9/14- Nephrologist's Approach to Hypertension Flashcards
1
Q
What factors weigh into blood pressure?
A
BP = CO x PVR
Cardiac output
- Blood volume (Na, mineralocorticoids)
- Cardiac factors (heart rate, contractility)
Peripheral vascular resistance:
- Vasoconstricotrs (ang II, catecholamines- a-adrenergic)
- Vasodilators (prostaglandins, catecholamines- B-adrenergic, potassium)
- Local factors (adenosine, pH, hypoxia)
2
Q
How common is essential hypertension?
Among what populations?
- What may influence it
- What is it a risk factor for
A
- 1/3 people have HTN
- Accounts for > 90% of HTN
- Older Americans and blacks have increased risk
Influenced by:
- Genetics (positive FHx)
- Environment: obesity, fast food diet, high stress, type A
- Neurohormonal mediators
- Possibly also metabolic factors like hyperuricemia
Risk factor for:
- Coronary artery disease (CAD)
- Congestive heart failure (CHF)
- Stroke
- Kidney failure
3
Q
What organs are affected by essential HTN? Manifestations?
A
Kidney
- Chronic kidney disease
- Proteinuria
- Nephrosclerosis and interstitial fibrosis
CNS damage
- Stroke
Vascular damage
- Indicated by retinal exam
- AV nicking
Heart
- Cardiac hypertrophy
- Fibrosis
- Heart failure
- Coronary artery disease
4
Q
How does hypertension cause pathology in the kidneys?
A
Small arteries:
- Fibrous intimal thickening
- Reduplication and fragmentation of elastic lamina
- Medial hyperplasia
Tubules and Interstitium
- Tubule atrophy
- Interstitial inflammation and fibrosis
Glomerulus
- Collapse of capillaries
- General loss of cells
- Glomerulosclerosis
Picture is small blood vessel
5
Q
How does the kidney play a role in essential hypertension?
A
Increased peripheral resistance
- Renin-angiotensin system
- Sympathetic nerve system
Sodium retention
- Primary or secondary
- Inability to excrete sodium load
6
Q
What is “salt-sensitive hypertension”?
A
Loss of sensitivity of regulatory process in which sodium loading normally leads to “pressure natriuresis”
- “Guyton” hypothesis
- Chronically expanded vascular volume (but may be in upper range of normal)
- Relative increase in vascular resistance (but may be in upper range of normal)
7
Q
What are the genetic mechanisms of HTN?
A
- Multiple genes (angiotensin, adducin…) involved with renal sodium excretion have been implicated (none clearly proven in 1’ HTN)
- Sodium retention with resultant volume expansion may initiate hypertension
8
Q
What is resistant HTN (def)?
A
Persistence of HTN despite concurrent use of adequate doses of 3 antihypertensive agents from different classes, including a diuretic
9
Q
What can cause resistant HTN?
A
Improper BP measurement
Volume overload
- Excess Na intake
- Volume retention from kidney disease
- Inadequate diuretic therapy
Drug-induced or other causes
- Nonadherence
- Inadequate doses
- Inappropriate combos
- NSAIDs (COX2 inhibitors)
- Cocaine, amphetamines, illicit drugs…
- Sympathomimetics
Oral contraceptive hormones
- Adrenal steroid hormones (anabolic)
- Cyclosporine and tacrolimus
- EPO
- Licorice
- Selected over-the-counter dietary supplements/meds
Associated conditions
- Obesity
- Excess alcohol intake
10
Q
What is secondary HTN (clues)?
A
- Onset of severe HTN (BP > 180 systolic or 120 diastolic) after the age of 55 yo
- Unexplained deterioration of kidney function during antiHTN therapy
- Esp an acute and sustained elevation in the serum creatinine concentration by > 50% that occurs within 1 wk of instituting therapy with ACEI or ARB
- Severe HTN in pts with diffuse atherosclerosis (particularly those over 50 yo)
- Severe HTN in pt with unexplained atrophic kidney or asymmetry in renal sizes > 1.5 cm
- Severe HTN in pts with recurrent episodes of acute (flash) pulmonary edema or refractory heart failure with impaired renal fucntion
- A systolic-diastolic abdominal bruit that lateralizes to one side
11
Q
Screening tests in secondary HTN for:
- Chronic kidney disease
- Coarctation of aorta
- Cushing’s syndrome
- Drug induced
- Pheochromocytoma
- Primary aldosteronism/mineralocorticoid excess
- Renovascular HTN
- Sleep apnea
- Thyroid/parathyroid disease
A
- Chronic kidney disease: estimated GFR
- Coarctation of aorta: CT
- Cushing’s syndrome: Hx; dexamethasone suppression test
- Drug induced: Hx, drug screening
- Pheochromocytoma: 24 hr urinary metanephrine an dnormetanephrine
- Primary aldosteronism/mineralocorticoid excess: 24 hr urinary aldosterone level or specific msmts
- Renovascular HTN: Doppler flow study, MRA
- Sleep apnea: sleep study with O2 sat
- Thyroid/parathyroid disease: TSH, serum PTH
12
Q
Goldblatt’s hypothesis of acquired kidney injury?
A
Ischemia -> increased renin
- Increased aldosterone and sodium retention increased blood volume
- Increased angiotensin II and vasoconstriction increases PVR
Both contribute to HTN
13
Q
Renal artery stenosis accounts for ___% of causes of HTN
A
Renal artery stenosis accounts for 2-5% of causes of HTN
14
Q
What is renal artery stenosis?
- Pathophysiology
- Prognosis
A
Narrowing of the renal a. causing restriction of renal blood flow that -> HTN
- Pathophysiology: activation of RAAAS
- Hemodynamically significant stenosis can lead to renal atrophy and reduction in kidney function
15
Q
Interrelation among renal artery stenosis, HTN, and chronic renal failure
A
16
Q
What is the etiology of renal artery stenosis?
A
Atherosclerosis
- 60-80%
- Elderly man
- Affects mainly the proximal third of the main renal artery
Fibromuscular dysplasia
- 20-40%
- Young women
- Involves the distal two thirds and branches of the renal arteries
Neurofibromatosis
Vasculitis
Radiation
17
Q
Pathophysiology of RVH
A
- Experimentally, produced by clipping the renal artery; will simulate renal artery stenosis
- Termed “Goldblatt Hypertension” or model/hypothesis
18
Q
What was Goldblatt’s Hypothesis on acquired renal injury?
A
- Primary renal microvascular disease that results in renal ischemia is the cause of hypertension.
- Renal ischemia leading to oxidative stress, inflammatory cell infiltration and sodium retention is central to the pathogenesis of hypertension
2 kidney, 1 clip model:
- Increase in aldosterone lead to hypokalemia
- Usually, need to have at least 70% stenosis prior to the mentioned cascade effect
- Key point: Pressure natriuresis by the contralateral kidney normalizes blood volume.
19
Q
What are the phases of RAS?
A
- Acute phase (I)
- Transitional phase (II)
- Chronic phase (III)
20
Q
What occurs in the acute phase of RAS?
A
- Renin, angiotensin II, aldosterone increased, sympathetic nervous system stimulated
- Vascular volume normal because normal kidney excretes sodium and water
- BP elevated due to vasoconstriction, increased CO
21
Q
What occurs in the transitional phase of RAS?
A
- System becomes more sensitive to Ang II and SNS
- Expanded volume / salt and water retention
- Hypertension is treatable with removal of stenosis
22
Q
What occurs in the chronic phase of RAS?
A
- Hypertension with normal / slightly increased RAA & SNS
- Hypertension not treatable after stenosis removal
- Contralateral kidney gets damaged from persistent high pressures, and volume may increase again
23
Q
What is the 2 kidney, 2 clip model?
A
- Initial increase in renin with rise in blood pressure
- No contralateral kidney to perform pressure natriuesis
- Therefore, volume increases.
- Increase in volume suppresses renin to near normal levels later on.
- HTN is volume-dependent.
24
Q
What is the clinical presentation of RAS?
A
- Onset of HTN under 30 or > 55 yo
- Severe HTN requiring 3 or more BP medications
- Development of resistant hypertension in a previously well-controlled patient
- Flash pulmonary edema
- Renal failure with ACE inhibitors
- Abdominal bruit or asymmetry of kidney size
- Hypertension with renal failure
25
The addition of ACE inhibitors in the presence of _______ (uni/bilateral) RAS will cause \_\_\_\_. Why?
The addition of ACE inhibitors in the presence of **bilateral** RAS will cause **kidney failure**
- The efferent arteriole is mostly dependent on angiotensin-II for its vascular tone.
- Alterations or blockade in angiotensin-II will affect the efferent arteriole the most.
26
How can RAS be diagnosed?
- Angiography\*\* (gold standard)
- Magnetic resonance angiography (MRA)
- Spiral CT scan with angiography
- Doppler ultrasonography
- Renogram and captopril renogram
- BOLD MRI
27
How to treat RAS?
- Medically
- Surgically
_Medical therapy_
- Optimal blood pressure control
- Cessation of smoking
- Lipid lowering agents with statins
- Anti-platelet agents
- RAS Blockade
_Surgical therapy_
- Percutaneous transluminal renal angioplasty with stenting
- Surgical revascularization
28
What is pheochromocytoma?
Excessive catecholamine production by tumor from adrenal medulla or sympathetic nerve chain
29
How does pheochromocytoma present?
_5 Ps:_
- **Pressure** (HTN) in 90%
- **Pain** (headache) in 80%
- **Perspiration** in 71%
- **Palpitation** in 64%
- **Pallor** in 42%
- (**Paroxysms**)
30
What is the "rule of 10" in pheochromocytoma?
10% **extra-adrenal** (closer to 15%)
10% occur in **children**
10% **familial** (closer to 20%)
10% **bilateral** or **multiple** (more if familial)
10% **recur** (more if extra-adrenal)
10% **malignant**
10% discovered **incidentally**
31
How can pheochromocytoma be diagnosed?
**Biochemical tests**
- Urine studies are more specific (?)
- Plasma metanephrines are very sensitive; may indicate need for further testing Imaging
**- CT abdomen**: adrenal pheo, extra-adrenal
**- MRI:** mores sensitive than CT for extra-adrenal
32
Management for pheochromocytoma?
- Medication with combined **alpha and beta** adrenergic **blockers** (phentolamine and propanolol).
- Surgical resection
33
What is the mechanism behind primary hyperaldosteronism?
Excessive secretion of aldosterone by the adrenal cortex due to adenoma or bilateral adrenal cortical hyperplasia
34
How does 1' hyperaldosteronism present?
- Hypkalemia
- Metabolic alkalosis
35
Diagnosis of 1' hyperaldosteronism?
- Document renal K wasting (\>20 mEq/24 hr)
- Plasma aldosterone/renin ratio \> 20 is suggestive
- 24 hr urine aldosterone \>14 µg on 250 mEq Na X 3 days
- Abdominal CT is helpful if adenoma is found
36
Treatment for 1' hyperaldosteronism?
- Spironolactone or Eplerenone
- Adrenalectomy\*
37
Look at this picture of biosynthesis of aldo & cortisol
38
What causes glucocorticoid-remediable aldosteronism (GRA)?
Familial hyperaldosteronism type I Genetic defect in chimeric gene
- ACTH responsive regulatory region of the 11-beta-hydroxylase gene PLUS
- Structural region of the aldosterone synthase gene
39
Mechanism behind GRA (glucocorticoid-remediable aldosteronism)?
- Hypokalemia and metabolic alkalosis
- Decreased Plasma renin activity.
- Increased Aldosterone levels
- Presence of 18-hydroxycortisol and 18-oxocortisol in urine
40
What is the treatment for GRA (glucocorticoid-remediable aldosteronism)?
Low dose glucocorticoids, amiloride, and spironolactone
- Blocks binding of aldosterone to the mineralocorticoid receptor
41
What is the syndrome of apparent mineralocorticoid excess? Results in?
- Both cortisol and aldosterone are potent activators of renal MCRs.
- In the kidney, 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) converts cortisol to cortisone, which does not activate the renal MCR.
- 11β-HSD-2 gene mutations lead to elevated levels of cortisol that activates MCR
_Results in:_
- Low K
- Low plasma renin activity
- Low aldosterone
42
What is treatment of syndrome of apparent mineralocorticoid excess?
Spironolactone
- Blocks binding of both cortisol and aldosterone to the MCR
43
What is Liddle's Syndrome?
- Genetics
- Mechanism
- Observed
- Mutations in gene coding the beta or gamma subunits of ENaC of the principal cell
- Results in constitutive expression of ENaC leading to increased rates of Na reabsorption and HTN
- Early-onset severe HTN, hypokalemia, and metabolic alkalosis
- Low plasma renin activity and aldosterone
44
What is treatment for Liddle's syndrome?
Amiloride or triamterene
45
What is Gordon's Syndrome
- Genetics
- Mechanism
- Observed
Pseudo hypoaldosteronism type II
- Genetically-inherited condition
- Constitutive activation of thiazide-sensitive Na channels in the distal convoluted tubule
- (Mirror image of Gitelman's syndrome (inactivation of the thiazide-sensitive Na channels
---- the exact opposite metabolic abnormalities
---- hypokalemia and metabolic alkalosis))
_Exhibit:_
- **salt-sensitive hypertension**
- **hyperkalemia**, and
- **non-anion gap metabolic acidosis**
in association with a **normal GFR**
46
Treatment for Gordon's syndrome?
Highly responsive to thiazide diuretics
(- Correctly implying the disease is due to a constitutive activation of thiazide-sensitive Na channels in the distal convoluted tubule)
47
Treatment of HTN
_BP targets_
- 150/90 in anyone \> 60 yo
- 140/90 for those \< 60 yo, with **diabetes**, or **CKD** (chronic kidney disease)
Initial drug treatment options for HTN with **chronic kidney disease** = **ACEI or ARB**
_NEW SPRINT DATA BP_
under **120/80 vs. 140/80** showed decreased
- Heart attack, heart failure, and stroke by 1/3
- Risk of death by 1/4
48
Initial drug choice of HTN drugs?
- 4 classes for nonblack pts and 2 classes for black
- Beta blockers no longer recommended for initial therapy b/c they might not protect as well from stroke
49
Summary:
**Essential Hypertension :** Impaired pressure natriuresis.
**Renal Artery Stenosis** : If bilateral, renal function worsens with Ace I as it acts on efferent arteriole
**Pheochromocytoma:** Treat with both Alpha and Beta Blockers.
**Hyperaldosteronism:** Hypokalemic Metabolic alkalosis, treat with MRB s.
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