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

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Abstract
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.
Funding Information
  • NIH/NIDDK (K08DK089015)
  • NIH/NIDDK (R03DK106451)
  • Norges Idrettshøgskole (R21DK106584)
  • NIH/NIDDK (R01DK096177)
  • Halpin Foundation-American Society of Nephrology Research Grant (N/A)
  • Faculty Scholar Award from the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (MD-FR-2013-336)
  • Doris Duke Charitable Foundation (Clinical Scientist Development Award (2015100))
  • Nephrotic Syndrome Study Network (Career Development Award)
  • Central Society for Clinical and Translational Research (Early Career Development Award)
  • Washington University Division of Nephrology (Renal Translational Innovation Grant)
  • National Kidney Foundation (New Investigator Award)
  • Midwest Stone Institute Grant (N/A)
  • Ministry of Education, Youth and Sports of the Czech Republic (LQ1604 NPU II)
  • The National Center for Medical Genomics (LM2015091)
  • NIH/NIDDK (R01 DK105056A1)
  • Brazil (FAPESP)
  • The Ministry of Education, Youth and Sports of the Czech Republic (LQ1604 NPU II)
  • the Ministry of Health of the Czech Republic (NV17-29786A)
  • NIH/NIDDK (RO1 HL085757)
  • NIH/NIDDK (the O’Brien Kidney Center Grant P30DK079310.)

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