Outcomes and Risk Factors of Widened Difference in Estimated Glomerular Filtration Rate Based on Creatinine or Cystatin C: Adjust Model Development With More Than 300,000 UK Biobank Participants

Rationale & Objective Recent studies have highlighted the clinical significance of the discrepancies between cystatin C--based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) estimated glomerular filtration rate (eGFR) (eGFRcys) and creatinine-based CKD-EPI eGFR (eGFRcr). This study explores the implications of the differences between eGFRcys and eGFRcr (eGFRdiff) on clinical outcomes and aims to develop an adjustment model using eGFRcr and associated clinical variables. Study Design Retrospective cohort study. Setting & Participants A total of 343,854 UK Biobank participants. Exposure eGFRdiff (mL/min/1.73 m 2 ): lower (eGFRcys - eGFRcr < -15), middle (-15 ≤ eGFRcys - eGFRcr ≤ 15), and upper (eGFRcys - eGFRcr > 15). Outcome Death, myocardial infarction (MI), and ischemic stroke. Analytical Approach We analyzed the risks of death, MI, and ischemic stroke in groups with eGFRdiff < -15 and eGFRdiff > 15 using Cox proportional hazards models. Logistic regression analysis was used to identify variables associated with eGFRdiff. In addition, we developed and validated a regression model using eGFRcr and variables associated with eGFRdiff to approximate eGFR with optimal performance. Results Individuals with eGFRdiff < -15 were associated with increased risks of death (HR, 1.37 [1.30-1.44]), MI (HR, 1.23 [1.15-1.33]), and ischemic stroke (HR, 1.19 [1.08-1.31]). Variables associated with eGFRdiff < -15 included high waist/hip circumference, high body weight, low fat-free mass, high fat/carbohydrate intake, low protein intake, diabetes, and smaller kidney volumes. A simplified regression model approximating eGFRcys was developed, using only eGFRcr, sex, age, height, weight, and body mass index. In the validation, applying the simplified linear model to eGFRcr significantly enhanced its correlation with eGFRcys and improved clinical outcome prediction, as demonstrated by favorable net reclassification indices for death, MI, and ischemic stroke. Limitations The absence of true GFR data. Conclusions This study confirmed that eGFRdiff < -15 is associated with increased risks of clinical outcomes and identified diverse factors associated with eGFRdiff. We developed an adjusted model to approximate eGFRcr to eGFRcys, demonstrating superior clinical outcome association using the adjusted values. Plain-Language Summary Kidney function is often estimated using blood markers such as creatinine or cystatin C. However, large gaps between these estimates can signal hidden health risks. In 343,854 UK Biobank participants, we found that those whose cystatin C–based eGFR was much lower than their creatinine-based eGFR faced higher risks of death, heart attack, and stroke. We identified body size, diet, and kidney volume factors linked to these gaps. Using these factors and creatinine-based eGFR, we built a simple regression model that closely approximates cystatin C–based eGFR and improves risk prediction. This tool can support clinicians in settings in which cystatin C testing is not available.