Proenkephalin improves cardio-renal risk prediction in acute coronary syndromes: the KID-ACS score

Abstract

Background and aims: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndrome (ACS).

Methods: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n = 4787) and in validation cohorts from the UK (n = 1141), Czechia (n = 927), and Germany (n = 220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated.

Results: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI [per log2 increase: adjusted odds ratio 1.53, 95% confidence interval (CI) 1.13-2.09, P = .007] and 30-day mortality (adjusted hazard ratio 2.73, 95% CI 1.85-4.02, P < .001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of .72 (95% CI .68-.76) for in-hospital AKI and .91 (95% CI .87-.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC .73, 95% CI .70-.77; Czechia: AUC .75, 95% CI .68-.81; Germany: AUC .71, 95% CI .55-.87) and 30-day mortality (UK: AUC .87, 95% CI .83-.91; Czechia: AUC .91, 95% CI .87-.94; Germany: AUC .96, 95% CI .92-1.00), outperforming the contrast-associated AKI score and the Global Registry of Acute Coronary Events 2.0 score, respectively.

Conclusions: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple six-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

Keywords: Acute coronary syndromes; Acute kidney injury; Mortality risk; Proenkephalin; Risk prediction.

Structured Graphical Abstract

Circulating proenkephalin (PENK) was identified as a novel marker of in-hospital acute kidney injury (AKI) and increased mortality risk in patients with acute coronary syndrome (ACS). Circulating PENK levels were measured at presentation in three independent prospective ACS cohorts from Switzerland, the UK, Czechia, and Germany. In the multicentre Swiss cohort (SPUM-ACS Biomarker Study), PENK levels were additionally measured after 12–24 h. High levels of PENK were independently associated with increased risk of in-hospital AKI (per log₂ increase, adjusted odds ratio 1.53) and 30-day mortality (per log₂ increase, adjusted odds ratio 2.73) beyond established risk factors. Patients with dynamic increase in PENK levels at 12–24 h displayed 2.88-fold higher in-hospital AKI risk when adjusting for established risk factors. The newly developed six-item KID-ACS risk score for in-hospital AKI and 30-day mortality integrates PENK levels outperforms established risk models. KID-ACS showed excellent predictive performance upon external validation and requires fewer patient variables.

Figure 1

Circulating proenkephalin predicts renal outcomes in acute coronary syndrome. (A) Multivariable-adjusted odds ratio for in-hospital acute kidney injury according to proenkephalin quartile (Q). (B) Multivariable-adjusted odds ratio for incident chronic kidney disease at 1 year after the index acute coronary syndrome according to proenkephalin quartile. (C) Dynamic increases of proenkephalin within the first 12–24 h after presentation relate to the risk to develop in-hospital acute kidney injury. The fully adjusted regression model for in-hospital acute kidney injury included sex, body mass index, systolic blood pressure, and the contrast-associated acute kidney injury risk score (Model 1). The fully adjusted regression model for 1-year chronic kidney disease included sex, body mass index, history of smoking, and the Framingham Risk Score for the Development of Chronic Kidney Disease. Squares indicate the mean estimates of the odds ratio, and line lengths equal corresponding 95% confidence intervals

Figure 2

Performance of the KID-ACS score. (A) Receiver operating characteristics curves of the KID-ACS score for predicting in-hospital acute kidney injury (left) and 30-day mortality (right). (B) Smoothed calibration plot of the KID-ACS score for predicting in-hospital acute kidney injury (left) and 30-day mortality (right). (C) Importance of KID-ACS score features in the model prediction of in-hospital acute kidney injury (left) and 30-day mortality (right) measured by partial Wald χ² minus the degrees of freedom. AUC, area under the receiver operating characteristic curve; CI, confidence interval; NT-proBNP, N-terminal pro-B-type natriuretic peptide

Figure 3

The KID-ACS score nomogram for bedside application. Risk curves refer to in-hospital acute kidney injury (left) and 30-day mortality (right). The histogram shows the KID-ACS score distribution in the derivation cohort with adjacent bars referring to in-hospital acute kidney injury and to 30-day mortality, respectively. NT-proBNP, N-terminal pro-B-type natriuretic peptide; PENK, proenkephalin