Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

Abstract

RATIONALE & OBJECTIVE:

An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.

STUDY DESIGN:

Individual patient-level meta-analysis.

SETTING & STUDY POPULATIONS:

Individual data of 1,037 patients from 12 randomized trials.

SELECTION CRITERIA FOR STUDIES:

Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome.

ANALYTICAL APPROACH:

For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria.

RESULTS:

Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years.

LIMITATIONS:

Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions.

CONCLUSIONS:

These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

• Authors: Lesley A Inker, Hiddo J L Heerspink, Hocine Tighiouart, Juhi Chaudhari, Shiyuan Miao, Ulysses Diva, Alex Mercer, Gerald B Appel, James V Donadio, Jürgen Floege, Philip K T Li, Bart D Maes, Francesco Locatelli, Manuel Praga, Francesco P Schena, Andrew S Levey, Tom Greene
• Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation (Am J Kidney Dis) Vol. 78 Issue 3 Pg. 340-349.e1 (09 2021) ISSN: 1523-6838 [Electronic] United States
• PMID: 33775708 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Creatinine

Topics

• Bayes Theorem
• Creatinine (metabolism)
• Disease Management
• Disease Progression
• Glomerular Filtration Rate (physiology)
• Glomerulonephritis, IGA (physiopathology, therapy, urine)
• Humans
• Research Design
• Urinalysis