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CONNEXI 2016-08 Nephrologie

Kidney Experts Forum

Kidney Experts Forum Education Kidney Experts Forum Table 2: Overview of pretransplant risk factors for acute rejection after kidney transplantation Risk factor Importance Comment Recipient age Younger age Adolescence ++ +++ patients and may aid in developing a more complete definition of high risk. Therefore, the set-up of a working group to refine immunological risk status of both donor and recipient, and consequently the conditions for kidney allocation through development/adaptation of scores, algorithms or recommendations to improve decision-making strategy, should be thoroughly considered. Sanofi approval no. SADE.THYM.16.08.2192 Stronger immune response Higher risk for non-adherence Donor age + Trend towards higher immunogenicity in older organs Recipient gender + Trend to fewer rejections in males Ethnicity +++ Significantly higher risk of rejection in African Americans Deceased vs living donor + Diminishing differences (also little difference between deceased donation after cardiac vs brain death, or expanded versus criteria donation) Previous transfusion + Considered 'low immunologic responder' if patient is unsensitized despite previous transfusion Previous transplantation ++ No relevant increase in risk if the patient remains unsensitized despite prior transplantation. Early loss of previous graft to immunological causes increases risk of rejection after next graft Previous pregnancy ++ Increasing risk with succesive pregnancies PRA >0% (HLA antibodies) +++ Applies to both historic and current PRA level, HLA antibodies Class I and/or Class II Preformed HLA DSA (>500 MFI) ++++ No preformed HLA DSA at transplant is associated with low immunological risk; low levels of non-cytotoxic HLA antibodies confers intermediate risk. De novo HLA DSA post-transplant monitoring is required AT1 receptor antibodies ++ Test is relatively widely available T cell ELISPOT ++ Time-consuming (1-2 days) and requires large blood volume; may be more relevant for living-donor transplants Soluble CD30 + Inconclusive data Sensitisized patients after desensitization ++/+++ Increased risk of AMR appears to be sustained after desensitization in DSA-positive patients with negative cytotoxicity and flow cross-match, but to a far lesser extent than in patients with positive cytotoxic (profound increase in risk) or flow crossmatch (moderate increase in risk) HLA mismatch +++ Marked and well-documented effect on cellular and antibody-mediated rejection. Particularly pronounced for HLA DR mismatch CMV mismatch – No association between CMV mismatch and acute rejection in the era of CMV prophylaxis EBV mismatch – No effect per se on acute rejection Cold ischemia time + Less important with current shorter ischemic times Machine preservation + Minor effect versus cold storage; not well-documented Delayed graft function +++ Delayed function may prompt changes to the planned protocol in the first few days post-transplant References 1. Dunn, T.B., et al., Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant, 2011. 11(10): p. 2132-43. 2. USRDS 2014. Annual Data Report. Volume 2-ESRD. 3. Meier-Kriesche, H.U., et al., Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant, 2004. 4(3): p. 378-83. 4. McDonald, S., et al., Kidney transplant rejection in Australia and New Zealand: relationships between rejection and graft outcome. Am J Transplant, 2007. 7(5): p. 1201-8. 44

Kidney Experts Forum 5. Opelz, G. and B. Dohler, Influence of time of rejection on long-term graft survival in renal transplantation. Transplantation, 2008. 85(5): p. 661-6. 6. Willicombe, M., et al., Acute cellular rejection: impact of donor-specific antibodies and C4d. Transplantation, 2014. 97(4): p. 433-9. 7. Krisl, J.C., et al., Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation, 2015. 99(10): p. 2167-73. 8. Ekberg, J., et al., An in-progress, open-label, multi-centre study (SAILOR) evaluating whether a steroid-free immunosuppressive protocol, based on ATG induction and a low tacrolimus dose, reduces the incidence of new onset diabetes after transplantation. Transplant Res, 2014. 3: p. 12. 9. Grafals, M., et al., Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study. PLoS One, 2014. 9(8): p. e104408. 10. Pilch, N.A., et al., Prospective randomized controlled trial of rabbit antithymocyte globulin compared with IL-2 receptor antagonist induction therapy in kidney transplantation. Ann Surg, 2014. 259(5): p. 888-93. 11. Richter, R., et al., Pre-transplant HLA Antibodies Detected by Single Antigen Bead Assay are a Risk Factor for Long- Term Kidney Graft Loss Even in the Absence of Donor Specific Antibodies. Transpl Int, 2016. 12. Pratschke, J., et al., Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev (Orlando), 2016. 30(2): p. 77-84. 13. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant, 2009. 9 Suppl 3: p. S1-155. 14. Tullius, S.G. and E. Milford, Kidney allocation and the aging immune response. N Engl J Med, 2011. 364(14): p. 1369-70. 15. Greenstein, S. and B. Siegal, Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation, 1998. 66(12): p. 1718-26. 16. Narayanan, M., et al., Outcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression. Transplantation, 2013. 95(4): p. 566-72. 17. Ahmad, N., et al., Living-unrelated donor renal transplantation: an alternative to living-related donor transplantation? Ann R Coll Surg Engl, 2008. 90(3): p. 247-50. 18. Ge, F., et al., Gender issues in solid organ donation and transplantation. Ann Transplant, 2013. 18: p. 508-14. 19. Heinbokel, T., et al., Impact of immunosenescence on transplant outcome. Transpl Int, 2013. 26(3): p. 242-53. 20. Goto, N., et al., Association of Dialysis Duration with Outcomes after Transplantation in a Japanese Cohort. Clin J Am Soc Nephrol, 2016. 11(3): p. 497-504. 21. Lafranca, J.A., et al., Body mass index and outcome in renal transplant recipients: a systematic review and meta-analysis. BMC Med, 2015. 13: p. 111. 22. Legendre, C., G. Canaud, and F. Martinez, Factors influencing long-term outcome after kidney transplantation. Transpl Int, 2014. 27(1): p. 19-27. 23. Duquesnoy, R.J., et al., Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level? Am J Transplant, 2015. 15(4): p. 923-30. 24. Higgins, R., et al., Pregnancy-induced HLA antibodies respond more vigorously after renal transplantation than antibodies induced by prior transplantation. Hum Immunol, 2015. 76(8): p. 546-52. 25. Otten, H.G., et al., Pretransplant donor-specific HLA class-I and -II antibodies are associated with an increased risk for kidney graft failure. Am J Transplant, 2012. 12(6): p. 1618-23. 26. Hricik, D.E., et al., Interferon Gamma ELISPOT Testing as a Risk-Stratifying Biomarker for Kidney Transplant Injury: Results From the CTOT-01 Multicenter Study. Am J Transplant, 2015. 15(12): p. 3166-73. 27. Hirt-Minkowski, P., et al., Soluble CD30 correlates with clinical but not subclinical renal allograft rejection. Transpl Int, 2013. 26(1): p. 75-83. 28. Cole, E.H., et al., Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival. Clin J Am Soc Nephrol, 2008. 3(3): p. 814-21. 29. Konvalinka, A. and K. Tinckam, Utility of HLA Antibody Testing in Kidney Transplantation. J Am Soc Nephrol, 2015. 26(7): p. 1489-502. 30. Wongsaroj, P., et al., Modern approaches to incompatible kidney transplantation. World J Nephrol, 2015. 4(3): p. 354-62. 31. Vo, A.A., et al., Factors Predicting Risk for Antibody-mediated Rejection and Graft Loss in Highly Human Leukocyte Antigen Sensitized Patients Transplanted After Desensitization. Transplantation, 2015. 99(7): p. 1423- 30. 32. Kuo, H.T., et al., Cytomegalovirus serostatus pairing and deceased donor kidney transplant outcomes in adult recipients with antiviral prophylaxis. Transplantation, 2010. 90(10): p. 1091-8. 33. Debout, A., et al., Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. Kidney Int, 2015. 87(2): p. 343-9. 34. Moers, C., et al., Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med, 2009. 360(1): p. 7-19. Report prepared by Lead-Up, Paris, France. Kindly supported by Sanofi-Aventis Deutschland GmbH. Education Kidney Experts Forum 45

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