Changes in Glomerular Filtration Rate After Renal Revascularization Correlate With Microvascular Hemodynamics and Inflammation in Swine Renal Artery Stenosis

Abstract

Background Selection of patients with renal artery stenosis (RAS) likely to improve glomerular filtration rate (GFR) after percutaneous transluminal renal angioplasty (PTRA) is difficult. We examined basal hemodynamic and inflammatory factors linked to improved stenotic kidney (STK) function after PTRA in swine RAS. Methods and Results Fifteen pigs after 6 weeks of hemodynamically-significant RAS were studied before and 4 weeks after technically-successful PTRA+stenting. STK and contralateral kidney (CLK) hemodynamics and function were evaluated by multi-detector computed-tomography before and after acetylcholine challenge. Single-kidney deoxyhemoglobin (R2*, reciprocal to blood relaxation) and energy-dependent tubular function were assessed using blood-oxygen-level-dependent magnetic resonance imaging (BOLD-MRI) before and after furosemide. Baseline renal vein (RV) and inferior vena cava (IVC) levels of inflammatory markers were measured, and their gradient and net release calculated. Baseline parameters were compared to normal (n=7) and sham RAS (n=7) pigs, and correlated with the change in STK-GFR after revascularization (ΔGFR). Four weeks after PTRA blood pressure was normalized in all animals, but STK-GFR improved in 10/15 (ΔGFR=+22.0±8.5mL/min). ΔGFR correlated inversely with basal STK-GFR, renal release of inflammatory markers, and medullary R2* response to furosemide, but directly with GFR response to acetylcholine. Basal CLK-GFR directly correlated with ΔGFR. Conclusions Low basal STK-GFR with preserved response to acetylcholine may predict benefit from revascularization in RAS, while renal inflammation and robust STK-R2* responses to furosemide (possibly reflecting avid tubular oxygen consumption) are associated with less favorable outcomes. These tools may be useful for identification of patients likely to improve renal function after revascularization.

Revascularization in Experimental Atherosclerotic Renal Artery Stenosis: Role of Mitochondrial Targeted Peptides (Bendavia)

“…In line with these observations, we have recently shown in swine ARAS that systemic infusion of Bendavia during the PTRS procedure (from 30min before to 3.5 hours after PTRS), promoted renal mitochondrial biogenesis and attenuated microvascular remodeling, apoptosis, oxidative stress, tubular damage, and fibrosis evaluated four weeks after revascularization [20]. Furthermore, renal inflammation, one of the main determinants of disease progression and response to revascularization in ARAS [21], was restored to normal levels in Bendavia-treated pigs. Remarkably, stenotic-kidney blood flow and glomerular filtration rate were normalized in animals treated with Bendavia, suggesting a unique potential of this drug for limiting renal reperfusion injury in chronic experimental ARAS.…”

Early atherosclerosis aggravates renal microvascular loss and fibrosis in swine renal artery stenosis

“…[2] In a previous study, we found that stenotic swine kidneys in ARAS have increased tissue levels of the pro-inflammatory chemokine monocyte chemo-attractant protein (MCP-1), which is associated with endothelial dysfunction and microvascular loss. [26] Elevated systemic levels of tumor necrosis factor (TNF)-α and MCP-1 in ARAS patients also persist after revascularization.…”

“…Mean arterial pressure (MAP) was subsequently measured by a PhysioTel® telemetry system (Data Sciences International, St. Paul, MN) implanted at baseline in the left femoral artery and averaged in the last 2–3 days before study completion. [2,7–9] …”

“…[17] The degree of stenosis was calculated as the decrease in renal arterial luminal area, as previously described. [2] …”

“…RAS is an important cause of secondary hypertension in the elderly population, [1] that may ultimately lead to advanced kidney injury. [2] The reported prevalence of clinically manifest atherosclerotic RAS (ARAS) in the Medicare population is approximately 0.5% overall, and 5.5% in those with chronic kidney disease. [3] Because atherosclerotic renovascular disease is often asymptomatic, the true frequency may be higher.…”