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

Evelyn M Templeton,Torsten Kleffmann,Suetonia C Palmer,Anna P Pilbrow,Zoltan H Endre,Vicky A Cameron,John W Pickering,Miriam T Rademaker,Leigh J Ellmers,Moritz Lassé,Trent Davidson,A Mark Richards,Nicola J A Scott,Christopher J Charles

doi:10.3390/ijms23021009

Abstract

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Highlights

Heart failure (HF) affects more than 60 million people worldwide [1], and is associated with high mortality and morbidity [2]
This study aimed to identify candidate protein biomarkers of kidney injury during acute decompensated heart failure (ADHF), recovery from ADHF, and long-term renal impairment after ADHF, using an established ovine model of pacing-induced ADHF
SWATH–MS identified 20 proteins that differed in abundance in the kidneys in response to the development of and/or recovery from ADHF, and that may be detectable in biofluids, 14 of which had not been associated with acute kidney injury (AKI) previously

Summary

Introduction

Heart failure (HF) affects more than 60 million people worldwide [1], and is associated with high mortality and morbidity [2]. AKI complicating ADHF is associated with a near-doubling of death in patients with HF after one year [5,6], and efforts to improve the treatment of AKI in ADHF have been unsuccessful to date [6]. Prophylactic measures—including care in drug selection and dosing, and control of blood pressure—are valuable, but there is no proven specific pharmacotherapy for AKI [7]. This is in large part due to the failure to detect AKI at a stage where injury might be remediated. Detection of AKI is clearly vital for timely introduction of effective interventions, and will remain crucial once effective agents are identified

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Conclusion