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Indications for and Barriers to Preemptive Kidney Transplantation: A Review
Indications for and Barriers to Preemptive Kidney Transplantation: A Review S. Kallab, N. Bassil, L. Esposito, I. Cardeau-Desangles, L. Rostaing, and N. Kamar ABSTRACT Preemptive kidney transplantation is the treatment of choice for end-stage renal disease. Compared with nonpreemptive transplantation, preemptive transplantation is significantly associated with improved kidney allograft survival in recipients of either cadaver or living-donor transplants. This seems to be related to better patient survival. It can be proposed to all patients, but still needs to be evaluated for repeat transplantation. The main barriers are organ-allocation policies and late referral of patients to transplantation centers. REEMPTIVE TRANSPLANTATION is defined by absence of exposure to dialysis before transplantation and, thus, applies to only a small percentage of transplantation procedures worldwide. However, the many advantages of preemptive transplantation include avoidance of dialysis-induced morbidity, avoidance of dialysis access and its complications, reduction in severity of chronic kidney disease–related sequelae, improvement in patient quality of life, and reduction of end-stage renal disease.1 Duration of dialysis therapy has a harmful effect on posttransplantation kidney allograft survival.2 Furthermore, preemptive transplantation is significantly associated with improved kidney allograft survival in recipients of either a cadaver or livingdonor transplant.3,4 Patients who undergo preemptive kidney transplantation experience fewer acute rejection episodes.4 There is a greater degree of impairment of the immune system in patients who do not undergo dialysis compared with those who undergo long-term dialysis,5 and initiation of hemodialysis leads to improvement in T-cell proliferation.6
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WHY DO PREEMPTIVE KIDNEY TRANSPLANT RECIPIENTS HAVE AN ALLOGRAFT SURVIVAL ADVANTAGE?
The reasons for the advantage in allograft survival in preemptive transplant recipients are not well known. In a retrospective study that included 4046 recipients of a first kidney transplant from a living donor, Ishani et al7 found no correlation between pretransplantation estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease equation and graft survival. Similarly, no correlation was observed between pretransplantation and 6-month posttransplantation eGFR.7 More recently, 0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.02.031 782
Akkina et al8 demonstrated that a higher pretransplantation eGFR does not improve renal allograft function or survival in patients with or without end-stage renal disease (ESRD) caused by diabetes mellitus. Gill et al9 performed a large retrospective study that included 11,290 living-donor recipients and 29,673 cadaver donor recipients. Of these, 2999 living-donor recipients (27%) and 2967 cadaver-donor recipients (10%) underwent preemptive transplantation. All patients were recipients of a first kidney transplant and had a functioning graft at 2 years. Mean (SD) follow-up was 5.7 (2.3) years. There was statistically less acute rejection only in the living-donor recipients, which suggests a difference in immune reactivity due to dialysis avoidance, and the importance of donor factors. The eGFR at 6 months posttransplantation was statistically better in patients who underwent no preemptive kidney transplantation: 51.4 (14.8) mL/min/1.73 m2 vs 50.4 (14.8) mL/min/1.73 m2 in living-donor recipients (P ⫽ .002) and 48.9 (15.9) mL/min/1.73 m2 vs 47.9 (15.3) mL/min/1.73 m2 in cadaver donor recipients (P ⫽ .003). However, this difference was not clinically different between the 2 groups, which suggests lack of a lead-time bias as an explanation for the advantages of preemptive transplantation. Preemptive transplantation has also been found to be an independent From the Department of Nephrology, Dialysis and Organ Transplantation (S.K., N.B., L.E., I.C.-D., L.R., N.K.), and INSERM U858, IFR–BMT (N.K.), CHU Rangueil, and INSERM U563, IFR–BMT, CHU Purpan (L.R.), Toulouse, France. Address reprint requests to Nassim Kamar, MD, PhD, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: [email protected] © 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 42, 782–784 (2010)
PREEMPTIVE KIDNEY TRANSPLANTATION
protective factor in annual GFR change, which is not diminished by inclusion of the incidence of acute rejection, delayed graft function, and duration of dialysis. Hence, the less rapid loss in renal function after preemptive kidney transplantation was not related to immunologic and nonimmunologic factors after kidney transplantation. Both patient and graft survival were significantly better after preemptive transplantation. Hence, Gill et al9 hypothesize that the apparent allograft survival advantage of preemptive transplantation is the result of greater patient survival, which is a consequence of patient selection, or to the reduced severity of comorbid diseases associated with avoidance of uremia and dialysis. INDICATIONS FOR PREEMPTIVE TRANSPLANTATION
The advantages observed after preemptive kidney transplantation prompt transplant physicians to propose preemptive kidney transplantation in all patients with ESRD eligible for kidney transplantation. However, perhaps we should wonder whether preemptive transplantation be proposed in older patients and patients with diabetes who may have a shorter life expectancy and may survive only a few months with dialysis. In a retrospective study, Innocenti et al10 showed that 3-year survival rates in patients older than 60 years and in patients with diabetes were similar regardless of whether transplantation was preemptive. However, in patients with type I or type II diabetes, preemptive kidney transplantation alone or preemptive simultaneous kidney-pancreas transplantation has been associated with improved patient and graft survival compared with nonpreemptive transplantation.11,12 These data suggest that preemptive transplantation should also be offered to these high risk patients. In contrast, with respect to preemptive repeat transplantation, in a registry study, kidney allograft survival was shown to be improved in patients undergoing nonpreemptive transplantation compared with preemptive transplantation.13 This may have been related to undetected donorspecific antibodies that patients had while still receiving immunosuppressants. A BK virus nephropathy could have been ongoing and relapsed after repeat transplantation. Therefore, further studies are required to assess the effect of preemptive kidney repeat transplantation. BARRIERS TO PREEMPTIVE KIDNEY TRANSPLANTATION
Cadaver kidney allocation policies are the main barrier to preemptive kidney transplantation. Indeed, in the Eurotransplant program, patients can accrue waiting time for a cadaver kidney transplant only if they are receiving dialysis. The United Network for Organ Sharing requires creatinine clearance of less than 20 mL/min before a patient can be placed on a cadaver donor waiting list. Hence, preemptive transplantation is relevant virtually only in living-donor cases and when there are a number of donor options.14 When donors are scarce, ethical issues can be raised.15
783
Another barrier to preemptive kidney transplantation is late referral from nephrologists to the transplantation center. The nephrologists’ view of preemptive transplantation was assessed in the United States by means of an Internet survey.16 The survey was sent to 5901 nephrologists; however, only 476 responses were received, and of these, 460 were analyzed. Seventy-one percent of nephrologists declared that preemptive transplantation is the therapy of choice in patients with ESRD. Respectively, 25% and 13% declared that dialysis centers and nephrologists lose a source of revenue after referring patients for preemptive transplantation. In addition, kidney transplantation may be delayed because of patient concern about the consequences of kidney removal to the donor’s health, as well as financial issues.16 The survey also showed that patients with chronic kidney disease are referred at such an advanced state that there is not enough time to plan for preemptive transplantation.16 An additional barrier is compliance. Adherence to immunosuppressive medications after transplantation may be reduced if patients do not first experience the morbidity of dialysis.
CONCLUSION
Preemptive transplantation is the treatment of choice for ESRD. It can be proposed for all patients but still needs to be evaluated for repeat transplantation. The main barriers are organ allocation policies and late referral to transplantation centers.
REFERENCES 1. Liem YS, Weimar W: Early living-donor kidney transplantation: a review of the associated survival benefit. Transplantation 87:317, 2009 2. Meier-Kriesche HU, Kaplan B: Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 74:1377, 2002 3. Kasiske BL, Snyder JJ, Matas AJ, et al: Preemptive kidney transplantation: the advantage and the advantaged. J Am Soc Nephrol 13:1358, 2002 4. Mange KC, Joffe MM, Feldman HI: Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 344:726, 2001 5. Descamps-Latscha B, Herbelin A, Nguyen AT, et al: Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis: relationships with activation markers of T cells, B cells, and monocytes. J Immunol 154:882, 1995 6. Kaul H, Girndt M, Sester U, et al: Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease. Am J Kidney Dis 35:611, 2000 7. Ishani A, Ibrahim HN, Gilbertson D, et al: The impact of residual renal function on graft and patient survival rates in recipients of preemptive renal transplants. Am J Kidney Dis 42:1275, 2003 8. Akkina SK, Connaire JJ, Snyder JJ, et al: Earlier is not necessarily better in preemptive kidney transplantation. Am J Transplant 8:2071, 2008 9. Gill JS, Tonelli M, Johnson N, et al: Why do preemptive kidney transplant recipients have an allograft survival advantage? Transplantation 78:873, 2004 10. Innocenti GR, Wadei HM, Prieto M, et al: Preemptive living donor kidney transplantation: do the benefits extend to all recipients? Transplantation 83:144, 2007
784 11. Israni AK, Feldman HI, Propert KJ, et al: Impact of simultaneous kidney-pancreas transplant and timing of transplant on kidney allograft survival. Am J Transplant 5:374, 2005 12. Pruijm MT, de Fijter HJ, Doxiadis, II, et al: Preemptive versus non-preemptive simultaneous pancreas-kidney transplantation: a singlecenter, long-term, follow-up study. Transplantation 81:1119, 2006 13. Goldfarb-Rumyantzev AS, Hurdle JF, Baird BC, et al: The role of pre-emptive re-transplant in graft and recipient outcome. Nephrol Dial Transplant 21:1355, 2006
KALLAB, BASSIL, ESPOSITO ET AL 14. Salvadori M, Bertoni E, Rosso G, et al: Preemptive cadaveric renal transplantation: fairness and utility in the case of high donation rate; pilot experience of Tuscany region. Transplant Proc 41:1084, 2009 15. Petrini C: Ethical issues in preemptive transplantation. Transplant Proc 41:1087, 2009 16. Pradel FG, Jain R, Mullins CD, et al: A survey of nephrologists’ views on preemptive transplantation. Clin J Am Soc Nephrol 3:1837, 2008
P
WHY DO PREEMPTIVE KIDNEY TRANSPLANT RECIPIENTS HAVE AN ALLOGRAFT SURVIVAL ADVANTAGE?
The reasons for the advantage in allograft survival in preemptive transplant recipients are not well known. In a retrospective study that included 4046 recipients of a first kidney transplant from a living donor, Ishani et al7 found no correlation between pretransplantation estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease equation and graft survival. Similarly, no correlation was observed between pretransplantation and 6-month posttransplantation eGFR.7 More recently, 0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.02.031 782
Akkina et al8 demonstrated that a higher pretransplantation eGFR does not improve renal allograft function or survival in patients with or without end-stage renal disease (ESRD) caused by diabetes mellitus. Gill et al9 performed a large retrospective study that included 11,290 living-donor recipients and 29,673 cadaver donor recipients. Of these, 2999 living-donor recipients (27%) and 2967 cadaver-donor recipients (10%) underwent preemptive transplantation. All patients were recipients of a first kidney transplant and had a functioning graft at 2 years. Mean (SD) follow-up was 5.7 (2.3) years. There was statistically less acute rejection only in the living-donor recipients, which suggests a difference in immune reactivity due to dialysis avoidance, and the importance of donor factors. The eGFR at 6 months posttransplantation was statistically better in patients who underwent no preemptive kidney transplantation: 51.4 (14.8) mL/min/1.73 m2 vs 50.4 (14.8) mL/min/1.73 m2 in living-donor recipients (P ⫽ .002) and 48.9 (15.9) mL/min/1.73 m2 vs 47.9 (15.3) mL/min/1.73 m2 in cadaver donor recipients (P ⫽ .003). However, this difference was not clinically different between the 2 groups, which suggests lack of a lead-time bias as an explanation for the advantages of preemptive transplantation. Preemptive transplantation has also been found to be an independent From the Department of Nephrology, Dialysis and Organ Transplantation (S.K., N.B., L.E., I.C.-D., L.R., N.K.), and INSERM U858, IFR–BMT (N.K.), CHU Rangueil, and INSERM U563, IFR–BMT, CHU Purpan (L.R.), Toulouse, France. Address reprint requests to Nassim Kamar, MD, PhD, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: [email protected] © 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 42, 782–784 (2010)
PREEMPTIVE KIDNEY TRANSPLANTATION
protective factor in annual GFR change, which is not diminished by inclusion of the incidence of acute rejection, delayed graft function, and duration of dialysis. Hence, the less rapid loss in renal function after preemptive kidney transplantation was not related to immunologic and nonimmunologic factors after kidney transplantation. Both patient and graft survival were significantly better after preemptive transplantation. Hence, Gill et al9 hypothesize that the apparent allograft survival advantage of preemptive transplantation is the result of greater patient survival, which is a consequence of patient selection, or to the reduced severity of comorbid diseases associated with avoidance of uremia and dialysis. INDICATIONS FOR PREEMPTIVE TRANSPLANTATION
The advantages observed after preemptive kidney transplantation prompt transplant physicians to propose preemptive kidney transplantation in all patients with ESRD eligible for kidney transplantation. However, perhaps we should wonder whether preemptive transplantation be proposed in older patients and patients with diabetes who may have a shorter life expectancy and may survive only a few months with dialysis. In a retrospective study, Innocenti et al10 showed that 3-year survival rates in patients older than 60 years and in patients with diabetes were similar regardless of whether transplantation was preemptive. However, in patients with type I or type II diabetes, preemptive kidney transplantation alone or preemptive simultaneous kidney-pancreas transplantation has been associated with improved patient and graft survival compared with nonpreemptive transplantation.11,12 These data suggest that preemptive transplantation should also be offered to these high risk patients. In contrast, with respect to preemptive repeat transplantation, in a registry study, kidney allograft survival was shown to be improved in patients undergoing nonpreemptive transplantation compared with preemptive transplantation.13 This may have been related to undetected donorspecific antibodies that patients had while still receiving immunosuppressants. A BK virus nephropathy could have been ongoing and relapsed after repeat transplantation. Therefore, further studies are required to assess the effect of preemptive kidney repeat transplantation. BARRIERS TO PREEMPTIVE KIDNEY TRANSPLANTATION
Cadaver kidney allocation policies are the main barrier to preemptive kidney transplantation. Indeed, in the Eurotransplant program, patients can accrue waiting time for a cadaver kidney transplant only if they are receiving dialysis. The United Network for Organ Sharing requires creatinine clearance of less than 20 mL/min before a patient can be placed on a cadaver donor waiting list. Hence, preemptive transplantation is relevant virtually only in living-donor cases and when there are a number of donor options.14 When donors are scarce, ethical issues can be raised.15
783
Another barrier to preemptive kidney transplantation is late referral from nephrologists to the transplantation center. The nephrologists’ view of preemptive transplantation was assessed in the United States by means of an Internet survey.16 The survey was sent to 5901 nephrologists; however, only 476 responses were received, and of these, 460 were analyzed. Seventy-one percent of nephrologists declared that preemptive transplantation is the therapy of choice in patients with ESRD. Respectively, 25% and 13% declared that dialysis centers and nephrologists lose a source of revenue after referring patients for preemptive transplantation. In addition, kidney transplantation may be delayed because of patient concern about the consequences of kidney removal to the donor’s health, as well as financial issues.16 The survey also showed that patients with chronic kidney disease are referred at such an advanced state that there is not enough time to plan for preemptive transplantation.16 An additional barrier is compliance. Adherence to immunosuppressive medications after transplantation may be reduced if patients do not first experience the morbidity of dialysis.
CONCLUSION
Preemptive transplantation is the treatment of choice for ESRD. It can be proposed for all patients but still needs to be evaluated for repeat transplantation. The main barriers are organ allocation policies and late referral to transplantation centers.
REFERENCES 1. Liem YS, Weimar W: Early living-donor kidney transplantation: a review of the associated survival benefit. Transplantation 87:317, 2009 2. Meier-Kriesche HU, Kaplan B: Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 74:1377, 2002 3. Kasiske BL, Snyder JJ, Matas AJ, et al: Preemptive kidney transplantation: the advantage and the advantaged. J Am Soc Nephrol 13:1358, 2002 4. Mange KC, Joffe MM, Feldman HI: Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 344:726, 2001 5. Descamps-Latscha B, Herbelin A, Nguyen AT, et al: Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis: relationships with activation markers of T cells, B cells, and monocytes. J Immunol 154:882, 1995 6. Kaul H, Girndt M, Sester U, et al: Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease. Am J Kidney Dis 35:611, 2000 7. Ishani A, Ibrahim HN, Gilbertson D, et al: The impact of residual renal function on graft and patient survival rates in recipients of preemptive renal transplants. Am J Kidney Dis 42:1275, 2003 8. Akkina SK, Connaire JJ, Snyder JJ, et al: Earlier is not necessarily better in preemptive kidney transplantation. Am J Transplant 8:2071, 2008 9. Gill JS, Tonelli M, Johnson N, et al: Why do preemptive kidney transplant recipients have an allograft survival advantage? Transplantation 78:873, 2004 10. Innocenti GR, Wadei HM, Prieto M, et al: Preemptive living donor kidney transplantation: do the benefits extend to all recipients? Transplantation 83:144, 2007
784 11. Israni AK, Feldman HI, Propert KJ, et al: Impact of simultaneous kidney-pancreas transplant and timing of transplant on kidney allograft survival. Am J Transplant 5:374, 2005 12. Pruijm MT, de Fijter HJ, Doxiadis, II, et al: Preemptive versus non-preemptive simultaneous pancreas-kidney transplantation: a singlecenter, long-term, follow-up study. Transplantation 81:1119, 2006 13. Goldfarb-Rumyantzev AS, Hurdle JF, Baird BC, et al: The role of pre-emptive re-transplant in graft and recipient outcome. Nephrol Dial Transplant 21:1355, 2006
KALLAB, BASSIL, ESPOSITO ET AL 14. Salvadori M, Bertoni E, Rosso G, et al: Preemptive cadaveric renal transplantation: fairness and utility in the case of high donation rate; pilot experience of Tuscany region. Transplant Proc 41:1084, 2009 15. Petrini C: Ethical issues in preemptive transplantation. Transplant Proc 41:1087, 2009 16. Pradel FG, Jain R, Mullins CD, et al: A survey of nephrologists’ views on preemptive transplantation. Clin J Am Soc Nephrol 3:1837, 2008