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Telmisartan Promotes the Differentiation of Monocytes Into Macrophages M2 in Diabetic Nephropathy?

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ClinicalTrials.gov Identifier: NCT02768948
Recruitment Status : Unknown
Verified July 2018 by Centre Hospitalier Universitaire de Nice.
Recruitment status was:  Recruiting
First Posted : May 11, 2016
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Nice

Study Description
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Brief Summary:

The severity of the diabetic nephropathy is proportional to proteinuria rate and degree of renal interstitial fibrosis. Despite many treatments available today, diabetic nephropathy is responsible for a quarter of cases of end-stage renal disease (ESRD) requiring the use of renal replacement therapy or kidney transplantation. It develops as follows: chronic hyperglycemia of diabetes abyss renal glomeruli that allow proteins in the urine room. In response, the tubular epithelium produces monocyte chemoattractant protein-1 (MCP-1) that attracts monocytes circulating in the renal interstitium. Monocytes then differentiate into M1 or M2 macrophages. M1 macrophages increased MCP-1 production while M2 macrophages produce transforming growth factor beta (TGF-β) pro-fibrogenic. Renal fibrosis is negatively correlated with the glomerular filtration rate itself proportional to the number of nephrons. The decrease in the number of nephrons majorises secondarily proteinuria by the onset of focal segmental glomerulosclerosis lesions. Production of MCP-1 increases with the renal proteinuria because M1 macrophages earning kidneys reinforce the production of MCP-1, and fibrosis worsens because M2 macrophages infiltrate in turn kidneys and produce TGF -β.

A way of limiting renal fibrosis would be to decrease renal monocytic infiltration by promoting the differentiation of monocytes towards macrophages M2. Although more numerous, M2 macrophages no longer benefit the kidneys because the decline of M1 macrophages decrease renal MCP-1 production. Ex vivo IL1-β orients the differentiation of monocytes towards macrophages M1 and IL-4 to M2. By cons in vivo, the differentiating factors are poorly known. It is remarkable that metformin and telmisartan increase M2 macrophages M1 macrophages and decrease, respectively, in humans and mice. Moreover, telmisartan reduces proteinuria more than losartan in diabetic nephropathy in humans and Metformin decreases the amount of TGF-β intra-renal mice. This effect of telmisartan is independent of the type 1 receptor of angiotensin II (AT1R) since it is not obtained with losartan.

Telmisartan is a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma), the working assumption is that telmisartan fosters the transition of monocytes to macrophages M2 form, and limit the recruitment of more monocytes in the kidneys and therefore proteinuria and renal fibrosis. To show this, it will be compared the ability of monocytes to differentiate ex vivo in M1 or M2 macrophages in diabetic nephropathy patients treated with losartan or telmisartan then it will characterize the role of PPARgamma in the monocyte / macrophage transition. Finally, it will be compared the urinary excretion of amino terminal propeptide of procollagen type 3 (PIIINP), considered a marker of renal fibrosis in patients receiving losartan or telmisartan.


Condition or disease Intervention/treatment Phase
Diabetic Nephropathy Drug: telmisartan during 6 months Drug: Losartan during 6 months Procedure: blood sample Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Telmisartan Promotes the Differentiation of Monocytes Into Macrophages M2 in Diabetic Nephropathy?
Actual Study Start Date : May 5, 2017
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: telmisartan
treatment with telmisartan at doses of 80 mg / day for 6 months
 Drug: telmisartan during 6 months
telmisartan during 6 months

Procedure: blood sample
blood sample
Experimental: losartan
Losartan at a dose of 100 mg / d for 6 months.
 Drug: Losartan during 6 months
Losartan during 6 months

Procedure: blood sample
blood sample


Outcome Measures
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Primary Outcome Measures :
  1. number of differentiation marker [ Time Frame: 6 months ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes ;
  • Proteinuria ≥ 0.5 g / g motivating the prescription of ACE inhibitors or ARA2 full dose;
  • Processing statin;
  • Processing metformin;
  • court treatment with GLP-1 agonists and DPP-4 inhibitor;
  • About who signed the informed consent;
  • affiliated to the social security issue

Exclusion Criteria:

  • Diabetic nephropathy not;
  • GFR <30 ml / min / 1.73 m2;
  • Type 1 diabetes;
  • Maturity Onset Diabetes of the Youth (MODY);
  • Use of telmisartan in the 6 months prior to enrollment;
  • Liver cirrhosis (potential production of PIIINP);
  • chronic inflammatory disease;
  • active cancer;
  • immunosuppression;
  • Pregnant or breastfeeding women (urine pregnancy test will be performed for women of childbearing age);
  • adult person under guardianship;
  • Hospitalized person without his consent and not protected by law; person deprived of liberty
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02768948


Contacts
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Contact: Guillaume FAVRE, PH 33492038824 favre.g@chu-nice.fr
Contact: Mélanie Bonnard bonnard.m@chu-nice.fr

Locations
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France
CHU de Nice Recruiting
Nice, France, 06000
Contact: Guillaume FAVRE, PH       favre.g@chu-nice.fr   
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nice
More Information
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Responsible Party: Centre Hospitalier Universitaire de Nice
ClinicalTrials.gov Identifier: NCT02768948    
Other Study ID Numbers: 16-AOI-09
First Posted: May 11, 2016    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Diabetic Nephropathies
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Losartan
 Telmisartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action