Proenkephalin/penKid in renal dysfunction: An integrative review of laboratory and clinical evidence

Proenkephalin A 119–159 (PENK/penKid) is a circulating peptide increasingly investigated as a functional biomarker of glomerular filtration and acute kidney dysfunction. This integrative review critically examines diagnostic, prognostic, analytical, and implementation evidence relevant to laboratory medicine. A structured search of MEDLINE/PubMed, Embase, Web of Science, Scopus, and Cochrane CENTRAL covered January 2009–2026 and was complemented by a targeted PubMed/MEDLINE search through July 31, 2026. Diagnostic-performance metrics were extracted only when explicitly reported. Across 11 observational studies included in a 2023 meta-analysis, PENK showed pooled sensitivity of 0.69, specificity of 0.76, and summary receiver operating characteristic area under the curve of 0.77 for acute kidney injury, with substantial heterogeneity and a pooled optimal threshold of 57.3 pmol/L. More recent studies demonstrate marked scenario dependence, including high negative predictive value in selected perioperative and transplantation settings but variable specificity and positive predictive value. Circulating PENK is strongly influenced by glomerular filtration itself; advanced chronic kidney disease, dialysis status, hemodynamic instability, sepsis, and cardiovascular comorbidity complicate interpretation. Analytical studies support favorable sample stability and serum/plasma comparability for specific assay formats, whereas biological-variation data remain limited and cross-platform harmonization is incomplete. PENK should therefore be interpreted as a functional and risk-stratification biomarker rather than assumed to be a stand-alone diagnostic test. Its most credible current role is complementary to creatinine and, where appropriate, injury/stress biomarkers, pending multicenter validation of standardized assays, cut-offs, sampling windows, and biomarker-guided clinical pathways.