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Abstract
Purpose
A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue toxicities in exposed victims. With the advent of advanced treatment options for the mitigation of hematological injuries, there are likely to be survivors of total body irradiation (TBI) exposures as high as 8–10 Gy. These survivors are at risk for a range of delayed multi-organ morbidities including progressive renal failure.
Material and methods
Here, we established the WAG/RijCmcr rat as an effective model for the evaluation of medical countermeasures (MCM) for acute hematologic radiation syndrome (H-ARS). The LD50/30 dose for adult and pediatric WAG/RijCmcr rats was determined for both sexes. We then confirmed the FDA-approved MCM pegfilgrastim (peg-GCSF, Neulasta®) mitigates H-ARS in adult male and female rats. Finally, we evaluated survival and renal dysfunction up to 300 d post-TBI in male and female adult rats.
Results
In the WAG/RijCmcr rat model, 87.5% and 100% of adult rats succumb to lethal hematopoietic acute radiation syndrome (H-ARS) at TBI doses of 8 and 8.5 Gy, respectively. A single dose of the hematopoietic growth factor peg-GCSF administered at 24 h post-TBI improved survival during H-ARS. Peg-GCSF treatment improved 30 d survival from 12.5% to 83% at 8 Gy and from 0% to 63% at 8.5 Gy. We then followed survivors of H-ARS through day 300. Rats exposed to TBI doses greater than 8 Gy had a 26% reduction in survival over days 30–300 compared to rats exposed to 7.75 Gy TBI. Concurrent with the reduction in long-term survival, a dose-dependent impairment of renal function as assessed by blood urea nitrogen (BUN) and urine protein to urine creatinine ratio (UP:UC) was observed.
Conclusion
Together, these data show survivors of H-ARS are at risk for the development of delayed renal toxicity and emphasize the need for the development of medical countermeasures for delayed renal injury.
Disclosure statement
The authors have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
Additional information
Funding
Notes on contributors
Tracy Gasperetti
Tracy Gasperetti is a lab manager in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Anne Frei
Anne Frei is a research program coordinator in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Guru Prasad Sharma
Guru Prasad Sharma, PhD, is Postdoctoral fellow in the laboratory of Dr. Himburg in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Lauren Pierce
Lauren Pierce is a research technician in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Dana Veley
Dana Veley is a research technician in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Nathan Szalewski
Nathan Szalewski is a research technician in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Srishti Munjal Mehta
Srishti Munjal Mehta, PhD, is a scientist in research and development at Myelo Therapeutics Gmbh, Berlin, Germany.
Brian L. Fish
Brian L. Fish is Program Director of Radiation Biology in the Department of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, WI, USA.
Dirk Pleimes
Dirk D. Pleimes, MD, is a physician-scientist in research and drug development and Chief Executive Officer at Myelo Therapeutics Gmbh, Berlin, Germany.
Heather A. Himburg
Heather A. Himburg, PhD, is an Associate Professor of Radiation Oncology and Biomedical Engineering at the Medical College of Wisconsin, Milwaukee, WI, USA.