Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation

Abstract

It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) "Animal Efficacy Rule", we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar®) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m(2)/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.

FIG. 1

Relationship of measured blood urea nitrogen (BUN) after TBI and time to development of uremia, where uremia is defined as a degree of azotemia incompatible with survival. Data are from animals described previously by Moulder et al. (19, 20) and Cohen et al. (14). Open circles show medians and ranges (minimum–maximum) for groups of animals (n = 20) that received TBI alone or TBI plus ineffective mitigators (i.e., low-salt diets, verapamil); closed circles are for individual animals that were given effective mitigators (i.e., captopril, enalapril, high-salt diet). Up-arrows indicate that some animals in the group had not developed azotemia sufficient to require euthanasia after more than 23 weeks of further follow-up. BUN was measured between 17 and 47 weeks after irradiation.

FIG. 2

Time to reach BUN ≥ 120 mg/dl as a function of total-body radiation dose. Data are shown as medians and ranges (minimum–maximum, n = 5–6 per group) for animals receiving TBI alone (●), TBI plus captopril at 17 mg/kg/day (○), or TBI plus losartan at 11 mg/kg/day (□). Drug therapy started 10 days after TBI and continued for 26 weeks. Up-arrows indicate that some animals in the group had still not reached 120 mg/dl after 47 weeks. At 8.9 Gy, four of six animals in the captopril group and three of six animals in the losartan group had still not reached 120 mg/dl after 47 weeks.

FIG. 3

Incidence of renal failure (defined as BUN ≥ 120 mg/dl) after 26 weeks of follow-up as a function of total-body radiation dose. Data are shown for groups (n = 5–6 per group) of animals receiving TBI alone (●), TBI plus captopril at 17 mg/kg/day (○), or TBI plus losartan at 11 mg/kg/day (□). Drug therapy started 10 days after TBI and continued for 26 weeks. Curves are fitted by probit analysis, and horizontal lines at an incidence of 0.5 show the 95% confidence interval for that incidence.

FIG. 4

Azotemia (as BUN) after 17 weeks of follow-up as a function of total-body radiation dose. Data are shown as medians and ranges (minimum–maximum, n = 5–6 per group) for animals receiving TBI alone (●), TBI plus captopril at 17 mg/kg/day (○), or TBI plus losartan at 11 mg/kg/day (□). Drug therapy started 10 days after TBI and continued for 26 weeks. Two animals each in the captopril and losartan groups at 12.2 Gy were euthanized prior to 17 weeks because of high BUN levels. At 12.2 Gy, where animals were euthanized prior to 17 weeks because of high BUN levels, the medians assume infinite BUN values for those animals. Reproduced with permission from Cohen et al. (33).

FIG. 5

Cumulative incidence of renal failure in animals after 8.9–12.2 Gy TBI (10.5 Gy median dose). Data are shown for animals receiving TBI alone (solid line, n = 22), animal receiving TBI plus captopril at 17 mg/kg/day (dotted line, n = 23), and animals receiving TBI plus losartan at 11 mg/kg/day (dashed line, n = 24). Number in parentheses is the number at risk at 38 weeks. Renal failure is significantly delayed by either captopril or losartan (P < 0.001), but the results for the two mitigators did not differ significantly from each other (P > 0.20).