Secondary Hypertension

Y Kandarini
Division of Nephrology & Hypertension
Department of Internal Medicine
Udayana School of Medicine/Prof Ngoerah General Hospital
2023
 Hypertension Prevalence in Indonesia

63 Mio
of hypertensive patients
in Indonesia3

From those who received antihypertensive medication

1. Published in European Society of Cardiology (ESC) 2018. 2.Riset Kesehatan Dasar (RISKESDAS).2018.Page 66-69. 3.
http://p2ptm.kemkes.go.id/kegiatan-p2ptm/dki-jakarta/hari-hipertensi-dunia-2019-know-your-number-kendalikan-tekanan-
darahmu-dengan-cerdik
Prevalensi Hipertensi Berdasarkan Hasil Pengukuran Pada
Penduduk Umur ≥ 18 Tahun Menurut Provinsi, 2007-2018
 Burden of Hypertension
• 77.9 million (1 in 3) US adults: ≥ 20 years of age have
hypertension

• 69% of people with a first heart attack

• 77% of those with a first stroke Have a BP >
• 74% of those with heart failure 140/90 mmHg
• Hypertension is associated with shorter overall life
expectancy

• Poor medication adherence is a major barrier to

effective BP control.
• Only about 57% remain adherent to their BP meds at 2
years follow-up.
1.Mozaffarian D et al. Circulation 2015; 131: e29-322.
2.Roger VL, et al. Circulation. 2012;125:e2–e220.
3.Rapsomaniki, E et al. Lancet. 2014;383:1899-1911.
10 mmHg reduction in SBP is associated with

SBP= Systolic Blood Pressure

Ettehad D, at al. Lancet. 2016;387;957-367.

 Hypertension is still the biggest contributor to
global burden of disease and mortality1

“biggest single contributor to the global burden of disease and to global

mortality,
leading to 9.4 million deaths each year.”

7 1. Poulter N et al. Lancet. 2015. doi: 10.1016/S0140-6736(14)61468-9.

 2 out 3 treated hypertensive patients have
uncontrolled blood pressure1

International, multicentre, cross-sectional study of 153996 adults, 35-70 yo; Control = <140/90 mm Hg among those receiving treatment

1. Chow CK et al. JAMA. 2013;310(9):959-968.

 Cara Pengukuran Tekanan Darah

• Ruangan tenang, suhu nyaman

• Tidak merokok, minum kopi, olahraga
Punggung 30 menit sebelum pemeriksaan
bersandar Tidak berbicara selama dan di antara pengukuran • Kandung kemih kosong
• Bersantai selama 3-5 menit
Manset sesuai ukuran lengan (kecil, biasa, besar) • Pengukuran dilakukan 3 kali dengan
Lengan ditopang meja. Tengah lengan sejajar jantung interval 1 menit
• Gunakan rerata 2 pengukuran
terakhir

Alat elektronik tervalidasi

dengan manset lengan atas
atau alat auskulatotrik manual • Untuk alat auskultatorik manual, inflatable
bladder pada manset harus meliptui 75-10%
Kaki datar lingkar lengan. Untuk alat elektronik, manset
di atas lantai disesuaikand engan instruksi alat
• Alat elektronik tervalidasi dapat di lihat di
www.stridebp.org

Hypertension. 2020;75:1334-57
Hypertension Screening and Diagnosis (INaSH
2019)

Indikasi untuk
ABPM atau
HBPM
 Diagnosis of Hypertension
o Most guidelines of HT agree that diagnosed of HT if BP on the in-clinic ≥ 140/90
mmHg.
o Confirmation diagnosed of HT → repeated 1 to 4 weeks after the first visit, except in
patients with a TDS ≥ 180 mmHg or proven HMOD
o Measuremant of BP at clinic or out of clinic (HBPM or ABPM)
o Clinical BP measurement is most frequent and forms the basis of HT diagnosis and
follow-up treatment
o The BP measurement outside the clinic is a BP measurement that is free from
medical influence, it is more reflective of the BP value.
o HMBP : detection WCH and isolated HT
o AMBP :
o Provides information on BP variability, morning surge, night time dipping, WCH,
o Evaluatia of the effect of therapy on the 24-hour BP profile.
 Diagnosis HT according InaSH 2019
Kategori TDS (mmHg)
TD Klinik ≥140 dan/atau ≥90

ABPM

Rerata pagi-siang hari (atau bangun) ≥135 dan/atau ≥85

Rerata malam hari (atau tidur) ≥120 dan/atau ≥70

Rerata 24 jam ≥130 dan/atau ≥80

Rerata HBPM ≥135 dan/atau ≥85

 Definition of Hypertension
• The classification of BP and the definition of hypertension is
UNCHANGED from previous ESC/ESH guidelines.

• Classification of office BP and definitions of hypertensions grade

Category Systolic (mmHg) Diastolic
(mmHg)
Optimal < 120 And < 80

Normal 120-129 And/or 80-84

High Normal 130-139 And/or 85-89

Grade 1 hypertension 140-159 And/or 90-99

Grade 2 hypertension 160-179 And/or 100-109

Grade 3 hypertension ≥ 180 And/or ≥ 110

Isolated systolic hypertension ≥ 140 And < 90

BP: Blood Pressure

Williams, Mancia, et al. Eur Heart J. 2018; 00, 1-98
 CLINICAL EVALUATION
• Diagnosis and degree of HT
• Screen for possible secondary causes of hypertension
• Identify factors that contribute to development of hypertension (family
history, overweight, drugs)
• identification cardiovascular risk factor : synd metabolic, DM, lipid disorder
(cholest and HDL), HU
• Other risk factor: male, age > 65 yo, early onset of menopause, smoking,
sedentary habits
• Assesment HMOD: albuminuria, LVH, retinopati, intima media tichness &
carotic plaque, PAD

ISH 2020, JNC 8, INaSH consensus 2019

 Compelling indication for Specific Antihypertensive Treatment
Compelling Indication Recommeded Antihypertensives
Cerebrovascular disease ACE Inhibitor + diuretic
CHF Asymptomatic patients w/ ventricular dysfunction:
* ACE inhibitor
Symptomatic ventricular dysfunction or end stage heart disease:
* ACE inhibitor * Beta-blocker
* Angiotensin II antagonist * Thiazide diuretic
* Beta-blocker
DM Combination of ≥ 2 drugs are typically needed to reach target BP < 130/80
mmHg
* ACE inhibitor * Ca antagonist
* Angiotensin II antagonist * Thiazide diuretic
* Beta-blocker
LV dysfunction ACE inhibitor
Non-diabetic nephropathy * ACE Inhibitor * Beta-blocker
Post MI * ACE Inhibitor
* Aldosterone inhibitor
Type 1 diabetic nephropathy * ACE Inhibitor
Type 2 diabetic nephropathy * Angiotensin II antagonist * Beta-blocker
 Inisiasi pengobatan dan target tekanan darah (JNC8)

Populasi Insisiasi Terapi Target

Umum ≥ 60 thn TDS ≥150 mmHg atau TDS <150 mmHg dan
TDD ≥90 mmHg TDD <90 mmHg
Umum usia lebih muda dari TDD ≥ 90 mm ​Hg <90 mmHg
60 thn
Umum <60 thn TDS ≥140 mmHg TDS < 140 mmHg
≥ 18 thn dengan CKD TDS ≥140 mmHg atau TDD TDS <140 mmHg dan
≥140 mmHg 90 TDD < 90 mmHg
≥18 thn dgn DM TDS ≥140 mmHg atau TDS <140 mmHg dan
TDD ≥ 90 mm ​Hg TDD < 90 mmHg
MANAGEMENT STRATEGY OF HT

ISH 2020, ESH 2018, INaSH consensus 2019

Hypertension
• Essential hypertension
• 95% have “essential HTN” without identifiable and treatable
cause
• Secondary hypertension
• Secondary” HTN accounts for ~5-10% of other cases and
represents potentially curable disease
• Often overlooked and underscreened
• Controversy over screening and treatment in some cases
Secondary Hypertension
New patient evaluation
• Identify comorbidities / other risk factors

• Assess for target organ damage

• Exclude secondary causes

Screening
• Testing can be expensive and requires clinical suspicion and
knowledge of limitations of different tests
• General principles:
• New onset HTN if <30 or >50 years of age
• Considerable target organ damage
• HTN refractory to medical Rx (>3-4 meds)
• Specific clinical/lab features typical for dz
• i.e., hypokalemia, epigastric bruits, differential BP in
arms, episodic HTN/flushing/palp, etc
Karakteristik klinis yang mengarah hipertensi sekunder
• Pasien usia muda (<40 tahun) dengan hipertensi derajat 2 atau hipertensi
dengan berbagai derajat pada anak
• Perburukan hipertensi akut pada pasien dengan hipertensi stabil
• Hipertensi resisten
• Hipertensi berat (derajat 3) atau hipertensi emergensi
• Terdapat HMOD ekstensif
• Tampilan klnis atau biokimia mengarah pada gangguan endokrin atau PGK
• Kecurigaan OSA
• Gejala atau riwayat keluarga feokormositoma

HMOD=hypertension mediated organ damage; OSA = obstructive sleep apnea; PGK=penyakit ginjal kronik

Konsensus Hipertensi di Indonesia, 2018

Causes of Secondary HTN
1. Renal Parenchymal Disease
2. Renovascular HTN
3. Primary Aldosteronism
4. Obstructive Sleep Apnea
5. Pheochromocytoma
6. Cushing’s syndrome/ hypercortisolism
7. Coarctation of Aorta
8. Hyperthyroidism
9. Hypothyroidism
1. Renal Parenchymal Disease
• Common cause of secondary HTN (2-5%)
• HTN is both cause and consequence of renal disease
• Multifactorial cause for HTN including disturbances in Na/water
balance, depletion or antagonism of vasodepressors/
prostaglandins.
• Renal disease from multiple etiology, treat underlying disease,
dialysis/ transplant if necessary
Renal Parenchymal Disease which can cause
secondary hypertension

• Glomerulonephritis
• Obesity related glomerulopathy
• Lupus nephritis
• Pyelonephritis
• Reflux nephropathy
• Kidney tumor
Differential diagnosis between hypertensive renal
impairement and renal hypertension

Li, N. Secondary Hypertension. 1st ed.

Singapore: Springer; 2020. p. 125-86
2. Renovascular HTN
• Incidence 1-30% of secondary Hypertension
• Etiology
• Atherosclerosis 75-90%
• Fibromuscular dysplasia 10-25%
• Other
• Aortic/renal dissection
• Takayasu’s arteritis
• Thrombotic/cholesterol emboli
• CVD
• Post transplantation stenosis
• Post radiation
Renovascular HTN

Safian & Textor. NEJM 344:6;p 432

Renovascular HTN - Pathophysiology
▪ Decrease in renal perfusion pressure activates RAAS, renin
release converts angiotensinogen→ Ang I; ACE converts Ang I→
Ang II
▪ Ang II causes vasoconstriction (among other effects) which
causes HTN and enhances adrenal release of aldosterone; leads
to sodium and fluid retention
▪ Contralateral kidney (if unilateral RAS) responds with diuresis/
Na, H2O excretion which can return plasma volume to normal.
▪ Bilateral RAS or solitary kidney RAS leads to rapid volume
expansion and ultimate decline in renin secretion
Renovascular HTN - Clinical
• History
• onset HTN age <30 or >55
• Sudden onset uncontrolled HTN in previously well controlled
pt
• Accelerated/malignant HTN
• Intermittent pulm edema with nl LV fxn
• PE/Lab
• Epigastric bruit, particulary systolic/diastolic
• Azotemia induced by ACEI
• Unilateral small kidney
Renovascular HTN - diagnosis

• Physical findings (bruit)

• Duplex U/S
• Captopril renography
• Magnetic Resonance Angiography
• Renal Angiography
 RAS screening/diagnostics
Sens Spec Cost Limitation/Etc

Duplex U/S 90-95% 60-90% $117 Operator dependent, 10-20%

Meds, accuracy reduced in pt with

Captopril
83-91% 87-93% $968 renal insufficiency, lacks anatomical
Renography info; good predictor of BP response

False positive artifact resp,

MRA 88-95% 95% $572 ? peristalsis, tortuous vessels; cost

Insensitive, severe stenosis may be

Bruit 39-65% 90-99% - silent

Invasive, nephrotoxicity, little value

Angiography Gold std Gold std ? in predicting BP response
Fibromuscular dysplasia
• 10-25% of all RAS
• Young female, age 15-40
• Medial disease 90%, often involves distal RA
• ~ 30% progressively worsen but total occlusion is rare
• Treatment – PTRA (percutaneous transluminal renal angioplasty)
• Successful in 82-100% of patients
• Restenosis in 5-11%
• “Cure” of HTN in ~60%
Atherosclerotic RAS
• 75-90% of RAS
• Usually men, age>55, other atherosclerotic dz
• Progression of stenosis 51% @ 5years, 3-16% to occlusion, with
renal atrophy noted in 21% of RAS lesions >60%
• ESRD in 11% ( higher risk if >60%, baseline renal insufficiency,
SBP>160)
• Treatment
• PTRA success 60-80% with restenosis 10-47%
• Stent success 94-100% with restenosis 11-23% (1yr)
• “Cure” of RV HTN <30%
 Fibromuscular Dysplasia,
before and after PTRA

Atherosclerotic RAS
before and after stent
Safian & Textor. NEJM 344:6;
Renovascular HTN – Medical Rx

• Aggressive risk fx modification (lipid, tobacco, etc)

• ACEI/ARB safe in unilateral RAS if careful titration
and close monitoring; contraindicated in bilat RAS
or solitary kidney RAS
Renovascular HTN - principles
• Not all RAS causes HTN or ischemic nephropathy
• Differing etiology of RAS has different outcomes in regards to
treatment (FMD vs atherosclerosis)
• No current rationale for “drive-by” interventions
• Importance of medical rx
• No current consensus guidelines for
screening/outcomes/treatment ( as opposed to carotid artery
stenosis, AAA, etc)
3. Primary Aldosteronism
• Prevalence .5- 2.0% (5-12% in referral centers)
• Etiology
• Adrenal adenoma
• Other: bilat adrenal hyperplasia, glucocorticoid suppressible
hyperaldo, adrenal carcinoma
• Clinical:
• May be asymptomatic; headache, muscle cramps, polyuria
• Retinopathy, edema uncommon
• Hypokalemia (K normal in 40%), metabolic alkalosis, high-nl Na
 Primary Aldosteronism- Dx
• Aldosterone / Plasma Renin Activity ratio
• Early am after ambulation ~10-15 min
• Ratio >20-25 with PRA <1 and Aldo >15 should prompt further testing,
endo referral
• Confirmatory/physiologic testing
• Withold BP meds 2 wks
• High serum aldo after IV saline (1.25L x 2hr) load followed by low PRA
after salt restricted diet (40mg/d) or diuretic (lasix up to 120mg)
• serum aldo <8.5 ng/dL after IV saline rules out primary aldosteronism
• Imaging – CT, scintography
 Diagnosis workup of
Primary Aldosteronism

Rossi., GP. In: Giuseppe, M.

Primary Aldosteronisme. 3th ed.
Milan:CRC Press; 2020. p. 511-22.

ARR, aldosterone:renin ratio. LDFS, logistic

discriminant function score; AVS, adrenal vein
sampling.
Primary Aldosteronism - Treatment

• Surgical removal of adrenal tumor, can be done laparoscopically

• Pretreatment for 3-4 wks with spironolactone minimizes
postoperative hypoaldosteronism and restores K to normal levels,
response of BP to spiro treatment is predictor of surgical outcome
Aldosteronoma
4. Obstructive Sleep Apnea

• Published reports estimate incidence of 30-80% of pt with essential HTN

have OSA and 50% pt with OSA have HTN1
• Prospective studies show link between OSA (apneic-hyponeic index) and
development of HTN independent of other risk fx2
• Clinical
• Daytime somnolescence, am headaches, snoring or witnessed apneic
episodes
• Dx – Sleep studies
• Rx – wt loss, CPAP, surgical (UPPP)

1Silverberg, et al.Curr Opinion Nephrol Hyperten 1998:7;353-361

2
OSA – BP improvement with Rx

Pankow, et al. NEJM 343:966-967

5. Pheochromocytoma

• Rare cause of HTN (.1-1.0%)

• Tumor containing chromaffin cells which secrete catecholamines
• Young-middle age with female predominance
• Clinical
• Intermittent HTN, palpitations, sweating, anxiety “spells”
• May be provoked by triggers such as tyramine-containing
foods (beer,cheese,wine), pain, trauma, drugs (clonidine,
TCA, opiates)
 Pheochromocytoma - Screen
• Best detected during or immediately after episodes

Sensitivity Specificity

Plasma free metanephrine >.66nmol/L 99% 89%

24hr urine metanephrine 77% (95%) 93% (96%)

(>3.7nmol/d)

24 urine VMA 64% 95%

Lenders, et al. JAMA 2002 Mar 20;287(11):1427-34

Pheochromocytoma - Diagnosis

• Imaging for localization of tumor

Sens Spec PPV NPV
(MIBG) scintigraphy 78% 100% 100% 87%
CT 98% 70% 69% 98%
MRI 100% 67% 83% 100%

Akpunonu, et al. Dis Month.October 1996, p688

Pheochromocytoma - treatment
• Surgical removal of tumor
• Anesthesia- avoid benzo, barbiturates or demerol which can
trigger catechol release
• Complications include ligation of renal artery, post op
hypoglycemia, hemorrhage and volume loss
• Mort 2%, 5 yr survival 95% with <10% recurrence
• Caution with BB – can cause unopposed alpha stimulation/pheo
crisis
• BP control with alpha blockers (phentolamine,
phenoxybenzamine, and prazosin)
6. Cushing’s syndrome/ hypercortisolism
• Rare cause of secondary HTN (.1-.6%)
• Etiology: pituitary microadenoma, iatrogenic
(steroid use), ectopic ACTH, adrenal adenoma
• Clinical
• Sudden weight gain, truncal obesity, moon facies,
abdominal striae, DM/glucose intolerance, HTN,prox
muscle weakness, skin atrophy, hirsutism/acne
Cushings syndrome
Cushings syndrome - dx
• Screen:
• 24 Hr Urine free cortisol
• >90ug/day is 100% sens and 98% spec
• false + in Polycystic Ovarian Syndrome, depression
• Confirm
• Low dose dexamethasone suppression test
• 1 mg dexameth. midnight, measure am plasma cortisol (>100nmol
is +)
• Other tests include dexa/CRH suppresion test
• Imaging
• CT/MRI head (pit) chest (ectopic ACTH tumor)
Cushings syndrome - Rx
• Cushings dz/ pit adenoma
• Transphenoidal resection
• Pituitary irradiation
• Bromocriptine, octreotide
• Adrenal tumors - adrenalectomy
• Removal of ACTH tumor
7. Coarctation of Aorta
• Congenital defect, male>female
• Clinical
• Differential systolic BP arms vs legs (=DBP)
• May have differential BP in arms if defect is prox to L
subclavian art
• Diminished/absent femoral art pulse
• Often asymptomatic
• Assoc with Turners, bicuspid AV
• If uncorrected 67% will develop LV failure by age 40 and 75%
will die by age 50
• Surgical Rx, long term survival better if corrected early
Coarctation of Aorta

Brickner, et al. NEJM 2000;342:256-263

8. Hyperthyroidism
• 33% of thyrotoxic pt develop HTN
• Usually obvious signs of thyrotoxicosis
• Dx: TSH, Free T4/3, thyroid RAIU
• Rx: radioactive ablation, propanolol
9. Hypothyroidism
• 25% hypothyroid pt develop HTN
• Mechanism mediated by local control, as
basal metabolism falls so does
accumulation of local metabolites; relative
vasoconstriction ensues
Drugs that Raises Blood Pressure
• Immunosuppressive agents
Minerocorticosteroids
• Cyclosporine, tacrolimus,
corticosteroid Fludrocortisone
• NSAID
Antiparkinsonian
• Ibuprofen, naproxen, piroxicam Bromocriptine
• COX-2 inhibitors
Monoamine oxidase inhibitors
• Celecoxib, rofecoxib, valdecoxib Phenelzine
• Estrogens
Anabolic steroids
Testosterone
• Weight-loss agents
• Sibutramine, phentermine,
Sympathomimetics
ephedrine pseudoephedrine
• Stimulants
• Nicotine, amphetamines
 Select Drugs That May Elevate Blood Pressure
Drug class Common examples
Anti-infective Ketoconazole
Anti-inflammatory Cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs

Chemotherapeutic Vascular endothelial growth factor inhibitors

Herbal Ephedra, ginseng, ma huang
Illicit Amphetamines, cocaine
Immunosuppressive agents Cyclosporine (Sandimmune), sirolimus (Rapamune), tacrolimus
(Prograf)
Psychiatric Buspirone (Buspar), carbamazepine (Tegretol), clozapine (Clozaril),
Lithium, monoamine oxidase inhibitors, selective serotonin reuptake
inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic
antidepressants
Sex hormones Estrogen and progesterone in oral contraceptives; androgens
Steroid Methylprednisolone, prednisone
Stmpathomimetic Deconestants, diet pills
Am Fam Physician, 2010;82(12):1173
 Causes of secondary hypertension and suggestive findings (1)

Condition Symptom/sign Investigation

Renal artery stenosis • Renal bruit • Ultrasonography (US) of the kidneys (one
• Worsening in serum creatinine level > 30% after use kidney smaller by > 1.5 cm compared with
of angiotensin-converting enzyme inhibitor or contralateral)
angiotensin II receptor blocker • Duplex Doppler US of renal arteries
• Magnetic resonance/computed
tomographic renal angiography
• Percutaneous renal arteriogram
Renal parenchymal disease Mostly asymptomatic • Serum creatinine test (elevated level)
• Urinalysis
Primary aldosteronism Mostly asymptomatic • Aldosterone and renin levels (with ratio)
• Hypokalaemia (in a minority)

Pheochromocytoma • Episodic headaches, sweating, palpitations and 24-hr urinary fractionated metanephrines
flushing
• Labile blood pressure (BP)/hypertensive episodes
precipitated by drugs: D2-antagonists (e.g.
metoclopramide), beta-blockers, sympathomimetics,
opioids, tricyclic antidepressants

Singapore Med J 2016; 57(5): 228-232

 Causes of secondary hypertension and suggestive findings (2)

Condition Symptom/sign Investigation

Cushing’s syndrome • Moon facies, central obesity, thin skin, easy 24-hr urinary free cortisol
bruising
• Exogenous steroid use

Hypothyroidism/ Symptoms of hypothyroidism or hyperthyroidism Thyroid function tests

hyperthyroidism (e.g. gain/loss of weight, cold/heat intolerance)
Coarctation of the aorta • Radio-femoral delay Transthoracic echocardiogram (less
• Differential BP in arms and legs (systolic BP > 20 accurate in adults)
mmHg)

Obstructive sleep apnoea • Obesity Polysomnography

• Daytime somnolence, fatigue
Medication • Oral contraceptives, nonsteroidal -
anti-inflammatory drugs
• Steroids, sympathomimetic drugs (decongestants,
diet pills)
• Illicit drugs (cocaine, amphetamines,
Ecstasy/3,4-methylenedioxymethamphetamine)

Singapore Med J 2016; 57(5): 228-232

Volume 96, Number 7 ◆ October 1, 2017
 TAKE HOME MESSAGES
• Secondary hypertension is a common cause of hypertension in adults.
• Important to appropriately screen pt suspected of having potentially
correctable causes of HTN
• Failure to recognise secondary causes can lead to resistant hypertension,
cardiovascular complications or complications of the underlying
condition.
• Diagnosis and treatment of causes of secondary hypertension can lead
to good clinical outcomes.