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

Heart failure (HF) and renal failure (RF) frequently coexist as cardiorenal syndrome, but their underlying causal mechanisms remain poorly defined. 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. 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. 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.