When and how to perform a secondary hypertension work up? Docteur Cédric RAFAT Urgences Néphrologiques et Transplantation rénale Hôpital TENON

When and how to perform a secondary hypertension work up? Docteur Cédric RAFAT Urgences Néphrologiques et Transplantation rénale Hôpital TENON

Conflict of interest None related to the topic

When to look for secondary hypertension?.why look for secondary hypertension AHT avec SAP > 180 and/or DAP > 130 Severe AHT? Accelerated AHT or «malignant hypertension» Resistant AHT Young patient < 30 yo Curable AHT? Hypokalemia JNC7, ESH, HAS Recommendations

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/paraganglioma Cushing disease Chronic kidney disease Genetic AHT

Drug/toxic associated AHT Drug causing AHT Toxic related AHT Anti HTA drug interaction NSAID Cocaine +/- NSAID Glucocorticoids Phenythelamine Ketoconazole CNI inhibitors (ciclosporine ++) Licorice Grapefruit Serotonine/ norepinephrin recapture inhibitor Café EPO Anti-VEGF therapy Estrogen based contraception Farese NEJM 1991, Grossman Eur J Pharmaco 2015

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/PGL Cushing disease Chronic kidney disease Genetic AHT

Obstructive sleep apnea and AHT: an epidemiological conundrum Obstructive sleep apnea Arterial hypertension AHT /OSA patients : 35-80%, «Dose-effect» AHI>30 AHT>67% OSA/ AHT patients: ~40%, «Dose-effect» Resistant AHT OSA 65% Nieto JAMA 2000 Gonzaga Hypertension 2011

Obstructive sleep apnea and AHT The physiopathological chain reaction Systemic inflammation Heart rate OSA Hypoxemia Hypercapnia Oxydative stress Endothelial dysfunction Σ nerve & RAAS activation Peripheral arterial resistance Arterial stiffness AHT Cai Hypertension Research

OSA as a common cause of AHT Age > 50 y Neck circumference Snoring Pedrosa Hypertension 2011

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/PGL Cushing disease Chronic kidney disease Genetic AHT

Primary hyperaldosteronism 12% < 1% 10,5 % Rossi JACC 2006 Gordon Clin Exp Pharmaco 1993 Mulatero JCEM 2004 The prevalence of PA is on the rise The likeliness of PA increases with the severity of AHT Resistent AHT SBP > 180 mmhg Severe consequences Adenoma 10 mm Widespread use of Aldostérone/rénine ratio

Primary hyperaldosteronism PA cannot be ruled out on the basis of normokalemia Rossi JACC 2006

Primary hyperaldosteronism : diagnostic strategy 1. Wash out of anti AHT drug interference 2 weeks Beta blocker Diuretics Angiotensinogen Renin Renin inhibitor Normokalemia restored Normalt salt intakes 6 weeks Angiotensinogen I ACE Angiotensinogen II Sartan 2 weeks 2 weeks ACE inhibitor Kalemia Aldosterone 6 weeks Spironolactone Mineralocorticoid inhibitor

Primary hyperaldosteronism : diagnostic strategy 1. Aldosterone/ renin ratio (ARR) Morning > 2 h wake, sitting 2. Urine aldosterone / 24 h 3. Sodium loading test Direct renin = Renin C +++ Better standardized Plasma renin activity = PRA +/- Time consuming Adrenal CT with CI Surgery if signs of malignancy 1.< 55 yo AND 2. Cleared for surgery Adrenal venous catheter sampling Drug therapy if no lateralization Surgery if lateralized

Primary hyperaldosteronism : Adrenal venous catheterism sampling Selectivity criteria : cortisol sampling (Cort) Cort adrenal vein / Cort inferior vena cava > 2 Lateralization : cortisol and aldosterone (Ald sampling) Aldo/Cort dominant side /Aldo/Cort non dominant side > 4 Steichen Curr Opin in endoc 2016 Giachetti trends in metabo 2008

Adrenal venous sampling.to avoid : Primary hyperaldosteronism in a 63 yo patient. Das G Endoc Diabetes & Metabo 2015

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/PGL Cushing disease Chronic kidney disease Genetic AHT

Renal vascular disease 65 yo Caucasian Multiple CV Risk Factors +/- Ischemic cardiomyopathy, peripheral vascular disease 40-50 yo Female (90%) No CV Risk Factors +/- Carotid FMD, other middle sized vessels (35% 2) Relationship with coronary dissection Renal atheromatous stenosis Renal fibromuscular dysplasia Courtesy of Dr E. Vidal-Petiot, HEGP Presad Am j cardiol 2015 Olin Circulation 2012

Renal Artery Stenting with a a special focus on the CORAL and ASTRAL trials ASTRAL CORAL Primary outcome Renal function The occurrence of a major cardiovascular or renal event Enrolment protocol Uncontrolled or refractory AHT Unexplained renal dysfunction «Substantial» RAS 750 patients SAP>155 mmhg 2 antihypertensive medications. SAR > 60% 947 patients Death HR: 0.90; p=0.61 HR: 0.80; p=0.20 Major cardiov events HR= 0.94; p= 0.88 HR= 0.97; p=0.88. Renal events HR= 0.97; p=0.88 Progressive renal insufficiency. HR= 0.86; p = 0.34 Blood pressure Revascularization: 141 ± 26/73 ± 12 Medical: 141 ± 25/70 ± 13 ns Systolic BP decreased in: Revascularization: 15.6 ± 25.8 Medical: 16.2 ±21.2 ; p=0.03

Ongoing controversies White Cath and cardio int 2010 Serac semin in vasc Surg 2011

When should renal revascularization should be contemplated? Initial diagnostic work-up «Flash» pulmonary Edema GFR / ACE inhibitor Multidrug resistance & significant RAS Follow-up Accelerated renal dysfunction Renal atrophy?? Beware!! Renal atrophy Significant proteinuria Distal renal vascular disease Rooke circulation 2011

Renal Fibromuscular dysplasia : typical and less typical presentations PHACTR1 variant?? Estrogens? Others? Multifocal Monofocal Renal vascular Aneurysm 30% Renal vascular Dissection 10% Other localization? Plouin Neph Ther 2015 Kadian Dodov JACC 2016 Kiando Plos genet 2016

Diagnostic screening strategy in renal fibromuscular dysplasia Renal doppler US AHT young F CT scan or angio MRI Negative exam AND strong suspicion Cervical FMD Renal infarct Abdominal bruit Negative exam AND strong suspicion Positive exam Renal angiography Angioplasty Positive exam Positive exam Cervico-cerebrovascular CT or MRI

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/PGL Cushing disease Chronic kidney disease Genetic AHT

Pheochromocytoma/PGL when to look for it? Rare cause of AHT 0,1-0,6% AHT patients Headache 60 90% Palpitations 50 70% Sweating 55 75% Pallor 40 45% Nausea 20 40% Flushing 10 20% Weight loss 20 40% Tiredness 25 40% Psychological symptoms 20-40% Sustained hypertension 50 60% Paroxysmal hypertension 10-30% Orthostatic hypotension 10 50% Hyperglycaemia 40% Family history Incidentaloma Young patients Clinical signs & Paroxysmal AHT (after anesthesia/surgery ++) Refractory AHT Hyperglycemia Lenders Lancet 2005

Pheochromocytoma/PGL where to look for it? 10% extra adrenal 10% malignant Baez Cancer imaging 2012

Pheochromocytoma/PGL, how to look for it? Urinary free metanephrines and normetanephrines MN+NMN/CreatU < 0,354 µmol/mmol Plasma free metanephrines and normetanephrines Anatomical imaging CT scan ++ or MRI Functional imaging 123 MIBG, 18 FDG PET Life long follow up Surgery Genetic testing NF1, VHL, RET, SDHB,SDHC ou SDHD.. Familial/sporadic Benign/malignant

Causes of AHT II AHT Drug / toxic associated AHT Sleep apnea syndrome Primary hyperaldosteronism Renal vascular disease Pheochromocytoma/PGL Cushing disease Chronic kidney disease Genetic AHT

Hypercortisolism : who should undergo testing and how? Rare cause of AHT i= 0.7-2.4 / 10 6 p per Y Cushing syndrome Incidentaloma Young patients with unusual features Osteoporosis HTA 24 hour urinary free cortisol X 2 Cyclical Cushing syndrome, pregnancy Late night salivary cortisol X 2 Incidentaloma 1 mg overnight DXM suppression test Stage IV/V CKD

How to perform testing for Cushing s syndrome Urinary free cortisol X 2 Late night salivary cortisol X 2 1 mg overnight DXM suppression test Longer low dose suppression test (2mg/48 h) Exclude non-cushing related clinical hypercortisolism Morbid obesity Alcohol Depression Poorly controled DM Exclude non-cushing related biological hypercortisolism Physical stress, surgery Exclude drugs which interfere with GC metabolism (CYP3A4) Confirmation of Cushing syndrome Expert endocrinologist Reference centre ACTH dependent/independent Cushing syndrome Complications and treatment Wong W J of radio 2016 Lim An ped J endoc dis 2014