Long-term renal transplantation: Recent successes and new problems

There has been continued improvement in preventing early biopsy-proved acute rejections and increasing 1-year allograft success rates, and, after some delay, the conditional half-life of grafts. Beneath these impressive achievements are several troubling concerns: unrecognized subclinical rejections; the emergence of acute and chronic humoral rejection; the different effect of certain acute rejections on the development of chronic rejection; the possibility that the current improvements in reducing early acute rejection may not be translated into longer half-life for the graft unless important adjunctive therapy is included. The use of cyclosporine (CSA) has been reshaped by lower dosing, conversion and avoidance protocols, C2 blood level monitoring, availability of generics, and application to non-transplant immunologically-mediated renal diseases. The enigma of chronic allograft nephropathy (CAN) unfortunately still remains, but recent studies on the effects of hypomagnesemia are provocative. The actual cohort of truly long-term renal transplant successes is providing remarkable insights into the way such grafts and their recipients achieve 30-year success. More than half of these patients have experienced early acute rejections (even Banff II and III). Somewhat contrary to expectations, these recipients usually do not have subnormal levels of CD4+ and CD8+ lymphocytes. However, they are typically B cell depleted, a condition that may protect them from late humoral rejection. Future directions will likely lead to the inclusion of important adjunctive agents having secondary anti-proliferative and anti-fibrogenic capabilities. Because chronic injury to renal allografts, as well as the dominant complications of renal transplantation such as cardiovascular disease and skin cancers, are woven together by a common theme of excessive proliferative activity, albeit of different cell types, long-term therapy will be directed at both protecting the allograft and the allograft recipient by incorporating as long-term therapy selected anti-proliferative agents that could include inhibitors of the renin-angiotensin-aldosterone system, statins, sirolimus, mycophenolic acid and leflunomide.