skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans

Abstract

Chronic kidney disease (CKD) has emerged as a major public health problem worldwide. It frequently progresses to end-stage renal disease, which is related to very high cost and mortality. Novel biomarkers can provide insight into the novel mechanism, facilitate early detection, and monitor progression of CKD and its response to therapeutic interventions. To identify potential biomarkers, we applied an UPLC-HDMS together with univariate and multivariate statistical analyses using plasma samples from patients with CKD of diverse etiologies (100 sera in discovery set and 120 sera in validation set) and two different rat models of CKD. Using comprehensive screening and validation workflow, we identified a panel of seven metabolites that were shared by all patients and animals regardless of the underlying cause of CKD. These included ricinoleic acid, stearic acid, cytosine, LPA(16:0), LPA(18:2), 3-methylhistidine, and argininic acid. The combination of these seven biomarkers enabled the discrimination of patients with CKD from healthy subjects with a sensitivity of 83.3% and a specificity of 96.7%. In addition, these biomarkers accurately reflected improvements in renal function in response to the therapeutic interventions. Lastly, our results indicated that the identified biomarkers may improve the diagnosis of CKD and provide a novel tool for monitoring ofmore » the progression of disease and response to treatment in CKD patients.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Northwest Univ., Shaanxi (China)
  3. Univ. of California, Irvine, CA (United States)
  4. Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine, Shaanxi (China)
  5. Xi'an No. 4 Hospital. Shaanxi (China)
  6. Water Technologies (Shanghai) Ltd., Shanghai (China)
  7. Northwest Univ., Shaanxi (China); Univ. of California, Irvine, CA (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1350944
Grant/Contract Number:
AC05-00OR22725
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Proteome Research
Additional Journal Information:
Journal Volume: 15; Journal Issue: 10; Journal ID: ISSN 1535-3893
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 5/6 nephrectomized rats; adenine-induced CKD rats; biomarker; chronic kidney disease; enalapril; irbesartan; metabolomics; plasma

Citation Formats

Zhang, Zhi -Hao, Chen, Hua, Vaziri, Nosratola D., Mao, Jia -Rong, Zhang, Li, Bai, Xu, and Zhao, Ying -Yong. Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans. United States: N. p., 2016. Web. doi:10.1021/acs.jproteome.6b00583.
Zhang, Zhi -Hao, Chen, Hua, Vaziri, Nosratola D., Mao, Jia -Rong, Zhang, Li, Bai, Xu, & Zhao, Ying -Yong. Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans. United States. doi:10.1021/acs.jproteome.6b00583.
Zhang, Zhi -Hao, Chen, Hua, Vaziri, Nosratola D., Mao, Jia -Rong, Zhang, Li, Bai, Xu, and Zhao, Ying -Yong. 2016. "Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans". United States. doi:10.1021/acs.jproteome.6b00583. https://www.osti.gov/servlets/purl/1350944.
@article{osti_1350944,
title = {Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans},
author = {Zhang, Zhi -Hao and Chen, Hua and Vaziri, Nosratola D. and Mao, Jia -Rong and Zhang, Li and Bai, Xu and Zhao, Ying -Yong},
abstractNote = {Chronic kidney disease (CKD) has emerged as a major public health problem worldwide. It frequently progresses to end-stage renal disease, which is related to very high cost and mortality. Novel biomarkers can provide insight into the novel mechanism, facilitate early detection, and monitor progression of CKD and its response to therapeutic interventions. To identify potential biomarkers, we applied an UPLC-HDMS together with univariate and multivariate statistical analyses using plasma samples from patients with CKD of diverse etiologies (100 sera in discovery set and 120 sera in validation set) and two different rat models of CKD. Using comprehensive screening and validation workflow, we identified a panel of seven metabolites that were shared by all patients and animals regardless of the underlying cause of CKD. These included ricinoleic acid, stearic acid, cytosine, LPA(16:0), LPA(18:2), 3-methylhistidine, and argininic acid. The combination of these seven biomarkers enabled the discrimination of patients with CKD from healthy subjects with a sensitivity of 83.3% and a specificity of 96.7%. In addition, these biomarkers accurately reflected improvements in renal function in response to the therapeutic interventions. Lastly, our results indicated that the identified biomarkers may improve the diagnosis of CKD and provide a novel tool for monitoring of the progression of disease and response to treatment in CKD patients.},
doi = {10.1021/acs.jproteome.6b00583},
journal = {Journal of Proteome Research},
number = 10,
volume = 15,
place = {United States},
year = 2016,
month = 9
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 5works
Citation information provided by
Web of Science

Save / Share:
  • A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrationsmore » exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200 mg/m{sup 3}. While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.« less
  • The growing number of patient reports of angina and myocardial infarction during cancer management prompted this review of coronary artery disease (CAD) in cancer patients. There is no definite evidence that cancer per se nor any particular tumor type predisposes to coronary atherosclerosis. Cardiac metastases can cause CAD via tumor emboli, extrinsic compression, or ostial obstruction; in these patients the diagnosis of CAD as a result of cardiac metastases often is not made until death. The course of these patients usually is fulminant. Tumor-associated coagulation disorders and non-bacterial thrombotic endocarditis can cause coronary thromboemboli; treatment should be initiated early asmore » these patients often are not in a terminal state when such CAD develops. Post-radiation CAD seen in experimental animals (via fibrosis and/or accelerated atherogenesis) can be extrapolated to the clinical situation. This is best evidenced by 10 young patients, with minimal coronary risk factors in most, who developed angina and/or myocardial infarction 2 to 100 months after chest radiotherapy; approximate mediastinal doses ranged from 1440 Roentgen to 5075 rad. In 5 patients there was no significant atherosclerosis beyond the radiation portals; 2 had successful saphenous vein bypass grafts. Lipid-lowering therapy may prevent post-radiotherapy atherogenesis in high risk individuals. Chemotherapy (acting directly or synergistically with radiotherapy) has caused angina and myocardial infarction within hours to days after the infusion of agents both classically cardiotoxic as well as others, although the exact mechanism(s) for coronary artery damage as a result of chemotherapy presently is unknown.« less
  • We have evaluated several transmission models for Alzheimer disease (AD), using the logistic regressive approach in 401 nuclear families of consecutively ascertained and rigorously diagnosed probands. Models postulating no major gene effect, random environmental transmission, recessive inheritance, and sporadic occurrence were rejected under varied assumptions regarding the associations among sex, age, and major gene susceptibility. Transmission of the disorder was not fully explained by a single Mendelian model for all families. Stratification of families as early- and late-onset by using the median of family mean onset ages showed that, regardless of the model studied, two groups of families fit bettermore » than a single group. AD in early-onset families is transmitted as an autosomal dominant trait with full penetrance in both sexes and has a gene frequency of 1.5%. Dominant inheritance also gave the best fit of the data in late-onset families, but this hypothesis was rejected, suggesting the presence of heterogeneity within this subset. Our study also revealed that genetically nonsusceptible males and females develop AD, indicating the presence of phenocopies within early-onset and late-onset groups. Moreover, our results suggest that the higher risk to females is not solely due to their increased longevity. 50 refs., 5 tabs.« less
  • Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO{sub 2} > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F{sub 2} alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expressionmore » in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure.« less