Chronic renal ischemia in humans: can cell therapy repair the kidney in occlusive renovascular disease?

Abstract

Occlusive renovascular disease caused by atherosclerotic renal artery stenosis (ARAS) elicits complex biological responses that eventually lead to loss of kidney function. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic and inflammatory cytokines as a result of atherosclerosis, hypoxia, and renal hypoperfusion in this disorder. Human studies emphasize the limits of the kidney adaptation to reduced blood flow, eventually leading to renal hypoxia with activation of inflammatory and fibrogenic pathways. Several randomized prospective clinical trials show that stent revascularization alone in patients with atherosclerotic renal artery stenosis provides little additional benefit to medical therapy once these processes have developed and solidified. Experimental data now support developing adjunctive cell-based measures to support angiogenesis and anti-inflammatory renal repair mechanisms. These data encourage the study of endothelial progenitor cells and/or mesenchymal stem/stromal cells for the repair of damaged kidney tissue.

FIGURE 1.

CT angiographic images CT angiographic images (top) of the right kidneys illustrating three patients with 1) no renal artery stenosis, 2) moderate renal artery stenosis, and 3) severe renal artery stenosis. Below each at bottom are Blood Oxygen Level-Dependent (BOLD) MR images with corresponding R2* parametric maps illustrating higher fraction of axial images with elevated deoxyhemoglobin evident with progressively more severe disease. Figure is from Ref. and used with permission.

FIGURE 2.

Schematic of multiple mechanisms responsible for renal dysfunction in renal artery stenosis Reduced renal blood flow and perfusion activates the renin-angiotensin-aldosterone system (RAAS), triggering oxidative stress and inflammation. Tubulointerstitial hypoxia also promotes oxidative stress and inflammation, leading to apoptosis, tissue injury, and impaired angiogenesis. This in turn leads to hypoxia and tubular dysfunction, tubulointerstitial fibrosis, and renal dysfunction.

FIGURE 3.

Micro-CT images of the kidney in experimental ARAS Micro-CT images of the kidney in experimental ARAS showing improved microvascular architecture in post-stenotic kidney treated with mesenchymal stem cell (MSC) in addition to renal revascularization. MSC, mesenchymal stem cell; ARAS, atherosclerotic renal artery stenosis; PTRA, percutaneous transluminal renal angioplasty. Figure is from Ref. and used with permission.