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Progressive improvement in short-term kidney transplant survival and reduction in acute rejection rates have restricted our ability to assess newer therapy. Past and present conventional endpoints, such as short-term graft survival and acute rejection rates, are no longer practical. This has prompted investigators to search for alternative endpoints. Long-term graft survival is an ideal endpoint. However, this requires a large cohort of patients with longer follow-up. A simpler approach would be to identify short-term markers, which can predict long-term survival. Short-term potential markers that can predict long-term survival are: clinical (renal function), histological (renal pathological markers) and immunological (anti-donor antibody, blood and urine cytokines). Post-transplant renal function estimated by serum creatinine, cystatin C and creatinine clearance within 1 year, and histological indices, as the Banff chronicity score, have the potential to predict long-term graft survival. Serum creatinine is limited as a marker by its variability based on recipient age, body weight, race and sex. Histological indices are limited, due to the invasive nature of evaluation. Post-transplant renal function and histological indices can be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. A practical approach for assessing newer therapies in future studies is to use composite endpoints, which combine conventional endpoints (graft loss, death, acute rejection) with newer endpoints (renal function, histological indices).
Significant improvements in short- and long-term kidney transplantation survival rates and declining incidents of acute rejection present a paradox for researchers who are attempting to assess the efficacy of newer immunosuppressive agents. The conventional endpoints of patient and graft survival and acute rejection, which have been customarily used to measure renal outcome, are not practical due to fewer such events as newer therapies have yielded greater success.
Over the past two decades, the improving results allowed investigators to shift the focus of outcome assessments from patient and graft survival endpoint to acute rejection endpoint. From the use of prednisone in the early 1950s and azathioprine (Aza) in 1960s to cyclosporine A (CsA) in the 1980s, the introduction of the next generation of immunosuppressive agents in the 1990s, such as mycophenolate mofetil (MMF), tacrolimus (TAC) and sirolimus (SR) and molecularly engineered humanized antibodies, have resulted in a steady decline in acute rejection rates and substantial improvements in short-term renal transplant survival. At the same time, long-termkidney graft survival has also substantially improved. Investigators are innovatively approaching the progress paradox by actively evaluating the use of alternative surrogate markers, such as renal function, histological findings and immunological markers, to assess immunosuppressive advances that will continue to improve long- and short-term outcomes.
This article briefly overviews the conventional endpoints that have been traditionally used to measure renal transplant outcome over the past 20 years, and discusses the advantages and disadvantages of using alternative short-term endpoints of renal function, histological findings and immunological markers. The discussion also includes the use of a composite endpoint, which is a combination of conventional endpoints (acute rejection, graft loss, death), and alternative newer endpoints (renal function, renal histology).
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