Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis

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• 作者：Lesley A. Inker ; MD ; MS¹ ; ^{linker@tuftsmedicalcenter.org" class="auth_mail" title="E-mail the corresponding author} ; Hasi Mondal ; MPH¹ ; Tom Greene ; PhD² ; Taylor Masaschi ; BA¹ ; Francesco Locatelli ; MD³ ; Francesco P. Schena ; MD⁴ ; Ritsuko Katafuchi ; MD⁵ ; Gerald B. Appel ; MD ; PhD⁶ ; Bart D. Maes ; MD⁷ ; Philip K. Li ; MD⁸ ; Manuel Praga ; MD⁹ ; Lucia Del Vecchio ; MD³ ; Simeone Andrulli ; MD³ ; Carlo Manno ; MD⁴ ; Eduardo Gutierrez ; MD⁹ ; Alex Mercer ; PhD¹⁰ ; Kevin J. Carroll ; PhD¹¹ ; Christopher H. Schmid ; PhD¹² ; Andrew S. Levey ; MD¹
• 关键词：Proteinuria ; urine protein ; surrogate endpoint ; IgA nephropathy (IgAN) ; end-stage renal disease (ESRD) ; prognostic marker ; clinical end point ; disease progression ; kidney disease ; glomerulonephritis ; meta-analysis
• 刊名：American Journal of Kidney Diseases
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：68
• 期：3
• 页码：392-401
• 全文大小：407 K

文摘

The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated.

Study Design

Individual patient–level meta-analysis.

Setting & Population

Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels.

Selection Criteria for Studies

Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome.

Predictor

9-month change in proteinuria.

Outcome

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

Results

Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, −19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32).

Limitations

Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events.

Conclusions

Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.