Tissue Oxygenation in Human Renovascular Hypertension

Chronic kidney disease (CKD) is increasing in the U.S., particularly in older individuals. More than eight million people in the US have reduced kidney function. Even minor degrees of CKD attributed to hyper- tension and diabetes predict major cardiovascular risks, including death from myocardial infarction. Both conditions are characterized by small vessel disease within the kidney. Atherosclerosis of the larger renal vessels can accelerate hypertension, is superimposed upon small vessel disease and produces renal injury. Renovascular disease both activates oxidative pathways and produces fibrosis. The regulation of these pathways in human disease is poorly understood. BOLD (Blood Oxygen Level Dependent) magnetic resonance (MR) provides a direct, non-invasive measure of deoxygenated hemoglobin. Experimental studies indicate that BOLD MR levels relate directly to regional oxygen tension within kidney cortex and medulla. Our preliminary results indicate that deoxyhemoglobin changes measured by BOLD MR during blockade of sodium reabsorption are related to levels of irreversible kidney dysfunction in atherosclerotic renovascular disease. The overall hypothesis to be examined in these studies is that deoxygenated hemoglobin signals (the basis for BOLD magnetic resonance methodology), which reflect regional kidney ischemia, predict activation of oxidative and fibrogenic pathways in kidneys with atherosclerotic vascular disease. We propose to utilize these methods as a means of elucidating the pathogenesis and guiding therapy in human atherosclerotic renovascular disease. Our specific aims will examine the role of age, ethnicity and large-vessel renovascular disease under conditions that modify kidney oxygen consumption to examine their role in regulating injury pathways: Aim No. 1 will examine the role of small vessel changes related to age and ethnicity to determine medullary and cortical changes in BOLD MR induced by furosemide and their relationship to regional blood flow (measured by multi-detector CT), oxidative pathways and fibrogenic biomarkers. Aim No. 2 will examine serial changes in medullary and cortical BOLD MR induced by furosemide in stenotic and non-stenotic kidneys after changing levels of oxygen consumption with endovascular revascularization. Aim No. 3 will examine serial changes in regional BOLD MR in stenotic and non-stenotic kidneys during systemic blood pressure reduction using antihypertensive therapy without renalrevascularization. These projects will provide a critical extension into humans from the other studies of our program project related to mechanisms of renovascular hypertension and injury (Romero), microvascular injury and repair (Lerman) and pathways of cell signaling in renal fibrogenic responses (Grande).