Primum non Nocere: Induction in Kidney Transplantation After Heart Transplantation.

Abstract

Kidney allograft transplantation after heart transplantation remains a rare event with 70 reported in 2007 and this number declining to 30 subsequently and more recently rose to 60 per year. The fact that renal allograft transplantation is needed at all is due to the well-known nephrotoxicity of calcineurin inhibitors, the mainstay of contemporary immunosuppression in cardiac transplant recipients.1 End-stage renal failure has increased significantly in nonrenal transplant recipients from 1998 to 2007.2 The Registry of the International Society of Heart and Lung Transplantation has reported that by 5 y posttransplant, 4.1% of heart transplant recipients develop end-stage renal disease requiring renal replacement strategies such as dialysis or renal transplantation and these percentages double by 10 y posttransplant.3 As survival after cardiac transplantation improves and patients are living longer, the number of patients requiring renal transplantation will be increasing, explaining the increase mentioned above. That these numbers have not been increasing more rapidly is a result of more assiduous attention to posttransplant management with mitigation of renal dysfunction by reduction in calcineurin inhibitor (CNI) target trough levels. This is a consequence of the study by Ojo et al.1 However, given the improving, long-term survival after heart transplantation resulting in longer-term exposure to CNIs, there will be more patients needing renal transplantation. Therefore, the identification of optimal immunosuppressive regimens guaranteeing successful outcomes in heart transplant recipients receiving renal transplants after their heart transplants as a consequence of CNI toxicity is important. Pre–heart transplant congestion and decreased cardiac output can impair renal function as well. Thus, the study by Riad et al4 published in this edition of Transplantation is important and novel. The authors reviewed the Scientific Registry of Transplant Recipient data from the United States of heart transplant recipients who subsequently, at a later date as a result of end-stage renal disease, underwent kidney transplantation (N=617) and compared post–kidney transplant outcomes as a function of type of induction or absence of induction in the early posttransplant period: depletional induction (ie, antilymphocyte globulin or alemtuzumab) (N = 307, 49.8%), nondepletional (ie, anti-interleukin-2 receptor agents such as basiliximab) (N = 253, 41.0%), or no induction (steroids) (N = 57, 9.2%). They studied reasonable numbers of patients and found no differences in outcomes such as rejection rates or renal function, reflected by serum creatinine at 1 y post–kidney after heart transplant. There was also no difference in recipient or graft survival. One difference that was noted was an increase in rehospitalization for the depletional induction group (51.7%) and nondepletional induction group (50.7%) versus the noninduction group (39.1%). The difference in rehospitalization rates between the noninduction group and the 2 induction groups while numerically lower did not reach statistical significance, likely due in part to the small numbers of patients in the noninduction group. Because the depletional group included patients receiving alemtuzumab, which is associated with profound lymphopenia, one wonders whether this exacerbated rehospitalization in this group.5 Details regarding the causes of rehospitalization were unfortunately not provided by the authors, but the presumption is that these would include lymphopenia and infection though neither appeared to impact survival or graft function. A reduction in rehospitalization is of considerable importance to reduce exposure of immunosuppressed patients to infections. There is also the issue of cost. While this article does not do a detailed cost analysis, it is quite clear that use of both depletional and nondepletional agents is far more expensive than the noninduction alternative, corticosteroids. When one adds the cost of additional rehospitalizations, the differential cost between the 2 induction strategies and the noninduction strategy would be excessive and ideally prohibitive. The authors sum up the preferred approach in their article: “No induction may be the preferred choice due to a lack of benefits and costly rehospitalizations associated with induction agents.”4 This statement should be tempered by the relatively small number of patients in the noninduction group and the lack of statistical differences as a result. There may well be patient groups such as sensitized heart transplant patients who might benefit from induction in kidney transplantation after heart transplant. Ideally, a randomized clinical trial of induction strategies versus noninduction would provide the most definitive information, but given the small numbers of patients who have kidney transplants after heart transplantation annually, this might take a long time to accomplish. It is important to remember the dictum Primum non Nocere: first, do no harm (either medical or financial).