Acute kidney disease (AKD) is associated with an increased long-term risk of incident chronic kidney disease (CKD), end-stage kidney disease and mortality. Although various biomarkers have demonstrated prognostic value in acute kidney injury and CKD, evidence regarding their utility in AKD remains limited. Proenkephalin A 119–159 (PENK) is a stable precursor fragment of the short-lived enkephalin peptide and has emerged as a promising biomarker for early detection of AKI. Elevated plasma PENK levels have also been independently associated with adverse outcomes, including worsening kidney function and increased mortality, across a variety of clinical settings such as acute heart failure, acute coronary syndromes, sepsis, and severe burns. Nonetheless, its utility in predicting outcomes in AKD remains uncertain.

We retrospectively analyzed a prospectively collected cohort of patients with acute kidney disease. Blood samples collected 7–14 days after discharge were used to measure creatinine and PENK levels. The primary outcome was death or dialysis within 180 days. Generalized additive models were used to assess the nonlinear association between PENK levels and the primary outcome and to explore a potential risk threshold. Associations between PENK levels and the outcome were evaluated using multivariable Cox proportional hazards models. The incremental prognostic value of PENK beyond NGAL, a kidney injury marker, was assessed using changes in the area under the curve (AUC).

Overall, 127 patients were evaluated, of whom 72.0% were men, with a mean age of 64.7 ± 13.9 years. Based on generalized additive modeling, a PENK level of 242.2 pmol/L was selected as a risk threshold. Patients with PENK >242 pmol/L had significantly lower event-free survival, than those with PENK ≤242 pmol/L by Kaplan–Meier analysis (Figure 1); this association remained significant after adjustment for age, sex, estimated glomerular filtration rate, and Charlson comorbidity index in multivariable Cox models (HR: 3.64, 95% CI: 1.03–12.84). Adding PENK to NGAL increased the AUC from 0.69 to 0.77, although the improvement did not reach statistical significance by the DeLong test (P = 0.08).

In patients with AKD, elevated plasma PENK levels may assist in the prediction of adverse outcomes. PENK may also provide incremental prognostic information beyond NGAL, although larger studies are needed to validate its clinical utility.