Secondary hypertension Renal ischemia part 2 Ústav patologické fyziologie LF MU Conceptual definition of hypertension • blood pressure > 140/90 mm Hg • artificial dichotomy between normoand hypertension • the level above which harm is accrued and treatment below that level mitigates the harm • benefit of drug treatment have been definitely established in randomized placebo-controlled trials Hypertension and target organ damage • types • primary and secondary • hypertension • major risk factor for premature cardiovascular disease • leading cause of death worldwide • incidence continues to grow • asymptomatic nature • treatment remains most commonly empiric • often 3 or more pharmacologic agents with complementary mechanisms • hypertension causes • 54 % of stroke • 47 % of ischemic heart disease • of all modifiablerisk factors, hypertension is exceeded only by smoking BP and ischemic heart disease mortality Framingham study • since 29.9.1948, Framingham, Boston, MA • identification of major cardiovascular risk factors • blood pressure, cholesterol, triglycerides, HDL, smoking, obesity, diabetes, physical inactivity,age, gender (male) a psychosocialfactors • Initial cohort • 5209 people, 30-62 years, detailedexaminationevery 2 years • II. cohort (since 1971) • 5,124 adult offspring • III. cohort • 3,500 children (grandchildrenof original participants) • late clinical manifestations of long-term uncontrolled hypertension • myocardialinfarction,stroke • heart failure • kidney failure • retinopathy Major forms of secondary hypertension • renal disorders • parenchymal • renovascular • endocrine disorders • Cushing syndrome • primary aldosteronism • vascular disorders • coarctation of the aorta • pregnancy • exogenic cause - medication - contraception - drugs - cocaine, amphetamine - licorice Screening for secondary hypertension • secondary forms are rare and screening for them expensive and laborious • it is not cost effective to search for secondary causes of hypertension in every patient • testing requires clinical suspicion and knowledge of limitations of different tests • general principles • new onset hypertension if <30 or >50 years of age • hypertension refractory to treatment (>3- 4 medications) • specific clinical/lab features typical for secondary HT • hypokalemia,differentialBP in arms, episodic hypertension… Kidney function • regulation of • extracelllularfluid volume and blood pressure • osmolarity • acid-base balance • ion balance • excretion of wastes • productionof hormones • kidney perfusion • 20 – 25 % of minute heart volume • 1200 ml/min, 90 % goes to cortex • markedly more than would correspond to kidney weight • reasons for high perfusion • high energy need of tubular cells • production of primary filtrate in glomeruli • 20 % of perfusion • 150-180 l/day –90 % reabsorption • glomerular filtration rate(GFR) • 100-120 ml/min Regulation of kidney perfusion • GFR is remarkably constantover a wide range of blood pressures • 80-180 mm Hg • autoregulation • locallycontrolledproces • relatively constant GFR in the face of normal fluctuations in blood pressure • protects filtration barrier fromhigh blood pressure • myogenic feedback • intrinsic to the smooth muscle blood vessels • if the pressure within a vessel is suddenly increased, the vessel responds by constricting • vascular smooth muscle cells depolarize when stretched, leading to contraction • tubuloglomerularfeedback • changes in the Na+, Cl−, and K+ concentrations in the tubular fluid are sensed by the macula densa via the Na+-K+-2Cl− cotransporter Juxtaglomerular apparatus • juxtaglomerular (JG) cells • specialised muscle cells • advanced endoplasmic reticulum and Golgi apparatus • production of renin • blood pressure receptor • macula densa • close to JG cells • senzitive to NaCl • mesangial cells • specialized pericytes • contraction • juxtaglomerular apparatus • sympathetic innervation RAAS overview RAAS overview RAAS manipulation Renal parenchymal disease • 2 – 5 % cases of hypertension • mechanisms • common pathway • impaired renal autoregulation • high perfusion pressure • damage of the glomerular cells • stiffnessof the arteries • ↑ SBP, ↓ DBP, ↑ pulse pressure CKD stages Renovascular hypertension • 1-2 % cases of hypertension • atherosclerosis • 70 – 90 % of cases • in older adults • fibromuscular dysplasia • more common in women • non-inflammatory vascular disease • affects more commonly youngwomen • often in the 3rd decade • mostly partial obstruction of one main renal artery • decreased RBF, activation ofRAAS • suspiction of renal artery stenosis • hypertension in previously normotensive person • < 30 or > 50 years • severe or resistanthypertension • smoking • accelerated hypertension in previously controlled person • worsening renal function after RAS inhibition • reduction in renal perfusion by 50 % • immediate and persistentincrease of renin secretion from ischemic kidney • renovascular vs. primary hypertension • hypokalemia • no family history of hypertension • duration< 1 year • administration of ACE inhibitors may cause a decline in renal function • diagnostic tests • assessment of renal function, RAAS • imaging studies • treatment • blood pressure control • renal function stabilization • angioplasty Renovascular hypertension • atherosclerosis • 90 % of RVH • affects mainly proximal third of the main renal artery • seen mostly in older men • bilateral in 30 % • fibromuscular dysplasia • 10 % of RVH • noninflammatory vascular disease • involving mainly distal 2/3 and branches of renal arteries • rarely bilateral • predilection in the right renal artery • appears most commonly in younger women Goldblatt‘s experimental hypertension • 2 kidneys/1 clip (2K1C) • hypertension + preserved regulation of extracellular volume • 1 kidney/1 clip (1K1C) • hypertension + disorder of extracelllular volume regulation 2K1C hypertension • unilateral stenosis may be present with an intact contralateral renal artery • counterregulatory processes in the contralateral kidney • sodium excretion in response to increased blood pressure 1K1C hypertension • bilateral stenosis and 1K1C lead to more severe hypertension Phases of experimental hypertension • early phase • elevated renin, hypertension • second phase • blood pressure responds to clip removal • third phase • no reduction of blood pressure after clip removal • microvascular injury of contralateral kidney • oxidative stress? Mineralocorticoid-induced hypertension Primary aldosteronism • the most common of syndromes with mineralocorticoid excess • common in patients with resistant hypertension • renin-independent overproduction of aldosterone • several types • solitary aldosterone-producing adenoma • bilateral hyperplazia • profibrotic effect of aldosterone • more CV events in patients with primary aldosteronims than in patients with primary hypertension Hypertension induced by cortisol • Cushing syndrome • serious disease • hypertension in  75 % • often difficult to treat • incompletely controlled • 4-fold excess of mortality Causes of endogenous Cushing syndrome Classification and mechanisms of hypertension • mechanisms of hypertension • Na retaining action of cortisol • ↑ cortisol overwhelms 11β-HSD2 • cortisol acts on mineralocorticoid receptor (MR) • direct action on smooth muscle cells • ↑ production of mineralocorticoids • ↓ activity of eNOS • ↑ angiotensinogen Increased access of cortisol to MR • deficiencies of 11β-HSD2 • enzyme deficiency • autosomalrecessive • apparent mineralocorticid excess (AME) • enzyme inhibition • glycerrhizic acid • confectionery licorice • 50 g/daily for 2 weeks - ↑BP • treatment • competitiveblockade of MR with spironolactone Coarctation of aorta • distal to the origin of subclavial arteries • signs • hypertension in the arms • weak or absent femoral pulses • BP on lower extremities is normal or low • reduced blood flow to the lower part of the body • kidneys – RAAS activation • increased stroke volume • probably also generalized vasoconstrictormechanism • diagnosis • pressure diference > 20 mm Hg • treatment • surgical • angioplasty Pheochromocytoma • tumor of chromaffin tissue • adrenalmedulla • sympathetic ganglia • 0.1 – 0.5 % of people with hypertension • can cause serious hypertensive crisis • production of epinephrine and norepinephrine • paroxysmalor continuous • episodes of headache, sweating, palpitations • weakness, fatigue, weight loss • marked BP variability • diagnostic test • urinary catecholamines • localizationof tumor • treatment • surgery • blockadeof catecholaminesaction or synthesis 50 % have paroxysmal episodes of hypertension other 50 % have sustaines hypertension some may be normotensive Hypertension in pregnancy • 5-10 % of all pregnancies • blood pressure changes during pregnancy • decrease during the first semester • lowest in the second trimester • rise during the third trimester • changes of cardiac output (CO) and peripheral vascular resistence(PR) • large increase of CO in early pregnancy • high throughoutpregnancy • decreased PR • pregnancy is normally accompanied by • increased renin, ang I and II, estrogen, progesterone and aldosterone • women with preeclampsia • new-onset hypertension with proteinuria • develops after 20 weeks of pregnancy • sensitive to the RAAS • also responsive to other vasoconstrictors • insulin resistence may predispose to hypertension Oral contraceptive drugs and hypertension • the most common cause of secondary hypertension in young women • mechanism • volume expansion • estrogens and progesterons cause sodium retention Sleep apnea syndrome • prevalent in middle-aged and older adults • mechanisms • obesity • craniofacial changes • alteration in upper airway muscle function • consequences • intermittent hypoxia and hypercapnia • recurrent arousals and increase in respiratory efforts • secondary sympathetic activation, oxidative stress and systemic inflammation • daytime sleepiness Malignant hypertension • acute and life-threatening condition associated with a sudden increase in BP • usuallyin younger people • black men, kidney damage • diastolic> 120 mm Hg • organ dysfunction • hypertensiveencephalopathy • cerebral vasoconstriction • homeostatic response • brain edema • damage of kidney vessels • ↑ creatinine, urea • metabolic acidosis, hypocalcemie, proteinuria • prolonged exposure to high BP • arterioles injury • intravascularcoagulation andRBC fragmentation • renal damage • ↑ creatinine • proteinuria Practical part • weight of • animal • kidneys • heart • suture • microscopic detection of renin