Discordance Between Creatinine- and Cystatin-C-Based EGFR As A Predictor Of Frailty, Cardiovascular Events and Mortality in Patients With Diabetes

Abstract

Background: Estimated glomerular filtration rate (eGFR) is central to the assessment of kidney disease in diabetes, but creatinine- and cystatin-C-based equations do not always classify an individual similarly. This discordance may contain clinical information beyond the absolute eGFR value. Creatinine is influenced by muscle mass and creatinine generation, whereas cystatin C is influenced by several non-GFR determinants including inflammation, adiposity, thyroid status and corticosteroid exposure. Consequently, a markedly lower cystatin-C-based eGFR than creatinine-based eGFR may identify a phenotype of reduced physiologic reserve that is not fully captured by conventional creatinine-based kidney staging.

Objective: To determine whether discordance between creatinine-based eGFR (eGFRcr) and cystatin-C-based eGFR (eGFRcys) is associated with frailty, incident cardiovascular events and all-cause mortality among adults with diabetes, and to determine whether discordance provides incremental prognostic information beyond conventional kidney-function measures and established cardiovascular risk factors.

Methods: This proposed prospective cohort study will enroll adults with diabetes with contemporaneous serum creatinine and cystatin C measurements. eGFR will be calculated using validated contemporary equations, preferably the 2021 CKD-EPI creatinine and cystatin-C equations and the combined creatinine-cystatin-C equation where applicable. The principal exposure will be negative discordance, defined a priori as eGFRcys at least 30% lower than eGFRcr; absolute and alternative relative thresholds will be examined in sensitivity analyses. Frailty will be assessed using a validated instrument, and participants will be followed for cardiovascular events and mortality. Multivariable Cox and logistic regression models will evaluate associations after adjustment for age, sex, diabetes duration, albuminuria, kidney function, cardiovascular risk factors and relevant non-GFR determinants.

Conclusion: The study is designed to test whether eGFR discordance is a clinically meaningful phenotype in diabetes. Current evidence supports an association between lower eGFRcys relative to eGFRcr and adverse outcomes, but the optimal discordance threshold and the mechanisms linking discordance to frailty remain incompletely established. The proposed study therefore treats discordance as a prognostic exposure rather than assuming that it represents a direct measurement of measured GFR.