PATHOPHYSIOLOGY OF HYPERTENSION. Samuel Makar. Prof of Pediatrics and Pediatric Nephrology, Cairo University

Transcription

1 PATHOPHYSIOLOGY OF HYPERTENSION Samuel Makar Prof of Pediatrics and Pediatric Nephrology, Cairo University

2 SCOPE Introduction Definition BP Measuring Types Pathophysiology Overview Pathophysiology of Specific HTN Diseases

3 INTRODUCTION There is increasing evidence that HTN has its antecedents during childhood and that atherosclerosis is already present in adolescents. Thus, early detection and intervention are crucial. The prevalence of primary HTN is increasing among school children and adolescents due to an epidemic of obesity. Younger children are more likely to have secondary HTN, The definition of HTN as well as normative values of blood pressure (BP) should be well known to clinicians in order to identify HTN

4 SCOPE Introduction Definition BP Measuring Types Pathophysiology Overview Pathophysiology of Specific HTN Diseases

5 HTN DEFINITION Definition of Pediatric HTN: Average SBP and/or DBP 95th percentile - gender, age, and height -on 3 or more separate occasions. Pre-HTN : BP levels 90th percentile but < 95th percentile is termed prehypertension.

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7 BP MEASURING Casual Blood Pressure Ambulatory BP monitoring (ABPM) Home BP monitoring (HBPM)

8 AMBULATORY BP MONITORING (ABPM) Provides multiple readings over time enabling computation of the mean, daytime, and nighttime ambulatory BP (ABP) by measuring BP during regular activities and BP variability More reliable and reproducible than casual BP Detects white coat effect (high casual BP than 24-h or daytime ABP) or reversed white coat effect (low casual BP than 24-h or daytime ABP) ABPM correlates better with target organ damage than casual BP

9 HOME BP Self measurement of BP has the following advantages: 1. Distinguishing sustained HTN from white coat HTN(WCH) 2. Detection of masked HTN 3. Assessing response to medication, 4. Improving patient adherence to treatment 5. Reducing costs by avoiding ABPM or drug therapy. Midori Awazu, Pedatric Nephrology Textbook 2016

10 IV Diretriz Brasileira de Hipertensão Arterial. Arq Bras Cardiol 2004

11 IV Guideline for Ambulatory Blood Pressure Monitoring, Arq. Bras. Cardiol, 2005

12 TYPES OF HTN According to the cause: Primary HTN Secondary HTN According to the setting White coat HTN Reversed white coat HTN Persistent HTN

13 WHITE COAT HTN (WCH) In Children : BP measured in a physician s office >95th percentile whereas average BP being <90th percentile outside of a clinical setting. (National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, Pediatrics, 2004) Adults : in the office (equal to or higher than 140/90 mmhg) and by 24-hour ABPM (lower than 130/80 mmhg) or by HBPM (lower than 135/85 mmhg)

14 WHITE COAT HTN (WCH) In WCH casual BP is high, while the BP during ABPM is normal WCH is considered relevant when the difference is higher than 20 mmhg and 10 mmhg for systolic pressure and diastolic pressure, respectively Myers MG et al,am J Hypertens 1999

15 REVERSE WHITE COAT HYPERTENSION (MASKED HTN) Reverse WCH or WC normotension or Masked HTN (MA) MH, a high Ambulatory BP in the presence of normal office BP Recognized as a risk factor for cardiovascular complications in the adults Pickering TG et al, Hypertension 2002 High prevalence of MH in renal transplant, CKD, obesity, sicklecell disease, repaired coarctation of aorta, obstructive sleep apnea, a parental history of HTN, increased BMI, and prehypertension Lurbe E et al, Hypertension 2005

16 IV Guideline for Ambulatory Blood Pressure Monitoring, Arq. Bras. Cardiol, 2005

17 SCOPE Introduction Definition BP Measuring Types Pathophysiology Overview Pathophysiology of Specific HTN Diseases

18 Pathophysiology Overview Equals: Cardiac output ( CO) x Systemic vascular resistance (SVR) SV HR Preload SympNS Force Exerted by circulating blood on artery walls Remodeling Rarefaction Stiffness

19 IMPORTANT KEY-PLAYERS IN PATHOPHYSIOLOGY OF HTN Systemic Vascular Resistance SVR RAAS Other Important Molecules

20 SYSTEMIC VASCULAR RESISTANCE (SVR) SVR mainly a function of small, peripheral arterioles Cross-sectional area of a vessel decreases, resistance to flow increases Remodeling : Thickening of the media is the earliest structural change due to matrix deposition, smooth muscle cell hypertrophy and hyperplasia creating smaller lumen Rarefaction : Finally, there may be resorption and loss of blood vessels in the periphery Stiffness: In larger vessels, the content of elastin and collagen in the media increases, and the number of smooth muscle cells decreases leading to a loss of elasticity

21 HE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) Major stimuli for secretion of Renin: 1. Glomerular underperfusion 2. Reduced sodium intake 3. Sympathetic Nervous System activity. Renin cleaves hepatic-derived angiotensinogen to form angiotensin I (ANG-I) ACE in the lungs transforms it to angiotensin II (ANG-II). ACE also degrades bradykinin, a potent vasodilator, into inactive metabolites. ANG-II is a potent vasoconstrictor and thus directly increases BP. It also stimulates the release of aldosterone from the zona glomerulosa of the adrenal gland, which results in a further rise in BP from aldosterone-mediated sodium and water retention..

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25 The functions of Ang-(1 9) are not completely understood, but Ang- (1 7) has vasodilatory and renoprotective effects Reduced ACE2 levels are thought to contribute to the pathogenesis of primary HTN via impaired degradation of ANG-II and reduced formation of vasodilator by-products at the level of the renal endothelium. Stergiou GS et al, Am J Hypertens. 2008

26 NB: Primary HTN is showing more and more to be NOT Primary HTN: 1. ACE 2 Mutation (reduced level of AT1-7)

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28 ATRIAL NATRIURETIC PEPTIDE (ANP) Family of natriuretic peptides including B-type (BNP) and the C- type (CNP) natriuretic peptides with similar functions ANP has potent diuretic, Natriuretic ( by inhibiting tubular sodium reabsorption and renin and aldosterone biosynthesis ) Vasorelaxant effects. In the kidney ANP increases glomerular filtration rate (GFR) through vasodilatation of the afferent arteriole and vasoconstriction of the efferent arteriole. Beltowski J et al, Clin Res. 2002

29 ATRIAL NATRIURETIC PEPTIDE (ANP) Mutations in the ANP gene appear to be associated with the development of HTN in humans There is also evidence that ANP gene polymorphisms may affect the development of hypertensive sequelae such as left ventricular hypertrophy. Xue H et al Clin Sci (Lond). 2008

30 NB: Primary HTN is showing more and more to be NOT Primary HTN: 1. ACE 2 Mutation (reduced level of AT1-7) 2. ANP Polymorphism

31 RENALASE Renalase is a protein composed of 342 amino is recently discovered as a new renal hormone Renalase degrades circulating catecholamines (primarily epinephrine) via a mechanism different than monoamine oxidase Desir G. Pediatr Nephrol 2012

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33 Renalase knockout mice are hypertensive and have evidence of increased sympathetic tone, suggesting renalase may modulate SNS activity Recombinant renalase has been developed and appears to be a potent antihypertensive agent in experimental models. Desir G. Pediatr Nephrol 2012

34 NB: Primary HTN is showing more and more to be NOT Primary HTN: 1. ACE 2 Mutation (reduced level of AT1-7) 2. ANP Polymorphism 3. Renalase activity

35 SCOPE Introduction Definition BP Measuring Types Pathophysiology Overview Pathophysiology of Specific HTN Diseases

36 PATHOPHYSIOLOGY OF SPECIFIC HTN DISEASES Primary HTN Secondary HTN

37 SECONDARY HTN A) Mendelian Forms of Hypertension (single-gene mutations ) Most of the mutations found to date affect renal sodium handling. These disorders lead to 3 groups of diseases: 1. Aberrant distal tubular sodium reabsorption and volume expansion due to hyperaldosteronism (Aldosterone is increased) 2. Defects in steroid biosynthetic enzymes (causing increased mineralocorticoid activity) 3. Activation of sodium channels or transporters (depressed Aldosterone)

38 SECONDARY HTN A) Mendelian Forms of Hypertension (single-gene mutations ) Most of the mutations found to date affect renal sodium handling. These disorders lead to 3 groups of diseases: 1. Aberrant distal tubular sodium reabsorption and volume expansion due to hyperaldosteronism (Aldosterone is increased) 2. Defects in steroid biosynthetic enzymes (causing increased mineralocorticoid activity) 3. Activation of sodium channels or transporters (depressed Aldosterone)

39 GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM (GRA) FAMILIAL HYPERALDOSTERONISM TYPE 1 (FH1) (FH-I) is AD Early onset of HTN with normal or elevated aldosterone levels despite suppressed plasma renin activity Lifton RP. Proc Natl Acad Sci U S A Caused by a chimeric gene that results from unequal crossingover between the aldosterone synthase (CYP11B2) gene and the 11β-hydroxylase

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41 The resulting chimeric gene (CYP11B1/CYP11B2) is expressed in the adrenal fasciculata and encodes a protein product with aldosterone synthase enzymatic activity whose expression is regulated by ACTH. Consequently, aldosterone synthase activity is ectopically expressed in the adrenal fasciculata under control of ACTH rather than by ANG-II or potassium.aldosterone secretion becomes linked to cortisol secretion, and maintenance of normal cortisol HTN is suppressed by Dexamethazone admmistration

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43 ACTH Cortisol ACTH Aldoster. Dexamethazone Familial Hyperalsdosteronism I (GRA)

44 FAMILIAL HYPERALDOSTERONISM TYPE II (NON-GRA) Familial hyperaldosteronism type II (FH-II) Similar to GRA (FH-I), with excess production of mineralocorticoids, but is not suppressed by dexamethasone The molecular basis of the disorder remains to be determined.

45 FAMILIAL HYPERALDOSTERONISM TYPE III (NON-GRA) Familial hyperaldosteronism type III (FH-III) recently identified Mutations in the potassium channel KCNJ5 This results in depolarization of the glomerulosa cells, leading to increased calcium entry and aldosterone production. Massive adrenal hyperplasia with refractory HTN Geller DS, J Clin Endocrinol Metab.2008

46 KCNJ5 Aldoster. Familial Hyperalsdosteronism II and III (Non- GRA)

47 FIRST GROUP : FAMILIAL HYPERALDOSTERONISM Early onset HTN, normal or high Aldosterone FH -I..Chimeric gene GRA FH II excess production..not GRA FH-III excess production..not GRA

48 SECONDARY HTN A) Mendelian Forms of Hypertension (single-gene mutations ) Most of the mutations found to date affect renal sodium handling. These disorders lead to 3 groups of diseases: 1. Aberrant distal tubular sodium reabsorption and volume expansion due to hyperaldosteronism (Aldosterone is increased) 2. Defects in steroid biosynthetic enzymes (causing increased mineralocorticoid activity) 3. Activation of sodium channels or transporters (depressed Aldosterone)

49 THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS (AME) AR Early-onset HTN with hypokalemia and metabolic alkalosis Accompanied by suppressed plasma renin activity And the virtual absence of circulating aldosterone.

50 THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS (AME) Steroids other than aldosterone activate the mineralocorticoid receptor (MR). i.e.apparent excess of MC action Cortisol activates MR with potency similar to aldosterone. Cortisol, normally, is transformed to Cortisone by 11-hydroxysteroid dehydrogenase (11HSD) enzyme Mutation in the gene encoding the renal i11-hydroxysteroid dehydrogenase (11HSD), results in impaired conversion of cortisol to cortisone. In AME, the absence of this enzyme allows cortisol to activate the MR, resulting in HTN mediated by increased sodium retention.

51 AME Aldosterone Cortisol 3BHSD2 Mineralocorticoid Receptor MR Cortisol 3BHSD2 Cortisone Epithelial Na channel ENaC Cortisone

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53 OTHER STEROIDS CAUSING HTN Congenital adrenal hyperplasia results from two known defects: β-hydroxylase α-hydroxylase

54 SECONDARY HTN A) Mendelian Forms of Hypertension (single-gene mutations ) Most of the mutations found to date affect renal sodium handling. These disorders lead to 3 groups of diseases: 1. Aberrant distal tubular sodium reabsorption and volume expansion due to hyperaldosteronism (Aldosterone is increased) 2. Defects in steroid biosynthetic enzymes (causing increased mineralocorticoid activity) 3. Activation of sodium channels or transporters (depressed Aldosterone)

55 LIDDLE S SYNDROME AD disorder Gain mutations in the epithelial Na channel (ENaC) (Amiloride sensitive ) in the collecting ducts, which are responsible for elevated renal sodium reabsorption in Liddle s syndrome Severe HTN, metabolic alkalosis, and hypokalemia Low renin Low aldosterone. Unresponsive to Aldosterone antagonist (aldactone) but responsive to amiloride and triametrene

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57 Liddle s Syndrome Aldosterone Aldactone Mineralocorticoid Receptor MR Epithelial Na channel ENaC(Amiloride sensitive) Amiloride triametrene Na reabsorption

58 LIDDLE S SYNDROME AND PSEUDOHYPOALDOSTERONISM TYPE I In Liddle's syndrome, gain-of-function mutations in the beta or gamma ENaC subunits have been found. In PHA-1, loss-of-function mutations in the alpha, beta, or gamma subunits have been found

59 GORDON S SYNDROME (PSEUDOHYPOALDOSTERONISM TYPE II) The WNKs [ with no lysine ] mutations of the WNK1 and WNK4 have been found to be responsible for Gordon s syndrome. Wild-type WNK1 and WNK4 inhibit the thiazide-sensitive Na-Cl cotransporter in the distal tubule. Mutations of these proteins are associated with gain of function and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion. Increased WNK1 expression also decreases potassium excretion by inhibiting the renal outer medullary potassium channel(romk).

60 GORDON S SYNDROME (PSEUDOHYPOALDOSTERONISM TYPE II) AD HTN hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. Thiazides responsive This syndrome maybe associated with short stature, intellectual impairment, dental abnormalities, muscle weakness

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62 RENOVASCULAR HTN (RVH) 10%(5 25 %) of all secondary HTN in children. RVH is second only to coarctation of the aorta as a correctable cause of HTN in children.

63 RENOVASCULAR HTN (RVH) Fibromuscular dysplasia (FMD ) is the most common cause of RVH in children. FMD Significantly different from that in adults ( with the classic string of beads in the main artery ) FMD in children produces focal unilateral isolated web like stenosis, and the majority of the lesions are in branch vessels or accessory arteries.

64 RENOVASCULAR HTN (RVH) Genetic syndromes such as NF-I Tuberous sclerosis Williams syndrome, Marfan s syndrome, Turner s syndrome Alagille syndrome Vasculitidies such as Takayasu s disease, polyarteritis nodosa, Kawasaki

65 RENOVASCULAR HTN (RVH) Other etiologies of RVH include Extrinsic compression of the renal arteries, Radiation, Umbilical artery catheterization Trauma Congenital rubella syndrome Aneurysms AVM/AVF, Transplant renal artery stenosis

66 RENOVASCULAR HTN (RVH) The stenosis needs to occlude at least 70%of the lumen before it begins to reduce renal blood flow and raise arterial pressure In the late phase, HTN persists despite removal of the stenosis or ischemic kidney, due to hypertensive damage to the contralateral kidney and probably also due to systemic vascular changes

67 CKD/AKI HTN Depends on the etiology of underlying kidney disease rather than on the degree of renal dysfunction (children with congenital urogenital anomalies such as renal dysplasia often do not have HTN because of tubulopathy leading to salt and water wasting.) HTN resulting from renal parenchymal disease is multifactorial in origin. impaired excretion of salt and water, reduced renal blood flow Activation of the RAAS

68 POST-RX HTN The major contributing factors : History of pre-transplant HTN Persistent native kidney presumably via persistent release of renin Effects of immunosuppressive medications Transplant renal artery stenosis Chronic allograft dysfunction

69 POST-RX HTN Calcineurin inhibitors cause: Increased production of the vasoconstrictor endothelin Decreased production of vasodilatory substances Activation of the SNS. Afferent artery vasoconstriction. Na retention. Many studies suggest that calcium channel blockers can minimize calcineurin-induced vasoconstriction thereby ameliorating HTN and preventing chronic graft injury. Rose C et al, Eur J Pediatr. 2001

70 HYPERTENSION IN ENDOCRINE DISEASES Pheochromocytomas and paragangliomas Primary hyperaldosteronism (PAL) Cushing s syndrome Glucocorticoid-remediable aldosteronism (GRA) Familial hyperaldosteronism II and III Reninoma. Primary hyperparathyroidism (PHPT) Hyperthyroidism( activation of the RAAS and increased sodium reabsorption ) Diabetes mellitus (DM).

71 Drug Induced HTN

72 PRIMARY (ESSENTIAL) HTN Most HTN in adults has no identifiable underlying etiology; therefore, the term essential HTN has been utilized for those hypertensive individuals without underlying secondary causes.

73 PRIMARY (ESSENTIAL) HTN In children, primary HTN was traditionally considered uncommon, accounting for less than 25 % of hypertensive children in the early 1990s. However, recently the rate has increased (up to 90 % in some USA series) mainly due to increased obesity Din-Dzietham R et al. Circulation. 2007

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75 SYMPATHETIC NERVOUS SYSTEM ACTIVATION Children with primary HTN : Resting tachycardia compared to normotensive children heightened cardiovascular reactivity to stress Elevated plasma norepinephrine levels

76 NB: Primary HTN is showing more and more to be NOT Primary HTN: 1. ACE 2 Mutation (reduced level of AT1-7) 2. ANP Polymorphism 3. Renalase activity

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80 QUESTIONS

81 Choose one correct answer : A) Familial hyperaldosteronism type III (FH-III) has been recently identified with mutations in the potassium channel KCNJ5 and is Glucocorticoid remediable B) Familial Hyperaldosteronism Type I (Glucocorticoid Remediable Aldosteronism) shows early onset of HTN with normal or elevated aldosterone levels despite suppressed plasma renin activity C) A chimeric gene under the effect of TSH is formed in Familial Hyperaldosteronism Type I (Glucocorticoid Remediable Aldosteronism) D) Cortisone causes HTN much more than Cortisol

82 Choose one correct answer : A) Liddle s Syndrome is an AD disease with gain of function of Thiazide sensitive NCC in distal Tubules B) Gordon s Syndrome is caused by a gain of function in the Amiloride sensitive ENaC in the collecting ducts C) Aldactone is the drug of Choice in Liddle s Syndrome to treat both hypokalemia and HTN in one act D) Gordon s Syndrome shows Type IV RTA

83 Choose one correct answer : A) Renalase maybe decreased in Primary HTN B) ANP polymorphism may contribute to the pathophysiology of primary HTN C) ACE 2 mutations can lead to more vasoconstriction in primary HTN D) All of the above

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90 In 2008, American Heart Association issued a guideline trying to standardize the use of ABPM in children, including the detailed recommendations for the use of ABPM and for the interpretation of the data Urbina E et al. Hypertension Subsequently, the European Society of Hypertension recommended the use of ABPM in children in certain settings Lurbe E et al. J Hypertens. 2009;

91 functional changes specifically decreased relaxation and increased contraction [9]. Decreased relaxation has been attributed primarily to endothelial dysfunction, and increased contraction has been attributed to enhanced smooth muscle cell vasoreactivity. Sensitivity to vasoconstrictors may also be increased. Decreased relaxation is an effect of impaired endothelial production of vasodilatory substances (mainly nitric oxide [NO] and prostacyclin) or increased production of vasoconstricting substances (endothelin, platelet-derived growth factor [PDGF]), or both.

92 Sympathetic Innervation/CNS Renal vessels, tubules, and the juxtaglomerular apparatus are innervated by the renal sympathetic nerves. Renal sympathetic nerve activity (RSNA) influences renal hemodynamics, solute and water handling, and hormonal release. Increased RSNA is found in animal models of HTN and also in hypertensive humans [13]. SNS activation, as confirmed by increased circulating noradrenaline, muscle sympathetic nerve traffic, and systemic noradrenaline spillover, has for many decades been established as almost universally present in primary HTN

93 that was blocked by an ANG-II receptor antagonist Increased RSNAconstricts the renal vasculature and decreases GFR and renal blood flow. The hypertensive response to chronic renal adrenergic stimulation is associated with a sustained increase in plasma renin activity and is dependent on an increase in plasma angiotensin II (ANG-II) concentration [16]. Sympathetic nerve activation appears to enhance the response to circulatingang-ii [17]. The renal effects of ANG-II on proximal tubular chloride and water reabsorption are decreased by 75 % in animals after experimental renal denervation. Thus only about 25 % of ANG-II effect is mediated directly via type 1 angiotensin receptors, with the majority of the effect being dependent on intact renal innervation. In experimental renal sympathetic nerve stimulation, ANG-II enhanced the renal venous outflow of norepinephrine, an effect

94 The AT2 receptor is a seven-transmembranetype, G protein-coupled receptor comprising 363 amino acids. It has low amino acid sequence homology (~34 %) with AT1A or AT1B receptors [36]. The expression of the AT2 receptor is upregulated by sodium depletion [48] and is inhibited by ANG-II and growth factors such as PDGF and EGF [49]. Under physiologic conditions, the AT2 receptor mainly antagonizes AT1-mediated actions. Cardiovascular effects of the AT2 receptor generally appear to be opposite to those of the AT1 receptor and may be protective [50, 51]. In the kidney, stimulation of the AT2receptor promotes natriuresis through interactions with the renal dopaminergic system [52].

95 gene (CYP11B1) on chromosome 8. Aldosterone synthase is the rate-limiting enzyme for aldosterone biosynthesis in the adrenal glomerulosa, and 11β-hydroxylase is an enzyme involved in cortisol biosynthesis in the adrenal fasciculata whose expression is regulated by adrenocorticotropic hormone (ACTH). The resulting chimeric gene (CYP11B1/CYP11B2) is expressed in the adrenal fasciculata and encodes a protein product with aldosterone synthase enzymatic activity whose expression is regulated by ACTH. Consequently, aldosterone synthase activity is ectopically

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97 Congenital adrenal hyperplasia results from two known defects in either 11-β-hydroxylase or17-α-hydroxylase activity and may cause HTN. These defects lead to overproduction of 21-hydroxylated steroids, which activate mineralocorticoid receptors, resulting in increased sodium reabsorption in distal tubules [295, 296].

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101 HYPERTENSION IN ENDOCRINE DISEASES Pheochromocytomas and paragangliomas Although most pheochromocytomas are sporadic, there is a familial predisposition in patients Multiple endocrine neoplasia type II(MEN II) Von Hippel Lindau disease NF-I and familial paraganglioma [ ]. Rarely, in tuberous sclerosis, Sturge Weber syndrome, and ataxia telangiectasia.

102 HYPERTENSION IN ENDOCRINE DISEASES Primary hyperaldosteronism (PAL) is now believed to be much more common than previously thought [397, 412, 413]. PAL was first reported by Conn as aldosterone-producing adenoma (APA) [414] and commonly results from adrenal hypertrophy ( idiopathic hyperaldosteronism ; IHA)

103 Hypertension in Dialysis Patients Children receiving chronic dialysis have a significant incidence of HTN: % of children receiving hemodialysis and % of children receiving peritoneal dialysis in the NAPRTCS dialysis database were receiving antihypertensive

104 The aldosterone/mr cascade exerts its effects in the so-called aldosterone-sensitive distal nephron (ASDN), which includes the late distal convoluted tubule, connecting tubule, and collecting duct. Upon binding of aldosterone, MR undergoes conformational changes, dissociation from chaperone proteins, dimerization, and translocation to the nucleus, where it binds to the responsive elements in the promoter regions of target genes to regulate transcription. Among the aldosterone-induced genes, serum/glucocorticoid regulated kinase 1 (SGK1) plays a major role in the control of sodium reabsorption. Studies have clarified the detailed mechanism of epithelial sodium channel (ENaC) regulation by SGK1 (Fig. 1). Nedd4-2 (neural precursor cell expressed, developmentally downregulated 4-2) is a HECT domain containing E3 ubiquitin ligase that interacts with the C terminus of ENaC subunits and maintains the plasma membrane ENaC at low levels through ubiquitination-dependent mechanisms. Aldosterone-induced SGK1 phosphorylates the Nedd4-2, which disrupts the tonic inhibition of ENaC by Nedd4-2, leading to indirect stimulation of sodium transport. SGK1 phosphorylation of Nedd4-2 results in binding and suppresses Nedd4-2 ENaC interaction [11]. ENaC mutations in Liddle s syndrome also affect the Nedd4-2 interaction, leading to constitutive ENaC expression and increased sodium reabsorption [12]. SGK1 may also modulate ENaC activity though a mechanism independent of Nedd4-2 [13].Fig. 1

105 The major pathophysiologic mechanism in most dialysis patients seems to be volume overload related to sodium and water retention. Evidence in favor of fluid overload being the major mechanism can be found in the many studies that demonstrate correction of HTN by increased fluid removal in both peritoneal dialysis and hemodialysis patients [359, 360]. However, numerous other factors have been implicated, including overactivity of the SNS, activation of the RAAS, erythropoietin treatment, parathyroid hormone, and nocturnal hypoxemia [361]. Recent studies have also implicated altered endothelial cell function, with increased vasoconstrictors such as endothelin and a reduction of vasodilators such as NO being involved in the pathogenesis of dialysis HTN

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107 POST-RX HTN HTN is a common complication following renal transplantation. 85% of deceased donor recipients and 79 % of live donor recipients are receiving antihypertensive medications immediately post-transplant (decreasing to 69 % and 59 %, respectively 5 yrs after TX) [370].

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110 Endothelin-1 Endothelin-1 (ET-1) is an endothelial-derived, potent vasoconstrictive peptide containing 21 amino acids [110]. Three isopeptides of endothelin (ET-1, ET-2, ET-3), encoded by separate genes, have been identified [111]. Endothelial ET-1 synthesis is activated by vasoactive hormones, growth factors, hypoxia, shear stress, lipoproteins, free radicals, endotoxin, and cyclosporine and is inhibited by NO, natriuretic peptides, heparin, and prostaglandins [112]. Apart from endothelial cells, ET-1 is also produced by

111 ET-1 primarily appears to be a locally acting paracrine substance. ET-1 closes membrane K+ channels [115], which prevents cellular efflux of K+, thereby favoring membrane depolarization, leading to smooth muscle cell contraction. In the kidney, ET-1 causes constriction of both afferent and efferent glomerular arterioles, thereby reducing both renal plasma flow and glomerular filtration rate [116]. It blocks reabsorption of sodium by inhibiting tubular Na+/K+ ATPase activity in the proximal tubule and collecting duct [117]. Endothelin signals through two receptor subtypes

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113 NO is a vasodilator, and the balance between NO and various endothelium-derived vasoconstrictors and the SNS maintains physiologic vascular tone [133]. In addition, NO suppresses

114 platelet aggregation, leukocyte migration, and cellular adhesion to the endothelium. It attenuates vascular smooth muscle cell proliferation and migration, as well as inhibits activation and expression of certain adhesion molecules and has an influence on production of superoxide anion [134]. Endothelium-dependent relaxation is decreased in patients with primary HTN [135] and appears to be related to defective L-arginine transport.

115 Treatment with inhibitors of NO synthesis induces a hypertensive response, while L-arginine treatment prevents the development of HTN in salt-sensitive rats [137] and also causes a rapid reduction in systolic and diastolic pressures when infused into both healthy subjects and patients with primary HTN [138]. Methylated L-arginine derivatives, including NG-NG-dimethylarginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of NOS, and symmetric dimethylarginine, its inactive isomer, are present in human plasma and urine. Elevated levels of ADMAand other markers of oxidative stress have been demonstrated in patients with primary HTN and have been postulated to contribute to the endothelial dysfunction that accompanies HTN [139].

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117 Shibata S and Fujita T. Curr. Hypertens. Rep.2011

118 Shibata S and Fujita T. Curr. Hypertens. Rep.2011

119 UP TO DATE INTRODUCTION Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1 are rare genetic disorders associated with abnormalities in the function of the collecting tubule sodium channel, also called the epithelial sodium channel (ENaC) or the amiloride-sensitive sodium channel: ENaC function is increased in Liddle's syndrome, leading to manifestations similar to those caused by mineralocorticoid excess, such as hypertension and, in some patients, hypokalemia and metabolic alkalosis. Presentation at a young age, which occurs in most patients, suggests the possibility of a genetic disorder rather than an adrenal adenoma. In addition, plasma and urinary aldosterone levels are reduced, not increased as in primary aldosteronism. ENaC function is decreased in autosomal recessive pseudohypoaldosteronism type 1, resulting in aldosterone resistance. Affected patients present in infancy with sodium wasting, hypovolemia, and

120 ANG II Angiotensin II and angiotensin III (ANG-II, ANG-III) induce aldosterone synthesis Potassium, endothelin, adrenocorticotropic hormone (ACTH) and vasopressin stimulate its secretion. Inhibitors of aldosterone secretion include atrial natriuretic peptide, somatostatin, and dopamine. Dietary sodium restriction increases aldosterone secretion in order to restore plasma volume. Aldosterone acts via type I mineralocorticoid receptors causing retention of sodium and potassium excretion. It also activates the SNS