Prim Care Clin Office Pract 35 (2008) 489500

Secondary Causes of Hypertension

Sandra J. Taler, MD
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA

Secondary hypertension is uncommon in traditional primary care practice, yet it may cause major morbidity for a subset of patients. Depending on the conditions included, it may aect 5% to 10% of hypertensive patients. Investigation of all to detect these few would be costly and impractical and may exaggerate the risk to some patients without benet, particularly because some secondary causes may not be correctable and others may be potentially treatable but at substantial risk. Nevertheless, for the few with a treatable secondary cause, detection and correction may be highly rewarding, even life prolonging. Knowledge of key clinical clues to secondary hypertension is essential to select which patients should be evaluated further and to what extent. This article provides an overview of the range of secondary causes, including key clinical features and appropriate diagnostic and treatment options. Details on the merits of surgical and other invasive interventions are beyond the scope of this discussion, and the reader is encouraged to refer these patients for subspecialty consultation and management.

Denition and approach Secondary hypertension is the presence of a specic condition known to cause hypertension. This condition may be the sole cause for hypertension in an individual, or a contributing factor in a patient who already has primary hypertension. A classication of secondary causes is shown in Table 1. Renal parenchymal disease, commonly termed chronic kidney disease (CKD), is the most common secondary cause, but urinary outlet obstruction should be considered. Renovascular disease occurs in young women as bromuscular dysplasia and in older individuals because of atherosclerotic renal artery stenosis. Endocrine causes include primary aldosteronism, pheochromocytoma,

E-mail address: taler.sandra@mayo.edu 0095-4543/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.001 primarycare.theclinics.com

490 Table 1 Causes of secondary hypertension Renal Renovascular

TALER

Endocrine

Other

Renal parenchymal disease Ureteral or bladder outlet obstruction Renovascular hypertension Fibromuscular dysplasia Atherosclerotic disease Aortic coarctation Primary aldosteronism Pheochromocytoma Cushings disease Hypo- or hyperthyroidism Hyperparathyroidism OSA

cortisol excess, and thyroid or parathyroid abnormalities. In the current obesity epidemic, obstructive sleep apnea (OSA) is an increasingly common problem and may comprise sympathetic nervous system activation [1] and a relative aldosterone excess state [2]. Secondary hypertension may cause drug resistance, which is related to increased severity of the blood pressure (BP) elevation or to the presence of underlying hormonal abnormalities. Although the reported prevalence is 5% to 18% in referral hypertension practices [35], the authors own experience suggests it may be more common, as noted in 31% of a group of 104 patients enrolled in a resistant hypertension treatment trial [6]. Further, reported prevalence rates vary widely depending on the extent of screening and the denitions used. Even with secondary hypertension, some individuals can be treated to goal BP levels using lifestyle changes and medication. For others, treatment of an identied secondary cause, even if feasible, does not resolve the hypertension. In most cases, unusual clinical features or resistance to eective therapy triggers the search for secondary hypertension. When making decisions regarding the extent of evaluation that is appropriate, the provider must consider the patients age, comorbidities, and long-term prognosis in addition to the ecacy of medical therapy; these are balanced against the risks for leaving the condition undetected and the risks for potentially invasive treatment. Here, the specic clinical questions to be answered may direct the extent of testing to be undertaken. Is the issue whether bromuscular renovascular disease is present and may be treated with endovascular intervention or whether bilateral atherosclerotic disease is present and threatening renal functional viability? Selection of testing may change considerably depending on the clinical question and the potential for modifying therapy as a result. If the risks for intervention are prohibitive, it is best to avoid the use of complex diagnostic procedures. A patients response to medical treatment and tolerance of that treatment must also be considered. Because recent trends in primary hypertension management emphasize lifestyle changes and early initiation of drug treatment with limited

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laboratory investigation [7], many patients begin antihypertensive therapies without specic testing to exclude secondary causes. If medical therapy fails, the provider should then go back and expand the diagnostic testing to consider the presence of a secondary cause. In this context, the most common indication for secondary evaluation becomes the failure to achieve BP targets using escalating numbers and doses of medication [8]. In older patients, a progressive decline in renal function should prompt reconsideration of a secondary cause. Declining renal function in an elderly patient presents a dicult dilemma in which it may be reasonable to pursue a more invasive evaluation in the hope of preventing the major morbidity of kidney failure. For the patient unable to tolerate multiple attempts at medical therapy, a secondary evaluation may also be appropriate. The overriding goal of additional testing is to evaluate and correct potential contributing causes, and thereby improve BP response to the prescribed antihypertensive medications, perhaps resulting in fewer in number and lower dosages. Although this discussion focuses on rare causes of hypertension that are potentially curable if properly identied and corrected, it is important to remember that most patients who have secondary hypertension do not attain complete resolution even if a cause is determined. Clinical clues for secondary causes Secondary hypertension is more likely when there are atypical features of the patients history, clues on physical examination, or unexpected laboratory ndings (Table 2). Although rare, these features suggest that a potentially curable form of hypertension may be present. The diagnosis of hypertension in a young person (younger than the age 30 years and especially without contributing features, such as obesity) merits a more aggressive evaluation, because the nancial and medical costs of drug treatment are substantial over his or her lifetime, even if BP is well controlled. In this setting, early diagnosis may provide an opportunity for cure that may be lost later as the hypertension persists over time. Other historical clues include a more severe or accelerated hypertension course and the absence of a family history of hypertension. Specic drug intolerances may be a clue to a secondary cause. The development of hypokalemia that is disproportionate in severity to that anticipated, or the need for large amounts of potassium supplementation to maintain normokalemia, suggests excessive aldosterone production, whether primary or secondary. The development of acute renal failure with the introduction or dose increase of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker suggests the presence of severe bilateral renal artery stenosis. Specic symptom constellations also merit further investigation. These include hypertensive spells and lability suggesting pheochromocytoma, urinary obstructive symptoms (obstructive uropathy), and snoring with daytime hypersomnolence (OSA). The rapid onset of pulmonary edema

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Table 2 Atypical features suggesting secondary hypertension Historical Early age of onset Severe or accelerated course Absent family history of hypertension Resistant hypertension Specic drug intolerances Marked hypokalemia while taking a diuretic medication Worsening hypertension after beta-blockade Acute renal failure after initiation or dose increase of ACEI, ARB Symptoms Spells, lability, orthostatism Prostatism Snoring, daytime hypersomnolence Flash pulmonary edema Physical examination signs Cafe au lait spots, neurobromas Cervical fat pad, moon facies, pigmented striae Thigh BP lower than brachial BP, continuous murmur over back Goiter or thyroid nodule Large neck, narrow pharynx with soft tissue crowding Abdominal systolic-diastolic bruit, multiple arterial bruits Large palpable kidneys Laboratory ndings Hyperkalemia Hypokalemia Elevated serum creatinine Abnormal urinalysis Loss or blunting of nocturnal BP decrease Disproportionate target organ damage (cerebral lacunar infarcts, hypertensive retinopathy, left ventricular hypertrophy, renal failure) Possible causes Any Any Any Any secondary secondary secondary secondary cause cause cause cause

Primary or secondary hyperaldosteronism, corticosteroid excess Pheochromocytoma Renovascular hypertension

Pheochromocytoma Urinary obstruction OSA Renovascular hypertension Pheochromocytoma Cushings disease Aortic coarctation Thyroid disease OSA Renovascular hypertension Polycystic kidney disease Renal parenchymal disease, urinary obstruction Renovascular hypertension, primary or secondary hyperaldosteronism Renal parenchymal disease, urinary obstruction, renovascular hypertension Renal parenchymal disease Any secondary cause Any secondary cause

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

(ash pulmonary edema) in a patient who has normal cardiac function may indicate tight bilateral renal artery stenoses. Physical ndings are infrequent and require additional studies to conrm a diagnosis. Still, the presence of these signs should point to the need for

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further evaluation of the associated conditions (see Table 2). An examination for secondary causes should include thorough skin, cardiovascular, thy roid, and oropharyngeal examinations. Specic features include cafe au lait spots or neurobromas (eg, pheochromocytoma, paraganglioma); moon facies; cervical fat pad and pigmented striae (Cushings disease); reduced thigh and, for some, left arm BP (aortic coarctation); redundant pharyngeal soft tissues with airway crowding and large shirt collar size (OSA); carotid or femoral bruits or an abdominal bruit (renovascular disease); and enlarged palpable kidneys (polycystic kidney disease). Laboratory abnormalities relate primarily to reduced or elevated serum potassium levels or to evidence for decreased renal function. Secondary hypertension is associated with disturbances in circadian BP rhythm by ambulatory blood pressure monitoring (ABPM), and thereby an increased risk for target organ damage [9]. The presence of target organ damage out of proportion to oce BP levels suggests nocturnal hypertension and a potential secondary cause. Diagnostic evaluation If secondary hypertension is suspected, one should begin with a general evaluation encompassing multiple causes and then focus on contributing mechanisms based on abnormal test results. Beyond the basic laboratory tests advised by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [7], preliminary testing should include a noninvasive imaging study of the kidneys and renal arteries, along with hormonal screening for excess aldosterone, cortisol, and catecholamine states. It is important to distinguish renal parenchymal disease from renovascular hypertension to direct further testing appropriately. Secondary hypertension is traditionally classied by organ system into renal causes, endocrine causes, and other causes, including OSA (see Table 1). Renal parenchymal disease is the most common cause of secondary hypertension. A basic classication of renal diseases is included in Table 3. Although full coverage of renal diseases and their treatment is beyond the scope of this review, it is essential that the clinician recognize major types of renal disease in order to initiate early treatment and appropriate referral. A recent movement to have clinical laboratories report an estimated glomerular ltration rate (eGFR) concurrent with serum creatinine measurements should assist practitioners in recognizing renal function impairment (CKD) earlier, initiating renal protective measures, and making earlier specialist referrals [10]. Hypertension may be a presenting sign of renal disease and may be severe, even before a decline in renal function is evident. Further, aggressive treatment of hypertension in this setting may delay progressive renal function decline. Diabetic nephropathy is now the most common cause of end-stage renal disease, aecting 50% of those with diabetes over time [11]. Further, it

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Table 3 Broad classication of kidney diseases and appropriate testing options Renal parenchymal disease Manifestations Glomerular diseases Hypertension, edema, hematuria, cellular casts, proteinuria Reduced renal function with or without urinary abnormalities (casts) Painful hematuria, urinary retention, overow incontinence Conrmatory testing Serologic testing, ultrasound, renal biopsy Serologic testing, ultrasound, renal biopsy Ultrasound, urodynamic studies, CT imaging for nephrolithiasis, urinary supersaturation testing Ultrasound, CT, MRI (see text for limitations), arteriography

Tubulointerstitial diseases

Collecting system injury, including obstruction

Vascular disease, arterial

Vascular disease, venous Renal mass or masses

Hypertension, often severe without urinary abnormalities, decline in renal function if late or bilateral Edema, proteinuria, nephrotic Ultrasound, CT, MRI (see text syndrome for limitations), venography Ultrasound, CT, MRI (see text Pain related to pressure from mass lesion, obstruction, for limitations), biopsy or resection incidental nding on imaging study, may be asymptomatic

carries risk for multiple medical comorbidities, especially cardiovascular disease. Other glomerular diseases may also present with hypertension and proteinuria. With slowly progressive renal diseases, including interstitial diseases, hypertension may occur later in the disease course related to reduced eciency of sodium and water handling. Parenchymal renal disease is characterized by elevated serum creatinine and, in some settings, active urinary sediment. Referral to a nephrologist for a renal biopsy may be necessary for denitive diagnosis. Renal outow tract obstruction attributable to prostatic obstruction, a mass lesion, or complications of prior surgery should also be excluded before moving to invasive vascular imaging. Renal ultrasound is a practical rst imaging study to visualize the renal parenchyma and the collecting system. Normal renal parenchymal imaging, the absence of hydronephrosis, and a negative urinary sediment test result suggest renal vascular disease; coupled with drug-resistant hypertension, this merits further vascular imaging. The choice of modality is currently limited to computed tomography angiography (CTA) requiring iodinated contrast or magnetic resonance angiography (MRA) using gadolinium, because most specialists would avoid the more invasive renal angiography unless other studies implicate signicant and treatable arterial stenosis. Current concerns regarding the risk for nephrogenic systemic brosis (NSF), a life-threatening sclerosis of the skin and connective tissues [12,13], have reversed prior selection algorithms to favor CTA in patients who have renal

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insuciency. This practice change further underscores the importance of careful consideration of the individual patient and the risk/benet ratio of further testing before proceeding down this path. Contrast agentinduced renal failure is uncommon and can be prevented in part by using preprocedural saline hydration and N-acetylcysteine [14]. For most patients, it is generally reversible if it occurs, whereas NSF is irreversible and may be fatal. Signicant renal vascular disease causing resistant hypertension or progressive renal dysfunction may respond well to renal revascularization, and for selected individuals, percutaneous or, less commonly, surgical intervention may salvage critical renal function [15]. Whether renal revascularization is a superior method for treatment of renovascular hypertension remains unproved, with large multicenter studies currently in progress [16,17]. Clinical features should guide the investigation of hormonal secondary causes. Primary hyperaldosteronism is increasingly recognized as a correctable cause for resistant hypertension; thus, screening should be considered early in the evaluation. Once regarded as rare, primary aldosteronism is reported in up to 20% of patients who have resistant hypertension [18,19]. In its classic form, primary aldosteronism refers to excess aldosterone secretion caused by an adrenal cortical adenoma. More commonly, no distinct adenoma is identiable, but there is diuse or nodular hyperplasia of both adrenal cortices. In this form, a positive relation between angiotensin II and aldosterone remains; however, it has a dierent set point, such that aldosterone is produced in relative excess [20]. Spontaneous hypokalemia, once considered a diagnostic requirement, is reported in approximately 30% of cases, likely those with greater severity. Most specialists begin with concurrent measurements of plasma aldosterone and plasma renin activity, preferably drawn in the morning when production is greater, although the sensitivity and specicity of this screen have not been well validated [21,22]. Using 0.5 ng/mL/h as the lowest threshold for renin measurement, an aldosterone-to-renin ratio (ARR) of greater than 20 is considered a positive screen for primary aldosterone excess but not sucient for diagnosis. The diagnosis is made by a 24-hour urine aldosterone level greater than 12 mg in the setting of salt loading, demonstrating inappropriate aldosterone production in a sodium-replete state. It is important to remember that a single positive ARR is not diagnostic, nor does a negative ARR exclude the diagnosis of primary aldosteronism, even in the setting of an aldosterone-producing adenoma. Adrenal imaging should be withheld unless inappropriate aldosterone production is conrmed. The detection of an adrenal mass lesion may not correlate with the overproducing adrenal gland, and adrenal vein sampling is needed to conrm laterality before adrenalectomy. An obese patient who has resistant hypertension may have a relative aldosterone excess but fall short of the classic criteria for primary aldosteronism. Chemokines in visceral fat may stimulate the renin angiotensin aldosterone system, particularly in patients who have concurrent sympathetic activation from untreated sleep apnea [2].

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Once a diagnosis of primary aldosteronism is conrmed, lateralizing aldosterone production supports the diagnosis of an independent aldosterone-producing adenoma. Bilateral adrenal hyperplasia should be treated medically with an aldosterone receptor antagonist, such as spironolactone or eplerenone. For patients intolerant to these agents, amiloride may be eective. Some specialists require successful response to an aldosterone receptor antagonist before adrenalectomy to ensure that the correct diagnosis has been made. Pheochromocytoma is rare but should be considered in patients who have marked BP lability, particularly those with orthostatic hypotension, tachycardia, or spells. Fractionated plasma metanephrines have the highest sensitivity (97%) and are ideal for evaluation of hereditary pheochromocytoma states [23]. The levels are unrelated to episodic catecholamine release or production of metabolites at sites remote from the tumor mass, which may be particularly useful in patients who have hereditary pheochromocytoma and lack clinical signs or symptoms or who may harbor small tumors that release lower levels of catecholamines. Lower specicity (85%) means a lower likelihood of actually having pheochromocytoma, particularly in settings in which the prevalence is low, as in the patient who has hypertension or an adrenal incidentaloma. For those with sporadic pheochromocytoma, which is more likely seen in clinical practice, sensitivities of plasma metanephrines or urinary measurements are comparable (96%), but the urinary measurements more specic [24]. Increasing age is associated with a greater likelihood of false-positive fractionated plasma metanephrine measurements. Thus, negative measurements of fractionated plasma metanephrines and 24-hour urinary total metanephrines with catecholamines are eective in ruling out the diagnosis of pheochromocytoma. For patients undergoing evaluation for sporadic pheochromocytoma, particularly older hypertensive patients, 24-hour urinary metanephrine and catecholamine measurements are preferred to the more convenient plasma metanephrine measurement so as to provide adequate sensitivity with a lower rate of false-positive results. Once a diagnosis is made, the patient should be referred to an experienced endocrinologist for alpha- and then beta-receptor blockade before resection of the lesion. All patients who have hypertension should be evaluated for thyroid disease (hyperthyroid and hypothyroid states), particularly if their BP is not controlled. Directed testing of the adrenal cortisol axis is usually reserved for patients with clinical evidence of cortisol excess (eg, central obesity, pigmented striae, hyperglycemia) or for those with an incidentally discovered adrenal mass. An overnight dexamethasone suppression test is used for screening and excludes cortisol excess if negative. Positive testing should result in referral to an endocrinologist for localization of the tumor and removal. Epidemiologic evidence supports a link between OSA and hypertension. Potential mechanisms whereby OSA may contribute to hypertension include

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sympathetic activation, hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and inammatory stress, endothelial dysfunction, impaired baroreex function, and eects on renal function. The Wisconsin Sleep Cohort Study demonstrated an independent doseresponse relation between sleep-disordered breathing at baseline and development of new hypertension 4 years later [25]. The odds ratio was graded with the severity of apneic frequency. In a recent case-control study of overweight or obese patients who had resistant hypertension, the diagnosis of OSA conveyed a 4.8-fold greater risk for resistant hypertension compared with body mass index (BMI)matched subjects with treated and controlled hypertension [26]. The prevalence of resistant hypertension was directly related to the intensity of OSA by the apnea-hypopnea index. Others have shown a correlation between plasma aldosterone concentration and OSA severity (apnea-hypopnea index) in subjects who have resistant hypertension but not in those who have OSA without resistant hypertension [27]. The diagnosis of OSA requires a high index of suspicion combined with direct questioning, a focused examination, and conrmatory testing. The key to detection is to consider the diagnosis in every patient but particularly in those who have obesity and resistant hypertension. Symptoms primarily relate to chronic fatigue with daytime hypersomnolence in permissive settings. The physical examination may suggest the diagnosis, with a narrow oropharyngeal opening on direct oral examination as a result of crowding by a large uvula, tonsillar enlargement, or other soft tissue redundancy, in addition to the classic nding of a large neck (shirt collar size in a man). OSA-induced hypoxemia and increased upper airway resistance trigger a stress response manifested by chronically elevated circulating catecholamine levels [1]. Characteristically, patients show mild elevations in plasma and urinary metanephrines or catecholamine levels, which are low enough not to suggest pheochromocytoma strongly but are higher than normal ranges. Treatment of sleep apnea with continuous positive airway pressure (CPAP) often corrects the endocrine abnormalities and dramatically improves the fatigue symptoms. Whether treatment of OSA with CPAP fully corrects the contribution to resistant hypertension is unclear [28,29]. Less common secondary causes may present with subtle ndings, and directed testing may be appropriate. At each step in the pathway, the clinician must decide whether the condition has been suciently excluded in the individual patient or whether more denitive testing is indicated. Such decisions should consider patient age, long-term prognosis, risks for leaving the condition undetected, risks for intervention, and adequacy of medical therapy. Role of ambulatory blood pressure monitoring As with the diagnosis of primary hypertension, misdiagnosis of resistant hypertension and estimates of severity may occur in the treated patient

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based on oce BP measurements. Oce or white coat hypertension may not extinguish with familiarity. Before embarking on a full evaluation for secondary causes, ABPM may be justied, using a 24-hour monitoring time [30] or an abbreviated method [31]. Analysis of nocturnal readings may be of particular utility in this setting, because several types of secondary hypertension are associated with absence or even reversal of the normal nocturnal BP decrease. A blunted or absent nocturnal BP decrease is characteristic of secondary forms, including renal parenchymal disease with reduced renal function, Cushings disease or posttransplant hypertension in the setting of exogenous corticosteroid use, OSA, renovascular hypertension, and primary aldosteronism [9]. The use of multiple home readings is increasingly favored as a more cost-eective modality but does not provide circadian or nocturnal information.

When to refer patients for more specialized consultation Decisions on referral depend largely on the comfort and experience of the treating practitioner. This article begins with a discussion directed to the level of the internist or subspecialist physician with expertise in the selection and use of multiple agents for the treatment of hypertension. Decisions regarding the extent of secondary evaluation require consideration of the likelihood of diagnosis, the patients overall health status and prognosis, and balancing the risks for intervention against the risks for missing a diagnosis. Referral is advised when these risks seem prohibitive, when there are questions regarding selection of the most optimal studies, or when there are questions about the extent of intervention to pursue when BP remains uncontrolled. Referral patterns vary with regional expertise. Resources include nephrologists (eg, renal parenchymal disease, renovascular hypertension, volume overload), pharmacists and pharmacologists (eg, drug interactions, regimen simplication, adherence), endocrinologists (eg, endocrine secondary causes, referral and interpretation of adrenal imaging, adrenal vein sampling), and sleep specialists for overnight polysomnography.

Summary The primary rationale for secondary hypertension evaluation is to achieve BP control more eectively and prevent morbidity and mortality related to the disease. Selection of patients for testing incorporates historical and clinical clues, previous treatment course, and comorbidities. Renal parenchymal disease, now termed CKD, is increasingly detected in an aging population. Renovascular disease is increasingly associated with impaired renal function and may not improve after high-risk interventions. Whether improvements in renal function may improve long-term survival merits

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further study. Although imperfect, the ARR has become the screening test of choice for primary aldosteronism. Prevalence rates of primary aldosteronism increase with severity of hypertension, and for many patients, aldosterone excess is attributable to bilateral adrenal hyperplasia. For these patients, the treatment is likely to be medical, incorporating an aldosterone receptor antagonist. The ideal test for pheochromocytoma depends on clinical suspicion and risk for hereditary disease. With the adoption of newer more sensitive assays, it is essential that the clinician understands their strengths and drawbacks. Plasma-free metanephrines are most sensitive and the best test for those at highest risk, as with hereditary pheochromocytoma. For sporadic pheochromocytoma, urinary metanephrines and fractionated catecholamines provide high sensitivity with fewer false-positive results. OSA is increasingly common in patients who have resistant hypertension and often remains unrecognized. Although treatment may improve cardiovascular prognosis, benets to BP control are uncertain.

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