Thanks to a new study headed by Ying Maggie Chen, MD, PhD, it may soon be possible to diagnose certain human kidney diseases in their earliest stages of development using a noninvasive biomarker of endoplasmic reticulum (ER) stress. The study, Elevated Urinary CRELD2 is Associated with Endoplasmic Reticulum Stress-mediated Kidney Disease, was published online in the journal JCI Insight, December 7, 2017.
The ER is the central site for folding, posttranslational modifications and transport of secretory and membrane proteins. When there is a mismatch between the load of unfolded/misfolded proteins and the folding capacity, “ER stress” occurs. If ER stress is prolonged or is too severe, cell suicide can be triggered, usually in the form of apoptosis.
ER stress contributes to the pathogenesis of various human kidney diseases such as congenital nephrotic syndrome, familial focal segmental glomerulosclerosis, Alport syndrome and ischemic acute kidney injury (AKI). The development of ER stress biomarkers that detect the very beginning stages of ER stress-mediated kidney disease, even before a kidney biopsy is clinically indicated, would allow for early therapeutic intervention.
Dr. Chen’s team, including Yeawon Kim, MS and Sun-Ji Park, PhD, has pioneered the development of urinary ER stress biomarkers. MANF (mesencephalic astrocyte–derived neurotrophic factor) was the first ER stress biomarker they discovered in mouse models (click here to read their paper published in 2016 in JASN). Now, they are the first to report that CRELD2 (cysteine-rich with EGF-like domains 2), a newly identified protein that is induced and secreted under ER stress, is a sensitive urinary biomarker for ER stress in certain murine models of ER stress–induced nephrotic syndrome and AKI.
More importantly, through the collaboration with different disease consortiums, they demonstrated that the CRELD2 biomarker has potential use in human disease. In samples from their Wake Forest Cohort, an increase in urinary CRELD2 occurs in patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) due to mutations in the UMOD gene encoding uromodulin, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery who were enrolled in NIH-funded TRIBE-AKI consortium, urine CRELD2 levels were detectable within 6 hours after surgery and were strongly associated with severe post-surgery AKI.
The availability of CRELD2 as a biomarker has broad clinical applications for patients. The biomarker will serve in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in a select subgroup of patients in the emerging era of precision nephrology.
“ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases and targeting ER stress will provide novel mechanistic treatments,” says first author Yeawon Kim. “I feel very excited about our discovery, which may facilitate early diagnosis and risk prediction and ultimately change the treatment paradigm.”
Dr. Chen and Yeawon Kim, through the Office of Technology Management at Washington University, have a patent application on the technology using CRELD2 as a novel urine biomarker of ER-stress kidney disease.
The study has also been featured in ASN in the Loop.
The full article can be read here.