CicloSAAR: Ciclosporin A Preconditioning for Renal Artery Stenosis

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT03382301

Collaborator

(none)

Enrollment

Location

Arms

50.1

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Artery Stenosis	Drug: Ciclosporin A preconditioning before renal artery stenosis dilation Drug: NaCl preconditioning before renal artery stenosis dilation	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Aug 28, 2018

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)