Title: Predicting the 2- and 5-year risk of kidney failure for patients with chronic kidney disease in the United Kingdom: external validation and update of the Kidney Failure Risk Equation
Funder: Department of Health and Social Care

Abstract: Background One in ten UK adults has chronic kidney disease (CKD). CKD may progress to kidney failure, requiring dialysis or a kidney transplant. Identifying CKD patients at the highest risk of kidney failure facilitates the early implementation of risk-reducing interventions and renal referral. A patient's risk can be estimated using the Kidney Failure Risk Equation (KFRE), predicting their risk of kidney failure at 2 and 5 years. An update of the NICE CKD guideline to be published in August 2021 will recommend using KFRE to counsel patients about their risk of kidney failure and for general practitioners to refer patients with a >5% 5-year risk to renal services. However, previous work suggests KFRE, which was developed in Canada, is miscalibrated when predicting kidney failure risk for UK patients. Further, its predictive performance in patients from minority ethnic groups is uncertain. KFRE must therefore be validated, including for patients from minority ethnic groups, and updated before it is used to counsel UK CKD patients and make referral decisions, as NICE will recommend. Our research will aim to achieve this. Objectives Validate the predictive performance of KFRE for UK CKD patients, overall and by ethnicity. Update KFRE, optimising risk prediction for UK CKD patients (the updated model is termed KFRE-UK). Externally validate KFRE-UK and compare it to KFRE, overall and by ethnicity. If KFRE-UK has superior predictive performance, disseminate it for patients and healthcare professionals (HCP). Methods Adults with CKD and no history of kidney failure will be included from three large UK databases of anonymised primary care records (1. Clinical Practice Research Datalink [CPRD] Aurum, 40 million patients; 2. CPRD GOLD, 20 million patients; 3. Secure Anonymised Information Linkage [SAIL], 3 million patients). First, KFRE will be externally validated and updated using CPRD Aurum. External validation for predicting kidney failure at 2 and 5 years will include assessment of discrimination (time-dependent C-statistics), calibration (calibration plots and curves, calibration-in-the-large, calibration slope), and clinical utility (net benefit and decision curves). KFRE will be updated (producing KFRE-UK) by re-estimating the baseline hazard and regression coefficients (using a Fine and Gray subdistribution model to account for the competing risk of death). Further, additional predictors (ethnicity, diabetes status, or both) will be included in KFRE-UK if they improve predictive performance. KFRE-UK will then be independently and externally validated, as above, by separate researchers in CPRD GOLD and SAIL, comparing its performance to KFRE, both overall and by ethnicity. Anticipated Impact and Dissemination KFRE-UK will be published in an open-access peer-review journal and presented at the major UK renal conference. In addition, we will make it available to patients and HCPs as a user-friendly Web calculator and maximise awareness with communications via leading UK kidney organisations. Further, we would communicate with NICE and seek KFRE-UK to replace KFRE as the recommended prediction model in its guideline. For UK CKD patients, KFRE-UK will facilitate more accurate risk counselling and stratified medicine, helping ensure high-risk patients receive early risk-reducing interventions, nephrology referrals, and timely preparation for dialysis or transplantation.

Lay abstract: Background Kidney disease affects 1 in 10 adults in the UK. Some kidney patients develop kidney failure, meaning they need dialysis or a transplant. However, until recently, it was difficult to predict which kidney patients might be affected. A tool called the Kidney Failure Risk Equation (KFRE), developed in Canada, has now made it possible to predict a patient's chance of kidney failure. New guidelines suggest doctors use KFRE to: inform kidney patients about their kidney failure risk refer people at high risk to a kidney specialist. However, KFRE has not been thoroughly tested on UK kidney patients or patients from minority ethnic groups. Our research will address this. Aims Assess how accurate KFRE is for UK kidney patients and patients from minority ethnic groups. Update KFRE to try to improve it (we call the new version KFRE-UK). Compare KFRE-UK to KFRE for UK kidney patients, including patients from minority ethnic groups. If KFRE-UK is more accurate, make it available for patients and doctors. Design and methods We will use three databases of primary care records, covering around 20% of the UK population. These databases have been designed to provide anonymised data for approved research. We will only include data from patients with kidney disease. We will use one database to test the accuracy of KFRE and try to improve it (creating KFRE-UK). KFRE-UK will then be thoroughly tested by checking its accuracy and comparing it to KFRE in two separate databases. Patient and public involvement A group of kidney patients helped plan this research. Whether and when they develop kidney failure is a major concern for them, so they would value a model that could accurately assess their risk. They also suggested other factors, such as diabetes, they would like us to consider. Patients will continue to be involved in this research to make sure KFRE-UK is widely accessible, easy to use, and provides clear, understandable information. They will also influence how doctors use KFRE-UK for patient care. Dissemination and impact KFRE-UK will help patients understand their kidney failure risk. It will also help doctors identify high-risk patients to start treatments early and refer them to a kidney specialist. Thus, KFRE-UK should help improve care for kidney patients, lower their chance of kidney failure, and cut NHS costs. We will make KFRE-UK freely available for kidney patients and doctors on a patient-friendly website with an easy-to-use calculator. In addition, we will use awareness campaigns to reach as many patients as possible. We will also publish KFRE-UK in a journal that is free to access, raise doctors' awareness of it at kidney conferences, and seek to get it included in medical guidelines.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL