TGF Expression and Macrophage Accumulation in Atherosclerotic Renal Artery Stenosis

Abstract

SummaryBackground and objectives Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow and is a potential cause of chronic kidney injury, yet little is known regarding inflammatory pathways in this disorder in human participants. This study aimed to examine the hypothesis that reduced renal blood flow (RBF) in ARAS would be associated with tissue TGF-b activation and inflammatory cell accumulation.Design, setting, participants, & measurements This cross-sectional study of ARAS of varying severity compared transjugular biopsy specimens in patients with ARAS (n=12, recruited between 2008 and 2012) with tissue from healthy kidney donors (n=15) and nephrectomy specimens from individuals with total vascular occlusion (n=65). ARAS patients were studied under controlled conditions to measure RBF by multidetector computed tomography and tissue oxygenation by blood oxygen level-dependent magnetic resonance imaging.Results Compared with the nonstenotic contralateral kidneys, RBF was reduced in poststenotic kidneys (2426149 versus 365+174 ml/min; P,0.01) as was single-kidney GFR (28617 versus 41619 ml/min; P,0.01), whereas cortical and medullary oxygenation were relatively preserved. Tissue TGF-b immunoreactivity was higher in ARAS patients compared with those with both normal kidneys and those with total occlusion (mean score 2.460.7 versus 1.5+1.1 in the nephrectomy group and versus 060 in donors; P,0.01). By contrast, the number of CD68+ macrophages was higher with greater disease severity (from 2.262.7 in normal to 22.4618 cells/highpower field in nephrectomy samples; P,0.001).Conclusions The results of this study indicate robust stimulation of TGF-b associated with macrophage infiltration within the human kidney with vascular occlusive disease.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…Under these circumstances cortical hypoxia is overt, leading to activation of the reninangiotensin-aldosterone system, loss of kidney function, rarefaction of small renal vessels, kidney fibrosis, atrophy, and end stage kidney disease designated "ischemic nephropathy". 221,223,[224][225][226][227][228] The connection between atherosclerosis-driven renal hypoxia and CKD is underscored by the finding that the preservation of microvascular architecture by intra-renal administration of vascular endothelial growth factor decreases renal fibrosis and maintains renal hemodynamics and function in an experimental model of renal artery stenosis. 224 In addition, when femoropopliteal angioplasty restores the lumen diameter in patients with generalized atherosclerosis, the incidence of renal disease is dramatically reduced.…”

Attending Rounds

“…Some have suggested that an index of kidney volume as determined by magnetic resonance with relatively reduced function by radionuclide scan may identify hibernating renal tissue (17). We have been impressed that advancing vascular occlusion does, indeed, produce cortical hypoxia at some point, which was illustrated using BOLD magnetic resonance in the right kidney ( Figure 4); it activated inflammatory injury pathways with accumulation of macrophages, which is known to attract T lymphocytes within the renal parenchyma (18,19). In the past, Kaylor et al (20) advocated for kidney biopsy before surgical renal artery bypass to identify kidney fibrosis and/or atheroembolic disease, although it has not been widely practiced.…”

Paradigm Shifts in Atherosclerotic Renovascular Disease

“…40,41 Biopsies from human subjects confirm that cellular infiltrates accumulate in poststenotic kidneys and that inflammatory signaling is correlated with the degree of tissue hypoxia within the poststenotic kidney cortex. 32 34 No such differences regarding B-lymphocyte (CD20 + ) cell counts were observed. Importantly, genetic knockout of downstream pathways (SMAD-3) for TGF-b in models of experimental renovascular disease protects the poststenotic kidney from occlusive vascular injury.…”

“…Histologic inflammation in patients with advanced ARVD is characterized by extensive T cell and macrophage infiltration in addition to fibrosis. 33,34 Hence, it is equally clear that beyond the limits of tolerable reduction in blood flow, overt cortical hypoxia associated with more severe inflammatory injury eventually develops in the poststenotic kidney, as illustrated in Figure 2.…”