Liver-Metabolic Phenotypes and Renal Vulnerability in Community-Acquired Sepsis: Insights from the SepsisFAT Cohort

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is associated with adverse outcomes in sepsis, but risk stratification within MASLD remains insufficiently defined. We investigated whether an admission liver-metabolic phenotype framework combining cardiometabolic burden with liver injury/fibroinflammatory risk markers identifies clinically relevant organ-support vulnerability in community-acquired sepsis. Methods: This secondary analysis of the prospective SepsisFAT cohort (378 adults with community-acquired sepsis) classified patients into four phenotypes by cardiometabolic burden (≥2 of: diabetes, hypertension, dyslipidemia, BMI ≥ 30 kg/m²) and liver-risk positivity (FIB-4 ≥ 2.67, APRI ≥ 1.0, liver stiffness ≥ 10 kPa, or FAST ≥ 0.55). The primary outcome was acute kidney injury (AKI), while continuous renal replacement therapy (CRRT), other organ-support outcomes and in-hospital mortality were secondary endpoints. Results: Phenotype distribution was Low-risk 137 (36.2%), Cardiometabolic-only 84 (22.2%), Liver-dominant 88 (23.3%), and Mixed liver-cardiometabolic 69 (18.3%). AKI and CRRT increased across phenotypes (13.9% to 40.6% and 5.1% to 26.1%, respectively), and in-hospital mortality was highest in the Mixed phenotype (26.1%). After Firth-penalized adjustment for age, sex, and admission SOFA, the Mixed phenotype remained independently associated with AKI (aOR 2.82, 95% CI 1.37-5.90) and CRRT (aOR 3.87, 1.50-10.80), confirmed in non-renal SOFA and admission eGFR-adjusted sensitivity analyses. Cardiometabolic burden alone did not confer excess organ-support risk. The same gradient persisted within the MASLD subgroup. Conclusions: Admission liver-metabolic phenotyping identified a renal-vulnerable sepsis subgroup not captured by binary MASLD classification alone. These findings support prospective, multicenter external validation of liver-metabolic phenotyping as a pragmatic approach to renal risk stratification in community-acquired sepsis.