GENERAL APPROACH TO SECONDARY HYPERTENSION

Secondary hypertension (HTN) is defined as HTN that has a known etiology and is potentially reversible by specific treatment. The prevalence of secondary HTN is approximately 5% to 10% of all hypertensive patients, but several factors resulted in a recent increase in these estimates. More aggressive screening and better laboratory methods led to a higher rate of identification of certain conditions, especially primary aldosteronism; advances in the knowledge of mechanisms involved in the pathogenesis of HTN uncovered new causes of secondary HTN; and changes in the characteristics of the hypertensive population increased the prevalence of secondary HTN if the above definition of “potentially modifiable” HTN is followed. For example, obesity is now “epidemic,” is associated with HTN, and its successful treatment improves or normalizes blood pressure (BP). Likewise, essential HTN is a common cause of chronic kidney disease (CKD), and thus both essential and secondary HTN may coexist in the same patient as CKD progresses. The same is true for the aging population where the prevalence of HTN and macrovascular atherosclerotic disease increase concomitantly; making it more likely that renal artery stenosis complicates the evolution of essential HTN. Lastly, secondary causes of HTN are frequently responsible for cases of resistant HTN. It is estimated that up to one-third of patients referred to specialty clinics for the evaluation of resistant HTN have secondary HTN; consequently, a very detailed screening for secondary HTN is imperative in the assessment of these patients. Other clinical circumstances (Table 21.1) also point to the need of more aggressive evaluation for secondary causes of HTN.

The initial evaluation of any hypertensive patient must include enough elements to provide an adequate screen for secondary causes. After all, it is in that initial encounter that the clinician has the unique opportunity of identifying a potentially curable process. The history should include specific inquiry for symptoms of diseases that may cause HTN (Table 21.2), as well as for the use of substances that elevate BP. The physical examination should include a search for differences in BP and pulses between the upper and lower extremities; an evaluation of peripheral vascular disease (auscultation for carotid, abdominal, and femoral bruits, and palpation of the abdomen for aortic aneurysms); palpation of the thyroid gland; and examination of the abdomen for enlarged polycystic kidneys or masses. Laboratory tests must include an evaluation of renal function (creatinine and urinalysis), blood glucose, hemoglobin, serum potassium, and calcium. These simple and inexpensive procedures will be enough to raise the suspicion of secondary (identifiable) causes of HTN in most patients. The paragraphs that follow present a more detailed discussion of the most relevant causes of secondary HTN.

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DRUGS AND CHEMICALS

Many chemical substances, used for a variety of reasons, can cause HTN or lessen the effect of antihypertensive agents (Table 21.3). These include prescription and non-prescription medications, as well as abused substances. It is important to remind clinicians to actively inquire about these chemicals when obtaining the history from a hypertensive patient.

Oral Contraceptives

Oral contraceptive drugs commonly raise BP. These effects, however, are mild. No more than 10% to 15% of patients using oral contraceptives fulfill the diagnosis of HTN. The pathophysiology of BP elevation with oral contraceptive use is unknown. The incidence of HTN has decreased with the use of modern, low-estrogen formulations in combination with new synthetic progestogens. It is recommended that every woman taking oral contraceptives have their BP measured regularly. Most cases of HTN related to oral contraceptives are cured with drug withdrawal, although it may take several months until BP normalizes. Therefore, if HTN is diagnosed in a patient who uses oral contraceptives, the pill is discontinued and another type of contraception recommended.

Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed class of drugs in the United States. Because their use is common in the elderly, the population at greatest risk for HTN, it is important to review the effects of these drugs on BP. Decreased pros-taglandin synthesis results in decreased renal blood flow and sodium retention, thereby contributing to HTN. Available data demonstrate that NSAIDs cause modest increases in BP, but this effect is primarily noticeable in patients with underlying HTN. Of greater relevance is that NSAIDs antagonize the effects of most antihypertensive drugs, with the exception of calcium channel blockers. Most NSAIDs have similar effects on BP, particularly nonselective agents. Selective cyclooxygenase-2 (COX-2) inhibitors are also associated with BP elevation. There are some nutraceuticals with COX inhibitory actions, such as cherry extract, willow bark, and devil’s claw. Therefore, similar BP effects could be observed in patients who consume large amounts of these products.

Substances Enhancing Sympathetic Activity

Remedies to relieve cold symptoms (oral or nasal sprays) often contain sympathomimetic amines such as pseudoephedrine and phenylpropanolamine. All such agents are associated with BP elevation. Other medications containing sympathomimetic activity include amphetamines used in the treatment of attention-deficit hyperactivity disorder or depression (dextroamphetamine, methylphenidate), and sibutramine, which is used for the treatment of obesity. Ephedra was a common component of nutritional supplements and nonprescription weight-loss preparations until its ban from the U.S. market in 2004. There are some nutraceuticals currently available on the market that can result in increased sympathomimetic activity and elevate BP, including bitter orange and Siberian ginseng. The designer drug known as “bath salts” contains several chemicals (methylenedioxopyrrovalerone, mephedrone) that cause HTN and associated end-organ injury.

Other drugs may enhance sympathetic nervous system tone and increase BP without direct sympathomimetic activity. These include several antidepressants such as selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, sertraline, citalopram, escitalopram), serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine, desvenlafaxine, duloxetine), the most commonly prescribed antidepressant agents, and monoamine oxidase inhibitors (MAOIs; eg, phenelzine and tranylcypromine). An important nonprescription substance is yohimbine, which has resurged in the market of supplements for improved male sexual performance. Finally, cocaine and ecstasy (methylenedioxymethamphetamine [MDMA]) are 2 illicit drugs that activate the sympathetic nervous system and may precipitate hypertensive crises.

Licorice

Licorice is a bush native to southern Europe and Asia, the roots of which are sweeter than sugar and are used in candies and tobacco flavoring. In this country, the most common source of licorice extract used to be nutritional “energy” supplements, although more recently many of these preparations are “deglycyrrhized,” that is, they are devoid of the hypertensogenic ingredient of licorice (glycyrrhizic acid). Glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase, the enzyme that converts cortisol to cortisone, thus increasing the levels of cortisol available to activate the mineralocorticoid receptor. It causes a form of pseudohyperaldosteronism with HTN, sodium retention, and potassium wasting, similar to the syndrome of apparent mineralocorticoid excess (AME). HTN generally reverses with stopping its ingestion.

Cyclosporine and Tacrolimus

Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressive agents commonly used in transplantation and in the treatment of certain immunemediated diseases. In kidney transplantation, the prevalence of HTN increased from 50% to 80% after the introduction of cyclosporine. Calcineurin inhibitors induce functional and morphologic changes in kidneys that are directly related to the pathogenesis of HTN. They produce renal vasoconstriction and decreased glomerular filtration rate (GFR) that impair sodium excretion, and long-term use may cause interstitial fibrosis. Nephrotoxicity, however, is not the only mechanism for calcineurin inhibitor-related HTN. Activation of the sympathetic nervous system, impaired nitric oxide production, increased endothelin release, and increased expression of the thiazide-sensitive NaCl cotransporter are other relevant factors. Although some publications suggest that calcium channel blockers are superior in treatment of calcineurin inhibitor HTN, any antihypertensive agent can be used, and it is possible that thiazide diuretics are particularly effective and underused. Importantly, previous concerns about concomitant angiotensin-converting enzyme (ACE) inhibitor use are unfounded, and these drugs can be safely used to treat patients with HTN on a calcineurin inhibitor.

Erythropoietin

Recombinant human erythropoietin (EPO) is used for treatment of anemia in CKD, human immunodeficiency virus (HIV), postchemotherapy, and in certain hematologic disorders. Most patients have a mild BP increase when they initiate EPO therapy, and frank HTN can become manifest or made worse in approximately 30%. The BP rise is attributed to increased blood viscosity and direct EPO effects on vascular resistance, where it causes increased cytosolic calcium, endothelin1 concentration, and resistance to nitric oxide. Because BP elevations are usually mild and benefits of EPO outweigh this side effect in most patients, routine measures to control BP should take place while continuing EPO therapy.

Corticosteroids

Corticosteroids used either for antiinflammatory or immunosuppressive purposes may cause HTN. The proposed mechanism is the same as described for Cushing syndrome (see below), and usually occurs with high-dose therapy or long-term use.

Vascular Endothelial Growth Factor Antagonists

Antagonists of the vascular endothelial growth factor (VEGF) are commonly used in the treatment of several malignancies. These drugs can be either direct antagonists, such as the monoclonal antibodies bevacizumab, or can be tyrosine kinase antagonists that block the kinase activity of the VEGF receptors (eg, sorafenib, sunitinib). Overall, these agents are associated with a 20% to 25% incidence of HTN, which may be severe in as many as 8% of patients. The HTN is mediated by endothelial dysfunction, increased oxidative stress, microvascular rarefaction, and arterial wall injury as a result of loss of vasa vasorum, and typically resolves with removal of the drug. When continued therapy with these agents is needed, HTN can be treated with any drug class. Recent reports have also linked intravitreal administration of VEGF antagonists with endothelial damage and HTN.

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OBSTRUCTIVE SLEEP APNEA

A good example of “new” causes of secondary HTN is OSA. OSA is a frequent sleep disorder (20% of adults have at least mild OSA), characterized by partial or complete closure of the upper airway during sleep. BP increases not only during apneic episodes, but OSA is also independently linked to daytime HTN. The odds of daytime HTN increase with the number of apneic episodes and the magnitude of nocturnal O₂ desaturation. In patients with drug-resistant HTN, the prevalence of OSA is in the range of 60%.

Pathogenesis

Hypoxemia, CO₂ retention, acute changes in intrathoracic pressure, and arousal from sleep trigger neural and circulatory responses such as sympathetic activation and increased levels of endothelin-1. Other known risk factors for cardiovascular disease, such as oxidative stress, chronic inflammation, hypercoagulability, and aldosterone excess, also coexist in OSA, thus amplifying the cardiovascular risk of these patients.

Diagnosis

Patients with OSA are habitual snorers, have increased neck circumference, are uniformly overweight, and have daytime somnolence. In a hypertensive patient, knowledge of the neck circumference (>17 inches) and 2 features of the medical history (presence of habitual snoring or witnessed nocturnal choking or gasping) can predict polysomnographic abnormalities well and select patients for further investigation. Polysomnography is the best procedure to evaluate OSA, as it provides not only the diagnosis but also information on the severity of the problem. The number of obstructive events (apneas or hypopneas) per hour is commonly used to quantify OSA: mild = 5 to 15 events per hour; moderate = 15 to 30 events per hour; severe = more than 30 events per hour. Patients with more than 15 events per hour are more commonly hypertensive and are more refractory to antihypertensive drug therapy.

Treatment

Weight reduction is essential in obese patients. Avoiding the supine position during sleep also reduces OSA episodes (a tennis ball sewn to the back of pajamas is a useful tool). Nasal continuous positive airway pressure (CPAP) is the best available treatment for OSA. CPAP forces air down the nose and throat under positive pressure, thus keeping the upper airways open, eliminating apneas. Effective CPAP treatment significantly reduces BP. A Cochrane metaanalysis reported an average BP reduction of 7.2/3.0 mmHg. An important caveat is that these estimates are based on studies that also include patients without HTN, thus minimizing the effect. The BP-lowering effect is greater among patients with true drug-resistant HTN and patients who are more adherent with CPAP. The issue of adherence to CPAP is important, as it prevents long-term use in a substantial subgroup of patients. Drug use is usually needed in these patients. The best available data favor the use of β-blockers, α-blockers, and spironolactone (with or without concomitant use of a loop diuretic).

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RENAL PARENCHYMAL DISEASE

Renal parenchymal disease is the most frequent cause of secondary HTN (5% of all HTN cases). Most patients (80%) with progressive kidney diseases develop HTN, and the prevalence of HTN increases with worsening renal function. Unilateral parenchymal renal disease (cysts, tumors, reflux, hydronephrosis) may infrequently cause HTN.

Pathogenesis

The primary mechanism of HTN in bilateral kidney disease is the impaired fluid and sodium balance, leading to increased plasma volume. A compensatory increase in BP occurs to augment sodium and water excretion (see Chapter 20). Furthermore, complex mechanisms involving activation of the sympathetic nervous system, increased intracellular calcium, inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS), altered balance of endothelium-derived vasoconstrictor and vasodilating factors (especially endothelin-1 and nitric oxide, respectively), and increased arterial stiffness are also operative in these patients. In unilateral renal disease, activation of the RAAS is often the cause of HTN. The RAAS is also involved in HTN associated with unilateral reflux nephropathy and unilateral hydronephrosis. The presence of proteinuria is associated with worse BP control, partly as a result of induction of sodium avidity, largely through direct activation of the epithelial sodium channel (ENaC).

Diagnosis

Edema, hematuria, and/or foamy urine may be present. Physical examination may disclose abdominal masses representing polycystic kidneys, hydronephrosis, or renal tumors. More importantly, the diagnosis of parenchymal kidney disease in made by laboratory evaluation with elevated concentrations of blood urea nitrogen (BUN) and creatinine and/or abnormalities in the urinalysis (hematuria, proteinuria). Because BUN and creatinine concentration may underestimate the degree of renal dysfunction, formulas that estimate GFR are used to assess renal function more accurately (see Chapter 16). In adults, the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) equation, or the Cockcroft-Gault equation are most often used. They may be complemented by a 24-hour urine collection and the determination of the endogenous creatinine clearance. A more detailed diagnostic evaluation of kidney disease is found in Chapter 16.

Treatment

HTN is the most important factor in the progression of most parenchymal kidney diseases. A decrease in BP is associated with a fall in the rate of loss of glomerular function. Furthermore, BP control to less than 125/75 mmHg leads to substantial protection of renal function in patients with proteinuria. The threshold level of proteinuria that benefits from this low BP target is not certain. It is clear that patients with greater than 3 g proteinuria per day benefit the most. The same is likely true for those with proteinuria above 1 g per day, although lower levels of protein excretion experience less impressive results from aggressive BP lowering. BP targets for patients with nonproteinuric kidney diseases are not well established. The available evidence supports BP lowering to less than 140/90 mmHg, but there is no evidence that lower targets provide any further benefit.

Drugs that act on the RAAS, ACE inhibitors, and angiotensin II receptor blockers (ARBs), are more effective than other agents in renal protection and proteinuria reduction at the same level of BP control. Therefore, patients with CKD should receive an ACE inhibitor or an ARB as the first pharmacologic option for the treatment of HTN. Close follow-up of renal function and potassium must take place after initiation of any of these drugs. We routinely obtain serum chemistries 1 week after initiation and after each dose titration. It is well established that declines in GFR in the 20% to 30% range can be tolerated, as long as it stabilizes on repeat testing within 30 days. Hyperkalemia in the 5.5 mEq/L range is safe and acceptable. Control of hyperkalemia can be achieved with dietary counseling and diuretics.

To reach low BP targets, a combination of 2 to 3 drugs is often needed. In this decision-making process, the increased cardiovascular risk represented by kidney disease and the frequent cardiovascular comorbidity afflicting these patients must be accounted for. Therefore, a diuretic may be indicated because of its cardiovascular protective effects or as part of the management of volume overload or heart failure. β-Blockers are needed for coronary disease or heart failure. Calcium channel blockers may be helpful in coronary disease, and nondihydropyridine calcium channel blockers (verapamil and diltiazem) have antiproteinuric properties that are additive to ACE inhibitors or ARBs. Combining an ACE inhibitor and ARB may further decrease proteinuria, and may decrease the progression of kidney disease in nondiabetic patients. In the absence of any compelling reason to choose one class over another, the first agent to be added to an ACE inhibitor or ARB is either a calcium channel blocker or a diuretic. A recent trial observed better cardiovascular outcomes when an ACE inhibitor (benazepril) was combined with a calcium channel blocker (amlodipine) than with hydrochlorothiazide. On the other hand, a diuretic is often essential to achieve BP targets in patients with kidney disease. The choice of diuretic type is dependent on GFR: thiazide diuretics can be effectively used with a GFR greater than 30 to 50 mL/min; when below this range, a loop diuretic is usually required, although our anecdotal experience with the thiazide-type diuretic metolazone is quite positive in CKD. Third-line drugs are usually a calcium channel blocker or a β-blocker. The mineralocorticoid receptor antagonists (spirolactone, eplerenone) are effective agents to lower BP and control volume overload; however, their use in combination with an ACE inhibitor or ARB is associated with significant hyperkalemia, thus requiring very close monitoring. The renin inhibitor aliskiren provides additional antiproteinuric and BP-lowering effects when added to an ARB. However, a recent trial demonstrated worse cardiovascular and renal outcomes with this agent. In our opinion, renin inhibitors do not have a role in HTN management at this point.

In the unusual cases of unilateral disease with HTN, nephrectomy is indicated for HTN associated with unilateral renal tumors. In other unilateral parenchymal diseases, nephrectomy must be evaluated carefully, especially in kidneys with residual function. Surgical results are variable and often poor. Most patients can be managed successfully with drug therapy.

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