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.

Arkana Laboratories Little Rock Arkansas USA

Clinical Epidemiology Research Center Veterans Affairs Medical Center West Haven Connecticut USA

Division of Nephrology Department of Internal Medicine

Division of Urology Department of Surgery and Anatomy Ribeirao Preto Medical School University of Sao Paulo Ribeirao Preto Brazil

Division of Urology Department of Surgery Washington University School of Medicine St Louis Missouri USA

Institute for Inherited Metabolic Disorders Charles University Prague Prague Czech Republic

RTE Professor of Pathology and Immunology Washington University School of Medicine St Louis Missouri USA

Section of Nephrology Wake Forest School of Medicine Winston Salem North Carolina USA

Section of Nephrology Yale University School of Medicine New Haven Connecticut

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MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Ultrabright plasmonic fluor nanolabel-enabled detection of a urinary ER stress biomarker in autosomal dominant tubulointerstitial kidney disease