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Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease
Yeawon Kim, … , Anthony J. Bleyer, Ying Maggie Chen
Yeawon Kim, … , Anthony J. Bleyer, Ying Maggie Chen
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e92896. https://doi.org/10.1172/jci.insight.92896.
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Research Article Nephrology

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.

Authors

Yeawon Kim, Sun-Ji Park, Scott R. Manson, Carlos A.F. Molina, Kendrah Kidd, Heather Thiessen-Philbrook, Rebecca J. Perry, Helen Liapis, Stanislav Kmoch, Chirag R. Parikh, Anthony J. Bleyer, Ying Maggie Chen

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Figure 5

Early postoperative measure of urine CRELD2 can stratify pediatric patients for developing severe AKI and other adverse outcomes after cardiopulmonary bypass surgery.

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Early postoperative measure of urine CRELD2 can stratify pediatric patie...
AKI in B–E denotes severe AKI. (A) Representative preoperative (pre-op) and postoperative (post-op) WB analysis of CRELD2 (arrow) in crude urine specimens obtained from non-AKI and severe AKI patients at the indicated time points. Time points 0–6 hours, 6–12 hours, 12–18 hours, day 2, and day 3 are the sample collection times after the CPB surgery. The urinary excretion of CRELD2 was normalized to 2 μg of urine Cr excretion. Three more independent experiments were performed with similar results. (B) ELISA assay of urine CRELD2 concentrations normalized to urine Cr excretion in unconcentrated urine specimen before surgery and at the first postoperative collection (0–6 hours) in severe AKI (n = 8) and non-AKI (n = 15) patients. **P < 0.01 by Wilcoxon rank-sum test. (C) Pre- and post-op serum Cr measurements in severe AKI (n = 8) and non-AKI (n = 15) patients, by Wilcoxon rank-sum test. (D) ELISA assays of urine NGAL, IL-18, and KIM-1 concentrations before surgery and 0–6 hours after surgery in severe AKI (n = 8) and non-AKI (n = 15) patients. *P < 0.05 by Wilcoxon rank-sum test. (E) Length of stay in hospital, ventilation, and stay in ICU in patients with undetectable and detectable urine levels of CRELD2 within postoperative 6 hours, respectively. *P < 0.05 by Wilcoxon rank-sum test. AKI, acute kidney injury; CRELD2, cysteine-rich with EGF-like domains 2; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; ICU, intensive care unit.

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