Abstract
Secondary hypertension occurs in approximately 10% of hypertensive patients. The clinical evaluation should seek symptoms, signs, and laboratory evidence of common and/or life-threatening causes, including renal parenchymal disease, renovascular disease, sleep apnea, primary aldosteronism, Cushing syndrome, pheochromocytoma/paraganglioma, thyroid and parathyroid disease, acromegaly, coarctation of the aorta, and the use of hypertensogenic substances. Identification of secondary causes is important because timely treatment may result in curing the hypertension.
Keywords
hypertension, secondary hypertension, renal artery stenosis, fibromuscular dysplasia, obstructive sleep apnea, primary aldosteronism, Cushing syndrome, pheochromocytoma, coarctation of the aorta
Definition and Prevalence of Secondary Hypertension
Secondary hypertension is generally defined as hypertension associated with a specific cause and therefore is potentially curable if that cause is removed. The use of this definition generates two separate lines of diseases. The first are considered “classic” causes of secondary hypertension, which, if diagnosed in a timely manner, can be effectively cured. Examples include acute glomerulonephritis, primary aldosteronism, some cases of renal artery stenosis (RAS), pheochromocytoma, Cushing syndrome, hypothyroidism and hyperthyroidism, and coarctation of the aorta. Other conditions may be associated with higher blood pressure (BP) levels; however, given their complex pathophysiologic mechanisms and association with multiple other cardiovascular risk factors, their correction does not necessarily result in the resolution of hypertension. Examples in this category include chronic kidney disease (CKD), sleep apnea, and obesity.
The prevalence of secondary hypertension is estimated around 10% of all cases of hypertension in adults. Absent from most prevalence studies, all of which were conducted from the 1970s to the 1990s, is the recognition that primary aldosteronism was underdiagnosed, that the definitions of kidney disease were too conservative, and that sleep apnea was not considered as a diagnosis. Therefore it is likely that an updated survey of the prevalence of secondary hypertension would result in higher prevalence estimates.
The relationship between age and prevalence of secondary causes must be acknowledged. Among hypertensive children, secondary causes are the rule rather than the exception, with up to 90% of young children having an identifiable secondary cause, most commonly structural kidney disease. The prevalence of “classic” causes of secondary hypertension among hypertensive adolescents had been about 65% in older observations, although the obesity epidemic has somewhat masked this relationship. While obesity is associated with a higher prevalence of primary hypertension in children and adolescents, its presence does not exclude the presence of a typical secondary cause (~40%). Therefore the coexistence of obesity should not prevent the clinician from investigating secondary hypertension in children and adolescents.
The transition point of prevalence rates from childhood/adolescence numbers to more typical adult numbers is unknown. The only study that investigated the effect of age on the prevalence of secondary hypertension was unable to show a higher prevalence among patients aged 18 to 29 years (5.6%) compared with any other age bracket; in fact, because of the high rate of renovascular disease and primary aldosteronism in older patients, the prevalence of secondary hypertension was lowest among the youngest group. Mindful of these somewhat unexpected data, it must be recognized that there is a transition period and that ignoring it would inevitably lead to frequently missing the diagnosis of a secondary cause. Accordingly, our search for secondary hypertension in younger adults, especially those under the age of 30 years, is always more “aggressive” than in older patients. In this chapter, we will restrict discussion of secondary hypertension to adults.
Clinical Opportunities to Diagnose Secondary Hypertension
There are two critical opportunities to identify secondary hypertension during the evaluation and management of hypertensive patients. First, and most important, is during the initial evaluation of a patient diagnosed with hypertension. It is important to consider the breadth of possibilities at this time, especially as diagnostic tests often perform at their best when patients are not on treatment. Table 66.1 lists clinical features suggestive of each of the major causes of secondary hypertension. The clinician should explore the presence of these different clinical signs and symptoms in every patient. The list of general diagnostic tests recommended as part of the initial evaluation of hypertensive individuals (see Table 66.1 ) broadly addresses the identification of secondary causes. It should be reviewed carefully for every patient, and further investigations should be pursued if suggested by this initial review.
| Test | Possible Causes of Secondary Hypertension |
|---|---|
| Basic Metabolic Panel | |
| eGFR (based on creatinine) | Low: CKD (any etiology), RAS |
| Potassium | Low: aldosterone excess (primary or secondary), hypercortisolism, apparent mineralocorticoid excess syndromes, primary reninism High: Gordon syndrome, CKD |
| Bicarbonate | High: aldosterone excess (primary or secondary), apparent mineralocorticoid excess syndromes, primary reninism Low: Gordon syndrome, CKD (any etiology) |
| Calcium | High: Hyperparathyroidism |
| Urinalysis | |
| Hematuria | Glomerulonephritis, interstitial nephritis |
| Proteinuria | Glomerulonephritis |
| Complete Blood Count | |
| Hematocrit/Hemoglobin | High: sleep apnea, any polycythemic disorder (e.g., polycythemia vera) |
The second occasion to explore secondary causes is when patients are noted to be resistant to therapy. Resistant hypertension, identified in approximately 12% of treated patients with hypertension, is defined as BP that remains above target (in general, above 140/90 mm Hg) despite the use of three adequately dosed drugs, of synergistic drug classes, preferably including a diuretic. Patients with resistant hypertension have higher rates of secondary hypertension, in particular primary aldosteronism (~20%), renovascular disease (~25%), and obstructive sleep apnea (>50%). Therefore every patient with resistant hypertension should be reconsidered for secondary causes, and, if not previously screened, objective testing for these conditions should be considered.
Clinical Syndromes Suggestive of Secondary Hypertension
Hypertension and Hypokalemia
The coexistence of hypertension and spontaneous hypokalemia should always raise the possibility of secondary causes of hypertension. The approach should start with a clinical evaluation that confirms that the kidney is the source of potassium wasting. This can be achieved with measurement of the transtubular potassium gradient (TTKG) ([urine potassium/plasma potassium]:[urine osmolality/plasma osmolality]) or the urine potassium/creatinine ratio. In the presence of hypokalemia, a TTKG greater than 2 or a urine potassium/creatinine ratio greater than 13 mEq/g is diagnostic of renal potassium wasting. Once renal potassium wasting is confirmed, paired measurement of plasma renin activity (PRA; in ng/mL per hour) and plasma aldosterone (in ng/dL) allows a thoughtful differential diagnosis according to three different diagnostic patterns:
- 1.
High aldosterone (>15 ng/mL) with high PRA (>1.5 ng/mL per hour). This combination results in a variable aldosterone-to-renin ratio, but it is usually less than 20. These patients have secondary hyperaldosteronism, commonly caused by diuretic therapy (thiazides, loop diuretics), RAS (particularly unilateral), malignant hypertension (of any etiology), or the rare syndrome of primary reninism, which is usually caused by a benign renin-producing tumor of the juxtaglomerular cells, though several extrarenal tumors have been reported (teratomas, adenocarcinomas of the adrenal, lung, pancreas, or ovary, or hepatocellular carcinoma).
- 2.
High aldosterone with suppressed renin activity (<0.6 ng/mL per hour), leading to an aldosterone-to-renin ratio greater than 30. This is diagnostic of primary aldosteronism and should lead to further subtype differentiation (see specific section below).
- 3.
Low aldosterone (often suppressed to undetectable levels) and low renin activity . These patients behave clinically as if they had hyperaldosteronism but have undetectable aldosterone levels. This implicates one of three possibilities: (1) an alternative source of mineralocorticoid activity (e.g., deoxycorticosterone or cortisol from a tumor, or congenital adrenal hyperplasia due to 11β-hydroxylase or 21-hydroxylase deficiency); (2) a disorder of impaired degradation of cortisol, thus leaving it available to activate the mineralocorticoid receptor (e.g., licorice ingestion or primary 11β-hydroxysteroid dehydrogenase type 2 deficiency); or (3) mutations in the epithelial sodium channel (Liddle syndrome) or the mineralocorticoid receptor (Geller syndrome). Some of these conditions are briefly presented in Table 66.2 .
Table 66.2
Clinical Clues to Guide the Investigation in Young Hypertensive Patients With a Potential Hereditary Cause
Possible Causes of Familial Hypertension
Clinical Clues
Catecholamine-Producing Tumors
PPGL
Familial cases are responsible for up to 40% of cases
Paroxysmal palpitations, headaches, diaphoresis, pale flushing. Syndromic features of any of the associated disorders (see PPGL section for details)
Neuroblastomas (adrenal)
1%–2% of neuroblastomas are familial
Symptoms of the abdominal tumor (pain, mass) or catecholamine release (same as PPGL)
Parenchymal Kidney Disease
Glomerulonephritis
Alport disease (X-linked, AR or AD), familial IgA nephropathy (AD with incomplete penetrance)
Proteinuria, hematuria, low eGFR
Polycystic kidney disease
ADPKD type 1 or 2, ARPKD
Multiple kidney cysts (as few as 3 in patients under the age of 30)
Adrenocortical Disease
Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1)
AD chimeric fusion of the 11β-hydroxylase and aldosterone synthase genes
Cerebral hemorrhages at young age, cerebral aneurysms. Mild hypokalemia. High plasma aldosterone, low renin
Familial hyperaldosteronism type 2
AD. Unknown defect
Severe hypertension in early adulthood. High plasma aldosterone, low renin. No response to glucocorticoid treatment
Familial hyperaldosteronism type 3
AD mutation in the KCJN5 potassium channel
Severe hypertension in childhood with extensive target-organ damage. High plasma aldosterone, low renin. Marked bilateral adrenal enlargement
Congenital adrenal hyperplasia
AR mutations in 11β-hydroxylase or 21-hydroxylase
Hirsutism, virilization. Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin
Monogenic Primary Renal Tubular Defects
Gordon syndrome
AD mutations of KLHL3, CUL3, WNK1, WNK4. AR mutations of KLHL3
Hyperkalemia and metabolic acidosis with normal renal function
Liddle syndrome
AD mutations of the epithelial sodium channel
Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin
Apparent mineralocorticoid excess
AD mutation in 11β-hydroxysteroid dehydrogenase type 2
Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin
Geller syndrome
AD mutation in the mineralocorticoid receptor
Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin. Increased BP during pregnancy or exposure to spironolactone
Unknown Mechanisms
Hypertension-brachydactyly syndrome
AD mutation in the phosphodiesterase 3 (PDE3) gene
Short fingers (small phalanges) and short stature. Brainstem compression from vascular tortuosity in the posterior fossa
AD, Autosomal dominant; ADPDK, autosomal-dominant polycystic kidney disease; aldo, aldosterone; AR, autosomal recessive; ARPKD, autosomal-recessive polycystic kidney disease; PKD, polycystic kidney disease; PPGL, pheochromocytoma/paraganglioma.
Modified from Peixoto AJ. Attending rounds: a young patient with a family history of hypertension. Clin J Am Soc Nephrol. 2014;9:2164–2172.
Hypertension With a Strong Family History of Hypertension Early in Life
Hypertension has a significant genetic component, with multiple genes associated with small effects on BP. However, patients who have a strong family history of hypertension early in life should be approached more carefully, as they may have a genetic disorder responsible for the hypertension. The most common of these conditions is autosomal-dominant polycystic kidney disease (1 : 500 to 1 : 1000 live births), which can result in hypertension several years before producing symptoms or causing loss of kidney function. There are several rare monogenic causes of hypertension that the clinician should entertain in the right clinical setting; Table 66.2 summarizes their key clinical and genetic features.
Hypertension and Obesity
Obesity is strongly associated with hypertension. It is mediated by increased activity of the renin-angiotensin system and the sympathetic nervous system, increased production of aldosterone by adipocytes, and impaired production of natriuretic peptides. Localized fat accumulation in the liver (as in nonalcoholic steatohepatitis) or kidney (renal sinus fat) is also associated with an increased prevalence of hypertension.
Weight gain often results in loss of BP control, and weight loss, when significant, can lead to resolution of hypertension. This can be achieved with lifestyle changes (dietary caloric restriction, exercise, behavioral modification to adjust caloric intake patterns), with or without the addition of drugs (orlistat, lorcaserin, phentermine/topiramate) or bariatric surgery. It is important to remember that some drugs used to treat obesity, such as lorcaserin (a serotonin 5-HT2 receptor agonist) and phentermine (a sympathomimetic amine) can induce significant hypertension in some patients.
The impact of bariatric surgery on hypertension control in obese patients is now well established. A meta-analysis of 57 studies in over 50,000 patients showed that 64% of patients had improved BP levels, and up to 50% were able to fully come off medications. In general, the amount of weight loss is greater with a Roux-en-Y gastric bypass than with other techniques that are purely restrictive (gastric banding, gastric sleeve), and in many studies, this is also associated with greater BP reduction.
Drug-Induced Hypertension
Patients presenting with hypertension or whose BP control suddenly worsens should always be evaluated for exposure to hypertensogenic substances ( Table 66.3 ). These include substances of abuse and over-the-counter and prescription drugs. Oral contraceptive pills (OCP), especially earlier generation pills that had higher estrogen and progesterone content, can cause hypertension. Modern low-estrogen pills can also produce hypertension, though at rates much lower than with older preparations. Stopping the OCP cures the hypertension after several weeks to months in most, but not all, women. Nonsteroidal antiinflammatory drugs (NSAIDs) result in a modest average hypertensive effect (up to ~5 mm Hg), but some patients can have very large BP responses. In addition, NSAID-induced hypertension often presents as loss of BP control in patients taking a diuretic or a blocker of the renin-angiotensin system, whereas calcium channel blockers tend to be less affected in NSAID users.
| Oral contraceptives |
| NSAIDs (selective and nonselective) |
| Sympathomimetics: pseudoephedrine, phenylpropanolamine, phentermine, cocaine, amphetamines (prescription or illegal), yohimbine (α 2 -anatagonist) |
| SSRIs and SNRIs |
| MAOIs |
| Cyclosporine and tacrolimus |
| Erythropoietin and darbepoietin |
| Corticosteroids, mineralocorticoids (fludrocortisone) |
| Anti-VEGF antibodies (bevacizumab, ramucirumab) and certain tyrosine kinase inhibitors with anti-VEGF activity (e.g., sorafenib, sunitinib) |
| Licorice |
| Ethanol |
Sympathomimetic amines (legal or illegal) usually cause hypertension acutely, close to the time of ingestion. Alcohol has an acute hypotensive effect, but chronic use in large amounts (>4 to 5 drink-equivalents per day) is associated with increased BP. Glucocorticoids and mineralocorticoids can produce a dose-dependent rise in BP. Although generally seen only with systemic treatment, there are isolated reports of hypertension resulting from high-exposure topical therapy. Glucocorticoids with low mineralocorticoid activity (dexamethasone, budesonide) induce lesser pressor responses. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can produce a modest increase in BP. SNRIs are more commonly culprits, and the hypertensive response in some patients can be severe. Interestingly, when used for hypertensive patients with depression, BP often improves as depressive symptoms improve.
Angiogenesis inhibitors, such as anti–vascular endothelial growth factor (VEGF) antibodies (bevacizumab, ramucirumab) and tyrosine kinase inhibitors (sorafenib, sunatinib), can produce hypertension that often persists despite discontinuation. Most cases are related to systemic therapy, although there are isolated reports following intravitreal administration of bevacizumab. Because hypertension during the use of these drugs correlates with better tumor responses (likely a reflection of successful antiangiogenesis), treatment is usually continued unless BP control to acceptable levels is not achievable or if severe kidney injury develops.
Labile Hypertension or Hypertension With Symptoms of Catecholamine Excess
Some patients present with paroxysmal hypertension (isolated episodes interspersed with normotension), labile hypertension (wide fluctuations in BP during any given time interval), or hypertension accompanied by stereotypical spells suggestive of catecholamine excess (headaches, palpitations, diaphoresis, pallor). In these situations, ruling out pheochromocytoma/paraganglioma (PPGL) is the first initial step. However, because these symptoms are nonspecific and PPGL is rare, most patients turn out to have an alternative diagnosis, and often no specific etiology can be identified. Important considerations to be entertained in patients presenting as “pseudopheochromocytoma” include sympathomimetic drug use, alcohol withdrawal, hyperthyroidism, RAS, carcinoid, intracranial hypertension, neurovascular brainstem compression, panic disorder, and baroreflex failure (as in patients with bilateral carotid sinus injury due to trauma, surgery, or irradiation). Further testing is based on specific symptoms and signs associated with each of these conditions.
Specific Causes of Secondary Hypertension
Parenchymal Kidney Disease
Chronic kidney disease (CKD) of any etiology can lead to hypertension. Approximately 75% of patients with glomerular filtration rate (GFR) less than 45 mL/min are hypertensive. Patients with polycystic kidney disease and glomerulopathies tend to be hypertensive earlier in the course of the disease (at higher GFR) than patients with interstitial diseases. However, with progressive decline in kidney function, the prevalence of hypertension is relatively similar across all causes of CKD. Proteinuria is linked to increased sodium retention and hypertension. This relationship starts at relatively low levels of proteinuria and progressively strengthens with higher degrees of protein excretion. Low GFR and proteinuria have a synergistic association with higher BP.
The pathogenesis, diagnosis, and management of CKD (including hypertension), glomerular and interstitial diseases, and polycystic kidney disease are discussed elsewhere in this book.
Renovascular Disease
Renovascular hypertension due to RAS is present in 1% to 5% of hypertensive patients. There are two main types of RAS that can lead to hypertension: atherosclerotic RAS (ARAS, >90% of cases) and fibromuscular dysplasia (FMD, <10%). ARAS is an atherosclerotic process indistinct from atherosclerosis in any other vascular bed, with similar pathobiologic mechanisms. Conversely, FMD is a nonatherosclerotic, noninflammatory disease of the arterial wall that results in stenosis of the arterial lumen.
Many hypertensive patients may have renovascular atherosclerotic lesions without a role in the pathogenesis of hypertension. Renovascular atherosclerosis is associated with increased cardiovascular risk but should be differentiated from renovascular hypertension. In this chapter, I refer solely to RAS (atherosclerotic or fibromuscular) that leads to hypertension through ischemia-induced activation of the renin-angiotensin-aldosterone system (RAAS) as well as progressive endothelial dysfunction, capillary rarefaction, and kidney injury. In animal models of arterial flow restriction, unilateral RAS results in ipsilateral ischemia and renin production, which leads to increased angiotensin II levels that produce a systemic pressor response. Because the other kidney is normal, there is pressure-induced natriuresis and the animals do not become volume overloaded. In contrast, in bilateral disease natriuresis is impaired so hypertension is initially driven by angiotensin II–stimulated vasoconstriction but is maintained by sodium retention, which ultimately leads to decreased renin production. However, in humans, perhaps reflecting the chronicity of this process, there is wide variability in plasma renin levels in bilateral disease, although it is generally accepted that kidney tissue renin levels are high.
Recent animal models have provided new insights, especially on atherosclerotic disease, demonstrating that renal artery flow restriction induces a proinflammatory and profibrotic environment that results in endothelial dysfunction, microvascular rarefaction, and interstitial fibrosis. The degree of flow restriction to trigger these responses in humans is a matter of debate. Available evidence from a study testing ipsilateral renin generation during balloon inflation indicates that a 20% drop in perfusion pressure is required and that renin generation progressively increases with greater degrees of hypoperfusion ( Fig. 66.1 ). The degree of luminal stenosis necessary to produce this pressure gradient typically exceeds 70%, although it may occur with lesions in the 50% to 70% range.
