Change in albuminuria as a surrogate endpoint in chronic kidney disease – Authors' reply

Abstract

The goal of our meta-analyses1Heerspink HJL Greene T Tighiouart H et al.Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials.Lancet Diabetes Endocrinol. 2019; 7: 128-139Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2Coresh J Heerspink HJL Sang Y et al.Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.Lancet Diabetes Endocrinol. 2019; 7: 115-127Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar was to better quantify the extent to which treatment effects on albuminuria predict treatment effects on the clinical endpoint (ie, kidney failure treated with dialysis or transplantation, glomerular filtration rate of <15 mL/min per 1·73 m2, or doubling of serum creatinine) in clinical trials of progression of chronic kidney disease. Our results showed a moderately strong association in the randomised trials of chronic kidney disease available to us and suggested that treatments that decrease albuminuria by 20–30% compared with placebo have a high probability of providing a clinical benefit, as reflected in a hazard ratio for the clinical endpoint of less than 1. Accordingly, we agree with Lonnie Pyne and colleagues that non-zero treatment effects on albuminuria do not always predict a treatment effect on a clinical endpoint—eg, when albuminuria is applied as a surrogate endpoint beyond its proposed context of use or when the treatment effect on albuminuria is small. The ONTARGET study3Mann JF Schmieder RE McQueen M et al.Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.Lancet. 2008; 372: 547-553Summary Full Text Full Text PDF PubMed Scopus (1333) Google Scholar was a cardiovascular outcome trial and enrolled a population with predominantly normal albuminuria. We do not recommend applying albuminuria as an endpoint in such trials, but instead in clinical trials enrolling patients with elevated albuminuria at risk of progressive chronic kidney disease.1Heerspink HJL Greene T Tighiouart H et al.Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials.Lancet Diabetes Endocrinol. 2019; 7: 128-139Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar The VA NEPHRON-D study, which we were not able to include in our meta-analysis due to unavailability of the individual participant data, assessed treatments for progression of diabetic kidney disease in participants with a high baseline level of albuminuria (>300 mg/g). When the result of the VA NEPHRON-D study4Fried LF Emanuele N Zhang JH et al.Combined angiotensin inhibition for the treatment of diabetic nephropathy.N Engl J Med. 2013; 369: 1892-1903Crossref PubMed Scopus (796) Google Scholar, 5Heerspink HJ Kropelin TF Hoekman J de Zeeuw D Drug-induced reduction in albuminuria Is associated with subsequent renoprotection: a meta-analysis.J Am Soc Nephrol. 2015; 26: 2055-2064Crossref PubMed Scopus (170) Google Scholar is added to our trial-level analysis,1Heerspink HJL Greene T Tighiouart H et al.Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials.Lancet Diabetes Endocrinol. 2019; 7: 128-139Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar the point estimate for the treatment effect on the clinical endpoint closely aligns with the predicted effect from our model (figure). Our model predicts a moderate treatment effect on the clinical endpoint in VA NEPHRON-D because the estimated placebo-corrected decrease in albuminuria in VA NEPHRON-D was also moderate, at 19%.4Fried LF Emanuele N Zhang JH et al.Combined angiotensin inhibition for the treatment of diabetic nephropathy.N Engl J Med. 2013; 369: 1892-1903Crossref PubMed Scopus (796) Google Scholar, 5Heerspink HJ Kropelin TF Hoekman J de Zeeuw D Drug-induced reduction in albuminuria Is associated with subsequent renoprotection: a meta-analysis.J Am Soc Nephrol. 2015; 26: 2055-2064Crossref PubMed Scopus (170) Google Scholar Because VA NEPHRON-D was terminated early, its statistical power for the clinical endpoint was restricted, and this moderate effect size was insufficient to reach statistical significance. This study is thus consistent with the findings of our meta-analysis and does not dismiss a role for change in albuminuria of sufficient magnitude as a surrogate endpoint for trials of progression of chronic kidney disease (figure). We agree with both Pyne and colleagues and Hai-Lu Zhao and colleagues and believe that recognition that surrogates are useful for efficacy but not for safety is important. Safety should be monitored in large studies with specific assessment of adverse events. However, the possibility exists that for drugs with a good safety profile, some of this work could be completed after conditional approval based on a surrogate outcome for efficacy. With respect to the question of competing events, we did integrate mortality as a competing event in estimating the absolute risk of end-stage kidney disease in the meta-analysis of observational studies;2Coresh J Heerspink HJL Sang Y et al.Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.Lancet Diabetes Endocrinol. 2019; 7: 115-127Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar for the slope with end-stage kidney disease associations, we believe that relative hazards are superior to relative sub-hazards, but it is reassuring that in sensitivity analyses they were similar.2Coresh J Heerspink HJL Sang Y et al.Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.Lancet Diabetes Endocrinol. 2019; 7: 115-127Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar HJLH reports grants from the US National Kidney Foundation (NFK); grants and other support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen; and other support from Astellas, Fresenius, Gilead, and Merck. JC reports grants from NFK and the US National Institutes of Health (NIH). LAI reports grants from NIH and NKF; funding from NIH, NKF, Retrophin, Omeros, and Reata Pharmaceuticals (research and contracts [Tufts Medical Center]); and consulting agreements with Tricida and Omeros. LAI also reports a provisional patent (filed Aug 15, 2014; precise estimation of glomerular filtration rate from multiple biomarkers, patent no PCT/US2015/044567), and Tufts Medical Center, John Hopkins University, and Metabolon have a collaboration agreement to develop a product to estimate glomerular filtration rate from a panel of markers. RTG reports no competing interests. Change in albuminuria as a surrogate endpoint in chronic kidney diseaseWe write in response to the publication in The Lancet Diabetes & Endocrinology of two meta-analyses addressing the potential use of change in albuminuria as a surrogate endpoint for progression of kidney disease.1,2 Full-Text PDF Change in albuminuria as a surrogate endpoint in chronic kidney diseaseThe results of two recent meta-analyses published in The Lancet Diabetes & Endocrinology lend support to change in albuminuria as a surrogate endpoint for meaningful treatment response in patients with chronic kidney disease, particularly those with high baseline albuminuria.1,2 Although the analyses have several limitations, such as unexplained heterogeneity across studies, non-standardised measurements of albuminuria across cohorts, under-representation of women and non-white ethnic groups, and potential risk of a false conclusion of clinical benefit, the consistent findings of the two meta-analyses (one of observational studies1 and one of randomised trials2) provide a solid foundation concerning how to use change in albuminuria as a surrogate endpoint for progression of chronic kidney disease. Full-Text PDF Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studiesChange in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria. Full-Text PDF Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trialsOur results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Full-Text PDF