Effect of Immunosuppressive Medication Use on Patient Outcomes Following Kidney Transplantation Failure

Transplantation is the best treatment for patients with end stage kidney disease.1 However, despite the development of powerful immunosuppressant medications, transplantation still does not provide most patients with lifelong freedom from dialysis. The half-life (time to 50% failure) of a deceased donor kidney transplant is only 10.5 years.4, 5 As the number of prevalent patients who received a transplant more than a decade ago increases, the number of patients with failing transplants who must either return to dialysis or undergo repeat transplantation is also rapidly increasing.6 Repeat transplantation is clearly the best option for these patients.8 However, in Canada, only 10% of patients with first transplant failure will receive a second transplant.9 Consequently transplant failure is now the fifth leading individual cause of dialysis initiation in Canada.6, 10 Survival after transplant failure is very poor, with 40% mortality in the first 5 years after initiation of dialysis.9, 11, 12 In comparison, the 5 year mortality of de novo incident dialysis patients, including those who are not even transplant candidates, is 50%, 6, 10while that of first transplant recipients is < 10%.6, 10 However, the unique characteristics of the transplant failure population limit the validity of such comparisons with other chronic kidney disease patients. Transplant failure patients were initially selected to undergo transplantation because of their favorable age and health status, and thus differ from unselected de novo incident dialysis patients. Similarly, unlike first time transplant recipients, transplant failure patients already have prolonged exposure to immunosuppressant medications that can increase the risk of cardiovascular disease, cancer and metabolic bone disease. Notwithstanding these issues, we and others have published a number of studies documenting the poor outcomes, and stressing the need for prospective studies in this unique subset of chronic kidney disease patients.9, 12-16 To date, no study has systematically examined this patient population and basic questions about how to manage the failed kidney allograft remain. Although there are some clear indications for emergent surgical removal of the failed allograft (nephrectomy), the elective use of nephrectomy is highly variable and poorly described.17-19 Acute immunologic injury (rejection) in the failed transplant can occur as long as the allograft remains in situ, and can cause both local and systemic symptoms. In addition, the failed allograft may promote chronic inflammation leading to malnutrition, anemia and cardiovascular disease.20, 21 No prospective studies have examined whether nephrectomy and discontinuation of immunosuppressant medications is preferable to retaining the failed allograft. If the allograft is retained, it is not known whether the risk of continued exposure to immunosuppressant medications outweighs the risk of acute rejection or chronic inflammation when these drugs are discontinued. Importantly, management of the failed allograft can impact allosensitization,22-24 a primary determinant of a patient's ability to undergo repeat transplantation.

This prospective observational study is a necessary first step in defining the optimal management strategy for this unique and growing patient population. The primary and secondary research questions will determine the association of (i) immunosuppressant drug use and (ii) elective nephrectomy with clinical outcomes including death, sepsis, and rejection. Importantly, the study will also determine the association of these exposures with allosensitization (anti-HLA antibodies). The information obtained will inform the design of future interventional studies that will definitively define how to best manage these complex patients.