Clinical utility of proenkephalin A 119-159 for prediction of worsening renal function and prognosis in patients with sepsis -results of a patient-level meta-analysis.

BACKGROUND: Proenkephalin A 119–159 (penKid) is a functional kidney biomarker inversely correlating with the glomerular filtration rate. We conducted a patient-level meta-analysis to evaluate whether penKid provides additional value to serum creatinine (sCr) for assessing kidney function and outcome in patients with sepsis or septic shock. METHODS: To identify eligible studies, the database PubMed and internal resources have been searched in March 2025. Randomized controlled trials or observational trials enrolling patients with sepsis or septic shock admitted to ICU (> 100 patients per study) were included. The primary endpoint was worsening renal function (WRF) defined as a further increase of sCr equal or greater 0.3 mg/dL within 48 h from ICU admission value (baseline), or need for renal replacement therapy (RRT) or death within 48 h. Secondary endpoint was 28d-mortality. Subgroups were created applying upper normal reference values for penKid and sCr. RESULTS: Individual data from 2,203 patients with sepsis or septic shock enrolled in four studies were included. penKid was independently associated with WRF (OR 3.4, 95% CI 2.7–4.3, p < 0.0001) and 28d-mortality (OR 1.6, 95% CI 1.4–1.9, p < 0.0001). Among patients with normal sCr at admission, those with elevated penKid had a higher incidence of WRF compared to patients with normal penKid (27.1% vs. 11.1%, p < 0.0001) and the highest 28d-mortality (38.6% vs. 15.3%, p < 0.0001). CONCLUSION: penKid adds predictive value beyond sCr for identifying patients at risk for WRF and 28d-mortality. Importantly, elevated penKid identifies at-risk patients even when sCr is normal. Combining both biomarkers may therefore offer a valuable tool for risk stratification in patients with sepsis or septic shock. TRIAL REGISTRATION: This meta-analysis has been retrospectively registered at PROSPERO, CRD420251153702. Registered 23 September 2025.