Novel Albuminuria Endpoints May Improve CKD Progression Trials
Two companion meta-analyses show that early changes in albuminuria can predict the risk for end-stage renal disease.
Early changes in albuminuria can predict the risk of end-stage kidney disease (ESRD) and serve as a useful alternative endpoint for future clinical trials of drugs to slow chronic kidney disease (CKD) progression.
Current trials are often limited to patients with advanced CKD because they use clinical endpoints that occur late in the disease process, such as ESRD. The National Kidney Foundation (NKF), FDA, and European Medicines Agency (EMA) convened a 2018 scientific workshop on novel endpoints to enable intervention trials at earlier stages of CKD. Two new companion meta-analyses—one looking at randomized controlled trials (RCTs) and the other examining observational studies—stemming from the meeting have been published online ahead of print in the Lancet Diabetes & Endocrinology.
In the meta-analysis of RCTs, which included 29,979 participants and 41 treatment comparisons, Hiddo J. L. Heerspink, PharmD, of University Medical Center Groningen in Groningen, Netherlands, and colleagues found that the treatment effect on albuminuria significantly correlated with treatment effect on clinical endpoints over 6 months. Each 30% decrease in geometric mean albuminuria with treatment was associated with a significant 27% decreased risk of a composite endpoint of ESRD, estimated glomerular filtration rate (eGFR) below 15 mL/min/1.73 m2, or doubling of serum creatinine. Investigators found a stronger correlation in patients with high baseline albuminuria (urine albumin-to-creatinine ratio greater than 30 mg/g).
“When interpreted in conjunction with experimental evidence and findings from observational studies, including the companion meta-analysis of observational studies,” Dr Heerspink's team wrote, “the results of our trial-level analyses support a role for early change in albuminuria as a surrogate endpoint for progression of chronic kidney disease in clinical trials, particularly in trials with entry criteria that restrict enrollment to patients with high baseline albuminuria.”
Using a change in albuminuria as a surrogate endpoint shortens the required duration of clinical trials, “which can lead to more efficient and probably less expensive study designs,” they noted.
In the companion meta-analysis of observational studies, which included 693,816 individuals from the Chronic Kidney Disease Prognosis Consortium (CKD-PC), Josef Coresh, MD, of Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues found that a 30% decrease in albuminuria during a baseline period of 2 years was associated with a significant 22% adjusted reduction in ESRD risk. This meta-analysis also found a stronger association among patients with high baseline albuminuria.
“Change 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,” Dr Coresh and his colleagues wrote.
“These findings are reassuring with respect to the potential use of changes in albuminuria as a surrogate outcome in future trials,” Beatriz Fernandez-Fernandez, MD, PhD, Maria Dolores Sanchez-Niño, PhD, and Alberto Ortiz, MD, PhD, of Universidad Autonoma de Madrid in Madrid, Spain, commented in an accompanying editorial.
Potential sex differences merit additional attention, they wrote, adding that evidence from population-based studies suggests that the epidemiology of CKD differs by sex, with the disease being more common in women than in men.
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. DOI:10.1016/S2213-8587(18)30352-8. (Published online January 8, 2019)
Coresh 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. DOI:10.1016/S2213-8587(18)30313-9. (Published online January 8, 2019)
Fernandez-Fernandez B, Sanchez-Niño MD, Ortiz A, et al. Working towards novel albuminuria endpoints in chronic kidney disease. Lancet Diabetes Endocrinol DOI: 10.1016/S2213-8587(18)30352-8. (Published online January 8, 2019)