Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis

Abstract

Background: It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease.

Study design: Meta-analysis of individual patient-level data.

Setting & population: Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types.

Selection criteria for studies: Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least 1 further year of follow-up for the clinical outcome.

Predictor: Early change in proteinuria.

Outcomes: Doubling of serum creatinine level, end-stage renal disease, or death.

Results: Early decline in proteinuria was associated with lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from -7.0% (95%CI, -40.6% to 26.7%) to 43.9% (95%CI, 25.3% to 62.6%) across 5 intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the 2 end points agreeing for 4 of the 5 intervention types. The pooled treatment effects on both end points were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine whether differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies.

Limitations: Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials.

Conclusions: These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate end point, but do not provide sufficient evidence to establish its validity in all settings.

Keywords: Proteinuria; disease trajectory; end-stage renal disease (ESRD); kidney disease progression; prognostic marker; surrogate endpoint.