# 3 Frédéric Jaisser 1 MD, PhD Professor in Physiology, INSERM Head of the Department Integrative Physiology and Pathophysiology, Cordeliers Research Center, Paris, France
Repositioning of the Mineralocorticoid Receptor Antagonists in renal diseases: pathophysiological basis and therapeutic issues Frédéric JAISSER INSERM U 1138 Centre de Recherche des Cordeliers Paris
Emerging roles of in several diseases HEART: heart failure myocardial infarction arrhythmia fibrosis ADIPOSE TISSUE: obesity KIDNEY: hypertension ischemic insult glomerular injury IMMUNE CELLS: inflammation RETINA: retinal edema neoangiogenesis central serous chorioretinitis BLOOD VESSELS: vasoconstriction endothelial dysfunction hypertension atherosclerosis remodelling SKIN: epidermal atrophy Jaisser and Farman. Pharmacol Rev 68:49, 2016
Emerging roles of in several diseases HEART: heart failure myocardial infarction arrhythmia fibrosis Therapeutic target: MR antagonists Spironolactone,eplerenone, finerenone ADIPOSE TISSUE: obesity KIDNEY: hypertension ischemic insult glomerular injury IMMUNE CELLS: inflammation RETINA: retinal edema neoangiogenesis central serous chorioretinitis BLOOD VESSELS: vasoconstriction endothelial dysfunction hypertension atherosclerosis remodelling SKIN: epidermal atrophy MR antagonist repurposing from Hypertension to.. Jaisser and Farman. Pharmacol Rev 68:49, 2016
Mineralocorticoid receptor expression in the kidney mesangial cells Glomeru lar capillari es podocyt es ve sse ls A S D N
New paradigm in and renal diseases
New paradigm in and renal diseases
New paradigm in and renal diseases?
Clinical trials with benefit of MR antagonists in renal diseases Ma and Szeto. Renal Failure 2012
Ongoing clinical trials on MRAs in renal diseases CHRONIC KIDNEY DISEASE NCT01691053 Mineralocorticoid Receptor Antagonists (spironolactone) in End Stage Renal Disease (MiREnDa) Wuerzburg University Hospital NCT01427972 A Study of LY2623091 in Male and Females With Chronic Kidney Disease Eli Lilly and Company NCT01667614Effects of Spironolactone Combination Therapy on Proteinuria, Kidney Function, and Blood Pressure NCT01853553 Mineralocorticoid Antagonism (Spironolactone) and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD) University of Colorado, Denver NCT00430924 Inhibition of Aldosterone (Eplerenone) in Patients With Chronic Renal Disease, Rigshospitalet, Denmark ESRD NCT01855334 L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD (LAST-D) Brigham and Women's Hospital NCT01848639 ALdosterone Antagonist (spironolactone) Chronic HEModialysis Interventional Survival Trial (ALCHEMIST) University Hospital, Brest NCT01687699 Effects of Spironolactone on Cardio- and Cerebrovascular Morbidity and Mortality in Hemodialysis Patients Dialysis Outcomes Heart Failure Aldactone Study Group NCT01650012 Eplerenone in Hemodialysis Trial (PHASE) McMaster University DIABETIC NEPHROPATHY NCT01488877 a study to evaluate the safety and tolerability of PF-03882845 in patients with type 2 diabetic nephropathy Pfizer NCT00381134 Improving Outcomes in Patients With Kidney Disease Due to Diabetes (Spironolactone)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NCT01371747 RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN) Spironolactone NCT01874431 Safety and Efficacy of Different Oral Doses of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Nephropathy (ARTS-DN) Bayer TRANSPLANTATION NCT01510795 Mineralocorticoid Receptor Antagonist (Spironolactone) and Kidney Allograft Histology Clinical Hospital Merkur NCT01602861 The Effects of Spironolactone on Calcineurin Inhibitor Induced Nephrotoxicity (SPIREN) Odense UniversityHospital NCT01834768 EPLErenone in CsA-Treated Recipients (EpleCsAT): Safety, Reims, France
New paradigm in and renal diseases Clinical implications and Pathophysiological mechanisms Bertocchio, Warnock, Jaisser. Kidney Int, 2011 Warnock,, Jaisser. Nature Nephrology Review, 2014
, microvasculature and organ damage KIDNEY Renal Blood flow: 800 ml/mn/100 g tissue HEART Coronary blood flow :3 ml/mn/100 g tissue EYE Retina blood flow : 125 ml/min/100 g tissue Choroid Blood Flow: 2 000 ml/min/100 g tissue Collaboration: T. Hauet, INSERM U Poitiers P. Rieu, Nephro Unit Reims Collaboration: A. Ouvrard, P. Mulder, V. Richard INSERM U1096, Rouen Collaboration: F Behar-Cohen, U872 Team 17/Lausanne
Vascular MR and renal hemodynamics: implication in renal injury Ischemia/reperfusion injury warm ischemia: surgery cold ischemia: renal graft Ciclosporine (immunosupressor) nephrotoxicity acute/chronic vasculopathy Beneficial effects of pharmacological MR antagonism in rodents Hypothesis: Bobadilla, Mexico these renal injuries are associated to in the renal microvasculature
Working hypothesis Pharmacological or Vascular MR inactivation Vascular MR activation Oxidative stress inflammation Tubular lesions Renal damage
Mineralocorticoid Receptor Antagonists: from one to third generation Finerenone From J. Bauersachs. Eur Heart J, 2013
Vascular MR and renal hemodynamics: implication in renal injury Beneficial effects of pharmacological MR antagonism in renal ischemia/reperfusion injury Efficacy of a third-generation MR antagonist (BR4628) Barrera-Chimal J et al. J Am Soc Nephrol, In press
inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to decrease endothelial NO levels Normal Ischemia ET-1 ET-1 ETB ETB Cys-S-OH p-s1177- enos ROS NO endothelium p-s1177- enos NO Smooth muscle Barrera-Chimal J et al. J Am Soc Nephrol, In press
inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to decrease endothelial NO levels Normal Ischemia ET-1 ET-1 ETB ETB Cys-S-OH p-s1177- enos ROS NO endothelium p-s1177- enos NO Smooth muscle MR antagonists Barrera-Chimal J et al. J Am Soc Nephrol, In press
Vascular MR and renal hemodynamics: implication in renal injury Beneficial effects of pharmacological MR antagonism Clinical studies transplantation in RENAL ISCHEMIA/REPERFUSION limit Delayed Graft Function in renal from limit donors F Jaisser (CIC Nancy PI), S. Girerd (co-pi, CHU Nancy) L. Frimat (Nancy), P. Rieu (Reims), B. Moulin, (Strasbourg), D. Ducloux (Besancon) C. Mousson (Dijon), P. Grimbert (Créteil)
New paradigm in and renal diseases Clinical implications and Pathophysiological mechanisms Bertocchio, Warnock, Jaisser. Kidney Int, 2011 Warnock,, Jaisser. Nature Nephrology Review, 2014
Patho-physiological role of MR in diseases? Pharmacological MR antagonism: indications of old compounds PERSPECTIVES repositioning and novel HYPOTHESIS MR : «modifier» gene Aldo/MR molecular targets Phenotypes Aldosterone Animal model Human diseases - hypertension - heart failure - arrhythmia - metabolic diseases - kidney diseases
Patho-physiological role of MR in diseases? Pharmacological MR antagonism: indications of old compounds PERSPECTIVES repositioning and novel HYPOTHESIS MR : «modifier» gene Aldo/MR molecular targets Phenotypes Aldosterone Pet diseases -hypertension - heart failure - metabolic diseases - kidney diseases -??? Human diseases - hypertension - heart failure - arrhythmia - metabolic diseases - kidney diseases
# 3 23 Repositioning of the MRA in renal diseases: pathophysiological basis and therapeutic issues 1- Broad expression of the Mineralocorticoid Receptor beyond the classical targets Kidney (vessels, podocyte, ) Cardiovascular system Adipose tissue Inflammatory cells 2- Impact on kidney diseases Direct: glomerulopathies, inflammation, fibrosis Indirect: cardiovascular diseases (vascular, heart failure), metabolic 3- Benefit of MR antagonists in renal diseases Repositioning of available MR antagonists (alone or in combination)