Review of studies establishing the aging male spontaneously hypertensive rat as a detector and quantifier of the kidney toxicity of radiocontrast media and other chemicals

RATIONALE AND OBJECTIVES. There is a need for practical and sensitive precl inical tests for detecting the kidney toxicity of chemicals. The spontaneou sly hypertensive rat (SHR), as it ages, develops renal and cardiovascular c hanges 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 b rief 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 mod el for renal damage induced by contrast and other agents. METHODS. Systolic blood pressure was measured with a tail cuff before and a fter the administration of the experimental substances, and the left kidney and heart were studied histologically to determine the influence of age, d ose of contrast repeated at a short interval, gender and strain, the role o f the sympathetic adrenergic nervous system, osmolality, and apoptosis, RESULTS. AS the animals aged and the systolic blood pressure remained eleva ted, the animals developed progressive renal lesions that worsened after th e administration of contrast. The most advanced renal lesions occurred in a dult male SHRs that received two doses of contrast 6 hours apart. Female SH R 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 s ystolic blood pressure after contrast administration but did not protect th e kidneys against renal damage by contrast. Hypaque, Omnipaque, and mannito l caused renal damage in proportion to their osmolality, Apoptosis with Hyp aque, Omnipaque, and mannitol was observed in the kidney and heart. CONCLUSIONS. The results indicate that the aging male SHR develops spontane ous 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 med ia as well as other pharmaceuticals and assessing methods to protect the ki dneys and possible mechanisms of renal damage.