Frailty in Adults with Chronic Kidney Disease and Validation of the Kidney Failure Risk Equation in Frailty Sub-Groups

Background and hypothesis: Frailty is common amongst adults with chronic kidney disease (CKD) and its presence can influence clinical outcomes such as advancing CKD and mortality. Clinical guidelines recommend the use of the Kidney Failure Risk Equation (KFRE) to guide management of CKD. Our aim was to validate KFRE by frailty status and assess whether model performance could be improved by using cystatin based estimated glomerular filtration rate (eGFR) equations and to assess the impact of accounting for competing mortality risk. Methods: We studied adults from the prospective research cohort UK Biobank with CKD G3-5 (eGFR <60mL/min/1.73m 2 ) by any of the three CKD-EPI consortium eGFR equations: eGFR creatinine (eGFRcr), eGFR cystatin (eGFRcys) and eGFR creatinine-cystatin (eGFRcr-cys)). Frailty was assessed by a modified frailty phenotype and two cumulative deficit frailty indices. Kidney failure was defined as long-term dialysis or kidney transplantation. Model assessment included discrimination, calibration and overall fit at two- and five-years. Results: The prevalence of frailty by one or more measures was 35% (N=8,533). Those classed as frail had a higher discrepancy between eGFRcys and eGFRcr compared to the non-frail group (-15.8 vs -6.9 ml/min/1.73m 2 ). Discrimination of KFRE was good (area under receiver operating characteristic curve ≥0.88 across all frailty sub-groups and eGFR equations). Kidney failure at five years was under-estimated in individuals with frailty (observed/expected (O/E) ratio 1.70; 95% CI 1.55-1.85). Calibration-in-the-large improved when eGFRcr was replaced by eGFRcys (five-years O/E ratio 1.20; 95%CI 1.05-1.35). Overestimation of kidney failure risk in analyses that do not account for competing mortality risk compared to those that do, was most apparent in the frailty group and the higher KFRE predicted risk groups. Conclusion: KFRE under-estimates kidney failure risk for individuals with CKD and frailty. Risk prediction improved for those with frailty when cystatin-based eGFR equations are utilized and when analyses account for competing risk of mortality. These factors should be considered when KFRE calculation is used in clinical practice in individuals with frailty.