Introduction
Patients who have a kidney transplant frequently experience allograft failure. When a transplant fails, difficult decisions must be made, such as when and how to wean immunosuppression and begin the transition to a second transplant or dialysis. These choices are made in light of serious concerns about competing risks such as sensitization and infection. Unfortunately, the management of failed allografts is currently guided by low-quality data, and as a result, practice patterns are inconsistent and suboptimal, despite the fact that patients with failed allografts have higher rates of morbidity and mortality than transplant-naive patients. We summarise the management strategies used during the often perilous transition from transplant to dialysis in this review, highlighting the scarcity of data and critical knowledge gaps that are necessary to inform the optimal care of the patient with a failing kidney transplant.
Relisting and Repeat Transplant
Over the past 2 decades, transplantation after a failed allograft has increased slowly in absolute terms and actually decreased overall in relative terms (Figure 1), which is somewhat surprising given the rising number of total transplants and the modest gains in long-term allograft outcomes. Preemptive waitlisting and transplantation is recognized as the transplantation strategy associated with the best outcomes for patients with kidney failure.
The rates of preemptive relisting and/or transplantation appear to be highly variable across transplant centers, declining over time, and significantly lower among racial minorities and socioeconomically disadvantaged populations although the total number of candidates being added to the waitlist has increased steadily, the number of candidates with a prior transplant has not kept up; instead, the absolute number of such candidates has remained relatively flat since 2007, resulting in a sharp decline as a proportion of the total number of candidates added to the waitlist (Figure 2).
While these proportions are marginally better than the overall incident kidney failure population, these are likely to be underestimates of the failure of nephrologists, given that many patients potentially continue to have functioning accesses that were placed before their initial transplant. Rather, these numbers underscore the failure of transplant centers and nephrologists who are caring for patients with failing allografts to adequately prepare their patients for life without a functioning kidney transplant on multiple fronts, beyond vascular access.
Immunosuppression Management
Reduced immunosuppression is commonly recommended in failing allografts, this approach may be counterintuitive in some individuals–such as those with ongoing, chronic, antibody-mediated rejection–and may contribute to more rapid loss of the allograft. Upon allograft failure, the benefits of continued immunosuppression must be weighed against the risk of complications from their ongoing exposure, such as infection, malignancy, secondary adrenal insufficiency, and cost. The higher risk of morbidity and mortality immediately after dialysis initiation for individuals with failed allografts appears to be driven largely by infection, underscoring the need for a better understanding of the appropriate immunosuppression strategy that would weigh the risks of infections with the benefit of avoiding sensitization, which would result from abrupt cessation of immunosuppression (Figure 3)
Allograft Nephrectomy
The role of graft nephrectomy remains controversial and clinical practice varies widely, largely dependent on regional preferences rather than compelling data. In the absence of urgent indications like infection or hemorrhage, the most salient reason for surgical removal is the treatment of the graft-intolerance syndrome. The potential benefits of nephrectomy must be weighed against the risks of the procedure. There is evidence that removal of the allograft generates donor-specific antibodies, independent of immunosuppression withdrawal. In a recent systematic review of 12 studies, levels of panel reactive antibody ranged from 10% to 55% in patients without allograft nephrectomy, compared with 20%–72% in patients who underwent the procedure. A few hypotheses have been proposed to explain this phenomenon beyond a notably higher risk of blood transfusions. For one, the kidney may behave like a “sponge” that attracts and absorbs formed donor-specific antibodies to their antigenic targets, preventing detection in the serum until the graft is removed. Alternatively, surgery may engender an inflammatory response that promotes antibody formation in the setting of mechanical manipulation, remnant allograft tissue, and increased exposure of antigens.
CKD Management and Dialysis
Modality
Although the initiation of dialysis is often determined by patient symptoms, estimates of glomerular filtration and rates of decline may provide additional information. There are several limitations in estimating GFR as a marker of CKD stage in the kidney allograft. Both the Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration creatinine equations likely do not perform as well in patients who have received a transplant compared with those without transplants. Recent studies that suggest the possibility of improved prognostication of outcomes after kidney transplant may help identify failing allografts sooner and encourage better planning of transitions of care. The optimal timing of dialysis initiation in patients who have received a transplant has been evaluated by several observational studies, but conclusions are limited due to inherent biases and the lack of a specific threshold of function, with similar measures used in native kidney disease to guide care; however, some have raised concerns that early initiation of dialysis could have detrimental consequences on patient outcomes. Moreover, dialysis modality should be individualized to each patient because there are no compelling data to support one form of replacement therapy over another at this time.
Palliative Care
Palliative care has a much broader scope beyond end-of-life care and has been associated with an improvement in various outcomes in other noncancer, advanced-organ-failure models–including quality of life, illness understanding, hospitalizations, health care costs, and even lower risk of death. Allograft failure is often associated with significant symptom burden, greater utilization of health care resources, transitions between health care systems, and high patient morbidity and mortality. Palliative care is uniquely equipped to address many of the needs of this patient population, yet routine integration of palliative care services has been slow and currently lacks supporting data. Helping patients understand the role of palliative care and offering referral may be important to include in their management plan, with particular consideration for patients who experience significant change in functional status, worsening disease symptoms, and increasing visits to the emergency department.
Future Directions
Critical questions about the ideal strategy for managing patients with failing allografts persist on several fronts. We urgently need more data to address the gaps in our clinical understanding of how to manage patients with failing allografts.
Conclusions
Many patients undergoing transplant ultimately experience loss of their allograft, and improving intermediateand long-term graft survival continues to be a paramount goal for the transplant community. Until this goal is achieved, it is critical that the care of patients with kidney failure acknowledge and optimize the transition to dialysis and, potentially, back to transplant. In the current environment, patients with a failing allograft often receive suboptimal chronic disease management and dialysis planning and poor continuity of care, and important decisions, with high stakes, are guided by low-quality data. Going forward, if we are to avoid failing our patients, it will be important for the transplant community to recognize these challenges and allocate resources to support the focused, higher-quality research that is required to improve long-term graft survival.
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