Mitigation of experimental radiation nephropathy by renin-equivalent doses of angiotensin converting enzyme inhibitors

Abstract

Purpose: We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system.

Method: 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals.

Results: PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipril.

Conclusions: Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis). Fosinopril is known to be an ineffective mitigator of radiation pneumonitis, and it also does not mitigate radiation nephropathy. These pre-clinical data are critical in planning human studies of the mitigation of normal tissue radiation injury.

Keywords: ACE inhibitors; captopril; mitigation; plasma renin activity; radiation nephropathy; total body irradiation.

Figure 1

Relationship between log of the drug dose (as mg/l in the drinking water and as mg/m²/day) and plasma renin activity (PRA) for captopril (●) vs. enalapril (○). PRA after 10 days on drug is plotted for individual unirradiated animals as a function of drug dose. Solid lines show parallel fits to the data (see Statistical Methods). The shaded area shows the 95% confidence interval for PRA in age-matched normal (unirradiated without drug) animals.

Figure 2

Relationship between log of the drug dose (as mg/m²/day) and PRA for captopril (●), fosinopril (□, dotted line), lisinopril (◊, dot-dash line) and ramipril (△, dashed line). The curve for enalapril (from Fig 1) is shown as a gray line. PRA after 10 days on drug in unirradiated animals is plotted (means with 95% confidence intervals) as a function of drug dose. The lines for fosinopril, lisinopril and ramipril show parallel line fits to captopril; the fits are based on the raw data. The shaded area shows the 95% confidence interval for PRA in age-matched normal (unirradiated without drug) animals.

Figure 3

Morbidity (BUN = 120 mg/l) incidence curves after 10 Gy TBI (plus BMT) for animals given ACEI at doses that caused equivalent elevation of PRA in normal animals that were on ACEI for 10 days. Drugs were given in the drinking water starting immediately after TBI and continuing for the duration. Data are shown for captopril at 300 mg/l (n=19), enalapril at 30 mg/l (n=9), fosinopril at 10 mg/l (n=8), lisinopril at 7–12 mg/l (n=14), and ramipril at 1.2 mg/l (n=9). Data are also shown for matched animals not given ACEI (n=16). Plotted incidence curves terminate at 44 weeks or when there were less than 2 animals still at risk.

Figure 4

Time to morbidity (BUN = 120 mg/l) after 10 Gy TBI (plus BMT) as a function of PRA measured 10 days after TBI in the same animals. Data are shown for animals not given ACEI (X) and for animals given captopril (●), enalapril (○) fosinopril (□), lisinopril (◊) or ramipril (△). There were 14 animals not given ACEI, 17 given captopril, and 7–9 per group for the other ACEI. Drugs were given in the drinking water starting immediately after TBI and continuing for the duration, and the dose (in mg/l) is shown next to each point. Time to morbidity is shown as medians with 10–90% ranges; up arrows on the error bar indicate that >10% of animals were still alive (with BUN<120 mg/l) at 44 weeks; for the two highest doses of lisinopril all animals still has BUN<120 mg/dl at 44 weeks. The dashed line shows the linear trend of the data, but the actual analysis used the Kendall τ-test which does not assume linearity.

Figure 5

Azotemia (as BUN) 21 weeks after 10 Gy TBI (plus BMT) as a function of PRA measured 10 days after TBI in the same animals. Data are shown for animals not given ACEI (X) and animals given captopril (●), enalapril (○) fosinopril (□), lisinopril (◊) or ramipril (△). Drugs were given in the drinking water starting immediately after TBI and continuing for the duration, and the dose (in mg/l) is shown next to each point. These are the same animals shown in Fig 4. BUN values are shown as means with 95% confidence intervals; and the shaded area shows BUN for normal age-matched animals. The dashed line shows the linear trend of the data, but the actual analysis used the Kendall τ-test which does not assume linearity.