13 (14%) 4 (7%) 9 (25%) Visočnik N, Arnol M et al. ESOT 2019

  37. #5: immunosuppression optimization

  38. Immunosuppression optimization Novel IS drugs: belatacept Graft function Graft and patient survival Vincenti F et al. N Engl J Med 2016; 374: 333

  39. Immunosuppression optimization Novel IS drugs: belatacept De-novo DSA Vincenti F et al. N Engl J Med 2016; 374: 333

  40. Immunosuppression optimization Novel IS drug combinations: mTOR & CNI TRANSFORM Study Pascual J et al. J Am Soc Nephrol 2018; 29: 1979

  41. #6: biomarkers: diagnostic/prognostic/predictive

  42. Biomarkers for optimizing outcomes Towards precision medicine in transplantation Adapted after Naesens M et al. J Am Soc Nephrol 2018; 29: 24

  43. Biomarkers for optimizing outcomes Towards precision medicine in transplantation Acute Post-Transplant Maintenance Optimal Immunosuppression Immunosuppression Immunosuppression noninv. biomarkers of over/under IS and graft injury: - clinical, molecular (genomic/trascriptomic/proteomic) Banff & Molecular Surveillance scores of graft injury Weeks triple IS Induction Weeks Adjusting / /Indication Years novel agents Years Optimizing IS graft biopsy eGFR / Proteinuria CVE / Infections / Tumors

  44. Biomarkers for optimizing outcomes Surveillance biopsies subclinical histologic changes 6 / 12 months after transplant UMC Ljubljana: since 2014 > 300 outpatient allograft Bx

  45. Biomarkers for optimizing outcomes Molecular microscope (MMDx) ◼ ATAGC – research collaboration since 2018 Halloran P et al. Alberta Transplant Applied Genomic Centre (ATAGC)

  46. Biomarkers for optimizing outcomes Noninvasive biomarkers: cell-free DNA

  47. Biomarkers for optimizing outcomes Noninvasive biomarkers: cell-free DNA dd-cf-DNA discriminates active rejection dd-cf-DNA levels are higher in ABMR than TCMR Bloom RD et al. J Am Soc Nephrol 2017; 28: 2221

  48. Biomarkers for optimizing outcomes Noninvasive biomarkers: cell-free DNA dd-cf-DNA discriminates active ABMR in DSA+ patients Jordan SC et al. Transplantation Direct 2018; 4: e379

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