Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

Abstract

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R 2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m 2 per year were associated with an HR of w0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings. Complete author and article information provided before references.

Clinical Implications of Estimating Glomerular Filtration Rate with Three Different Equations among Older People. Preliminary Results of the Project “Screening for Chronic Kidney Disease among Older People across Europe (SCOPE)”

“…Determination of kidney function has been a topic of discussion among experts and may impact clinical management of patients as well as setting endpoints in future clinical studies [21]. Over the past decade, several attempts have been made to test creatinine-based mathematical models for determination of kidney function in different cohorts of patients and healthy subjects [14].…”

“…Considering albumin-to-creatinine ratio (ACR) for staging of chronic kidney disease, the picture in ageing patients in daily clinical practice becomes even more complex [21]. Albuminuria and GFR are both relevant measures of the functionality of glomeruli.…”

“…Both parameters play an important role in detection and staging of CKD. The current evidence for the validity of these two surrogate markers for prediction and progression of CKD is stronger for GFR than for change of albuminuria over time [21]. However, during ageing the sensitivity of GFR determination and mathematical models applied to measure creatinine in the available test systems are strongly impacted by muscle mass.…”

Intravenous administration of iPS‐MSCSPIONs mobilized into CKD parenchyma and effectively preserved residual renal function in CKD rat

“…9,10 Despite pharmacomodulation, continuous patient education and clinical management guidelines, renal functional deterioration is progressive for the majority of CKD patients, ultimately leading to ESRD. [11][12][13][14][15][16] These findings [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] raise the need to develop new efficacious and safe treatment modalities for CKD patients, especially when they are refractory to conventional therapy.…”

Change in Albuminuria and Estimated GFR as End Points for Clinical Trials in Early Stages of CKD: A Perspective From European Regulators

“…The data presented constitute the largest meta-analyses of data derived from observational studies and randomized controlled trials in CKD currently available, and we congratulate the investigators for this accomplishment. Before, during, and after the workshop, EMA experts were involved in reflecting on the workshop objectives, study analyses, and results and provided comments on the workshop report 1 that is published in this issue of AJKD.…”