Role of oxidative stress and inflammation in the pathophysiology of chronic kidney disease : consequences on skeletal muscle function and vascular calcifications
The incidence of kidney disease increases dramatically partly due to ageing leading, as other chronic diseases, to comorbidity and mortality related to high risk of cardiovascular (CV) disease. It is now well recognized that oxidative Stress (OS) and inflammation, which are linked via amplification loops, are cornerstones in the pathophysiology of malnutrition-inflammation complex syndrome (MICS), contributing to worsen the outcome of CKD patients. Our group has long worked on metabolic components and biomarkers of MICS, including exploration of systemic inflammation, components of OS linked to both an increased production of reactive oxygen species (ROS) and a decrease in defense mechanisms, and biomarkers of CV disease (Morena et al., Free Radical Res, 2011).
On the other hand, OS and inflammatory cytokines could enhance transdifferentiation of VSMC to osteoblastic cells ostéoblastes (Sutra et al, Free Radic Res, 2008), leading to bone matrix protein expression into the vessel wall and further mineralization. As a consequence, bone turnover or phosphate/calcium metabolism regulators (osteoprotegerin/RANKL, sclerostin/DKK-1/LRP5/Wnt, FGF-23/Klotho) have emerged as vascular calcification or pronostic biomarkers (Morena et al, Nephrol Dial Transplant, 2009; Morena et al, PLoS One, 2012).
Our project is focused on three objectives :
1) to develop creatinine metabolism as a clinically available biomarker of muscle wasting and dysfunction,
2) to characterize and modulate the phenotypic skeletal muscle changes related to CKD and evaluate the effects of exercise training (benefiting the facilities and similar experimental design as previously used in the COPD study), and
3) to understand the involvement of OS/Inflammation in uremia-related vascular calcifications.
Objective 1 :
Creatinine index (CI) and LBM as biomarkers of muscle wasting and dysfunction. Alternatively to specialized methods involving radioisotopes, it has been shown that creatinine modelling could be a simple non invasive and clinically relevant method to assess muscle mass (Desmeules et al, Nephrol Dial Transplant, 2004) and predict poor outcome (Terrier et al, Nephrol Dial Transplant, 2006). However, the relationship with muscle dysfunction was not yet clearly defined.
a) With the respect to complexity of creatinine kinetic modelling, we plan to develop and test a simplified formula to estimate CI from a single predialysis creatinine determination and anthropometric characteristics in HD patients.
b) We also plan to assess global exercise tolerance and specific muscle function in CKD patients. In addition, as previously performed in COPD patients, the natural time-course of physical activity could be described using questionnaires (Gouzi et al., Arch Phys Med Rehabil, 2011).
c) The relationships between CI, OS/inflammation and exercise tolerance will be investigated in CKD patients.
d) The prognostic significance of short term variation of biological or physical parameters will be evaluated.
Objective 2 :
Study of phenotypic skeletal muscle changes associated with CKD.
Our team will focus on understanding how skeletal muscle cell changes its phenotype in response to uremia, both in animal models (5/6 nephrectomy) and clinical studies.
Objective 3 :
OS/Inflammation as effectors of vascular calcification pathway.
In collaboration with Team 2, we will explore the potential involvement of OS/Inflammation in vascular calcification pathway.
a) Bio-clinical studies based on existing cohorts will allow us to explore the potential relationships between OS/inflammation and biomarkers or imaging of the extent of vascular calcifications.
b) VSMC lines will allow us to investigate the molecular pathway leading to VSMC transdifferentiation in the presence of phosphate, proinflammatory cytokines or uremic plasma, with special attention on inflammatory and OS signaling via NFkB/ Nrf2 balance.
Main collaborations :
- P Delanaye and E Cavalier(Belgium, Liege University Hospital Center)
- B Canaud (Chairman of Fresenius Medical Care’s EMEALA (Europe, Middle East, Africa, Latin America Medical Board)
- HDF pooling project (P Blankestijn, Utrech, Netherlands; A Davenport, London, UK; F Kircelli, Izmir, Turkey; F Locatelli, Lecco, Italy; F Maduell, Barcelona, Spain)
- D Sess and A Monde (Abidjan, Ivory Coast)
- Y Dauvilliers and I Jaussent (Inserm U1061, Montpellier, France)
- C Coudray and Ch Feuillet-Coudray (UMR 866 INRA, Montpellier, France)
Financial support :
- Grant from the Francophone Society of Dialysis (SFD).
- AOI (Appel d’Offres Interne) from the french University Hospital Center.
- National PHRC (Programme Hospitalier de Recherche Clinique) (HD/HDF) from the french University Hospital Center.
- Regional PHRC (Vascular calcifications in CKD patients) from the french University Hospital Center.
Collaborations with industry:
- Dialpha Parc Agropolis (Cinnamon and chicory on post prandial glycemia in pre-diabetic and obese voluntaries)
- Hemotech (EVIA: Vitamin E-coated dialyzers for hemodialysis).
- Sania (Palm oil regimen).
Major publications :
- Morena M, Jaussent I, Halkovich A, Dupuy AM, Bargnoux AS, Chenine L, Leray-Moragues H, Klouche K, Vernhet H, Canaud B, Cristol JP. Bone biomarkers help grading severity of coronary calcifications in non dialysis chronic kidney disease patients. PLoS One. 2012;7(5):e36175.
- Aoun M, Feillet-Coudray C, Fouret G, Chabi B, Crouzier D, Ferreri C, Chatgilialoglu C, Wrutniak-Cabello C, Cristol JP, Carbonneau MA, Coudray C. Rat liver mitochondrial membrane characteristics and mitochondrial functions are more profoundly altered by dietary lipid quantity than by dietary lipid quality: effect of different nutritional lipid patterns.Brit J Nutr. 2012 Mar;107(5):647-59.
- Mangé A, Goux A, Badiou S, Patrier L, Canaud B, Maudelonde T, Cristol JP, Solassol J. HDL proteome in hemodialysis patients: a quantitative nanoflow liquid chromatography-tandem mass spectrometry approach. PLoS One. 2012;7(3):e34107.
- Feillet-Coudray C, Sutra T, Fouret G, Ramos J, Wrutniak-Cabello C, Cabello G, Cristol JP, Coudray C. Oxidative stress in rats fed a high-fat high-sucrose diet and preventive effect of polyphenols: Involvement of mitochondrial and NAD(P)H oxidase systems.. Free Radic Biol Med. 2009; 46(5):624-32.
- Ventura E, Durant R, Jaussent A, Picot MC, Morena M, Badiou S, Dupuy AM, Jeandel C, Cristol JP. Homocysteine and inflammation as main determinants of oxidative stress in the elderly. Free Radic Biol Med. 2009; 46(6):737-44.