Multiple metabolic factors and kidney dysfunction: Causal evidence and translational insights from a mendelian...

Chronic kidney disease is a major global public health burden. This study investigated the causal effects of systolic blood pressure (SBP), apolipoprotein B (ApoB), and serum urate on renal function and albuminuria, and explored potential mechanistic implications. Two-sample Mendelian randomization (MR) analyses were conducted using large-scale genome-wide association study summary statistics from European populations. Univariable MR estimated total causal effects on estimated glomerular filtration rate (eGFR) and albuminuria. Multivariable MR assessed independent effects of correlated exposures, and 2-step MR evaluated albuminuria as a mediator. Cis-MR analyses were performed to explore target-proximal genetic evidence for lipid-related drug targets. Genetically predicted SBP was causally associated with reduced eGFR, while ApoB was inversely associated with albuminuria risk. serum urate showed no significant causal effects. Multivariable and mediation analyses supported distinct roles of SBP and ApoB, with albuminuria partially mediating the SBP-eGFR association. Cis-MR analyses indicated heterogeneous renal effects of lipid-lowering targets. These findings provide genetic evidence linking SBP to renal dysfunction, suggest that albuminuria may partially mediate the association between SBP and renal function, and highlight the complex renal relevance of lipid-related pathways.