ACE inhibitors and AII receptor antagonists in the treatment and prevention of radiation nephropathy

Radiation nephropathy has emerged as a major complication of bone marrow transplantation when total body irradiation is used as part of the regimen. More recently, radiation nephropathy has also appeared as a complication of radionuclide radiotherapy. Classically, radiation nephropathy was assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, we demonstrated that established experimental radiation nephropathy could be treated with angiotensin converting enzyme (ACE) inhibitors, and that early use of ACE inhibitors could retard the development of radiation nephropathy. A placebo-controlled clinical trial of ACE inhibitors to prevent radiation nephropathy in bone marrow transplant patients is now underway at our institution. In further studies, we showed that an angiotensin II (AII) type-1 receptor antagonist was also effective in treatment and prophylaxis of radiation nephropathy, and most recently we have found that combined use of AII type-1 and type-2 receptor antagonists is even more effective than ACE inhibitors or type-1 receptor antagonists alone. An obvious explanation for the efficacy of AII receptor blockade in radiation nephropathy would be that radiation leads to activation of the renin-angiotensin system. However, studies done to date have found no evidence that renal irradiation leads to excess levels of renin or AII, and no evidence for radiation-induced up-regulation of AII receptors. An alternative explanation for the efficacy of these agents in prophylaxis would be that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that the prophylactic efficacy of ACE inhibitors and AII receptor blockers may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. However, while prevention of radiation nephropathy with ACE inhibitors and AII receptor antagonists may work via suppression of the renin-angiotensin system, their efficacy in treatment of established radiation nephropathy appears to depend on blood pressure control as well