Renal end points in clinical trials of kidney disease.
Weldegiorgis M., de Zeeuw D., Heerspink HJ.
PURPOSE OF REVIEW: End-stage renal disease and doubling of serum creatinine are established hard end points in clinical trials of chronic kidney disease (CKD). These end points are debated, as their accuracy and precision may not be optimal, and as they are late events in the progression of CKD, thereby requiring large and complex trials. The purpose of this review is to examine the validity of the currently used established renal end point by comparing the end-stage renal disease part, involving renal replacement therapies (RRTs) (dialysis or renal transplantation), and the glomerular filtration-based end points involving the doubling of serum creatinine. RECENT FINDINGS: Emerging data demonstrate that the RRT decision depends not only on serum creatinine but also on a range of subjective factors involving a patient's well-being, availability of RRTs, or local guidelines. Thus, initiation of RRT is not representative of (estimated) glomerular filtration rate [(e)GFR] decline alone. In contrast, a doubling of serum creatinine reflects a sustained loss in a patient's starting GFR. The disadvantage of an end point based on a filtration marker is that many drugs exert opposite effects on the GFR. Initially, they cause a reduction in GFR followed by a stabilization of GFR decline. This ambiguous pattern complicates the interpretation of the drug effect, in particular when the end point is based on lesser declines in GFR, such as a 30% or 40% decline. SUMMARY: The currently used end points in CKD trials reflect different functions of the kidney. In the future, we have to establish whether we want to characterize the effect of a novel drug on a renal filtration marker alone, on a combination of parameters involving a patient's well-being, or on a composite of these.