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

JCI Insight. 2017 Dec 7;2(23):e92896. doi: 10.1172/jci.insight.92896.


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.

Keywords: Cell stress; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / diagnosis
  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / urine*
  • Animals
  • Biomarkers / urine
  • Cardiac Surgical Procedures
  • Cell Adhesion Molecules / physiology
  • Cell Adhesion Molecules / urine*
  • Child
  • Endoplasmic Reticulum Stress / physiology*
  • Extracellular Matrix Proteins / physiology
  • Extracellular Matrix Proteins / urine*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mutation
  • Nephritis, Interstitial / genetics
  • Nephritis, Interstitial / physiopathology
  • Nephritis, Interstitial / urine
  • Nephrotic Syndrome / diagnosis
  • Nephrotic Syndrome / physiopathology
  • Nephrotic Syndrome / urine*
  • Podocytes / metabolism
  • Postoperative Complications / urine
  • Uromodulin / genetics


  • Biomarkers
  • CRELD2 protein, human
  • Cell Adhesion Molecules
  • Extracellular Matrix Proteins
  • Umod protein, mouse
  • Uromodulin