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Presentation on theme: "Kidney In PaTHoPHYSIOLOGY OF HYPERTENSION"— Presentation transcript:

Vinod K Bansal, M.D . Professor of Medicine, Division of Nephrology &Hypertension Loyola University Chicago Stritch School of Medicine October 23, 2018

2 Objectives Identify the hemodynamic determinants of systemic hypertension Discuss the role of the kidney in systemic hypertension Describe the role of angiotensin II, aldosterone, and the sympathetic nervous system in the pathogenesis of hypertension Differentiate primary and secondary forms of hypertension

3 Blood Pressure Blood Pressure is the product of Cardiac Output (CO) and Systemic Vascular resistance (SVR) Blood Pressure is generated by cardiac contraction against Vascular resistance; MAP = CO X SVR. If one component increases the other must decrease proportionately to maintain normal BP or hypertension will result.

4 Blood pressure modulation by effects on cardiac output and peripheral resistance
Kumar, Figure 10-13

5 Cardiac Output Stroke volume is affected by pre-load, after-load, and contractility The primary determinant of CO in normal individuals is volume status (sodium content) An increase in CO is rarely the cause of persistent hypertension

6 Systemic Vascular Resistance
SVR is affected by humoral and local factors: Humoral factors: Balance of vasoconstrictors and vasodilators Renin-Angiotensin System and norepinephrine are two of the more important factors. Local factors: Some arterioles are able to auto-regulate flow in their capillary beds, constricting at times of high BP and dilating at times of low BP. This is common in the brain and the kidney, and mediated by Endothelium Derived Relaxing Factor (EDRF )

7 Role of Renin-Angiotensin-Aldosterone System in Regulation of Blood Pressure
Oparil S. et al. Nature Rev 2018 (doi /nrbp )

8 Sympathetic Nervous System
Increased adrenergic tone leads to hypertension. Blockade of the sympathetic nervous system reduces BP Adrenergic tone increases Vascular tone Na+ retention Cardiac inotropy

9 Major Neuroendocrine Systems Involved in Regulation of Blood Pressure
Oparil S. et al. Nature Rev 2018 (doi /nrbp )

10 Hypothetical scheme for the pathogenesis of essential (primary) hypertension
Kumar, Figure 10-15

11 Guyton Hypothesis and Renal Function Curves
Fundamental mechanism of long term control of BP is the fluid volume feedback mechanism by Kidneys. Kidneys regulate arterial pressure by altering renal excretion of Na and water (Pressure Natriuresis) thereby controlling circulatory volume and cardiac output Guyton AJM 52: :1972 Guyton Hypertension: 10:1-6:1987

12 Urine Na and Volume Excretion Arterial Pressure (mmHg)
7 6 Renal Function Curve 5 4 Urine Na and Volume Excretion 3 Equilibrium Pressure 2 Net Intake 1 50 100 150 200 Arterial Pressure (mmHg) Guyton AC Hypertension Jan;19(1 Suppl):I2-8.

13 Intake and Output of Water and Salt Arterial Pressure (mmHg)
Normal 6 5 Essential Hypertension 4 High Intake Intake and Output of Water and Salt D 3 2 Normal Intake A 1 B Low Intake C 50 100 150 200 Arterial Pressure (mmHg) Hall JE J Hum Htn 1992:10;


15 Renal Pressure Natriuresis
Elevated BP raises sodium excretion usually accompanied by pressure diuresis (increased water excretion) In hypertension, sodium excretion (equal to sodium intake) is maintained at higher BP levels than that would normally result in natriuresis and diuresis Thus, in hypertensive subjects, pressure and diuresis are reset

16 Case History Mr. Brown is a 48 year old Caucasian man who works as a computer programmer. Recently he had physical examination at work and was told that his BP is elevated and advised to contact his physician. He has no problems or symptoms or complaints. He underwent a fully physical examination by his PCP. Systemic examination was normal but his BP was 145/92 (normal less than 140/90 in adults). His physician repeated his BP for three readings 2 minutes apart and they all were in that range. He tells his physician that no one in his family has hypertension. The patient is very active, goes to gym almost daily, and is normal weight for his height. He was advised to restrict his salt intake and return for follow-up in a week. His BP was now of 148/94. Rest of physical examination is normal. An extensive work done reveals no known cause of hypertension. His physician tells him he has Essential Hypertension and he will have to be on life-long therapy( life style modification and medications) for hypertension. He is started on an ACEI and two weeks later his BP is now 130/85. Mr. Brown feels well and continues to work and engage in his normal activities.

17 Primary or Essential Hypertension
No known etiology accounts for about 90-95% of hypertension. Occurs in cluster of families but it is not hereditary Polygenic, no single gene identify Monogenic hypertension is defined when a single gene is identified as the cause for hypertension

18 Derived Curves of Renal Handling of Salt and Water Intake in Normal People and in Patients with Essential Hypertension 200 150 Essential Hypertension Blood Pressure (mmHg) 100 Normal 50 1 2 3 4 Intake and Output of Salt and Water (x Normal)

19 Renal Pressure Natriuresis in Hypertension
Renal pressure natriuresis is impaired and shifted in all forms of hypertension studied It may be due to either intra-renal or extra-renal factors yet to be fully described Intra-renal factors lead to reduced renal blood flow, decreased glomerular filtration rate or increased tubular reabsorption Extra-renal factors include increase sympathetic nervous system activity or increased anti-natriuretic hormones

20 Kidneys in Pathogenesis of Essential Hypertension
No obvious renal defects identified in hypertensive patients so far but almost all experimental hypertension is caused by insult to kidneys altering either renal homodynamic or tubular reabsorption Renal pressure natriuresis mechanism is abnormal in all types of experimental and clinical hypertension Hall, Hypertension 1990,15:

21 Kidney Regulation of Normal Blood Pressure
Maintenance of volume by regulating sodium excretion Pressure natriuresis an essential function of kidneys Resetting of pressure natriuresis at high level in essential hypertension Most monogenic hypertension due to increase sodium retention

22 Monogenic Hypertension
Glucocorticoid remedial aldosteronism (GRM) Syndrome of apparent mineralocorticoid excess (AME) Mineralocorticoid receptor mutation (increases Na Ca activity) Liddle Syndrome: gain of function ENac T594M mutation African-American subtype salt sensitive (increases ENac activity)

23 Pathways Affected in a Single Gene: Mendelian Hypertension and Hypotension Syndrome
Oparil S. et al. Nature Rev 2018 (doi /nrbp )

24 Secondary Hypertension
An explainable cause for hypertension is present May be superimposed on pre-existing essential hypertension Overall incidence is about 5-10% although in specific populations it may be >15-20%


26 Renovascular Hypertension
Defined as resulting from stenosis of unilateral or bilateral renal artery stenosis Stenosis doesn’t necessarily mean hypertension Degree of stenosis is critical

27 Renal Artery Stenosis Clinical presentations
Severe and difficult to control hypertension Kidney failure Flash pulmonary edema Two disease processes Atherosclerotic renal artery stenosis Fibromuscular dysplasia

28 Renovascular Hypertension
Unilateral renal artery stenosis with normal contralateral kidney Bilateral renal artery stenosis Renal artery stenosis in a solitary kidney

29 Goldblatt Model- I of Unilateral Renal Artery Stenosis with two kidneys
A clip is applied to one renal artery in an animal with two functioning kidneys. That results renal artery stenosis on clipped artery. Results in hypo perfusion in clipped kidney, leads to increase secretion of renin–angiotensin. Increase BP results in pressure natriuresis in contralateral normal kidney, keeping near normal volume. Increase blood pressure maintained by increased TPR and some impaired pressure natriuresis.

30 Goldblatt Model II A clip is applied to one renal artery in an animal with one functioning kidney, a model of renal artery stenosis in a single kidney (such as renal artery stenosis in transplanted kidney). Bilateral renal artery stenosis: Similar mechanism of hypertension. Total renal mass is hypo-perfused Impaired clearance No off-setting pressure natriuresis (in contralateral kidney ,thus absence or marked impairment of pressure natriuresis.)

31 Intrarenal Hemodynamics
Contralateral Kidney Stenotic Kidney Ischemia Renin Angiotensin Intrarenal Hemodynamics Suppressed Renin Pressure Natriuresis Aldosterone Vasoconstriction.

32 Two Kidney-One Clip (Unilateral Renal Artery Stenosis
BP  Blood Volume  Plasma Renin  Response to ACE-I (+)

33 One Kidney-One Clip (Renal Artery Stenosis of a Solitary Kidney)
BP  Blood Volume  Plasma Renin  Response to ACE-I (-)

34 Two Kidney-Two Clip (Bilateral Renal Artery Stenosis)
BP  Blood Volume  Plasma Renin  Response to ACE-I (-)

35 Renovascular Hypertension: Pathogenesis
Unilateral renal artery stenosis with presence of normal contralateral kidney is vasoconstrictive maintained by increased RAS system Renal artery stenosis in solitary kidney or bilateral renal artery stenosis is volume dependent

36 Case 2 Ms. Smith is a 61 year old woman with history of hypertension, hypothyroidism and asthma presents to renal clinic for evaluation of HTN. She reports that she was diagnosed with HTN about 5 years ago. Her BP has been difficult to control with systolic BP in 160s. Her regimen included Amlodipine 10mg daily and Metoprolol 50 mg twice daily. She had an episode of syncope and as part of work up had imaging of her brain. She also had CT angiogram of renal arteries and a subsequent procedure.





41 Renal Artery Stenosis Therapy
Medical – antihypertensives +/- ACE inhibitors Interventional – renal artery angioplasty +/- stenting Surgical – renal artery bypass

42 Aldosterone and Hypertension
Aldosterone, a mineralocorticiod, is a sodium retainer Excess aldosterone leads to sodium and volume retention resulting in hypertension Primary aldosterone tumor is relatively rare but primary aldosteronism may result from adrenal hyperplasia and may be more common

43 Aldosterone Aldosterone results in Na retention and hypervolemia
Excess potassium excretion leads of hypokalemia Volume expansion may be clinically absent due to “aldo-escape” Increased aldosterone leads to expanded ECV and hypertension.

44 Case 3 52 year old male was diagnosed with HTN for many years and was treated sporadically. His initial work up was normal with normal electrolytes except for low potassium of 3.3 mEq/L. His medications included Lisinopril and Amlodipine and Potassium chloride. His BP was better controlled with this regimen but low potassium persisted and Amiloride was added. He was lost to follow up. 3 years later, he had cardiac arrest in his office and was revived and his lab results showed serum potassium level of 2.5mEq/L. He had stopped taking Amiloride for an unspecified time.

45 Further work up Plasma renin activity: 0.17ng/ml/h
Serum Aldosterone: 13ng/dl Serum Metanephrines: within normal range MRI abdomen: Left Adrenal adenoma 1 cm, Right adrenal normal. Adrenal vein sampling for aldosterone: -Right adrenal: 235 ng/dl -Left adrenal ng/dl


47 Chronic Kidney Disease and Hypertension
As kidney function falls (↓ GFR), its ability to excrete sodium and water is impaired This leads to excess volume which causes and worsens hypertension

48 Impaired Sodium Excretion
BP incidence increases with patients with chronic kidney disease BP is very responsive to manipulations of volume status Seems to be mediated by abnormal vasoregulation and increased SVR

49 Kidney Failure With the loss of kidney function, virtually 100% of patients become hypertensive Chronic kidney disease is the most common form of secondary hypertension Hypertension can be controlled with diuretics and other hypotensive agents and in ESRD by hemodialysis and ultrafiltration.


51 Mean Arterial Pressure (% of Control) Arterial Pressure (mmHg)
0.9% NaCl Tap Water 0.9% NaCl 150 35-45% of Left Kidney Removed 140 Entire Right Kidney Removed 130 Mean Arterial Pressure (% of Control) 120 110 100 90 20 40 60 80 100 Arterial Pressure (mmHg)

52 Effect of Decrease in Body Fluid
Effect of Decrease in Body Fluid Volume by Dialysis Therapy Upon BP of a Patient With Chronic Renal Disease -2 -4 Bodyweight (kg) Change in -6 -8 -10 180 Mean 160 140 Blood Pressure (mmHg) 120 Diastolic 100 80 Start Dialysis Treatment 5 10 14 18 22 26 30 Clinical Hypertension Norman Kaplan 2006 Pg.189

53 Oparil S. et al. Nature Rev 2018 (doi 10.1038/nrbp.2018.14)

54 Hypertensive Renal Injury
Two patterns of Hypertension injury to Kidneys Essential hypertension Benign nephrosclerosis. Malignant hypertension Intimal thickening Proliferative arteritis Fibrinoid necrosis Renal auto regulation.

55 Essential Hypertension and Nephrosclerosis
Contracted kidneys in essential hypertension Progressive reduction in size Cortical atrophy and diffuse fibrosis Afferent arteriolar hyaline arteriosclerosis Subintimal hyaline homogenous eosinophilic deposits Ischemic atrophy

56 Nephrosclerosis

57 “Benign” hypertension – hyaline arteriolopathy

58 Malignant Hypertension
Marked elevation of BP Evidence of widespread acute arteriolar injury Fundoscopic finding of hypertensive neuroretinopathy Nolan 2001

59 Arteriole With “Onion” Skin Appearance
Malignant HTN Arteriole With “Onion” Skin Appearance

60 “Fibrinoid” Necrosis of Small Artery
Malignant HTN “Fibrinoid” Necrosis of Small Artery

61 Autoregulation Autoregulation of glomerular filtration rate (GFR) and renal blood flow (RBF) is due to pre-glomerular vasoconstriction that impedes the transmission of elevated systemic arterial pressure to glomerulus and peritubular capillaries of the kidneys Autoregulation protects kidneys from hypertensive injury but may be altered in chronic kidney disease and diabetic kidney disease

62 Autoregulation of Renal Blood Flow & GFR
Ensures that renal blood flow and GFR remain relatively constant even while systemic arterial pressures fluctuate Depends primarily on two mechanisms: Myogenic Response Tubuloglomerular Feedback RBF or GFR Outside this range, the autoregulatory mechanisms fail and renal blood flow parallels changes in systemic arterial pressure. Could stress that the details of the myogenic response or tubuloglomerular feedback are not particularly important. Though it’s good to know that they exist, the main thing to understand is the concept of autoregulation. [? I would consider just quickly explaining the gist of myogenic response and tubuloglomerular feedback and deleting the subsequent slides. -myogenic response: property of the afferent arteriole and its smooth muscle cells that allows it, in the setting increased arteriolar pressure, to reflexively vasoconstrict and, in the setting of decreased pressure, to reflexively vasodilate -tubuloglomerular feedback: mechanism by which GFR is regulated by the amount of filtrate generated, i.e., the amount of filtrate within the glomeruli ‘feeds back’ on GFR. With increased GFR, more NaCl is filtered, and the macula densa in the distal tubule senses an increased chloride concentration and generates a signal to the adjacent afferent arteriole that stimulates afferent arteriolar constriction, which decreases GFR.]



65 Myogenic Response Response to increased afferent arteriolar pressure:
stimulates reflexive vasoconstriction by stimulating smooth muscle cell contraction minimizes increase in PGC that would otherwise occur in response to increased systemic arterial pressure prevents damage to glomerular capillaries, which already function at hydrostatic pressures that are much greater than those in the systemic capillaries Response to decreased afferent arteriolar pressure: stimulates reflexive vasodilation by stimulating vascular smooth muscle relaxation increases blood flow and filtration pressure in the glomerulus, thereby helping maintain GFR The myogenic response is a property of the smooth muscle cells of the afferent arteriole. [? Delete.]

66 Renal autoregulation prevents transmission of systemic blood pressure to glomerular capillaries

67 Systemic hypertension would increase glomerular capillary pressure in absence of autoregulation

68 Dihydropyridine calcium antagonists abolish renal autoregulation and prevent normalization of glomerular capillary pressure DCA BP A E G

69 Kidney Autoregulation: Therapeutic role
Autoregulation of kidneys modulate blood flow and pressure transmission to glomerular tufts and protects them against injury. In CKD or diabetes, autoregulation is impaired making kidney more prone to hypertensive injury. Some antihypertensive drugs may abolish autoregulation and may worsen renal injury.

70 Treatment of Hypertension: Renal Considerations
Lowering BP will minimize damage to kidneys and slow down progression of renal failure In presence of chronic kidney disease, sodium and water are retained and volume becomes an important factor Diuretics are necessary in most instances of hypertension with CKD Drugs which preserve renal autoregulation help preserve renal functions

71 Summary Kidneys play a central role in long term regulation of blood pressure and hypertension There is shifting of pressure natriuresis curve to right in essential hypertension or reset at higher BP level

72 Summary Unilateral renal artery stenosis with a normal contralateral kidney is renin dependent and blocking the renin-angiotensin system is an effective treatment In bilateral renal artery stenosis and in stenotic solitary kidney, the hypertension is volume related

73 Summary Interaction of volume and vasoconstriction is responsible for the vast majority of essential hypertension Kidneys are prone to hypertensive injury and keeping blood pressure under control prevents development of renal failure

74 Questions?

75 Blood Pressure = Cardiac Output x Peripheral Resistance
Hypertension = Increased CO x Increased PR Stroke Volume Na Balance Contractibility Catecholamines Functional Constriction Renin Angiotensin Catecholamines

76 Renin Angiotensin System in Hypertension
Renin angiotensin system has major effect in pathogenesis and maintenance of hypertension via angiotensin II Direct vasoconstriction and increased SVR Enhanced Na reabsorption by the proximal tubule Stimulates aldosterone release which increases Na reabsorption by the collecting tubule

77 Renal Corpuscle Bowman’s Capsule and Glomerulus
Point out the macula densa again. Although not labeled, it is the specialized cells of the distal tubule (in BLUE) located next the specialized smooth muscle cells of the afferent arteriole (in GREEN) which comprise the juxtaglomerular apparatus. [The third component of the JGA are some extra-glomerular mesangial cells, whose function is less important.]


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