Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists

Abstract

Radiation nephropathy has emerged as a significant complication of bone marrow transplantation and radionuclide radiotherapy, and is a potential sequela of radiological terrorism and radiation accidents. In the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies have shown that enalapril (a non-thiol ACE inhibitor) is also effective in the treatment of experimental radiation nephropathy, as are both AII type-1 (AT(1)) and type-2 (AT(2)) receptor antagonists. ACE inhibitors and AII receptor antagonists are also effective in the mitigation (prevention) of radiation nephropathy. Other types of antihypertensive drugs are ineffective in mitigation, but brief use of a high-salt diet in the immediate post-irradiation period significantly decreases renal injury. There are differences between mitigation and treatment of radiation nephropathy that imply that different mechanisms are operating. First, a high-salt diet is effective in the mitigation of radiation nephropathy, but deleterious on the treatment of established disease. Second, AT(1) blockade is more effective than ACE inhibition for mitigation of radiation nephropathy, but equally effective for treatment. Third, the efficacy of AT(1) blockade and ACE inhibition is highly dependent on drug dose in mitigation of radiation nephropathy, but not so in treatment. Finally, while AT(2) blockade augments the benefit of AT(1) blockade in mitigation of radiation nephropathy, it does not do so in treatment. We hypothesize that while mitigation of radiation nephropathy works by suppression of the renin-angiotensin system, treatment of established radiation nephropathy requires blood pressure control in addition to (or possibly instead of) suppression of the renin-angiotensin system.