Is doubling of serum creatinine a valid clinical 'hard' endpoint in clinical nephrology trials?

Abstract

The composite of end stage renal disease (ESRD), doubling of serum creatinine and (renal) death, is a frequently used endpoint in randomized clinical trials in nephrology. Doubling of serum creatinine is a well-accepted part of this endpoint because a doubling of serum creatinine reflects a large sustained change in glomerular filtration rate (GFR) and predicts the development of ESRD. Although doubling of serum creatinine is frequently used, the validity of using this outcome as part of a composite endpoint is hampered by various factors. Firstly, serum creatinine may reflect changes in muscle mass unrelated to true GFR changes. Secondly, changes in serum creatinine may reflect hemodynamic changes in renal perfusion and not a structural effect on renal function. Finally, doubling of serum creatinine is an arbitrary choice and different proportional changes may represent a better indicator for ESRD. In this minireview, each of these factors will be discussed and recommendations are made for interpretation of clinical trials using doubling of serum creatinine as a composite endpoint in nephrology trials.