Title: COVID-19 survivors and kidney disease: The long term effects on kidney function, and health outcomes for people with pre-existing chronic kidney disease - a study using electronic health records
Funder: Department of Health and Social Care

Abstract: Research question What is the long-term impact of COVID-19 on renal function, and on health outcomes among people with pre-existing chronic kidney disease (CKD)? Background: COVID-19 hospitalisation is associated with acute kidney injury (AKI) but long-term effects on kidney function remain unknown. Outside of COVID-19, AKI is a risk factor for CKD, with potential complications including increased mortality, cardiovascular disease, and end-stage renal disease (ESRD). Given the volume of detailed digitised records, the UK is well placed to conduct studies to determine the long-term impact of COVID-19 including important and costly, but relatively rare, outcomes like ESRD. Aims and objectives: To investigate the impact of COVID-19 on renal function by comparing those who survived with matched population controls, for risk of: 30% reduction in renal function ESRD Hospital admissions with AKI To investigate the impact of COVID-19 on people with baseline CKD, by comparing those who survived with matched population controls, for risk of: Death Hospitalisation ESRD Cardiovascular events Thromboembolic events Anaemia Increased frailty To develop a clinically-accessible, externally-validated risk prediction model for renal impairment and ESRD amongst COVID-19 survivors.Methods: I aim to conduct this work in the OpenSAFELY platform if continued access is mandated. If not, I will use linked primary and secondary care electronic records from the UK Clinical Practice Research Datalink (CPRD). There will be two study cohorts: Study A: adults with confirmed/suspected COVID-19 matched 1:4 to controls by age, sex, and general practice Study B: adults with baseline CKD with confirmed/suspected COVID-19 matched 1:2 to controls by age, sex, and CKD stageAfter comparing the distribution of covariables between matched cohorts, using Cox regression, I will obtain adjusted hazard ratio estimates for outcomes (listed in objectives), with stratification by age, sex, ethnicity, CKD stage and diabetes. I will perform a series of sensitivity analyses. I will replicate my analysis for Study B using a Swedish data source to assess for international generalisability. Using the Study A cohort, I will develop routinely-applicable prognostic prediction models for 2-year risk of 30% reduction in renal function, and ESRD. I will quantify predictive performance of these models using internal validation methods within CPRD, before external validation studies using data from an alternative UK data source, and from Sweden. Timelines for delivery: 03/2021 - Obtain approvals for data access 03/2022 -h; PhD upgrading assessment 12/2022 -h; Publication 1: Impact of COVID-19 on renal function 04/2023 -h; Publication 2: COVID-19 outcomes in CKD in UK 11/2023 -h; Publication 3: Prognostic prediction model for decline in renal function 02/2024 -h; Publication 4: COVID-19 outcomes in CKD in Sweden 12/2024 -h; Thesis submissionFrom 2022 onwards, I will deliver national/international presentations at conferences annually. Anticipated impact and dissemination: Given the scale and international significance of the study, I aim to publish results in high-impact peer-reviewed scientific journals and disseminate my findings to policy makers, healthcare commissioners, and charities. I will meet with my patient and public advisory panel at regular intervals. .

Lay abstract: Aims of my research I aim to investigate whether people who survive COVID-19 are more likely to lose kidney function, partially or completely; I also aim to build and test a prediction tool to work out which survivors are most likely to be at longer-term risk of serious declines in kidney function. I will also be investigating the impact of COVID-19 on survivors who had kidney disease before they became unwell, and whether this increases risk of experiencing bad outcomes earlier, such as death, complete kidney failure, heart attacks, and frailty. Background When people are admitted to hospital with COVID-19, one of the common consequences is kidney injury. We are not certain why, or whether this has long-term effects in survivors, but there are strong reasons to be concerned that it may. Long-term kidney damage, known as chronic kidney disease (CKD), is associated with earlier death and heart attacks. When CKD leads to kidney failure, people require dialysis or a kidney transplant to stay alive. This has a big impact on quality and length of life, and comes at great cost to the NHS. Therefore, we need to find out what the long-term risks of COVID-19 are to kidney function, and determine who is at the greatest risk so they can be closely monitored and treated. Design and methods A way of addressing important health concerns relatively quickly is by analysing health records which cover millions of people. In the UK, we have electronically coded GP records, and for most people, we can combine these with records from hospitals. I will use these anonymised records for two study populations: Study A: I will compare risks of change in kidney function or complete kidney failure between COVID-19 survivors and people of the same age, sex, and under the same GP. Study B: Among people with pre-existing CKD, I will compare risks of death, hospital admissions, complete kidney failure, heart attacks, blood clots, low red blood cell levels, and frailty between COVID-19 survivors to people who are the same age, sex, and have the same level of pre-existing CKD. I will replicate my work with records from Sweden to understand if the findings are specific to COVID-19 or influenced by factors such as health-care system and the characteristics of the local population.I will account for many other factors like age, ethnicity, socio-economic status and pre-existing medical problems like diabetes, to establish whether our results are likely to be due to COVID-19 itself, or were due to differences in who developed severe infection. I will apply statistical modelling to records from Study A to create a straightforward tool using information like routine test results or medical history, to predict which patients are most at risk of kidney failure. I will then test this model on another large set of records from the UK and from Sweden to ensure that it is reliable. Patient and public involvement My ideas have been informed by meetings including patients, and several patients are keen to join my advisory panel. I will ensure this includes COVID-19 survivors with and without CKD, and a member of public who has not had COVID-19. We will meet at the start of my research to finalise plans, and then I will update them of my progress every six months. I will seek their advice on how to ensure my findings reach other patients and the public. Dissemination Because this is a big, important study, I will share findings with the media, charities, healthcare professionals, and policy makers to ensure that it has maximum benefit for patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;INFECTION