Risk Factors and Mechanisms of Acute Pancreatitis in Chronic Kidney Disease: A Comprehensive Analysis Based on UK Biobank Cohort Data and Mendelian Randomization with Mediator Insights

Background Observational inquiries have indicated a heightened propensity for acute pancreatitis (AP) among individuals afflicted with chronic kidney disease (CKD), particularly those advancing toward end-stage renal disease. Nevertheless, the definitive causal association between CKD and AP remains unclear and the risk factors that predispose CKD patients to comorbid AP, along with their underlying mechanisms remain inadequately elucidated.Methods This study utilized Cox proportional hazards model and multi-state survival model, leveraging large-scale cohort data from UK Biobank, to estimate the relationship and risk factors between CKD and AP. Additionally, to explore their causal relationship, Mendelian Randomisation (MR) analysis was conducted. Mediation MR analysis and enrichment analysis were also employed to discern plasma proteins exhibiting mediating effects and the pathways they activate.Results The results of Cox proportional hazards model reveal that the risk of AP significantly increased in CKD patients. Gallstone was a risk enhancer for AP in CKD revealed by multi-state survival model. The MR analysis results further demonstrated that CKD could promote AP onset. Through proteomic mediation analysis, 20 proteins were identified with mediating effects in CKD-induced AP onset. These proteins operate by triggering pathways such as the toxicity induced by botulinum toxin type C alongside 27 other signalling or metabolic pathways.Conclusion CKD patients are at increased risk of developing AP. Among the multiple AP risk factors, only cholelithiasis was found to increase the risk of AP development in CKD. Notably, the underlying mechanism of concurrent AP in CKD was revealed, providing a reference for future studies.