Acute kidney injury (AKI) occurs in roughly 25% of patients with acute decompensated heart failure (ADHF), representing a sudden loss of kidney function that correlates with higher long-term mortality. Identifying AKI early in ADHF remains a major clinical challenge, as no protein biomarkers currently offer adequate diagnostic or prognostic reliability for routine use. This study sought to uncover new protein biomarkers for AKI in ADHF by profiling kidney protein changes during disease progression and recovery using a sheep model. Kidney cortices from healthy controls (n = 5), sheep with rapid-pacing-induced ADHF (n = 8), and sheep approximately four weeks post-ADHF recovery (n = 7) were analyzed via SWATH–MS (sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry). Among 790 quantified proteins, 17 were identified as potential markers of kidney injury, one as a candidate for renal recovery, and two as indicators of persistent kidney impairment (fold change 1.2–2.6; adjusted p < 0.05). Six of these 20 candidates had prior evidence linking them to AKI, while 14 were novel. Proteins with altered abundance were enriched in inflammatory pathways, including glycoprotein VI (activated during ADHF; adjusted p < 0.01) and acute phase response signaling (suppressed during recovery; adjusted p < 0.01). These findings may provide new tools for early AKI detection in ADHF and offer insights for improving patient outcomes.
