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IMPORTANCEAs cystatin C is increasingly adopted to estimate glomerular filtration rate (eGFR), clinicians will encounter patients in whom cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr) differ widely. The clinical implications of these differences, eGFRdiff cys-cr , are unknown. OBJECTIVE To evaluate the associations of eGFRdiff cys-cr with end-stage kidney disease (ESKD) and mortality among individuals with chronic kidney disease (CKD). DESIGN, SETTING, AND PARTICIPANTSThis is a prospective cohort study of 4956 individuals with mild to moderate CKD from 7 clinical centers in the United States who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 to 2018. Statistical analyses were completed in December 2021.EXPOSURES eGFRdiff cys-cr (eGFRcys − eGFRcr) was calculated at baseline and annually thereafter for 3 years. Because 15 mL/min/1.73 m 2 represents a clinically meaningful difference in eGFR that also distinguishes CKD stages, eGFRdiff cys-cr was categorized as: less than −15 mL/min/1.73 m 2 , −15 to 15 mL/min/1.73 m 2 , and 15 mL/min/1.73 m 2 or greater. MAIN OUTCOMES AND MEASURESThe outcomes of ESKD, defined as initiation of maintenance dialysis or receipt of a kidney transplant, and all-cause mortality were adjudicated from study entry until administrative censoring in 2018. RESULTS Among 4956 participants with mean (SD) age of 59.5 (10.5) years, 2152 (43.4%) were Black, 515 (10.4%) were Hispanic, and 2113 (42.6%) were White. There were 2156 (43.5%) women and 2800 (56.5%) men. At baseline, eGFRcys and eGFRcr values differed by more than 15 mL/min/ 1.73 m 2 in one-third of participants (1638 participants [33.1%]). Compared with participants with similar baseline eGFRcys and eGFRcr (eGFRdiff cys-cr −15 to 15 mL/min/1.73 m 2 ), those in whom eGFRcys was substantially lower than eGFRcr (eGFRdiff cys-cr < −15 mL/min/1.73 m 2 ) had a higher risk of mortality (hazard ratio [HR], 1.86; 95% CI, 1.40-2.48) while those with eGFRdiff cys-cr of 15 mL/min/1.73 m 2 or greater had lower risks of ESKD (subHR [SHR], 0.73; 95% CI, 0.59-0.89) and mortality (HR, 0.68; 95% CI, CI 0.58-0.81). In time-updated analyses, participants with eGFRdiff cys-cr less than −15 mL/min/1.73 m 2 had higher risks of ESKD (SHR, 1.83; 95% CI, 1.10-3.04) and mortality (HR, 3.03; 95% CI,) compared with participants with similar eGFRcys and eGFRcr.Conversely, participants with eGFRdiff cys-cr of 15 mL/min/1.73 m 2 or greater had lower risks of ESKD (SHR, 0.50; 95% CI, 0.35-0.71) and mortality (HR, 0.58; 95% CI, 0.45-0.75). Longitudinal changes in eGFRdiff cys-cr were associated with mortality risk. Compared with participants who had similar slopes by eGFRcys and eGFRcr, those with smaller eGFRcr declines had an 8-fold increased mortality risk (continued) Key Points Question Are differences between estimated glomerular filtration rate by cystatin C (eGFRcys) vs creatinine (eGFRcr) associated with the risk of end-stage kidney disease (ESKD) and mortality among individuals with chronic kidney disease (CKD)? F...

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