Ciclosporin A Preconditioning for Renal Artery Stenosis (CicloSAAR)

Impact of a Ciclosporin A Preconditioning for Prevention of Ischemia-reperfusion Injury After Renal Artery Stenosis Dilation

Renal artery stenosis is one the leading cause of secondary hypertension. Previous randomized controlled trials in humans have failed to demonstrate an improvement of renal function after stenosis dilation, probably because of a selection bias with more severe patients being excluded from randomization. Renal ischemia-reperfusion injuries have also not been taken into account. Indeed, reperfusion leads to a rapid renal blood flow recovery associated with renal ischemia-reperfusion injuries.

Mitochondrial permeability transition pore (mPTP) is a key player in the occurrence of ischemia reperfusion injuries because its opening leads to mitochondria leakage and cell death. However, preconditioning whether pharmacological or ischemic can prevent mPTP opening and protect cells. Ciclosporin A can prolong mPTP closing during reperfusion and reduce renal and cardiac tissular lesions. Another mPTP blocker (Bendavia) has been associated with an improvement of renal blood flow (RBF) and glomerular filtration rate (GFR) after renal artery stenosis dilation at 6 weeks in pigs. Based on a recent study, dilation overall benefit could be secondary to an improvement of the contralateral kidney GFR and tissue oxygen content, requiring a single kidney evaluation of those renal functional parameters. The investigators previously demonstrated that dose and timing of ciclosporin A preconditioning is key to protect kidneys from ischemia-reperfusion injuries. Previous controlled trials that failed to demonstrate a benefit of ciclosporin A conditioning have used post conditioning on necrotic cells. Considering kidney ischemia-reperfusion injuries, preconditioning have led to more encouraging results compared to ciclosporin A post conditioning in animals. Therefore the investigators aim to conduct the first clinical study of ciclosporin A preconditioning for prevention of kidney ischemia-reperfusion injuries after renal artery stenosis dilation.

Using renal functional imaging and the new PET-MRI (Positron Emission Tomography-Magnetic Resonance Imaging) combined device, the investigators will evaluate kidney perfusion, oxidative metabolism, glomerular filtration rate and oxygen content before and 3 months after renal artery stenosis dilation with or without a ciclosporin A preconditioning.

Study Overview

• Status: Recruiting
• Conditions: Renal Artery Stenosis
• Intervention / Treatment: Drug: Ciclosporin A preconditioning before renal artery stenosis dilation; Drug: NaCl preconditioning before renal artery stenosis dilation

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sandrine LEMOINE, MD; Phone Number: +33 472 110 263; Email: Sandrine.lemoine01@chu-lyon.fr
• Study Contact Backup: Name: Gabrielle Laetitia NORMAND, MD; Phone Number: +33 472 110 263; Email: laetitia.normand@chu-lyon.fr

Study Locations

• France
  • Lyon, France, 69437
    • Recruiting
    • Service d'Exploration Fonctionnelle Rénale, Hôpital Edouard Herriot, Hospices Civils de Lyon
    • Contact: Sandrine LEMOINE, MD; Phone Number: +33 472 110 263; Email: Sandrine.lemoine01@chu-lyon.fr
    • Contact: Gabrielle Laetitia NORMAND, MD; Phone Number: +33 472 110 263; Email: laetitia.normand@chu-lyon.fr
    • Principal Investigator: Sandrine LEMOINE, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients over 50 years of age
• For women : only menopausal women
• Estimated Glomerular filtration rate ≥ 25 mL/min/1.73m2
• Renal artery stenosis with ≥ 70 % caliber reduction (Doppler or scanner or MRI)
• No controlateral stenosis
• Kidney size ≥ 7 cm
• Only atheromatous renal artery stenosis
• Resistant hypertension and/or rapid loss of kidney function and/or flash pulmonary edema
• Collective decision of dilation after a multidisciplinary meeting

Exclusion Criteria:

• Inclusion in another study
• Protected adults
• Person without a social security coverage
• Imprisoned person
• Systolic blood pressure >180 mmHg and/or diastolic blood pressure > 110 mmHg
• Non atheromatous renal artery stenosis
• Single kidney
• Multiple myeloma
• Iodine contrast agents allergy
• Ciclosporin A hypersensibility
• Severe other medical conditions that could be exacerbated by Iodine injection (cancer, lymphoma, active Hepatitis B, active Hepatitis C, uncontrolled HIV)
• Previous radiation exposure (above 20 mSv (millisievert) in the last 6 months before inclusion)
• MRI contra indications (MRI incompatible pacemaker or insulin pomp, metal clip, MRI incompatible cardiac valve, dental brace, claustrophobia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ciclosporin A preconditioning; Ciclosporin A preconditioning before renal artery stenosis dilation	Drug: Ciclosporin A preconditioning before renal artery stenosis dilation; Ciclosporin A perfusion (2.5 mg/kg) for 1 hour before renal artery dilation
Placebo Comparator: NaCl preconditioning	Drug: NaCl preconditioning before renal artery stenosis dilation; NaCl perfusion (Saline perfusion) for 1 hour (2.5 mg/kg) before renal artery dilation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in relative increase (baseline and 3 months after) of global renal perfusion between the two groups	Global renal perfusion is assessed by 15O labeled water PET (Positron Emission Tomography) imaging	3 months after renal artery stenosis dilation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in the relative increase (baseline and 3 months after) of global renal oxidative metabolism between the two groups	Global renal oxidative metabolism is assessed by 11C labeled acetate PET (Positron Emission Tomography) imaging	3 months after renal artery stenosis dilation
Difference in the relative increase (baseline and 3 months after) of global renal oxygen content between the two groups	Global renal oxygen content is assessed by BOLD MRI (Blood-Oxygen-Level Dependent Magnetic Resonance Imaging)	3 months after renal artery stenosis dilation
Difference in the relative increase (baseline and 3 months after) of global glomerular filtration rate between the two groups	Global glomerular filtration rate is assessed by Iohexol measured clearance	3 months after renal artery stenosis dilation
Difference in the relative increase (baseline and 3 months after) of single-kidney perfusion (ischemic versus contralateral kidney) between the two groups	Kidney perfusion is assessed by 15O labeled water PET (Positron Emission Tomography) imaging	3 months after renal artery stenosis dilation

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2018
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2023

Study Registration Dates

• First Submitted: December 13, 2017
• First Submitted That Met QC Criteria: December 18, 2017
• First Posted (Actual): December 22, 2017

Study Record Updates

• Last Update Posted (Actual): April 19, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Renal artery stenosis; Ischemia reperfusion injuries; Renal functional imaging
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arterial Occlusive Diseases; Kidney Diseases; Urologic Diseases; Postoperative Complications; Pathological Conditions, Anatomical; Reperfusion Injury; Constriction, Pathologic; Renal Artery Obstruction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 69HCL16_0823; 2017-002937-48 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No