Long-term effects of total-body irradiation on the kidney of Rhesus monkeys

Kleef, E. M. Van; Zürcher, C.; Oussoren, Y.; Poele, Johannes A. M. te; Valk, Martin A. van der; Niemer-Tucker, M. M. B.; Hage, M. H. van der; Broerse, J.J.; Robbins, Michael E.; Johnston, Dennis A.; Stewart, Fiona

doi:10.1080/095530000138303

Cited by 26 publications

(6 citation statements)

References 30 publications

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“…Also, the kidney has been shown to be one of the most radiosensitive late-responding organs in humans with chronic renal injuries occurring after single doses as low as 4–6 Gy. Histopathological evidence of radiation-induced nephropathy as a result of single dose exposure with 7.2 – 8.5 Gy has been demonstrated in rhesus NHPs [55]. …”

Section: Suitability Of Nhps As Animals Models For Studying Radiatmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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Introduction Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans. Area covered The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys. Expert opinion The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes to NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.

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Section: Suitability Of Nhps As Animals Models For Studying Radiatmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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“…The presence of infiltrating leukocytes has been reported in mouse kidney after 26–28 weeks after exposure to 12 Gy radiation [51]. But in the irradiated kidney of rhesus monkey the leukocyte numbers were unchanged between irradiated and control kidneys after 6–8 years of radiation [52]. In the present study, there was no change in the urinary level of an early inflammatory marker, monocyte chemotactic protein-1 (MCP-1) at 12 weeks after 11 Gy TBI (Fig.…”

Section: Discussionmentioning

confidence: 99%

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

et al. 2016

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Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP-epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analog, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared to non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared to control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen compared to control, and EET-A or captopril decreased BUN by 40–60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60–90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50–90%. Renal interstitial fibrosis, tubular, and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which EET-A or captopril mitigated. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on p53/Fas/FasL apoptotic pathway. Overall, this study demonstrates a novel EET-analog based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

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“…NHP models are advantageous due to the closer genetic similarity to humans over other animal models (i.e., murine models), the ability to minimize exogenous variability (e.g., diet) and intraspecific genetic differences seen in human studies (8). In addition, a wealth of information has been collected on primary radiation exposure effects in NHP models, such as postirradiation hematopoiesis (21, 22), damage to the gastrointestinal (GI) tract (23–25) and kidney (26). The acute and prolonged GI syndromes have been described and categorized in detail in total- and partial-body-irradiated NHPs (23, 24).…”

Section: Introductionmentioning

confidence: 99%

Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation

Pannkuk

Laiakis

Authier³

et al. 2015

Radiation Research

129

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Due to concerns surrounding potential large-scale radiological events, there is a need to determine robust radiation signatures for the rapid identification of exposed individuals, which can then be used to guide the development of compact field deployable instruments to assess individual dose. Metabolomics provides a technology to process easily accessible biofluids and determine rigorous quantitative radiation biomarkers with mass spectrometry (MS) platforms. While multiple studies have utilized murine models to determine radiation biomarkers, limited studies have profiled nonhuman primate (NHP) metabolic radiation signatures. In addition, these studies have concentrated on short-term biomarkers (i.e., <72 h). The current study addresses the need for biomarkers beyond 72 h using a NHP model. Urine samples were collected at 7 days postirradiation (2, 4, 6, 7 and 10 Gy) and processed with ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (QTOF) MS, acquiring global metabolomic radiation signatures. Multivariate data analysis revealed clear separation between control and irradiated groups. Thirteen biomarkers exhibiting a dose response were validated with tandem MS. There was significantly higher excretion of L-carnitine, L-acetylcarnitine, xanthine and xanthosine in males versus females. Metabolites validated in this study suggest perturbation of several pathways including fatty acid β oxidation, tryptophan metabolism, purine catabolism, taurine metabolism and steroid hormone biosynthesis. In this novel study we detected long-term biomarkers in a NHP model after exposure to radiation and demonstrate differences between sexes using UPLC-QTOF-MS-based metabolomics technology.

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Long-term effects of total-body irradiation on the kidney of Rhesus monkeys

Abstract: Renal damage after TBI of Rhesus monkeys with single doses of 4.5-8.5 Gy or two fractions of 5.4 Gy was mild, even after follow-up times of 6-8 years.

Cited by 26 publications

References 30 publications

Nonhuman primates as models for the discovery and development of radiation countermeasures

Nonhuman primates as models for the discovery and development of radiation countermeasures

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation

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