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

H J Lambers Heerspink1, V Perkovic, D de Zeeuw

  • 1Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. j.lambers.heerspink@med.umcg.nl

Nephron. Clinical Practice
|August 12, 2011
PubMed

Insights

Doubling serum creatinine is a common endpoint in kidney disease trials but may not accurately reflect kidney function due to muscle mass and blood flow changes. Recommendations are provided for interpreting these trials.

Area of Science:

  • Nephrology
  • Clinical Trial Design
  • Renal Biomarkers

Background:

  • The composite endpoint of end-stage renal disease (ESRD), doubling of serum creatinine, and renal death is standard in nephrology trials.
  • Doubling serum creatinine is used as a surrogate for sustained decline in glomerular filtration rate (GFR) and prediction of ESRD.

Purpose of the Study:

  • To critically evaluate the validity of using doubling of serum creatinine as a composite endpoint in nephrology clinical trials.
  • To discuss factors that may confound the interpretation of serum creatinine changes.
  • To provide recommendations for the interpretation of clinical trials employing this endpoint.

Main Methods:

  • Literature review and critical analysis of factors affecting serum creatinine.
  • Discussion of the relationship between serum creatinine, muscle mass, and GFR.
  • Examination of hemodynamic influences on serum creatinine levels.
  • Evaluation of the arbitrary nature of the doubling threshold.

Main Results:

  • Serum creatinine levels can be influenced by non-GFR factors such as muscle mass and hydration status.
  • Hemodynamic changes affecting renal perfusion can alter serum creatinine independently of structural kidney damage.
  • The 'doubling' threshold is an arbitrary metric and may not be the optimal indicator for predicting ESRD.

Conclusions:

  • The use of doubling of serum creatinine as a composite endpoint in nephrology trials requires careful interpretation due to potential confounding factors.
  • Alternative or adjusted endpoints may offer a more accurate reflection of renal function decline.
  • Recommendations are proposed to guide the interpretation of clinical trial results that include doubling of serum creatinine.

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