Supplementary Material for: Exploring potential causality and molecular mechanisms between heart failure and renal failure: insights from Mendelian randomization studies, the MIMIC-IV database and the GEO database

Background: Heart failure (HF) and renal failure (RF) frequently coexist as cardiorenal syndrome, but their underlying causal mechanisms remain poorly defined. Methods: This study applied Mendelian randomization (MR) using genome-wide association study (GWAS) datasets to investigate the causal effect of HF on RF. The inverse variance weighted (IVW) method assessed causality, and summary-data-based MR (SMR) was used to identify therapeutic targets. Additional analyses included 211 gut microbiota traits and 1,400 serum metabolites. Validation was performed using the MIMIC-IV database. Transcriptomic data were analyzed to identify differentially expressed genes (DEGs) and key transcription factors. Results: This study found that HF significantly increases the risk of RF (OR = 1.54, 95% CI: 1.07–2.23, P = 0.020). SMR analysis identified SURF1 and MAP3K11 as potential therapeutic targets for HF and RF. One gut microbiota genus and one serum metabolite showed causal associations with both diseases. MIMIC-IV data supported the HF–RF association (OR = 2.94, 95% CI: 2.81–3.07, P < 0.001). 11 overlapping DEGs were enriched in the MAPK cascade, with RELA identified as a key transcription factor. Conclusion: This study provides genetic and molecular evidence supporting a causal role of HF in RF, highlighting microbial, metabolic, and immune mechanisms as potential therapeutic targets.