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

• DOI: 10.1172/jci.insight.92896
• Publication Date: 2017-12-06T16:00:32Z
• Authors: Yeawon Kim; Sun-Ji Park; Scott R. Manson; Carlos A.F. Molina; Kendrah Kidd; Heather Thiessen-...; Rebecca J. Perry; Helen Liapis; Stanislav Kmoch; Chirag R. Parikh; Anthony J. Bleyer; Ying Maggie Chen
• Keywords: Male; 0301 basic medicine; Extracellular Matrix Proteins; Nephritis; Nephrotic Syndrome; Podocytes; Acute Kidney Injury; Inbred C57BL; Endoplasmic Reticulum Stress; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Postoperative Complications; Mutation; Uromodulin; Animals; Humans; Nephritis, Interstitial; Cardiac Surgical Procedures; Interstitial; Child; Cell Adhesion Molecules; Biomarkers

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.