Withdrawal of immunosuppression after renal transplant failure
- Brent W Miller, MD
Brent W Miller, MD
- Professor of Medicine
- Washington University School of Medicine
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Washington University School of Medicine
Over the last few decades, the long-term survival of renal allografts has significantly increased. Despite this success, a substantial number of renal allograft recipients eventually require the permanent reinstitution of renal replacement therapy because of allograft failure . As an example, approximately 13 percent of patients who received a renal allograft in 2006 had undergone a previous transplant . In addition, among over 100,000 patients beginning dialysis in 2002, 4 percent had a failed renal allograft [2,3].
The survival of such patients on dialysis appears to be relatively poor [4-7]. In a study of 4743 renal transplant recipients in Canada, for example, the risk of death was significantly higher with allograft failure versus those with continued allograft function (adjusted hazard ratio 3.4, 95% CI 2.75-4.2) .
The reinstitution of dialysis after renal transplant failure presents the clinician with the dilemma of whether to withdraw immunosuppressive medications and, if withdrawal is initiated, the optimal method of tapering such therapy. The issues that must be addressed with the withdrawal of immunosuppression after renal transplant failure are reviewed in this topic.
REASONS FOR WITHDRAWAL
The most compelling reasons to withdraw immunosuppressive medications in dialysis patients with a failed renal transplant are the increased risk of infection, malignancy, and complications associated with long-term corticosteroid immunosuppression use. Infection is the second leading cause of death in this setting . Another problem is that the dosing of some immunosuppressive agents is difficult in patients with renal failure.
Increased risk of infection — An increased risk of serious infections is observed in both transplant recipients (because of the direct effects of immunosuppressive medications) and dialysis patients (because of immune system derangements from uremia and access-related problems). These factors contribute to the unacceptably high incidence of infection in dialysis patients who continue to receive immunosuppressive medications after a renal allograft has failed. This is particularly concerning in the failed transplant patient utilizing a venous catheter on hemodialysis [9-12]:
- UNOS Registry Data www.optn.org (Accessed on February 01, 2009).
- Langone AJ, Chuang P. The management of the failed renal allograft: an enigma with potential consequences. Semin Dial 2005; 18:185.
- Cecka JM. The UNOS Renal Transplant Registry. Clin Transpl 2002; :1.
- Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. Am J Transplant 2002; 2:970.
- Gill JS, Abichandani R, Khan S, et al. Opportunities to improve the care of patients with kidney transplant failure. Kidney Int 2002; 61:2193.
- Knoll G, Muirhead N, Trpeski L, et al. Patient survival following renal transplant failure in Canada. Am J Transplant 2005; 5:1719.
- Kendrick EA, Davis CL. Managing the failing allograft. Semin Dial 2005; 18:529.
- Gill JS, Abichandani R, Kausz AT, Pereira BJ. Mortality after kidney transplant failure: the impact of non-immunologic factors. Kidney Int 2002; 62:1875.
- Gregoor PJ, Kramer P, Weimar W, van Saase JL. Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression. Transplantation 1997; 63:1528.
- Smak Gregoor PJ, Zietse R, van Saase JL, et al. Immunosuppression should be stopped in patients with renal allograft failure. Clin Transplant 2001; 15:397.
- Kiberd BA, Belitsky P. The fate of the failed renal transplant. Transplantation 1995; 59:645.
- Woodside KJ, Schirm ZW, Noon KA, et al. Fever, infection, and rejection after kidney transplant failure. Transplantation 2014; 97:648.
- Pham PT, Pham PC. Immunosuppressive management of dialysis patients with recently failed transplants. Semin Dial 2011; 24:307.
- van Leeuwen MT, Webster AC, McCredie MR, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ 2010; 340:c570.
- Vajdic CM, van Leeuwen MT, Webster AC, et al. Cutaneous melanoma is related to immune suppression in kidney transplant recipients. Cancer Epidemiol Biomarkers Prev 2009; 18:2297.
- Burn DJ, Bates D. Neurology and the kidney. J Neurol Neurosurg Psychiatry 1998; 65:810.
- Madore F, Hébert MJ, Leblanc M, et al. Determinants of late allograft nephrectomy. Clin Nephrol 1995; 44:284.
- Thomas PP, Jacob CK, Kirubakaran MG, et al. Indication for routine allograft nephrectomy in cases of irreversible rejection. Transplantation 1989; 48:155.
- DiSesa VJ, Tilney NL. Conservative management of the failed renal allograft: indications for transplant nephrectomy. Curr Surg 1982; 39:417.
- Freier DT, Haines RF, Rosenzweig J, et al. Sequential renal transplants: some surgical and immunological implications on management of the first homograft. Surgery 1976; 79:262.
- Noel C, Hazzan M, Boukelmoune M, et al. Indication for allograft nephrectomy after irreversible rejection: is there an ideal delay? Transplant Proc 1997; 29:145.
- Gourlay WA, Patterson R, Gill J, et al. Influence of transplant nephrectomy on panel reactive antibody titer and waiting time for second kidney transplants (abstract). Transplantation 1999; 67:S169.
- Matzinger P. Graft tolerance: a duel of two signals. Nat Med 1999; 5:616.
- Vanrenterghem Y, Khamis S. The management of the failed renal allograft. Nephrol Dial Transplant 1996; 11:955.
- Roberts CS, LaFond J, Fitts CT, et al. New patterns of transplant nephrectomy in the cyclosporine era. J Am Coll Surg 1994; 178:59.
- O'Sullivan DC, Murphy DM, McLean P, Donovan MG. Transplant nephrectomy over 20 years: factors involved in associated morbidity and mortality. J Urol 1994; 151:855.
- Johnston O, Rose C, Landsberg D, et al. Nephrectomy after transplant failure: current practice and outcomes. Am J Transplant 2007; 7:1961.
- Bia M. Indications for nephrectomy of a failed transplant. Semin Dial 1998; 11:196.
- López-Gómez JM, Pérez-Flores I, Jofré R, et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 2004; 15:2494.
- Ayus JC, Achinger SG. At the peril of dialysis patients: ignoring the failed transplant. Semin Dial 2005; 18:180.
- Ayus JC, Achinger SG, Lee S, et al. Transplant nephrectomy improves survival following a failed renal allograft. J Am Soc Nephrol 2010; 21:374.
- Delgado P, Diaz F, Gonzalez A, et al. Intolerance syndrome in failed renal allografts: incidence and efficacy of percutaneous embolization. Am J Kidney Dis 2005; 46:339.
- Cofan F, Real MI, Vilardell J, et al. Percutaneous renal artery embolisation of non-functioning renal allografts with clinical intolerance. Transpl Int 2002; 15:149.
- Verresen L, Vanrenterghem Y, Waer M, et al. Corticosteroid withdrawal syndrome in dialysis patients. Nephrol Dial Transplant 1988; 3:476.
- Sever MS, Türkmen A, Yildiz A, et al. Fever in dialysis patients with recently rejected renal allografts. Int J Artif Organs 1998; 21:403.
- Rodger RS, Watson MJ, Sellars L, et al. Hypothalamic-pituitary-adrenocortical suppression and recovery in renal transplant patients returning to maintenance dialysis. Q J Med 1986; 61:1039.
- Shapiro R, Carroll PB, Tzakis AG, et al. Adrenal reserve in renal transplant recipients with cyclosporine, azathioprine, and prednisone immunosuppression. Transplantation 1990; 49:1011.
- Ratcliffe PJ, Dudley CR, Higgins RM, et al. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Lancet 1996; 348:643.
- Lameire NH. The impact of residual renal function on the adequacy of peritoneal dialysis. Nephron 1997; 77:13.
- Sumrani N, Delaney V, Hong JH, et al. The influence of nephrectomy of the primary allograft on retransplant graft outcome in the cyclosporine era. Transplantation 1992; 53:52.
- Douzdjian V, Rice JC, Carson RW, et al. Renal retransplants: effect of primary allograft nephrectomy on early function, acute rejection and outcome. Clin Transplant 1996; 10:203.
- Khakhar AK, Shahinian VB, House AA, et al. The impact of allograft nephrectomy on percent panel reactive antibody and clinical outcome. Transplant Proc 2003; 35:862.
- Marrari M, Duquesnoy RJ. Detection of donor-specific HLA antibodies before and after removal of a rejected kidney transplant. Transpl Immunol 2010; 22:105.
- Del Bello A, Congy-Jolivet N, Sallusto F, et al. Donor-specific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy. Clin J Am Soc Nephrol 2012; 7:1310.
- Augustine JJ, Woodside KJ, Padiyar A, et al. Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure. Transplantation 2012; 94:738.
- Ramsdell F, Fowlkes BJ. Maintenance of in vivo tolerance by persistence of antigen. Science 1992; 257:1130.
- Nishinaka H, Nakafusa Y, Hirano T, et al. Graft persistence effectively induces and maintains donor-specific unresponsiveness. J Surg Res 1997; 68:145.
- Jackson A, McSherry C, Butters K, et al. Pretransplant exposure to donor HLA-DR antigen in random transfusion units and the development of donor antigen-specific hyporeactivity. Hum Immunol 1997; 55:148.
- Bennett WM. The failed renal transplant: in or out? Semin Dial 2005; 18:188.
- Andrews PA, Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant. Transplantation 2014; 98:1130.
- REASONS FOR WITHDRAWAL
- Increased risk of infection
- Increased risk of malignancy
- Complications of corticosteroid therapy
- Altered drug dosing
- COMPLICATIONS OF WITHDRAWAL
- Rejection and transplant nephrectomy after withdrawal
- Indications for nephrectomy
- Secondary adrenal insufficiency
- Implications of residual renal function
- Sensitization and retransplantation
- - Effect of nephrectomy on retransplantation
- METHODS OF WITHDRAWAL
- SUMMARY AND RECOMMENDATIONS