Uric Acid in Childhood Hypertension

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DESCRIPTION (provided by applicant): An association between hyperuricemia and hypertension has been observed repeatedly since the 1870s. Generally the link was dismissed as having no causal role because of an assumption that the increase in serum uric acid was merely a surrogate for decreased glomerular filtration rate. Recently the association has been reevaluated because of results from several large clinical trials that implicate hyperuricemia as an independent risk factor for poor cardiovascular outcomes. Our own data demonstrates a close correlation between serum uric acid and primary hypertension in children. Furthermore, data from experiments using a model of mild hyperuricemia in rats reveal that the hyperuricemia alone is (1) sufficient to lead to hypertension and (2) exacerbates the progressive renal injury associated with either Cyclosporin A nephrotoxicity or surgical 5/6 nephrectomy. In the animal model, the mechanisms involved in these processes include uric acid mediated activation of cyclooxygenase-II, activation of the renin angiotensin system and down regulation of renal nitric oxide synthase. If these animal studies can be generalized to human populations, control of mild hyperuricemia will provide a new approach to management of hypertension as well as a novel therapeutic target for the prevention of progressive renal disease and cardiovascular morbidity. We propose to test whether the use of the xanthine oxidase inhibitor allopurinol, a uric acid lowering drug, will (1) ameliorate primary hypertension in children and (2) control hypertension in renal transplant recipients receiving cyclosporin or tacrolimus. We will further investigate the physiological mechanism by which serum uric acid levels are elevated in hypertensive children and the biochemical mechanisms by which elevated serum uric acid lead to increased blood pressure.