C G Duarte1, J Zhang, S Ellis. 1. Division of Cardio-Renal Drug Products, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Laurel, Maryland 20857, USA. duarte@cder.fda.gov
Abstract
RATIONALE AND OBJECTIVES: There is a need for practical and sensitive preclinical tests for detecting the kidney toxicity of chemicals. The spontaneously hypertensive rat (SHR), as it ages, develops renal and cardiovascular changes similar to those considered as human risk factors for radiocontrast-induced renal damage. Age, male gender, and uncontrolled hypertension make these animals susceptible to the volume and osmolality of the administered contrast agent and the effect of repeated contrast administration after a brief interval. This article reviews studies in which the role of these and other factors were evaluated to validate the male SHR as a small animal model for renal damage induced by contrast and other agents. METHODS: Systolic blood pressure was measured with a tail cuff before and after the administration of the experimental substances, and the left kidney and heart were studied histologically to determine the influence of age, dose of contrast repeated at a short interval, gender and strain, the role of the sympathetic adrenergic nervous system, osmolality, and apoptosis. RESULTS: As the animals aged and the systolic blood pressure remained elevated, the animals developed progressive renal lesions that worsened after the administration of contrast. The most advanced renal lesions occurred in adult male SHRs that received two doses of contrast 6 hours apart. Female SHR rats and male Wistar Kyoto rats showed no effect or only minimal changes in heart and kidneys after the administration of contrast compared with age-matched male SHRs. Adrenergic blockade allowed only a small elevation in systolic blood pressure after contrast administration but did not protect the kidneys against renal damage by contrast. Hypaque, Omnipaque, and mannitol caused renal damage in proportion to their osmolality. Apoptosis with Hypaque, Omnipaque, and mannitol was observed in the kidney and heart. CONCLUSION: The results indicate that the aging male SHR develops spontaneous renal lesions that progress with age, increasing the susceptibility to the renal-damaging effects of contrast. Thus, the aging male SHR provides a laboratory tool for detecting the risk of renal damage of new contrast media as well as other pharmaceuticals and assessing methods to protect the kidneys and possible mechanisms of renal damage.
RATIONALE AND OBJECTIVES: There is a need for practical and sensitive preclinical tests for detecting the kidney toxicity of chemicals. The spontaneously hypertensiverat (SHR), as it ages, develops renal and cardiovascular changes similar to those considered as human risk factors for radiocontrast-induced renal damage. Age, male gender, and uncontrolled hypertension make these animals susceptible to the volume and osmolality of the administered contrast agent and the effect of repeated contrast administration after a brief interval. This article reviews studies in which the role of these and other factors were evaluated to validate the male SHR as a small animal model for renal damage induced by contrast and other agents. METHODS: Systolic blood pressure was measured with a tail cuff before and after the administration of the experimental substances, and the left kidney and heart were studied histologically to determine the influence of age, dose of contrast repeated at a short interval, gender and strain, the role of the sympathetic adrenergic nervous system, osmolality, and apoptosis. RESULTS: As the animals aged and the systolic blood pressure remained elevated, the animals developed progressive renal lesions that worsened after the administration of contrast. The most advanced renal lesions occurred in adult male SHRs that received two doses of contrast 6 hours apart. Female SHR rats and male Wistar Kyoto rats showed no effect or only minimal changes in heart and kidneys after the administration of contrast compared with age-matched male SHRs. Adrenergic blockade allowed only a small elevation in systolic blood pressure after contrast administration but did not protect the kidneys against renal damage by contrast. Hypaque, Omnipaque, and mannitol caused renal damage in proportion to their osmolality. Apoptosis with Hypaque, Omnipaque, and mannitol was observed in the kidney and heart. CONCLUSION: The results indicate that the aging male SHR develops spontaneous renal lesions that progress with age, increasing the susceptibility to the renal-damaging effects of contrast. Thus, the aging male SHR provides a laboratory tool for detecting the risk of renal damage of new contrast media as well as other pharmaceuticals and assessing methods to protect the kidneys and possible mechanisms of renal damage.