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JCI Insight. 2017 Dec 7;2(23). pii: 92896. doi: 10.1172/jci.insight.92896. [Epub ahead of print]

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease.

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Division of Nephrology, Department of Internal Medicine.
Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Division of Urology, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
Section of Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut.
RTE Professor of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Arkana Laboratories, Little Rock, Arkansas, USA.
Institute for Inherited Metabolic Disorders, Charles University in Prague, Prague, Czech Republic.
Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, Connecticut, USA.


ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress-mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress-induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion-induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.


Cell stress; Nephrology

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