Abstract
BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting long-term kidney outcomes after cardiac surgery.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1’s associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2–7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73–0.95 and 1.10, 95% CI 1.00–1.21, respectively). Intrarenal scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O’Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.
Highlights
Over 1 million patients undergo cardiac surgery every year [1, 2]
Urinary EGF and monocyte chemoattractant protein-1 (MCP-1) were each independently associated with chronic kidney disease (CKD) after cardiac surgery
The clinical detection of acute kidney injury (AKI) and CKD is currently based on a set of markers that primarily reflect glomerular function and structure
Summary
Over 1 million patients undergo cardiac surgery every year [1, 2]. perioperative mortality rate is low, many survivors develop long-term chronic kidney disease (CKD) as a late complication [3,4,5]. Cardiac surgery serves as an ideal setting to study both short-term and long-term kidney outcomes, given the predictable and clear timing of injury. The clinical detection of acute kidney injury (AKI) and CKD is currently based on a set of markers that primarily reflect glomerular function and structure (serum creatinine and proteinuria). The narrow definition of kidney function reflected by the selection of these clinical markers may limit the ability to detect early stages of impending AKI or CKD. Biomarkers have been increasingly studied across the spectrum of kidney disease, from AKI to CKD, to detect early or subclinical injury. Assessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting longterm kidney outcomes after cardiac surgery
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