For years the diagnosis, .evaluation of renal function and the treatment of renovascular hypertension has been the subject of intense debate. Most of these uncertainties are due to the lack of important information about the changes in intrarenal hemodynamics, glomerular filtration rate and proximal and distal tubular function in the stenotic kidney (ST-KD) as well as in the contralateral kidney (CONT-KD). Renal clearances are not useful in these conditions because of mixture of urine in the bladder whereas independent catheterization of ureters (split renal function) lead to pyelonephritis. In this proposal we intend to answer these questions by using a novel three-dimensional tomographer with high temporal resolution that measures accurately individual kidney blood flow (including cortical and medullary flow), proximal loop of Henle and distal tubular fluid flow and fluid reabsorption. Actual renal ischemia is measured in each kidney by estimating with magnetic resonance imaging (MRI), blood (capillary) oxygen (O2) levels of deoxyhemoglobin (BOLD technique). In the kidney O2 consumption is determined by sodium (Na) reabsorption in distal tubules by Na, K ATPase. Its inhibition with furosemide suppress O2 consumption (FSOC) and decrease blood levels of deoxyhemoglobin. The proposal contains three specific aims. In the first, the hypothesis to be tested is that the degree of arterial obstruction will determine a) the stage of functional deficit in the ST-KD;b) the degree of increase in blood pressure;and c) the functional compensation reaction (hypertrophy) of the CONT-KD. These different responses will correlate with either increases (CONT-KD) or decreases (ST-KD) of Na delivery and O2 consumption in distal nephrons. The second specific aim tests the hypothesis that the efficacy of PTRA to restore renal function is determined by a) the degree of atrophy and functional decline in the ST-KD;b) the amount of ST-KD function that has been transferred to CONT-KD;c) the degree of hypertension;and d) the inability of furosemide to induce O2 suppression. This study will define the conditions under which PTRA is successful in recovering renal function in both the ST- and CONT-KD. Finally, the third specific aims, tests the hypothesis that normalization of hypertension by medical treatment significantly aggravates the function of the ST-KD but may be beneficial to recover CONT-KD function. The conditions under which the CONT-KD may benefit from medical treatment are related to the possible reversal of vascular hyperplasia in preglomerular arterioles and that residual circulation is sufficient to meet the metabolic demands of tubular hypertrophy. It is also assumes that anti-hypertensives that suppress the production of angiotensin II or oxidative stress will be more effective in reversal of renal function to normal than non-specific vasodilators. Elucidation of all these issues will have enormous clinical repercussion in the diagnosis, follow up, and treatment of renovascular hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Mayo Clinic, Rochester
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Saad, Ahmed; Dietz, Allan B; Herrmann, Sandra M S et al. (2017) Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease. J Am Soc Nephrol 28:2777-2785
Wang, Wei; Saad, Ahmed; Herrmann, Sandra M et al. (2016) Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis. Nephrol Dial Transplant 31:1437-43
Kashyap, Sonu; Warner, Gina M; Hartono, Stella P et al. (2016) Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. Am J Physiol Renal Physiol 310:F372-84
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Saad, Ahmed; Wang, Wei; Herrmann, Sandra M S et al. (2016) Atherosclerotic renal artery stenosis is associated with elevated cell cycle arrest markers related to reduced renal blood flow and postcontrast hypoxia. Nephrol Dial Transplant 31:1855-1863
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