Combining Cystatin C and Creatinine Increases eGFR Slope Accuracy in ADPKD

Introduction In Autosomal Dominant Polycystic Kidney Disease (ADPKD) trials, creatinine-based estimated glomerular filtration rate (eGFR cr ) is a key endpoint, but variability in creatinine measurements may affect reliability. We compared routine eGFR cr to eGFR derived from batch-measured creatinine, cystatin C (eGFR cys ), or both (eGFR cr-cys ) using biobanked samples, against iothalamate-measured GFR (mGFR). Methods In 260 ADPKD patients from the DIPAK observational cohort, we compared 2021 CKD-EPI based eGFR based on (1) routine clinical creatinine, (2) batch-measured creatinine, and (3) batch-measured cystatin C to mGFR. Creatinine and cystatin batch measurements were performed on the same day to minimize variability. Cross-sectional performance was evaluated by bias (eGFR – mGFR), precision, accuracy (P30/P10), and CKD stage agreement. Longitudinal agreement between mGFR and eGFR slopes (ml/min/1.73m 2 /year) was assessed using concordance correlation coefficients (CCC). Sample size requirements for hypothetical trials were calculated based on slope variability. Results Cross-sectional performance of batch-measured eGFR cr was largely similar to routine eGFR cr . eGFR cys and eGFR cr-cys showed greater bias compared to eGFR cr , but eGFR cr-cys showed the highest precision. Longitudinally, batch-measured eGFR cr-cys slopes correlated more strongly with mGFR decline than eGFR cr (CCC 0.68 [95% CI: 0.59, 0.76] vs. 0.58 [95% CI: 0.47, 0.67]; p =0.02). eGFR cr-cys slopes also exhibited lower standard deviations compared to eGFR cr and eGFR cys . This reduction in slope variability translated to sample size reductions of 37-38% for clinical trials. Conclusions The use of eGFR cr-cys enhances precision and reduces eGFR slope variability. Using combined creatinine-cystatin C estimates may optimize trial efficiency and design in ADPKD.