Secondary Hypertension — Causes and Workup

Renal Parenchymal Disease Mechanisms

• Glomerulonephritis and chronic kidney disease: Loss of functional nephrons reduces salt and water excretion capacity, leading to volume expansion; simultaneously, ischemic kidneys activate the renin-angiotensin-aldosterone system (RAAS), amplifying vasoconstriction and sodium retention via angiotensin II and aldosterone. Progressive glomerular filtration rate (GFR) decline impairs 1,25-dihydroxyvitamin D3 production, promoting secondary hyperparathyroidism and calcium-phosphate dysregulation, which increases vascular stiffness.
• Sodium handling abnormalities: Diseased kidneys lose the ability to appropriately natriuresis in response to volume expansion, creating a rightward-shifted pressure-natriuresis relationship that mandates higher systolic pressure to maintain sodium balance.

Renovascular Hypertension Mechanisms

• Renal artery stenosis (RAS): Atherosclerotic or fibromuscular dysplastic narrowing of the renal artery reduces perfusion pressure to the juxtaglomerular apparatus, triggering renin release disproportionate to systemic sodium status. This generates excessive angiotensin II, causing both acute vasoconstriction (elevated BP within hours to days) and chronic aldosterone-mediated sodium retention (sustained elevation). The stenotic kidney becomes ischemic while the contralateral kidney experiences angiotensin II–induced glomerular hypertension; removal of the ischemic kidney or revascularization can cure hypertension in some patients.

Endocrine Mechanisms

• Primary aldosteronism: Autonomous aldosterone production (from adrenal adenoma, hyperplasia, or genetic mutations) independent of RAAS suppression causes inappropriate sodium retention and hypokalemia via principal cell aldosterone receptors; volume expansion raises BP while paradoxically suppressing plasma renin activity (suppressed renin with elevated aldosterone is pathognomonic).
• Pheochromocytoma: Catecholamine excess (epinephrine and norepinephrine) from chromaffin cell tumors activates α1-adrenergic receptors causing systemic vasoconstriction and β-adrenergic receptors causing increased cardiac output; episodes of massive catecholamine release produce paroxysmal hypertension with classic triad of headache, diaphoresis, and palpitations. Sustained activation of the sympathetic nervous system maintains baseline elevation between episodes.
• Hyperthyroidism: Excess thyroid hormone increases tissue sensitivity to catecholamines and directly enhances myocardial contractility and β-adrenergic receptor density, producing elevated cardiac output and decreased peripheral vascular resistance initially (widened pulse pressure), though total peripheral resistance may increase with severe disease.
• Hyperparathyroidism: Elevated parathyroid hormone (PTH) causes hypercalcemia, which increases vascular smooth muscle contractility and sensitivity to catecholamines; calcium elevation also activates calcium-sensing receptors on vascular endothelium, promoting vasoconstriction.
• Cushing's syndrome: Excess cortisol increases hepatic angiotensinogen synthesis, amplifies RAAS activation, potentiates catecholamine effects on vasculature, suppresses nitric oxide production (reducing vasodilation), and causes sodium retention via mineralocorticoid receptor activity.

Obstructive Sleep Apnea (OSA) Mechanism

• Recurrent hypoxic episodes activate sympathetic nervous system with surge catecholamine release; arousals disrupt sleep architecture and increase intrathoracic pressure swings, enhancing sympathetic tone. Intermittent hypoxia upregulates endothelin production and reduces nitric oxide availability, promoting vasoconstriction and endothelial dysfunction.

Drug-Induced and Other Mechanisms

• NSAIDs and decongestants: Inhibit renal prostaglandin synthesis (NSAIDs) or directly activate α-adrenergic receptors (sympathomimetics), raising BP through volume retention and/or vasoconstriction.
• Oral contraceptives: Estrogen-containing formulations increase hepatic renin substrate (angiotensinogen) production and angiotensinogen levels, amplifying RAAS activity; additionally impair vascular endothelial function and promote thrombosis.
• Aortic coarctation: Mechanical stenosis of the descending thoracic aorta increases left ventricular afterload and activates baroreceptor-mediated RAAS in response to perceived underperfusion of lower body; creates arterial narrowing-induced hypertension proximal to the lesion with hypoperfusion distally.

Renal Causes (Most Common; ~60% of Secondary HTN)

• Chronic kidney disease/glomerulonephritis: IgA nephropathy, lupus nephritis, post-infectious GN, FSGS, membranoproliferative GN; causes volume-dependent and RAAS-mediated hypertension as GFR declines
• Polycystic kidney disease (autosomal dominant and recessive): Early hypertension occurs even before significant renal dysfunction due to cyst-related renal ischemia and RAAS activation
• Renovascular hypertension:
• Atherosclerotic RAS (90% of cases): Occurs in older patients (>50 years) with atherosclerotic risk factors; unilateral or bilateral stenosis; more common in males; often associated with coronary and peripheral arterial disease
• Fibromuscular dysplasia (FMD) (10% of cases): Affects younger women (20–50 years); primarily involves renal artery, may be bilateral; can present with "string of pearls" angiographic appearance
• Reflux nephropathy/obstructive uropathy: Chronic pyelonephritis, ureteropelvic junction obstruction
• Renal infarction: Thromboembolism, dissection, trauma

Endocrine Causes (~10–15% of Secondary HTN)

• Primary aldosteronism (hyperaldosteronism):
• Conn's syndrome (aldosterone-producing adenoma): 35–40% of primary aldosteronism cases; usually unilateral; hypokalemia often present
• Bilateral adrenal hyperplasia (BAH): 60–65% of cases; more responsive to spironolactone than surgery
• Familial hyperaldosteronism types I–III: Autosomal dominant genetic forms (very rare)
• Pheochromocytoma/paraganglioma: Arises from chromaffin cells in adrenal medulla (85%) or extra-adrenal sympathetic chain (paraganglioma, 15%); ~10% malignant; ~30% associated with hereditary syndromes (MEN2, NF1, VHL, SDH mutations)
• Hyperthyroidism: Graves' disease, toxic multinodular goiter, thyroiditis, iodine-induced thyrotoxicosis
• Hypothyroidism: Increases systemic vascular resistance through reduced catecholamine sensitivity; less common cause but present in ~5% of hypothyroid patients
• Hyperparathyroidism: Primary adenoma, hyperplasia, or carcinoma; present in ~40% of hyperparathyroid patients
• Hypercalcemia from other causes: Sarcoidosis, vitamin D intoxication, malignancy, thiazide use (mild effect)
• Acromegaly: Growth hormone excess increases sympathetic tone and causes insulin resistance
• Cushing's syndrome: ACTH-secreting pituitary adenoma, ectopic ACTH (small cell lung cancer), primary adrenal tumor; hypertension in ~80% of cases

Vascular Causes

• Aortic coarctation: Congenital or acquired narrowing of descending thoracic aorta; occurs in ~5% of hypertensive children; associated with Turner syndrome, bicuspid aortic valve, hypoplastic left heart syndrome
• Aortic stiffness/isolated systolic hypertension: Aging, chronic kidney disease, atherosclerosis (primarily affects older patients)

Obstructive Sleep Apnea

• Associated with ~40–80% of resistant hypertension cases; prevalence increases with obesity, male gender, middle age, and increased apnea-hypopnea index (AHI)

Pregnancy-Related Hypertension

• Preeclampsia/eclampsia: Develops after 20 weeks gestation; characterized by hypertension + proteinuria ± end-organ dysfunction
• Gestational hypertension: New-onset BP elevation in pregnancy without proteinuria

Drug-Induced Hypertension

• NSAIDs: All classes, including COX-2 selective inhibitors; effect more pronounced in setting of volume depletion or renal impairment
• Decongestants: Pseudoephedrine, phenylephrine, oxymetazoline
• Oral contraceptives: Estrogen-containing formulations; effect proportional to estrogen dose; progestin-only methods safer
• Anabolic steroids and androgens: Including testosterone replacement in susceptible men
• Cyclosporine and tacrolimus: Calcineurin inhibitors used in transplantation; cause vasoconstriction and volume retention
• Stimulants: Cocaine, amphetamines, methylphenidate, atomoxetine
• Erythropoietin: Via hemoglobin increase and direct vasoconstriction
• Selective serotonin reuptake inhibitors (SSRIs): Less common; mechanism uncertain
• Licorice/mineralocorticoid excess: Licorice contains glycyrrhizin, which inhibits 11β-hydroxysteroid dehydrogenase and allows cortisol to activate mineralocorticoid receptors
• Amphetamine-like agents: Appetite suppressants, some herbal supplements

Other Causes

• Obstructive sleep apnea: As noted above
• Intracranial pathology: Intracranial hypertension, seizures, increased ICP from any cause (via Cushing's triad response)
• Hypoxemia: Chronic lung disease, high altitude
• Thyroid disease: Hyperthyroidism and hypothyroidism
• Systemic diseases: Scleroderma, SLE, vasculitis, neurofibromatosis (associated with pheochromocytoma and aortic coarctation)
• White coat hypertension: Elevated office BP with normal out-of-office readings; not truly secondary but must be distinguished

Symptoms and Presentation Patterns

• Sudden onset hypertension (within weeks to months) or abrupt worsening of previously stable BP
• Young age at presentation (<30 years) with no family history of hypertension
• Resistant hypertension (BP not controlled on ≥3 antihypertensive agents at adequate doses, or requiring ≥4 agents for control)
• Severe hypertension (BP ≥180/110 mmHg) at initial presentation without target organ damage history
• Hypertensive urgency or emergency as initial presentation

• Often asymptomatic until advanced; may present with symptoms of chronic kidney disease: fatigue, nausea, uremia
• Edema (peripheral, facial, or pulmonary) due to volume expansion
• Hematuria or proteinuria on urinalysis (depends on underlying glomerulonephritis)
• History of glomerulonephritis, recurrent UTIs, or known renal disease

• Acute severe hypertension or rapid worsening of controlled hypertension (classic for RAS)
• Abdominal bruit on examination (suggests atherosclerotic RAS, though absent in many cases)
• Recurrent flash pulmonary edema (especially in bilateral RAS or RAS with single kidney)
• Acute renal dysfunction or hyperkalemia after ACE-I/ARB initiation (classic presentation of bilateral RAS or RAS to single kidney)
• Claudication or other atherosclerotic manifestations if atherosclerotic RAS (prior MI, stroke, peripheral arterial disease)

• Often asymptomatic hypertension detected on screening
• Hypokalemia with associated weakness, cramps, palpitations, or polyuria (from hypokalemic nephrogenic diabetes insipidus)
• Metabolic alkalosis
• Absence of edema despite volume expansion (pseudohypoaldosteronism-like syndrome)
• May have muscle weakness or cardiac arrhythmias from severe hypokalemia

• Paroxysmal (episodic) hypertension with symptom-free intervals (classic but not required; some patients have sustained elevation)
• Classic triad during crisis: Severe headache, profuse diaphoresis, palpitations
• Associated symptoms during attacks: Pallor or flushing, tremor, chest or abdominal pain, dyspnea, nausea
• Orthostatic hypotension between episodes (paradoxically, due to catecholamine-induced volume depletion)
• Anxiety, panic attacks, feeling of impending doom
• Family history if hereditary syndrome (MEN2A, MEN2B, NF1, VHL)

• Heat intolerance, weight loss despite good appetite, fatigue, nervousness
• Tachycardia (may be persistent or paroxysmal atrial fibrillation)
• Tremor, proximal muscle weakness
• Thyroid enlargement (goiter), eye findings (exophthalmos in Graves')
• Warm, moist skin; hyperreflexia

• Weight gain with central/truncal obesity and proximal muscle weakness (classic)
• Easy bruising, violaceous striae, skin fragility
• Mood disturbance (depression, anxiety, psychosis)
• Amenorrhea or sexual dysfunction
• Osteoporosis with fractures
• Moon facies, buffalo hump

• Hypercalcemic symptoms: Nephrolithiasis, polyuria, polydipsia, constipation, cognitive dysfunction
• Bone pain or history of pathologic fractures (osteitis fibrosa cystica in severe disease)
• Often asymptomatic, detected on routine labs

• Often asymptomatic except for hypokalemia-related symptoms
• Metabolic alkalosis (may cause hypokalemic respiratory alkalosis if severe)
• Absence of edema (aldosterone "escape" phenomenon)

• Loud snoring, witnessed apneas by bed partner
• Excessive daytime somnolence, morning headaches, unrefreshed sleep
• Obesity, large neck circumference
• Nocturia

• Young patient with hypertension
• Weak or delayed femoral pulses compared to radial pulses (pathognomonic finding)
• BP discrepancy between upper and lower extremities (systolic BP ≥20 mmHg higher in upper extremities)
• Systolic murmur at left infraclavicular area and/or back (from collateral circulation, narrowing itself usually silent)
• Headaches, epistaxis, leg claudication (from lower body hypoperfusion)

Physical Examination Findings by Etiology

• **Severe

Step 1 — confirm the hypertension is real

• Out-of-office confirmation: the USPSTF and the ACC/AHA 2017 Hypertension Guideline recommend ambulatory (ABPM) or validated home BP monitoring before labeling a patient hypertensive, to exclude white coat hypertension and to detect the non-dipping nocturnal pattern typical of OSA, CKD, and primary aldosteronism.

Step 2 — screening panel obtained in every hypertensive patient (ACC/AHA 2017)

• Basic metabolic panel (Na, K, Cr/eGFR, HCO₃), urinalysis with urine albumin-to-creatinine ratio, TSH, calcium, lipids, glucose, CBC, and 12-lead ECG for LVH. Unprovoked hypokalemia with metabolic alkalosis is the single most useful clue and redirects the workup to mineralocorticoid excess.

Step 3 — targeted confirmatory testing

• Primary aldosteronism: screen with the plasma aldosterone-to-renin ratio (ARR) — an elevated aldosterone with suppressed renin. The Endocrine Society advises correcting hypokalemia first and withdrawing mineralocorticoid receptor antagonists for several weeks (doxazosin and verapamil are the "safe" agents during testing). Confirm autonomy with oral sodium loading, saline infusion, fludrocortisone suppression, or captopril challenge, then adrenal CT and, in surgical candidates (particularly age >35), adrenal vein sampling to lateralize.
• Pheochromocytoma: plasma free metanephrines (supine, drawn off interfering drugs such as TCAs, labetalol, acetaminophen) or 24-hour urinary fractionated metanephrines; markedly elevated values prompt CT/MRI of abdomen, with MIBG or ⁶⁸Ga-DOTATATE PET if unlocalized. Endocrine Society recommends genetic testing in all patients.
• Cushing syndrome: two abnormal screens among 1 mg overnight dexamethasone suppression (failure to suppress cortisol below ~1.8 mcg/dL), late-night salivary cortisol, and 24-hour urine free cortisol; then ACTH to separate ACTH-dependent from ‑independent disease, with pituitary MRI and inferior petrosal sinus sampling as needed.
• Renovascular disease: renal duplex ultrasound, CTA, or MRA; catheter angiography remains the gold standard and shows the string of beads of fibromuscular dysplasia versus ostial atherosclerotic plaque.
• OSA: STOP-BANG screening followed by polysomnography with the apnea–hypopnea index.
• Coarctation: four-extremity BP, echocardiography, CTA/MRA; CXR shows rib notching and the "3" sign.

Immediate stabilization (hypertensive emergency)

• IV titratable agents: dihydropyridine calcium channel blocker (nicardipine or clevidipine) or labetalol. Per ACC/AHA 2017, lower MAP by no more than ~25% in the first hour, then toward 160/100 over the next several hours. Exceptions: aortic dissection (rate control with IV esmolol before vasodilator, target SBP <120 mmHg) and eclampsia (IV labetalol or hydralazine plus magnesium sulfate, per ACOG).

Cause-directed therapy

• Primary aldosteronism: unilateral adenoma → laparoscopic adrenalectomy; bilateral hyperplasia → lifelong mineralocorticoid receptor antagonist (spironolactone, or eplerenone when gynecomastia occurs), per the Endocrine Society.
• Pheochromocytoma: alpha blockade first (phenoxybenzamine or doxazosin) for 1–2 weeks with liberal salt and fluid to re-expand the contracted volume, then a beta blocker for reflex tachycardia, followed by laparoscopic resection. Intraoperative crises are treated with phentolamine or nitroprusside.
• Renovascular disease: atherosclerotic renal artery stenosis is managed medically — RAAS blockade, high-intensity statin, antiplatelet, smoking cessation — since ASTRAL and CORAL showed no routine benefit of stenting; revascularization is reserved for flash pulmonary edema, refractory hypertension, or progressive renal dysfunction. Fibromuscular dysplasia is treated with balloon angioplasty without stenting and is frequently curative.
• CKD: ACE inhibitor or ARB when albuminuria is present, with KDIGO favoring an intensive systolic target using standardized office measurement.
• OSA: CPAP plus weight loss; the BP reduction is real but modest.
• Cushing syndrome: transsphenoidal resection or adrenalectomy; steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat) when surgery fails.
• Coarctation and drug-induced hypertension: surgical/catheter repair, and withdrawal of the offending agent (NSAIDs, decongestants, estrogen-containing contraceptives, calcineurin inhibitors, licorice).

Contraindicated

• Beta blocker before alpha blockade in pheochromocytoma — unopposed alpha stimulation precipitates crisis.
• ACE inhibitors and ARBs in pregnancy — all are teratogenic, including captopril, whose short half-life makes it useful only for rapid titration in nonpregnant patients.
• Avoid RAAS blockade in bilateral renal artery stenosis or stenosis to a solitary kidney without close creatinine monitoring.

Target-organ damage from sustained pressure load

• Concentric LVH → HFpEF and atrial fibrillation: pressure overload drives sarcomere addition in parallel; ECG voltage criteria or echo wall thickening signal it. Aldosterone adds direct myocardial and vascular fibrosis, so primary aldosteronism causes LVH, AF, and stroke out of proportion to the measured BP.
• Hypertensive nephrosclerosis: afferent arteriolar hyalinosis narrows the glomerular inlet; rising creatinine with bland urine and albuminuria.
• Stroke and hypertensive encephalopathy — emergency: loss of cerebral autoregulation causes vasogenic edema; headache, confusion, seizures, and posterior white-matter changes on MRI (PRES).
• Malignant hypertension with retinopathy — emergency: flame hemorrhages, cotton-wool spots, and papilledema, often with fibrinoid necrosis and a microangiopathic hemolytic picture.
• Aortic dissection — emergency: tearing pain, pulse/BP differential, widened mediastinum.

Cause-specific complications

• Renovascular disease: recurrent flash pulmonary edema (Pickering syndrome) and AKI after ACE inhibitor/ARB initiation from loss of efferent arteriolar tone; a creatinine rise beyond roughly 30% is the trigger to stop the drug and image the renal arteries.
• Pheochromocytoma: catecholamine (takotsubo-like) cardiomyopathy and intraoperative hypertensive crisis on tumor manipulation — an emergency.
• Cushing syndrome: diabetes, osteoporotic fracture, opportunistic infection, and VTE.
• Coarctation: berry aneurysm rupture, infective endarteritis, and dissection.
• Hypokalemia from mineralocorticoid excess: U waves, QT prolongation, ventricular arrhythmia.

Treatment-related complications

• Over-rapid BP lowering: watershed cerebral infarction and ischemic optic neuropathy — the reason for the ≤25% first-hour MAP rule.
• Post-adrenalectomy hyperkalemia/hypoaldosteronism from chronic suppression of the contralateral zona glomerulosa; adrenal insufficiency requiring glucocorticoid taper after cure of Cushing syndrome.
• Spironolactone: hyperkalemia, gynecomastia, menstrual irregularity (antiandrogen effect).
• Renal angiography: contrast nephropathy and cholesterol atheroembolism — livedo reticularis, blue toes, eosinophilia.
• Phenoxybenzamine: orthostatic hypotension and reflex tachycardia.

• Hypertension + spontaneous hypokalemia + metabolic alkalosis: the single best next step is the plasma aldosterone-to-renin ratio, not imaging. Ordering an adrenal CT first is the classic distractor — nonfunctioning incidentalomas are common and CT cannot lateralize reliably.
• Normokalemia does not exclude primary aldosteronism. Most patients are normokalemic; the Endocrine Society recommends screening all patients with resistant hypertension, hypertension with an adrenal incidentaloma, OSA, or early-onset stroke.
• Creatinine rises sharply (or hyperkalemia appears) after starting an ACE inhibitor → think bilateral renal artery stenosis; angiotensin II was maintaining efferent arteriolar tone and thus GFR.
• **Young woman, resistant hypertension, string of beads on angiography → fibromuscular dysplasia**; treat with angioplasty without stenting. Older smoker with an abdominal bruit and diffuse atherosclerosis → ostial atherosclerotic stenosis, managed medically.
• Never give a beta blocker before alpha blockade in pheochromocytoma — unopposed α1 vasoconstriction precipitates a hypertensive crisis. Alpha blockade plus salt loading comes first.
• Hypertension + hypokalemia + LOW renin AND LOW aldosterone is the differentiating pattern: licorice/glycyrrhizin or apparent mineralocorticoid excess (11β-HSD2 inhibition lets cortisol act on the mineralocorticoid receptor), versus Liddle syndrome (constitutively active ENaC), which responds to amiloride/triamterene but not spironolactone.
• Delayed or absent femoral pulses with an upper–lower extremity systolic gradient = coarctation; look for rib notching and the "3" sign on chest radiograph, and screen for bicuspid aortic valve and Turner syndrome.
• Spironolactone, eplerenone, and other interfering drugs must be withdrawn before ARR testing, and hypokalemia corrected — hypokalemia suppresses aldosterone secretion and produces a false-negative screen.