PracticeUpdate Diabetes March 2019

EDITOR’S PICKS 8

Change in Albuminuria as a Surrogate Endpoint for Progression of Kidney Disease The Lancet Diabetes & Endocrinology Take-home message • The authors performed a meta-analysis to determine whether albuminuria may be a surrogate endpoint for progression of chronic kidney disease in future randomized controlled trials. Patient-level data were available for 29,979 participants (71% with diabetes) from 41 eligible randomized trials. With a mean follow-up of 3.4 years, 3935 participants (13%) reached the composite clinical endpoint of treated end-stage kidney disease, eGFR <15 mL/min per 1.73 m 2 , and doubling of serum creatinine. The authors demonstrated, with a meta-regression analysis (slope, 0.89), that hazard ratios for the clinical endpoint were 27% lower for each 30% decrease in geometric mean albuminuria. • The results indicate that albuminuria may be a useful surrogate endpoint for the progression of chronic kidney disease, and it is of particular value among patients with high baseline albuminuria. I ncreased levels of urinary albumin excretion are a hallmark of many forms of kid- ney disease. One challenge for the renal community and for clinicians has been the need to have robust data supporting the reduction of albuminuria to improve kidney outcomes. Coresh and colleagues examined the association between albuminuria and devel- opment of end-stage kidney disease (ESKD) in nearly 700,000 individuals from 28 observational cohort studies. 1 In patients with a baseline albumin to creatinine ratio of 300 mg/g or higher, they found that a 30% reduction in albuminuria over 1, 2, or 3 years was linked to an approximate 20% relative reduction in ESKD. This is greater than a 1% absolute reduction in the 10-year risk of ESKD. The companion study led by Dr. Heerspink performed a similar analysis on nearly 30,000 individuals entered into randomized studies and found very similar results. 2 A 30% decrease in albuminuria with treatment led to a 27% reduction in a pooled out- come of ESKD, estimated glomerular filtration rate of <15 mL/min/1.73m 2 , or doubling of serum creatinine. They found the higher the baseline level of albuminuria, the greater the protective effect of lowering albuminuria was on the pooled clinical outcomes. The results of these two large meta-analyses examining both observation and rand- omized study results provide high confidence that lowering albuminuria is a prudent clinical approach to reducing the risk of progressive kidney disease. References 1. Coresh J, Heerspink HJL, Sang Y, et al. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortiummeta-analysis of observational studies. Lancet Diabetes Endocrinol 2019 Jan 8. doi: 10.1016/S2213-8587(18)30313-9. [Epub ahead of print.] 2. Heerspink 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 Jan 8. doi: 10.1016/S2213-8587(18)30314-0. [Epub ahead of print.] COMMENT By Keith C. Norris MD, PhD

Abstract BACKGROUND Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lack- ing. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrogate endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. METHODS In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease”, “chronic renal insufficiency”, “albuminuria”, “proteinuria”, and “randomized controlled trial”; key inclu- sion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the com- posite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m 2 , or dou- bling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and devel- oped a prediction model for the treatment effect on the clinical endpoint on the basis of the treat- ment effect on albuminuria.

Dr. Norris is a Professor in the Division of General Internal Medicine at David Geffen School of Medicine at UCLA in Los Angeles, California.

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