The Validity of Drug Effects on Proteinuria, Albuminuria, Serum Creatinine, and Estimated GFR as Surrogate End Points for ESKD: A Systematic Review

Abstract

Rationale & objective: Proteinuria, albuminuria, and serum creatinine level are widely used as surrogate end point measures of end-stage kidney disease (ESKD). We evaluated the correlation between antihypertensive drug effects on surrogate renal end points and ESKD.

Study design: Systematic review.

Setting & participants: Randomized controlled trials of blood pressure-lowering therapy.

Selection criteria for studies: Trials of pharmacological blood pressure-lowering strategies reporting drug effects on albuminuria, proteinuria, or serum creatinine level and ESKD through March 26, 2018.

Analytical approach: Bayesian bivariate meta-analysis to calculate correlations between drug effects on surrogate end points and drug effects on ESKD. Risks of bias were adjudicated using the Cochrane tool.

Results: 22 randomized controlled trials involving 69,642 participants were eligible. Risks of bias in the included trials were frequently unclear due to incomplete reporting. Relative risk for ESKD was statistically significant in 1 of 29 (3.4%) treatment comparisons. There appeared to be little or no correlation between antihypertensive drug effects on serum creatinine level, albuminuria, proteinuria, and the corresponding effects on ESKD. All correlations had wide 95% credible intervals that included the null effect.

Limitations: Low power due to infrequent outcomes of ESKD and incomplete data reporting in primary trials.

Conclusions: The association between antihypertensive drug effects on doubling of serum creatinine level and albuminuria or proteinuria with ESKD in treatment trials is not sufficiently certain to enable the confident use of these markers to guide clinical or regulatory decision making.

Keywords: Bayesian bivariate meta-analysis; Kidney disease; albuminuria; antihypertensive; blood pressure medication; dialysis; end-stage kidney disease (ESKD); estimated glomerular filtration rate (eGFR); patient-centered outcomes (PCO); proteinuria; serum creatinine; surrogate endpoint; systematic review.