Association between brain connectivity and renal pathophysiology: a multi-trait Mendelian randomization analysis.

To investigate the potential bidirectional causal relationships between resting-state functional brain activity and major kidney diseases. We accessed genome-wide association study (GWAS) summary data of 191 resting-state fMRI (rs-fMRI) phenotypes. Summary-level GWAS data for seven kidney diseases-diabetic nephropathy, chronic kidney disease, glomerulonephritis, nephrotic syndrome, cystic kidney disease, IgA nephropathy, and kidney cyst-were obtained from the FinnGen consortium or the Kiryluk Lab, all based on European ancestry (sample sizes ranging up to 11,265 cases and 436,208 controls). We employed inverse variance weighted (IVW) analysis as the primary MR approach, supplemented by MR-Egger, Weighted Median, Weighted Mode, and Robust Adjusted Profile Score (RAPS) to evaluate pleiotropy and heterogeneity. Forward MR demonstrated that certain brain networks, such as the central executive network, default mode network, limbic network, and other interconnected circuits, appear to influence susceptibility to various kidney diseases. Reverse MR indicated that disrupted kidney function, particularly CKD, may adversely affect key brain functional networks, including those responsible for sensory-motor processing and cognitive integration. Although the observed effect sizes were modest, our results provide evidence that kidney diseases and brain functional activity may be interlinked, aligning with clinical observations of neurological-urinary system correlations and emerging data on cortical structural changes in chronic kidney disease. The "kidney-brain axis" could be relevant to both renal and neurological pathophysiology.