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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Cystatin C has been shown to be a reliable and accurate marker of kidney function across diverse populations. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended using cystatin C to confirm the diagnosis of chronic kidney disease (CKD) determined by creatinine-based estimated glomerular filtration rate (eGFR) and to estimate kidney function when accurate eGFR estimates are needed for clinical decision-making. In the efforts to remove race from eGFR calculations in the United States, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN) Joint Task Force recommended increasing availability and clinical adoption of cystatin C to assess kidney function. This review summarizes the key advantages and limitations of cystatin C use in clinical practice. Our goals were to review and discuss the literature on cystatin C; understand the evidence behind the recommendations for its use as a marker of kidney function to diagnose CKD and risk stratify patients for adverse outcomes; discuss the challenges of its use in clinical practice and guide the clinicians on its interpretation.