Long-term Immunosuppression, Without Maintenance Prednisone, After Kidney Transplantation

Successful clinical allotransplants only became possible with the development of immunosuppression. Initially, 6-mercaptopurine, or its derivative azathioprine (AZA), was used.1–3 Shortly thereafter, Starzl et al4 reported improved graft survival when AZA was combined with prednisone. Since that time, transplant clinical research has focused on improving short- and long-term graft survival while simultaneously minimizing immunosuppression-related complications. Prednisone has a well-defined side effect profile, which includes hypertension, osteoporosis (and fractures), avascular necrosis, cataracts, mood alterations, posttransplant diabetes, easy bruisability, and skin changes. Some of these side effects are related to the cumulative steroid dose.5 Others develop rapidly posttransplant6 and can occur early, even with use of relatively low-dose steroids.7–9 Consequently, even early in the history of transplantation, attempts were made to minimize the daily prednisone dose.10 In general, however, kidney transplant recipients who began prednisone at the time of their transplant tended to have better long-term graft survival than those who did not take prednisone. Throughout the 1980s and 1990s, many transplant centers studied whether selected, clinically well, immunologically low-risk kidney transplant recipients, without a previous acute rejection episode, could undergo prednisone withdrawal. Those studies showed that, even in carefully selected recipients, prednisone withdrawal was associated with an increased risk of acute rejection11,12 and of graft loss.12 Of particular concern was a Canadian multicenter, prospective, randomized study in which recipients on cyclosporine (CSA) and prednisone, without active rejection, were randomized at 90 days posttransplant to continue on CSA and either low-dose prednisone or placebo. The Canadian study found no difference in graft survival for the first 3 years posttransplant, but thereafter the steroid-free group had significantly worse graft survival (P = 0.03 versus the low-dose prednisone group).13 More recently, with the introduction of new, more potent immunosuppressive agents, interest in steroid-sparing protocols has resurged. Two prospective randomized studies of steroid withdrawal in recipients on CSA, mycophenolate mofetil (MMF), and prednisone showed an increased incidence of acute rejection episodes in the steroid withdrawal arm.14,15 In contrast, numerous other studies have now shown a low acute rejection rate when steroids are completely avoided or discontinued in the first week after kidney or simultaneous kidney-pancreas transplants.16–24 Outcome at 1 year posttransplant has been excellent with protocols incorporating prednisone avoidance or rapid discontinuation. Yet concern remains, fueled by the results of the Canadian study, that long-term outcome will be worse in prednisone-free recipients. We herein report 4-year outcome in a cohort of kidney transplant recipients who discontinued their prednisone in the first posttransplant week.