Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure

Abstract

In patients with acute decompensated heart failure (ADHF), a quarter incur acute kidney injury (AKI), which doubles the risk of death at one year. No protein biomarkers have been validated as diagnostic or prognostic markers of AKI in ADHF. We aimed to identify novel candidate protein biomarkers of kidney injury, recovery, and long-term chronic kidney disease in ADHF. We quantified changes in protein expression in the kidney that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using Sequential Window Acquisition of All Theoretical Mass Spectrometry (SWATH-MS) in kidney tissue from healthy control sheep (n=5), sheep with established rapid pacing-induced ADHF (n=8) and sheep after ∼4 weeks recovery from ADHF (n=7). Proteins differing in expression between experimental groups were identified using Welch one-way tests, and predicted to be detectable in plasma, serum or urine using Ingenuity Pathway Analysis (Qiagen Inc.). Of 574 proteins quantified, seven candidate kidney injury markers (CCT3, CCT8, CRYZ, FLNA, PRDX1, TLN1, TCP1), one potential marker of kidney recovery (APOA4) and three markers of long-term chronic kidney disease (APOE, TPP1, CCT6A) were differentially expressed between groups (1.2–2.4 fold-changes, adjusted p≤0.05). Differentially expressed proteins were enriched in pro-inflammatory signaling pathways: Glycoprotein VI (activated during ADHF development, adjusted p<0.001) and acute phase response (repressed during recovery from ADHF, adjusted p<0.001). This research identified eleven candidate protein markers of kidney injury in ADHF, including three candidates supported by existing evidence and eight novel candidates not previously implicated in AKI.