The future of clinical trials in chronic renal disease: Outcome of an NIH/FDA/physician specialist conference

For people with chronic renal insufficiency the therapeutic goal is to prev ent progression to end-stage renal disease, a serious condition that can on ly be treated with dialysis and kidney transplantation. Although restrictio n of dietary protein slows the progression of renal disease somewhat, the p rincipal treatment to slow chronic renal disease is appropriate reduction o f blood pressure. Antihypertensive agents, particularly those that produce sustained, long-term reductions in proteinuria, such as angiotensin-convert ing enzyme inhibitors, not only decrease blood pressure but also preserve r enal function. Clinical trials to evaluate these and other drug therapies i n renal disease progression have used both "hard end points" (e.g., dialysi s, transplantation, death) and intermediate end points of renal disease pro gression (e.g., doubling of serum creatinine concentration, reductions in p roteinuria). Trials that have used hard end points typically recruited pati ents with advanced renal disease to demonstrate a difference in therapies w ithin a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabet ic renal disease, could demonstrate an altered natural history of renal dis ease. Although hard end points are indicators of a drug's efficacy in reduc ing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal di sease. For clinical trials of people with all but the most advanced renal d isease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectivenes s. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear t o provide an acceptable means of assessing a treatment's impact on slowing renal disease progression. (C) 2000 the American College of Clinical Pharma cology.