The Role of Hypoxia in Ischemic Chronic Kidney Disease

A gradually developing reduction in renal blood flow from atherosclerotic renovascular disease results in loss of kidney volume and a decrease in glomerular filtration rate that eventually becomes irreversible. Whether this process fundamentally reflects tissue hypoxia has been difficult to establish. Studies of human renovascular disease have indicated that reductions in blood flow of up to 30% to 40% can be tolerated with preservation of normal oxygenation and structural integrity. These observations are consistent with remarkable stability of poststenotic kidney function during sustained medical antihypertensive drug therapy in moderate renovascular disease. With more severe and sustained reductions, however, cortical oxygenation decreases and the magnitude of medullary hypoxia expands. These changes are associated with increasing renal venous levels of inflammatory cytokines, angiogenic markers, and infiltration of inflammatory cells, including tissue macrophages and T cells. Although restoring large-vessel blood flow can improve oxygenation, some of these processes reflect microvascular rarefication, remain activated, and do not depend on hemodynamic factors alone. Elucidation of tissue injury pathways associated with hypoxia opens the possibility of adjunctive therapeutic measures beyond renal revascularization. These include cell-based regeneration, mitochondrial protection, and/or angiogenic cytokine therapy to restore or preserve renal function in ischemic nephropathy.