Association of serum bilirubin level with renal outcomes in patients with type 2 diabetes and patients with essential hypertension

Date of ISAC Approval: 
10/07/2019
Lay Summary: 
Bilirubin is a substance naturally produced by the body when the red blood cells get old and break down. Its level in the body varies to a large degree between people. It has been proposed that the anti-oxidative effect of bilirubin may protect us from kidney diseases. Majority of published studies are supporting this protective effect of bilirubin while some researches are still sceptical. We wish to conduct high-quality analyses on high-quality data created from the CPRD GOLD population to provide supporting evidence to this scientific question. We propose to divide patients in the CPRD dataset into those with high and low-level bilirubin and compare how their kidney function changes over time. Patients with type 2 diabetes or with high blood pressure are at additional risk of losing kidney function. When kidney function is lost, the body cannot filter out the waste products in the blood effectively which leads to life threatening adverse events such as a heart attack. If we can show that bilirubin protects kidney function, then we can potentially predict the patients who are at higher risk of kidney disease based on bilirubin level. This will allow doctors to more closely monitor the patients for renal disease and provide better treatment
Technical Summary: 
Recent investigations and meta-analyses indicate a strong association between bilirubin and renal outcomes. We wish to conduct a retrospective study on CPRD GOLD dataset to investigate these associations in a real-world setting. Based on our preliminary feasibility count, we believe the cohorts retrospectively built using CPRD GOLD dataset will be at least one order of magnitude larger than the analyses that are currently available. Also, we should be able to adjust critical confounders such as haemoglobin level and smoking status that was previously not done or lead to inconclusive results. We will retrospectively build two cohorts with known risk factors for CKD: type 2 diabetes or hypertension. We will follow the patients from the date of diagnosis of either of these morbidities to one of the events indicating the degradation of renal function (eGFR decrease, serum creatinine increase, albuminuria, or proteinuria). We will fit the Cox proportional hazard models with inverse probability weighting to estimate the adjusted hazard ratio between the patients with elevated bilirubin vs. normal levels. We are aware that as this will only be the observational study and we will not be able to conclude the causality of bilirubin levels to CKD progression even if we can show an association. However, with careful analyses based on richer dataset than what is currently available, this analysis may increase our understanding of the association between bilirubin and CKD outcomes and guide further investigations
Health Outcomes to be Measured: 
1. Time to eGFR CKDEPI 30% decrease from the baseline; 2. Time to first observation of proteinuria; 3. Time to first observation of albuminuria.
Collaborators: 

Dr Dinko Rekic - Chief Investigator - Astra Zeneca R&D Molndal Sweden
Dr Claudia Cabrera - Collaborator - Astra Zeneca R&D Molndal Sweden
Dr Peter Greasley - Collaborator - Astra Zeneca R&D Molndal Sweden
Dr Yasunori Aoki - Corresponding Applicant - Astra Zeneca Ltd - UK Headquarters