Traditions and innovations in assessment of glomerular filtration rate using creatinine to cystatin C

Abstract

Purpose of review: Glomerular filtration rate (GFR) is the best index for kidney function and estimated GFR (eGFR) calculated from endogenous filtration markers like serum creatinine and cystatin C is widely used in clinical practice for chronic kidney disease diagnosis and prognostication. We sought to review the evolution of GFR estimating equations, nuances of eGFR interpretation, and utility of eGFR in drug dosing.

Recent findings: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) serum creatinine eGFR equation was recently updated to exclude the race variable and the CKD-EPI creatinine-cystatin C equation demonstrated the highest reliability. Although calculated creatinine clearance by Cockcroft Gault has been traditionally used for drug dosing, the use of eGFR is slowly being adapted by the Food and Drug Administration for pharmacokinetic studies. However, the individual-level accuracy of eGFR using the CKD-EPI 2021 equations remained low, with the distribution of measured GFR at a given eGFR value spanning several CKD stages.

Summary: Although current methods of estimating GFR have improved in population measures of reliability, all have significant individual-level inaccuracies that can be an issue when clinical decision-making is contingent on the actual level of GFR. Modern methods of GFR measurements should be made widely available to enhance individualized patient decision-making.

FIGURE 1.

Serum creatinine to cystatin C ratio as a marker of health status independent of kidney function. Data from a retrospective cohort study of US veterans showing the association of low creatinine-to-cystatin C ratio (<0.75 compared to the reference group 1 to <1.25) with mortality among both Black and non-Black veterans. In contrast, a higher creatinine-to-cystatin C ratio (≥1.25) was associated with reduced mortality compared to the reference group with race affecting the strength of these associations.

FIGURE 2.

Distribution of measured GFR at selected CKD-EPI 2021 eGFR threshold for CKD Diagnosis and Staging based on four prospective US cohorts - GENOA, ECAC, ALTOLD, and CRIC. eGFR was calculated using CKD-EPIcr 2021. Selected eGFR cut-off values correspond to the thresholds for CKD diagnosis and staging. GFR was measured using urinary clearance nonradiolabeled iothalamate in GENOA and ECAC, radiolabeled iothalamate in CRIC, and plasma clearance of iohexol in ALTOLD. Each percentile value is from a separate quantile (2.5th, 10th, 25th, 50th, 75th, 90th, and 97.5th) regression model of mGFR on CKD-EPIcr 2021. Sample interpretation: at an eGFR of 30, 50% of mGFRs ranged from 27 ml/min/1.73 m² to 38 ml/min/1.73 m², 80% of mGFRs ranged from 23 ml/min/1.73 m² to 44 ml/min/1.73 m², while 95% of mGFRs ranged from 17 ml/min/1.73 m² to 54 ml/min/1.73 m². ALTOLD, Assessing Long-term Outcomes in Living Kidney Donors Study; CKD, chronic kidney disease; CRIC, Chronic Renal Insufficiency Cohort; ECAC, Epidemiology of Coronary Artery Calcification Cohort Study; GGFR, glomerular filtration rate; ENOA, Genetic Epidemiology Network of Arteriopathy Study.