Obtaining a complete history and performing a good physical exam is very important when trying to find the underlying cause of hypertension. The following history and physical exam findings point towards a specific cause of secondary hypertension:

• Snoring, obesity, and daytime sleepiness could be indicative of obstructive sleep apnea.
• History of renal insufficiency, atherosclerotic cardiovascular disease, edema may warrant further evaluation of chronic kidney disease (renal parenchymal disease).
• History of recurrent urinary tract infections, kidney stones, acute/chronic abdominal/flank pain, hematuria, progressive renal failure may point towards autosomal dominant polycystic kidney disease (renal parenchymal disease).
• A systolic/ diastolic abdominal bruit is audible in reno-vascular disease.
• Use of sympathomimetics, acute stress, perioperative setting, tachycardia could all be in the context of excess catecholamines.
• Decreased or delayed femoral pulses are seen in coarctation of the aorta.
• Weight gain, fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, and truncal obesity present in Cushing syndrome/disease.
• Paroxysmal hypertension, headaches, diaphoresis, palpitations, and tachycardia are features in pheochromocytoma.
• Fatigue, weight loss, hair loss, diastolic hypertension, and muscle weakness are seen in hypothyroidism.
• Heat intolerance, weight loss, palpitations, systolic hypertension, exophthalmos, tremor, and tachycardia will occur in hyperthyroidism.
• Kidney stones, osteoporosis, depression, lethargy, and muscle weakness present in hyperparathyroidism.
• Headaches, fatigue, visual problems, enlargement of the hands, feet, and tongue are features in acromegaly.
• Heartburn, Raynaud phenomenon, nail pitting on the exam may be suggestive of scleroderma.

Laboratory tests and imaging modalities also help in diagnosing secondary hypertension. Some of the findings on common tests that can create suspicion for an underlying cause of hypertension are as follows: 

• Basic Metabolic Panel (BMP): Hypokalemia presents in primary hyperaldosteronism and Cushing syndrome/disease. Also seen on the BMP in primary hyperaldosteronism, is metabolic alkalosis and hypernatremia. Blood urea nitrogen (BUN) and creatinine become elevated in renal parenchymal disease.
• Complete blood count (CBC): Polycythemia can be present in obstructive sleep apnea.
• Urine analysis: Proteinuria can be a feature in renal parenchymal disease.
• Chest X-Ray in coarctation of aorta shows inferior rib notching and a figure of 3 sign (abnormality of the contour of the aorta).

Upon establishing suspicion for a particular cause based on history, physical exam findings, and common laboratory tests, certain tests can be used to specifically rule out or rule in a cause of secondary hypertension. They are as follows: 

• Obstructive sleep apnea (OSA): Polysomnography (preferably in-laboratory polysomnography) is the diagnostic study of choice when there is a suspicion of obstructive sleep apnea. 
• Primary hyperaldosteronism: A plasma aldosterone to renin ratio greater than 30, points towards a diagnosis of primary aldosteronism. A CT scan of the abdomen is also done to look for the presence of adenomas or hyperplasia of the adrenal glands.
• Renal parenchymal disease: A decreased creatinine clearance occurs in renal parenchymal disease. Renal ultrasonography can be further used to determine the cause for the decreased creatinine clearance. Multiple cysts demonstrate in polycystic kidney disease, and a small contracted kidney is a feature in chronic kidney disease. Genetic testing can also be useful in ADPKD. 
• Reno-vascular disease: Magnetic resonance angiography/CT angiography/doppler of renal arteries can all be used to look for the presence of stenosis of the renal arteries. Other tests that can be useful are captopril-augmented radioisotopic renography and renal arteriography.
• Excess catecholamine use: If the patient is normotensive in the absence of high catecholamines, it rules out excess catecholamines as the cause.
• Coarctation of the aorta: Doppler or CT imaging of the aorta will show a narrowing of the aorta. Echocardiography is another modality of choice.
• Cushing syndrome/disease: Overnight 1 mg dexamethasone-suppression test and adrenocorticotropic hormone can help diagnose Cushing disease and syndrome.
• Pheochromocytoma: Urinary catecholamine metabolites (vanillylmandelic acid, metanephrines, normetanephrines) become elevated in pheochromocytoma.
• Hyper/hypothyroidism: Serum thyroid stimulating hormone, thyroxine, and triiodothyronine levels help diagnosing hyperthyroidism and hypothyroidism.
• Hyperparathyroidism: Serum calcium and parathyroid hormone levels help in the diagnosis of hyperparathyroidism.
• Acromegaly: Elevated growth hormone level can point towards acromegaly.
• Scleroderma/ scleroderma renal crisis: Thrombotic microangiopathy, autoantibodies against RNA polymerase III, positive antinuclear antibody (ANA) will present in scleroderma. 

Management of secondary hypertension comprises of adequate control of blood pressure with antihypertensive drugs and addressing the secondary causes mentioned above. This section briefly discusses the management of the more common causes of secondary hypertension, viz: renal parenchymal disease, renovascular hypertension, primary hyperaldosteronism, obstructive sleep apnea, drug-induced hypertension, and pregnancy. 

A. Renal parenchymal disease:

Renal parenchymal disease-causing hypertension mainly involves chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD).

i. Management of chronic kidney disease comprises of treating the reversible causes responsible for causing CKD (e.g., treating hypovolemia with fluids, avoid nephrotoxin use, relieve urinary tract obstruction) and slowing the rate of progression of the disease. To slow the rate of progression, adequate blood pressure control, decreasing urine protein, glycemic control, lifestyle changes like dietary protein restriction, and smoking cessation help. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are the best anti-hypertensives to use in proteinuric CKD. Bicarbonate use in patients with chronic metabolic acidosis slows progression to end-stage renal disease.[6]

ii. Patients with ADPKD eventually require renal replacement therapy. Before that stage reached, hypertension management is with anti-hypertensives: ACE inhibitors or ARBs and sodium restriction. Tolvaptan is an option in patients who are at high risk for progression to CKD. It decreases the rate of estimated glomerular filtration rate decline.[7] 

B. Renovascular hypertension:

Management of renovascular hypertension (i.e., renal artery stenosis from either atherosclerotic disease or fibromuscular dysplasia) divides into medical therapy and revascularization. Medical therapy involves the use of anti-hypertensives to control blood pressure and in the case of atherosclerotic disease, the use of antiplatelets, statins, diet, and lifestyle changes. ACE inhibitors and ARBs are the anti-hypertensives of choice. Other anti-hypertensives that are treatment options are calcium channel blockers and thiazide diuretics.

Revascularization is usually done by percutaneous angioplasty with stenting of the renal artery.  Surgery (which frequently includes aorto-renal bypass or sometimes removal of the ‘pressor’ kidney) is only for patients with complex anatomy.

In the following patients, revascularization may be more beneficial than medical therapy alone:

• Patients with recurrent flash pulmonary edema
• Failure or intolerance to optimal medical treatment
• Refractory hypertension
• Unexplained, progressive, a decline in renal function,
• Recent initiation of dialysis in a patient with suspected renal artery stenosis
• An acute increase in creatinine after medical therapy and in patients with a renal resistive index of less than 80 mmHg on Doppler

C. Primary hyperaldosteronism:

Unilateral primary hyperaldosteronism (e.g., unilateral adrenal hyperplasia or aldosterone-producing adenoma) gets treated with unilateral laparoscopic adrenalectomy. If the patient is not a surgical candidate or a patient has the bilateral adrenal disease, then medical management with a mineralocorticoid receptor antagonist is recommended- with spironolactone being the primary agent and eplerenone being the alternative.[8] 

D. Obstructive Sleep Apnea:

Continuous positive airway pressure (CPAP) therapy is the mainstay of treatment for OSA. To note, however, lifestyle modifications like weight loss, along with usage of CPAP have a synergistic effect on lowering blood pressure, and is better than either intervention alone.[9] 

An alternative to CPAP, are oral appliances, used in mild to moderate OSA, which are non-inferior to CPAP in the reduction of blood pressure and may even help with better compliance in patients. In patients refractory to the above treatment, few upper airway surgeries can be performed to help with symptoms and reduction in blood pressure, like uvulopalatopharyngoplasty (UPPP) in adults and tonsillectomy and adenoidectomy in children.  Along with these, anti-hypertensive drugs also help, particularly the ones that modulate the renin-angiotensin system (ACE inhibitors, ARBs, aldosterone antagonists, and beta blockers are the best options).[10]

E. Drug-induced hypertension: In drug-induced hypertension, upon identification of the culprit drug, the management is to withhold it and look for improvement.

F. Pregnancy: Hypertension in pregnancy comprises of chronic hypertension, gestational hypertension, pre-eclampsia, and eclampsia. Chronic hypertension is when hypertension occurs before pregnancy or before 20 weeks of gestation, whereas the other three occur after 20 weeks. Pre-eclampsia is associated with proteinuria, and eclampsia is associated with seizures.

Interventions for hypertension in pregnancy are lifestyle modifications and anti-hypertensives. The anti-hypertensives commonly used in pregnancy are labetalol, nifedipine, and methyldopa.

In cases of severe hypertension (severe preeclampsia, eclampsia, and HELLP syndrome), the standard of care is delivery, especially after 37 weeks of gestation. If an acute decrease in blood pressure is required, intravenous labetalol or intravenous hydralazine are options. Magnesium sulfate prevents seizures.[11][12]

The differential diagnosis of secondary hypertension as stated above are: chronic kidney disease, autosomal dominant polycystic kidney disease, renal artery stenosis, fibromuscular dysplasia, primary aldosteronism, Cushing syndrome/disease,  hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, acromegaly, congenital adrenal hyperplasia, coarctation of aorta, obstructive sleep apnea, drug-induced hypertension, pregnancy, scleroderma.

The prognosis of secondary hypertension is good. With the treatment of the underlying condition, the blood pressure may decrease or even come back to normal.

The underlying medical condition that causes high blood pressure can be worsened by secondary hypertension. Some of the complications of secondary hypertension are atherosclerosis, aneurysm, heart failure, metabolic syndrome, chronic renal failure, and retinopathy.[13]

• Internal medicine
• Nephrology
• Cardiology
• Endocrinology
• Vascular surgery

The patient's primary care doctor and/or nurse practitioner may be the main person involved in diagnosing a secondary cause of hypertension. But an interprofessional team of specialists consisting of a nephrologist, cardiologist, endocrinologist, rheumatologist, and surgeons can help with diagnosing and managing the patient. Nurses also play an essential role in patient care, as do pharmacists. Hence, interprofessional communication and care coordination between physicians, nurses, and other health professionals are crucial to enhance patient outcomes. [Level V]