eGFR Based on Creatinine, Cystatin C May Offer Better CKD Threshold for Older Adults

Findings from a recent population-based cohort study in Sweden are supporting the need for age-adapted definitions of chronic kidney disease (CKD), highlighting the inadequacies of the current estimated glomerular filtration rate (eGFR) threshold in older adults.¹

Results showed eGFR based on creatinine and cystatin C levels (eGFR_cr-cys) < 60 mL/min/1.73 m2 was more strongly associated with adverse outcomes than low eGFR on the basis of creatinine level (eGFR_cr) alone, suggesting the broad range of risks associated with CKD at older age is more accurate when cystatin C is included in GFR estimation.¹

Although the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by GFR, obtaining an accurate measurement is challenging and ultimately impractical for both clinicians and patients. Instead, a formula is often used to estimate GFR and determine the stage of kidney disease. However, currently accepted cutoffs for CKD may not be appropriate for older adults and suggest the potential need for age-adapted definitions of kidney disease.²

“eGFR_cr levels of 60 mL/min/1.73 m2 or lower are less strongly associated with adverse outcomes in older adults than in young persons. This has led to substantial debate about the appropriateness of the current GFR threshold to define CKD in older adults,” wrote Shoshana Ballew, PhD, research associate professor at New York University Grossman School of Medicine, and colleagues.¹

Seeking to provide evidence for a revised definition and new staging of CKD in older adults, investigators examined associations between eGFR_cr-cys versus eGFR_cr with various clinical outcomes in adults ≥ 65 years of age receiving routine care in Sweden. Data was obtained from the Stockholm CREAtinine Measurements (SCREAM) project, which contains information about healthcare utilization for residents of Stockholm, Sweden, between 2006 and 2019.¹

A total of 82,154 SCREAM participants ≥ 65 years of age with same-day routine outpatient tests for creatinine and cystatin C between January 1, 2010, and December 31, 2018, were included in the present study.¹

The primary study exposures were eGFR_cr and eGFR_cr-cys, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equations. For comparisons with previous studies, investigators also evaluated eGFR_cys, calculated using the CKD-EPI 2012 equation. Covariates of interest included age, sex, hypertension, diabetes, history of cardiovascular disease, anti-hypertensive medication use, total and high-density lipoprotein cholesterol level, and urinary albumin–creatinine ratio.¹

The study outcomes were all-cause mortality; cardiovascular mortality; kidney failure with replacement therapy; all-cause hospitalization; and hospitalization with infection, myocardial infarction or stroke, heart failure, or acute kidney injury (AKI).¹

In the cohort with creatinine and cystatin C tests (n = 82,154), the mean age was 77 years and 50% of participants were female, 41% had a history of cardiovascular disease, and 25% had diabetes.¹

Over a median follow-up of 3.9 (Interquartile range [IQR], 2.0-6.2) years, 31,219 participants died, 9654 due to cardiovascular causes, and 841 progressed to kidney failure with replacement therapy. Counting first events only, investigators observed 51,096 hospitalizations, including 26,754 with infections, 16,074 with heart failure, 8549 with myocardial infarction or stroke, and 5014 with AKI.¹

Investigators noted lower eGFR_cr and eGFR_cr-cys were associated with increased hazard and incidence rate ratios across all study outcomes. Additionally, eGFR_cr-cys and eGFR_cys were more strongly associated with outcomes than eGFR_cr.¹

Absolute incidence rates for all events except kidney failure with replacement therapy and AKI were greater among persons 70 and 80 years of age. Investigators also pointed out the absolute incidence rates for all outcomes were increased with lower eGFR_cr-cys.¹

Use of eGFR_cr-cys versus eGFR_cr resulted in the reclassification of 31.2% of study participants, predominantly for those ≥ 75 years of age and to a more severe GFR category. Among those with eGFR_cr between 60 and 89 mL/min/ 1.73 m2, 24.0% were reclassified to 45 to 59 mL/min/1.73 m2 with eGFR_cr-cys. Additionally, 33.4% of those with eGFR_cr between 30 and 44 mL/min/1.73 m2 were reclassified to 15 to 29 mL/min/1.73 m2 with eGFR_cr-cys.¹

“The significance of this study is that it sheds light on the possibility that we are measuring more than kidney function with CKD staging. As we have more tools in the toolbox to consider management within the framework of cardio-vascular-kidney-metabolic syndrome, it is timely to gain insight on the appropriate use of kidney bio-markers in what is likely multisystemic disease, particularly in the aging population,” wrote Crystal Gadegbeku, MD, chair of the department of nephrology in the Glickman Urological and Kidney Institute of the Cleveland Clinic Health System, in an accompanying editorial.³

References:

1. Fu EL, Carrero JJ, Sang Y, et al. Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C. Ann Intern Med. https://doi.org/10.7326/M23-1138
2. National Kidney Foundation. Estimated Glomerular Filtration Rate (eGFR). Accessed January 30, 2024. https://www.kidney.org/atoz/content/gfr
3. Nakhoul GN, Gadegbeku CA. Glomerular Filtration Estimating Equations and Clinical Outcomes: What Are We Measuring? Ann Intern Med. doi:10.7326/M24-0111