Herrmann, Sandra M S

Background— Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function. We tested the hypothesis that elamipretide plus PTRA would improve renal function, oxygenation, and RBF in patients with atherosclerotic renal artery stenosis undergoing PTRA. Methods and Results— Inpatient studies were performed in patients with severe atherosclerotic renal artery stenosis scheduled for PTRA. Patients were treated before and during PTRA with elamipretide (0.05 mg/kg per hour intravenous infusion, n=6) or placebo (n=8). Stenotic kidney cortical/medullary perfusion and RBF were measured using contrast-enhanced multidetector CT, and renal oxygenation by 3-T blood oxygen level−dependent magnetic resonance imaging before and 3 months after PTRA. Age and basal glomerular filtration rate did not differ between groups. Blood oxygen level−dependent imaging demonstrated increased fractional hypoxia 24 hours after angiography and stenting in placebo (+47%) versus elamipretide (−6%). These were reverted to baseline 3 months later. Stenotic kidney RBF rose (202±29–262±115 mL/min; P =0.04) 3 months after PTRA in the elamipretide-treated group only. Over 3 months, systolic blood pressure decreased, and estimated glomerular filtration rate increased ( P =0.003) more in the elamipretide group than in the placebo group ( P =0.11). Conclusions— Adjunctive elamipretide during PTRA was associated with attenuated postprocedural hypoxia, increased RBF, and improved kidney function in this pilot trial. These data support a role for targeted mitochondrial protection to minimize procedure-associated ischemic injury and to improve outcomes of revascularization for human atherosclerotic renal artery stenosis. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01755858.

Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertension patients. Inflammatory biomarkers and EPC homing signal levels and renal release were calculated. Inferior vena cava and renal vein–obtained EPC function were similar in ARAS and essential hypertension patients and comparable to that in normal controls (tube length, 171.86±16.846, 191.09±14.222, 174.925±19.774 μm, respectively). Function of renal vein–obtained EPCs directly correlated with stenotic kidney glomerular filtration rate, EPC homing factors, and anti-inflammatory mediator levels in ARAS patients. Therefore, EPC function was relatively preserved in ARAS patients, although it directly correlated with renal function. Adequate EPC function supports the feasibility of using autologous EPCs as a therapeutic option in essential and renovascular hypertensive patients. Homing signals and inflammatory mediators may potentially regulate EPC angiogenic function.