Quantitative Analysis of a Novel Metabolite Panel to Estimate GFR (Panel eGFR) in Serum and Plasma Using LC-MS/MS

Abstract Background Estimated glomerular filtration rate (eGFR) using creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys) is not sufficiently accurate in many settings, often due to non-glomerular filtration rate (GFR) determinants of the filtration markers. In principle, using a panel of endogenous markers (panel eGFR) could reduce the impact of non-GFR determinants of each marker, improving the accuracy of eGFR. Using global untargeted metabolomics, we previously identified 33 endogenous metabolites that correlate highly with measured GFR. Methods A LC-MS/MS measurement procedure was developed to quantify 11 endogenous metabolites from serum and plasma. The assay was evaluated in 99 participants with measured GFR (mGFR) from 2 research studies, including a subgroup of 51 participants with large errors in eGFRcr and large discordance between eGFRcr and eGFRcys. Performance of eGFR models using single metabolites and all metabolites (panel eGFR-11) compared to mGFR was assessed by leave-one-out cross-validated root mean square error (RMSE). Results Assay CV for single metabolites ranged from 1.1% to 6.3% over the course of 21 days. RMSE of eGFR in single metabolite models ranged from 0.184 to 0.324. RMSEs for panel eGFR-11, eGFRcr, and eGFRcr-cys were 0.195, 0.251, and 0.201, respectively, and 0.155, 0.290, and 0.203, respectively, in the subgroup with large errors and large discordance. Conclusions A precise metabolite (LC-MS/MS) measurement procedure shows promise for more accurate GFR estimation when eGFRcr is unreliable, offering a potential new confirmatory test for GFR evaluation.