Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis

Ahmed Saad, Sandra Herrmann, Alfonso Eirin, Christopher M. Ferguson, James Glockner, Haraldur Bjarnason, Michael A. McKusick, Sanjay Misra, Lilach O Lerman, Stephen C Textor

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Abstract

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 (20229-262115 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..

Original languageEnglish (US)
Article numbere005487
JournalCirculation: Cardiovascular Interventions
Volume10
Issue number9
DOIs
StatePublished - Jul 1 2017

Fingerprint

Renal Artery Obstruction
Stents
Clinical Trials
Kidney
Angioplasty
Renal Circulation
arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
Placebos
Glomerular Filtration Rate
Oxygen
Blood Pressure
Cardiolipins
Reperfusion Injury

Keywords

  • angioplasty
  • Hypoxia
  • Kidney
  • Magnetic Resonance Imaging
  • Renal Artery Stenosis
  • Renovascular Hypertension
  • Reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{e60b64f5550748ab8839e13913948a0a,
title = "Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis",
abstract = "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 (20229-262115 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..",
keywords = "angioplasty, Hypoxia, Kidney, Magnetic Resonance Imaging, Renal Artery Stenosis, Renovascular Hypertension, Reperfusion injury",
author = "Ahmed Saad and Sandra Herrmann and Alfonso Eirin and Ferguson, {Christopher M.} and James Glockner and Haraldur Bjarnason and McKusick, {Michael A.} and Sanjay Misra and Lerman, {Lilach O} and Textor, {Stephen C}",
year = "2017",
month = "7",
day = "1",
doi = "10.1161/CIRCINTERVENTIONS.117.005487",
language = "English (US)",
volume = "10",
journal = "Circulation: Cardiovascular Interventions",
issn = "1941-7640",
publisher = "Lippincott Williams and Wilkins",
number = "9",

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TY - JOUR

T1 - Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis

AU - Saad, Ahmed

AU - Herrmann, Sandra

AU - Eirin, Alfonso

AU - Ferguson, Christopher M.

AU - Glockner, James

AU - Bjarnason, Haraldur

AU - McKusick, Michael A.

AU - Misra, Sanjay

AU - Lerman, Lilach O

AU - Textor, Stephen C

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 (20229-262115 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..

AB - 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 (20229-262115 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..

KW - angioplasty

KW - Hypoxia

KW - Kidney

KW - Magnetic Resonance Imaging

KW - Renal Artery Stenosis

KW - Renovascular Hypertension

KW - Reperfusion injury

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U2 - 10.1161/CIRCINTERVENTIONS.117.005487

DO - 10.1161/CIRCINTERVENTIONS.117.005487

M3 - Article

C2 - 28916603

AN - SCOPUS:85029758338

VL - 10

JO - Circulation: Cardiovascular Interventions

JF - Circulation: Cardiovascular Interventions

SN - 1941-7640

IS - 9

M1 - e005487

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