Association of Intraindividual Difference in Estimated Glomerular Filtration Rate by Creatinine vs Cystatin C and End-stage Kidney Disease and Mortality

Abstract

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...

Advantages, Limitations, and Clinical Considerations in Using Cystatin C to Estimate GFR

“…These differences between eGFRcr and eGFRcys are prognostic of ESKD, hospitalization, CVD, and mortality. [39][40][41] For an individual patient, the interpretation of the various eGFR estimates is crucial for clinical decisionmaking. Below, we present cases that highlight such clinical scenarios.…”

“…Emerging research implicates that CysC may have additional value when measured longitudinally within an individual and in the context of transplant nephrology. Chen et al 39 has shown that among individuals with CKD, those with faster decline in eGFRcys relative to eGFRcr had higher risk of progression to ESKD and mortality compared to individuals in whom the two eGFRs declined in parallel.…”

“…Individuals with eGFRcys values that were much lower than eGFRcr values generally were older, had a greater comorbidity burden, and had more proteinuria than individuals who had concordant or higher eGFRcys values relative to eGFRcr values. These differences between eGFRcr and eGFRcys are prognostic of ESKD, hospitalization, CVD, and mortality (39)(40)(41). For an individual patient, the interpretation of the various eGFR estimates is crucial for clinical decision making.…”

“…Emerging research implicates that CysC may have additional value when measured longitudinally within an individual and in the context of transplant nephrology. Chen et al (39) have shown that among individuals with CKD, those with a faster decline in eGFRcys relative to eGFRcr had higher risk of progression to ESKD and mortality compared with individuals in whom the two eGFRs declined in parallel. If replicated by other studies, these findings suggest that CysC may identify individuals whose CKD progression could be underappreciated due to the stability of sCr in the setting of worsening overall health.…”

Accuracy of GFR Estimating Equations in Patients with Discordances between Creatinine and Cystatin C-Based Estimations

“…Recent evidence suggests that there are often large discrepancies between eGFR solely based on creatinine (eGFR cr ) and that based on cystatin C (eGFR cys ). [7][8][9][10] Studies have suggested that intraindividual discrepancies between eGFR cys and eGFR cr are associated with adverse outcomes, 7,9,11 with a worse prognosis for individuals who have an eGFR cys that is lower than eGFR cr . However, it is unknown whether this difference reflects better estimation of GFR or merely captures additional confounders (e.g., inflammation).…”