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Am J Kidney Dis. 2016 Sep;68(3):392-401. doi: 10.1053/j.ajkd.2016.02.042. Epub 2016 Mar 29.

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

Author information

1
Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address: linker@tuftsmedicalcenter.org.
2
Division of Nephrology, Tufts Medical Center, Boston, MA.
3
Division of Epidemiology, University of Utah, Salt Lake City, UT.
4
Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
5
Renal, Dialysis & Transplant Unit, University of Bari, Bari, Italy.
6
National Fukuoka Higashi Medical Center, Koga City, Fukuoka, Japan.
7
The Glomerular Kidney Disease Center, Columbia University College of Physicians and Surgeons, New York, NY.
8
Department of Nephrology, AZ Delta, Roeselare, Belgium.
9
Department of Medicine, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong, China.
10
Nephrology, Department of Medicine, Hospital Universitario 12 de Octubre, Complutense University, Madrid, Spain.
11
Pharmalink AB, Stockholm, Sweden.
12
KJC Statistics Ltd and University of Sheffield, Sheffield, United Kingdom.
13
Department of Biostatistics and Center for Evidence Based Medicine, Brown University School of Public Health, Providence, RI.

Abstract

BACKGROUND:

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.

KEYWORDS:

IgA nephropathy (IgAN); Proteinuria; clinical end point; disease progression; end-stage renal disease (ESRD); glomerulonephritis; kidney disease; meta-analysis; prognostic marker; surrogate endpoint; urine protein

PMID:
27032886
DOI:
10.1053/j.ajkd.2016.02.042
[Indexed for MEDLINE]

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