Estimated GFR decline as a surrogate end point for kidney failure: A post hoc analysis from the reduction of end points in non-insulin-dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT)

Hiddo J. Lambers Heerspink, Misghina Weldegiorgis, Lesley A. Inker, Ron Gansevoort, Hans Henrik Parving, Jamie P. Dwyer, Hasi Mondal, Josef Coresh, Tom Greene, Andrew S. Levey, Dick De Zeeuw

Research output: Contribution to journalArticlepeer-review

Abstract

Background A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials. Study Design Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan. Setting & Participants 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy. Predictor Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15 mL/min/1.73 m2. Outcomes Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up. Results Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced. Limitations Post hoc analysis. Conclusions Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.

Original languageEnglish (US)
Pages (from-to)244-250
Number of pages7
JournalAmerican Journal of Kidney Diseases
Volume63
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Type 2 diabetes
  • angiotensin receptor blocker
  • clinical trial
  • disease progression
  • end-stage renal disease
  • kidney disease trajectory
  • kidney end point
  • nephropathy
  • renal function

ASJC Scopus subject areas

  • Nephrology

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