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

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ID: 314113
2026
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Abstract
Abstract 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.
Reference Key
openalex_W7161745282 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Jingjing Quan, Li S, Juan Peng, Dongdong Zhang, Le Chen, Zhijun Huang, Bin Yi
Journal qjm : monthly journal of the association of physicians
Year 2026
DOI
10.1093/qjmed/hcag126
URL
https://doi.org/10.1093/qjmed/hcag126
Keywords Keywords not found

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