Change in Proteinuria or Albuminuria as a Surrogate for Cardiovascular and Other Major Clinical Outcomes: A Systematic Review and Meta-analysis

Abstract

Background: There is ongoing controversy around the surrogacy of proteinuria or albuminuria, particularly for cardiovascular (CV) outcomes, which remain the leading cause of morbidity and mortality among patients with chronic kidney disease. We performed a systematic review and meta-analysis of the literature to assess the surrogacy of changing proteinuria or albuminuria for CV events, end-stage renal disease (ESRD), and all-cause mortality.

Methods: CENTRAL, EMBASE, and MEDLINE were searched (from inception to October 2017). All randomized controlled trials in adults that reported change in proteinuria or albuminuria and ≥ 10 CV, ESRD, or all-cause mortality events were included. We calculated treatment effect ratios (TERs), defined as the ratio of the treatment effect on a clinical outcome and the effect on the change in the surrogate outcome. TERs close to 1 indicate greater agreement between the clinical outcome and changing proteinuria or albuminuria.

Results: Thirty-six trials were included in the meta-analysis. We observed inconsistent treatment effects for proteinuria and CV events (20 trials; TER 1.11 [95% confidence interval (CI), 1.01-1.22]) with moderate heterogeneity (I² = 51%, P = 0.005). Treatment effects on proteinuria or albuminuria were also inconsistent with the effects on all-cause mortality (21 trials; TER 1.17 [95% CI, 1.07-1.28]; I² = 35%, P for heterogeneity = 0.06), although they were similar with the effects on ESRD (23 trials; TER 0.99 [95% CI, 0.88-1.13]; I² = 9%, P for heterogeneity = 0.337).

Conclusions: Change in proteinuria or albuminuria might be a suitable surrogate outcome for ESRD. However, overall treatment effects on these potential surrogates are inconsistent and overestimate the treatment effects on CV events and all-cause mortality.