Secondary hypertension is elevated blood pressure caused by specific diseases or identifiable underlying factors. Although secondary hypertension accounts for a relatively small proportion of hypertension cases, the absolute number of affected individuals is significant. In addition to the harm caused by hypertension itself, associated conditions such as electrolyte imbalances, endocrine disorders, and hypoxemia can independently lead to cardiovascular damage, which is often more severe than that caused by primary hypertension. Certain forms of secondary hypertension, such as primary aldosteronism, pheochromocytoma, and renovascular hypertension, can be cured or significantly improved through surgical intervention. Therefore, early and accurate diagnosis is crucial for improving cure rates and preventing disease progression.
Clinicians should consider screening for secondary hypertension in the following situations:
- Young patients with moderate to severe hypertension
- Patients with clinical symptoms, signs, or laboratory findings suggestive of secondary hypertension, such as asymmetric or absent limb pulses, coarse vascular bruits in the abdomen, and hypokalemia
- Patients with poor response to combination antihypertensive therapy or those whose blood pressure was previously well-controlled but has recently risen significantly
- Patients with malignant hypertension
Renal Parenchymal Hypertension
Renal parenchymal hypertension refers to hypertension caused by various kidney diseases, including acute and chronic glomerulonephritis, diabetic nephropathy, chronic pyelonephritis, polycystic kidney disease, and post-kidney transplantation conditions. It is the most common form of secondary hypertension, with 80%-90% of end-stage renal disease (ESRD) patients experiencing hypertension. The development of renal parenchymal hypertension is primarily due to the loss of numerous nephrons, leading to sodium and water retention, increased extracellular fluid volume, activation of the renin-angiotensin-aldosterone system (RAAS), and reduced sodium excretion. Hypertension further increases intraglomerular pressure, creating a vicious cycle that exacerbates kidney damage.
Clinically, it can sometimes be challenging to distinguish renal parenchymal hypertension from primary hypertension with renal damage. Generally, except in cases of malignant hypertension, primary hypertension rarely presents with significant proteinuria, hematuria, or reduced renal function. In primary hypertension, renal dysfunction typically begins with impaired tubular concentration ability, while glomerular filtration function remains normal or even enhanced for a long period, only declining in the final stages. In contrast, renal parenchymal hypertension often presents with proteinuria, hematuria, and reduced glomerular filtration rate (GFR) and creatinine clearance at the time of hypertension diagnosis. When feasible, histological examination through kidney biopsy can help establish a definitive diagnosis.
Management of renal parenchymal hypertension includes restricting dietary sodium intake and typically requires combination antihypertensive therapy. If there are no contraindications, ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) should generally be included in the treatment regimen.
Renovascular Hypertension
Renovascular hypertension is caused by stenosis of the main renal artery or its branches, either unilaterally or bilaterally. Common causes include Takayasu arteritis, fibromuscular dysplasia of the renal artery, and atherosclerosis. Renovascular hypertension occurs due to renal artery stenosis, which leads to renal ischemia and activates the RAAS. Early correction of the stenosis can restore normal blood pressure. However, in cases of long-standing hypertension or when renal artery stenosis develops on a background of preexisting hypertension, blood pressure may not return to normal even after the stenosis is corrected. Persistent and severe renal artery stenosis can lead to damage to the affected kidney or even overall renal function.
Rapidly progressive or suddenly worsening hypertension should raise suspicion for renovascular hypertension. During physical examination, vascular bruits may be heard in the upper abdomen or at the costovertebral angle on the back. Doppler ultrasound of the renal arteries, radionuclide renal scans, CT angiography, and MRI can assist in diagnosis, while renal arteriography provides a definitive diagnosis.
Treatment options include percutaneous transluminal renal angioplasty, surgical intervention, and medical therapy, depending on the condition and available resources. The goals of treatment are not only to lower blood pressure but also to protect renal function. Percutaneous transluminal renal angioplasty with stent placement is relatively simple and effective, particularly for unilateral, localized stenosis not involving the ostium. Surgical options include revascularization, kidney transplantation, and nephrectomy, and are suitable for patients who are not candidates for angioplasty. For patients who are not eligible for these procedures, combination antihypertensive therapy may be used.
It is important to note that ACEIs or ARBs should be used cautiously in patients with bilateral renal artery stenosis, those with impaired renal function, or those with poor renal function in the non-stenotic kidney.
Primary Aldosteronism
This condition is caused by excessive secretion of aldosterone due to adrenal cortical hyperplasia or tumors. Clinically, it is characterized by hypertension accompanied by hypokalemia, although some patients may have normal potassium levels. Primary aldosteronism accounts for approximately 5% of the general hypertensive population and about 7% of those with resistant hypertension. Due to electrolyte imbalances, symptoms such as amyosthenia, polydipsia, and polyuria may occur. Blood pressure is usually mildly to moderately elevated, and about 1/3 of patients present with refractory hypertension. Laboratory findings include hypokalemia, slightly elevated sodium levels, metabolic alkalosis, reduced plasma renin activity, and increased plasma and urinary aldosterone levels. The plasma aldosterone-to-renin activity ratio (ARR) has high diagnostic sensitivity and specificity. Adrenal ultrasound, CT, or other imaging may reveal adrenal masses or hyperplasia. Bilateral adrenal vein sampling for hormone levels can help determine whether there is unilateral dominance in aldosterone secretion, which is critical for selecting the appropriate treatment.
If the condition is caused by an adrenal adenoma or carcinoma, surgical removal is the best treatment option. For adrenal hyperplasia, aldosterone receptor antagonists are usually the first-line treatment, though adrenalectomy can also be performed, albeit with relatively poorer outcomes.
Pheochromocytoma and Paraganglioma
Pheochromocytomas and paragangliomas originate from the adrenal medulla, sympathetic ganglia, or other chromaffin tissues in the body. These tumors intermittently or persistently release excessive amounts of catecholamines such as adrenaline, noradrenaline, and dopamine. Clinical manifestations are highly variable, with the classic presentation being paroxysmal hypertension accompanied by tachycardia, headache, sweating, and pallor.
The preferred laboratory tests for diagnosis include measurements of plasma free metanephrines and urinary metanephrines (metanephrine and normetanephrine). Catecholamines or their metabolites, such as vanillylmandelic acid (VMA), can also be measured in blood or urine during an episode. Significant elevation suggests the diagnosis. Imaging techniques such as ultrasound, radionuclide scans, CT, and MRI can be used for localization of the tumor.
Most pheochromocytomas are benign, but about 10% are malignant. Surgical removal is highly effective. For patients undergoing surgery or those with malignant tumors that have metastasized and are inoperable, antihypertensive treatment with alpha-blockers and beta-blockers is recommended.
Cushing's Syndrome
Cushing's syndrome is mainly caused by excessive secretion of glucocorticoids from the adrenal glands due to various reasons. Patients may present with hypertension as well as other characteristic features such as central obesity, moon face, buffalo hump, purple striae on the skin, hirsutism, and hyperglycemia. Laboratory findings include increased 24-hour urinary 17-hydroxycorticosteroids and urinary free cortisol levels. The dexamethasone suppression test is helpful for diagnosis. MRI of the pituitary gland and CT of the adrenal glands can help identify the location of the lesion.
Treatment primarily involves surgery, medications, or radiotherapy, depending on the underlying cause and the extent of the disease.
Coarctation of the Aorta
Coarctation of the aorta is usually a congenital condition, though it may occasionally result from Takayasu arteritis. Clinically, it is characterized by elevated blood pressure in the upper extremities and reduced or normal blood pressure in the lower extremities. Collateral arterial pulsations and murmurs may be detected in the interscapular region, parasternal area, or axilla. Chest x-rays may reveal rib notching caused by collateral arteries. Enhanced CT or angiography of the aorta can confirm the diagnosis.
Treatment primarily involves stent placement or surgical correction.