Application of Mendelian Randomization to Investigate Causal Relationship with Chronic Kidney Disease

Abstract

CKD affects about 10% of the global population, causing a significant public health burden worldwide. It is essential to understand the pathological processes and the available drug treatments. In this thesis, I performed Mendelian Randomization (MR) to investigate the causal relationship between urate and kidney function, proxied by the estimated glomerular filtration rate (eGFR), with potential covariates, blood pressure (BP) and glycaemic traits in the general population, and the potential for drug repurposing of anti-PAR1 (Protease-Activated Receptor 1) treatment for nephrotic syndrome (NS).

In Chapter 4, findings suggested urate and BP, urate and eGFR had bidirectional causal effects. Higher urate increases BP and decreases eGFR. In Chapter 5, findings indicated potential bidirectional causal effects between urate and fasting insulin (FI) in the general population, but not between urate and glycosylated hemoglobin (HbA1c) or fasting glucose (FG). Higher eGFR
causes lower FI. Both chapters indicated that conditioning on BP or glycaemic traits did not change the effect of urate on eGFR.
In Chapter 6, given the experimental evidence of PAR1 inhibition on NS in mice, I examined the causal effects of genetically predicted PAR1 and F2R expression on renal biomarkers and disease outcomes. The results indicated genetically proxied decreased PAR1 and F2R expression on reduced venous thromboembolism risk (positive control) and increased CKD risk. However, evidence regarding the effect of PAR1 on reducing eGFR or NS risk remains unclear.

This thesis highlights the bidirectional causal effects between urate and kidney function in the general population, which may be independent of BP and several glycaemic traits, and the potential adverse effect of anti-PAR1 treatments on kidney function. Reducing urate by implementing lifestyle modifications or treatment might improve cardiovascular, insulin resistance, and renal health on a population scale. Further experiments and data are needed to support the use of anti-PAR1 treatment in NS patients.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Venexia M Walker (Supervisor) & Tom R Gaunt (Supervisor)