Proenkephalin improves risk prediction in acute coronary syndromes: derivation and external validation of the KID-ACS risk score

Background Early assessment of renal and mortality risk in patients with acute coronary syndromes (ACS) is essential to guide treatment decisions according to international guidelines. Circulating proenkephalin (PENK) is a stable opioid metabolite with fast response to changes in kidney function. Purpose This study examined the predictive value of PENK for acute kidney injury (AKI) and mortality in patients presenting with acute coronary syndromes (ACS). Methods Plasma PENK levels were measured using a validated sandwich immunoassay in a prospective multicentre ACS cohort from Switzerland (n = 4 787) and in validation cohorts from the UK (n = 1 141) and Czechia (n = 920). A biomarker-enhanced risk score for simultaneous prediction of both in-hospital acute kidney injury (AKI) and 30-day death (KID-ACS score) with model coefficients adjusted to the outcome was derived and externally validated. In the development of the in-hospital AKI model, patients from one participating study centre were reserved for external validation (Swiss validation cohort). Results Circulating PENK ranked among the top predictors of renal outcomes and mortality in patients with ACS. Accounting for established risk factors and risk models, circulating PENK levels at presentation were independently associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.56, 95% CI 1.14 – 2.12, P = 0.005) and with 30-day mortality (per log2 increase: adjusted OR 2.69, 95% CI 1.89 – 3.84, P < 0.001). Dynamic changes in PENK levels within the first 12-24 hours after presentation were strongly and independently associated with in-hospital AKI (increase vs. decrease: adjusted OR 2.83, 95% CI 1.98 – 4.05, P < 0.001). The simple 6-item KID-ACS risk score for in-hospital AKI and 30-day mortality integrates PENK levels at presentation and showed an AUC of 0.72 (95% CI 0.68 – 0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87 – 0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS had similarly high performance for in-hospital AKI (Swiss validation cohort: AUC 0.73, 95% CI 0.70 – 0.77; Czech validation cohort: 0.74, 95% CI 0.68 – 0.80) and 30-day mortality (UK validation cohort: AUC of 0.87, 95% CI 0.82 – 0.91; Czech validation cohort: 0.91, 95% CI 0.87 – 0.94). The simple 6-item KID-ACS score was non-inferior to established risk models and significantly outperformed the CA-AKI risk score in predicting in-hospital AKI (Zurich cohort: delta AUC 0.11, 95% CI 0.07 – 0.15, P = 0.001) and the GRACE 2.0 in predicting 30-day mortality (UK cohort: delta AUC 0.05, 95% CI 0.01 – 0.09, P = 0.027). Conclusions Circulating PENK was identified as independent predictor of in-hospital AKI and 30-day mortality in patients with ACS. The simple 6-item KID-ACS risk score integrates circulating PENK levels and provides a novel tool for simultaneous assessment of renal and mortality risk in patients presenting with ACS.