Purpose of review
There is a paucity of therapies for chronic kidney disease (CKD), in part because of the slow nature of the disease which poses challenges in selection of endpoints in randomized controlled trials (RCT). There is increasing evidence for the use of glomerular filtration rate (GFR)-based endpoints either as percentage decline using time-to-event analyses, or as difference in slope between treatment arms. We reviewed the rationale for using surrogate endpoints and optimal methods for their evaluation prior to their use and evidence for GFR-based endpoints and particularly GFR slope as validated surrogate endpoints and considerations for their use in RCTs.
Recent findings
In an individual patient meta-analysis of 47 studies (60 620 participants), treatment effects on the clinical endpoint were accurately predicted from treatment effects on 3-year total slope [median R
2 = 0.97 (95% Bayesian confidence interval (BCI), 0.78–1.00] and on the chronic slope [R
2 = 0.96 (95% BCI, 0.63–1.00)]. In a simulation study, GFR slope substantially reduced the required sample size and duration of follow-up compared to the clinical endpoint given high baseline GFR and absence of acute treatment effect. In the presence of acute effect, results were more complicated.
Summary
GFR decline is accepted, and GFR slope is being considered, by regulatory authorities as a validated surrogate endpoint for CKD RCTs.
Background
Establishment and improvement of glomerular filtration rate estimating equations requires accurate and precise laboratory measurement procedures (MPs) for filtration markers. The Advanced Research and Diagnostic Laboratory (ARDL) at the University of Minnesota, which has served as the central laboratory for the Chronic Kidney Disease Epidemiology Collaboration since 2009, has implemented several quality assurance measures to monitor the accuracy and stability of filtration marker assays over time.
Methods
To assess longitudinal stability for filtration marker assays, a 40-sample calibration panel was created using pooled serum, divided into multiple frozen aliquots stored at −80 °C. ARDL monitored 4 markers—creatinine, cystatin C, beta-2-microglobulin (B2M) and beta-trace protein—measuring 15 calibration panel aliquots from 2009 to 2019. Initial target values were established using the mean of the first 3 measurements performed in 2009–10, and differences from target were monitored over time. New MPs for cystatin C and B2M were added in 2012, with target values established using the first measurement.
Results
The mean percentage difference from mean target values across time was <2% for all original MPs (−0.59% for creatinine; −0.94% for cystatin C; −0.82% for B2M; 1.24% for beta-trace protein).
Conclusions
Close monitoring of filtration marker trends with a calibration panel at ARDL demonstrates remarkable long-term stability of the MPs. Routine use of a calibration panel for both research studies and clinical care is recommended for filtration markers where longitudinal monitoring is important to detect analytical biases, which can mask or confound true clinical trends in patients.
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