PCSK9 contributes to diabetes-associated chronic kidney injury beyond LDL cholesterol regulation: genetic and observational evidence

Aims This study integrates Mendelian randomization (MR) and observational data to investigate the causal roles of PCSK9 and LDL-C in chronic kidney injury (CKI) of various etiologies, with a focus on diabetes-associated CKI. Methods We performed two-sample MR analyses using GWAS summary statistics to assess the effects of circulating PCSK9, LDL-C, and PCSK9-inhibitor-modulated LDL-C on CKI risk, complemented by a 5-year prospective cohort study of 101 type 2 diabetes patients evaluating serum PCSK9 and composite renal endpoints. Results MR revealed genetically proxied elevated PCSK9 significantly increased diabetic nephropathy risk (OR = 1.985, 95% CI : 1.019-3.867, P = 0.044), whereas LDL-C reduction (including PCSK9-inhibitor-mediated) showed no association. This effect was specific to diabetic CKI, with sensitivity analyses confirming robustness. In the prospective cohort, elevated serum PCSK9 levels (>216.14 ng/mL) independently predicted a higher risk of adverse renal outcomes in T2DM patients (HR = 2.677; 95% CI: 1.094-6.548; P = 0.031), whereas LDL-C showing no prognostic relevance. Conclusion These findings establish PCSK9 as a causal factor in diabetic nephropathy potentially via lipid-independent mechanisms, highlighting its therapeutic potential beyond LDL-C modulation.