Renal Denervation in Diabetic Nephropathy

Study Overview
=================
Brief Summary
-----------------
The DERENEDIAB study is a proof-of-concept, multi-center, prospective, open, randomized, controlled study of the effectiveness of renal denervation in addition to standardized medical treatment compared to medical treatment alone in diabetic subjects with diabetic nephropathy and resistant proteinuria. Bilateral renal denervation will be performed using the Symplicity Catheter - a percutaneous system that delivers radiofrequency (RF) energy through the luminal surface of the renal artery.

Detailed Description
-----------------
The DERENEDIAB study is a proof-of-concept multi-center, prospective, open, randomized, controlled study of the effectiveness of renal denervation in addition to standardized medical treatment compared to medical treatment alone in diabetic subjects with diabetic nephropathy and resistant proteinuria. Bilateral renal denervation will be performed using the Symplicity Catheter - a percutaneous system that delivers radiofrequency (RF) energy through the luminal surface of the renal artery.

Official Title
-----------------
Renal Denervation in Patients With Diabetic Nephropathy and Persistent Proteinuria

Conditions
-----------------
Diabetic Nephropathy, Persistent Proteinuria With Type II Diabetes

Intervention / Treatment
-----------------
* Procedure: Percutaneous renal denervation and TMNS
* Drug: Standardized antiproteinuric medication regimen includes an angiotensin receptor blocker , a diuretic , 25OH vitamin D3 and a statin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetes mellitus male or female patient Individual is > 18 and ≤ 75 years old Diabetic nephropathy (if no pathological examination, diagnosis based on the association of history of diabetes, diabetic retinopathy and no hematuria) Proteinuria/creatininuria ratio > 0.1 g/mmol lasting for 8 weeks Under stable medication regimen including for at least 2 months full tolerated doses of al least 1 RAAS blocker (ACEI, renin inhibitor, ARB) and a diuretic 2 functional kidneys sizing ≥ 90 mm; eGFR > 20 mL/min/1.73m² (MDRD formula Suitable aorto-renal vascular anatomy compatible with the endovascular denervation procedure; Informed consent has been signed Health insurance policy active Exclusion Criteria: Patients with an estimated glomerular filtration rate (eGFR) of less than 20 mL/min/1.73 m2 Patients unable to sign an informed consent, to understand the protocol, living too far from the specialized center Non-diabetic renal disease Patients with severe hypertension (grade 3 ESH classification) Kaliemia ≥ 6mmol/L History of nephrogenic fibrosis-induced MRI contrast media Patient with single functioning kidney Patient with contrast media allergy Patient with any implantable device incompatible with low frequency waves delivery Patient with contra-indication to the anti-proteinuric standardized medication regimen Patient with transient or fixed cerebral ischemia within 3 months before inclusion Patient with myocardial infarction, unstable angina pectoris, coronary bypass or percutaneous angioplasty within 3 months before inclusion Patient with asthma or chronic obstructive pulmonary disease with a contra-indication to beta-blockers medication Patient with type 1 diabetes mellitus Uncontrolled type 2 diabetes mellitus (Hb1Ac > 10%) Patient with malignancy within the 5 past years Patient with any medical or surgical condition that could worsen the risk of the study, according to the investigator; Patient with chronic alcohol consumption Patient with atrial fibrillation and/or a brachial circumference of ≥ 42cm Patient is pregnant, nursing or planning to be pregnant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denervation + TMNS<br>Patients are treated with the renal denervation procedure after randomization and are maintained on standardized anti-proteinuric medications | Procedure: Percutaneous renal denervation and TMNS<br>* Patients are treated with the renal denervation procedure after randomization and are maintained on standardized anti-proteinuric medications<br>|
| Active Comparator: TMNS<br>Patients are maintained on standardized anti-proteinuric medications | Drug: Standardized antiproteinuric medication regimen includes an angiotensin receptor blocker , a diuretic , 25OH vitamin D3 and a statin<br>* Patients are maintained on Standardized antiproteinuric medication regimen includes an angiotensin receptor blocker (irbesartan 300mg), a diuretic (furosemide 40mg or indapamide LP 1.5mg according to the eGFR), 25OH vitamin D3 and a statin (atorvastatin 20mg)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proteinuria/creatininuria ratio |  | from baseline to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with a decrease of the PU/CrU >50% ratio |  | from baseline to 1 year | 
| Evaluation of the slope of decay of the PU/CrU |  | from baseline to 1 year | 
| eGFR is estimated by the MDRD formula, and is expressed in mL/min/1.73m². The direct GFR will be assessed by measuring the 51Cr-EDTA plasmatic clearance | eGFR is estimated by the MDRD formula, and is expressed in mL/min/1.73m². The direct GFR will be assessed by measuring the 51Cr-EDTA plasmatic clearance | from baseline to 1 year | 
| Outcome of the GFR assessed by 51Cr-EDTA clearance | Only in the experimental arm | from randomisation to 1 year | 
| Decrease of the blood pressure assessed on ABPM |  | From randomisation to 1 year | 
| Anti-hypertensive regimen score |  | from baseline to 1 year | 
| Evaluation of the renal arterial anatomy | in the experimental group:number of principal renal artery. Should be 1/ kidney of at least 4mm diameter and 10mm long. One accessory artery is acceptable if < | from baseline to 1 year | 
| Evaluation of safety and tolerance of renal denervation in diabetic patients with overt proteinuria | in the experimental group:Occurrence of adverse events: acute renal failure, damage on the renal artery (dissection, perforation, thrombosis), allergy to the contrast media, worsening of any dysautonomia | from baseline to 1 year | 
| Evaluate the outcome of biological parameters | eGFR (MDRD formula), proteinuria/creatininuria ratio | from baseline to 1 year | 
| Evaluate the diabetic neuropathy/dysautonomy | in the experimental:blood pressure in orthostatism, pulse wave velocimetry, RR interval on the Holter ECG, cutaneous baroreflex | from randomisation to 1 year | 
| Evaluate the outcome of specific kidney injury markers | in the experimental group:urinary levels of KIM1 and NGAL before and 1 year after the denervation | from randomisation to 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic nephropathy, renal denervation, nephroprotection, Renal failure, Renal injury, End stage renal disease