OVERVIEW AND SCREENING
Hypertension related to a specific etiology is termed secondary hypertension, markedly differing from essential hypertension, of which the etiology cannot be identified, in the condition and therapeutic strategies. Secondary hypertension is often resistant hypertension, for which a target blood pressure is difficult to achieve by standard treatment. However, blood pressure can be effectively reduced by identifying its etiology and treating the condition. Therefore, it is important to suspect secondary hypertension and reach an appropriate diagnosis.
Frequent etiological factors for secondary hypertension include renal parenchymal hypertension, primary aldosteronism (PA), renovascular hypertension and sleep apnea syndrome. Renal parenchymal hypertension is caused by glomerular diseases, such as chronic glomerulonephritis and diabetic nephropathy, interstitial kidney diseases, such as chronic pyelonephritis, and polycystic kidney disease (PKD). Hypertension is observed in approximately 50–70% of patients with CKD.981 The incidence of hypertension increases with the degree of renal hypofunction. In patients with PA, an excessive production of aldosterone in the adrenal glands is involved in the pathogenesis of hypertension. As therapeutic strategies differ between unilateral and bilateral lesions, localized diagnosis is important. Concerning renovascular hypertension, renal artery stenosis-related hyperactivity of the renin–angiotensin (RA) system contributes to an increase in blood pressure. In patients with sleep apnea syndrome, various factors such as hyperactivity of the sympathetic nervous and RA systems cause hypertension, increasing blood pressure fluctuation. As other etiological factors for secondary hypertension, the following conditions have been reported: in endocrine hypertension, pheochromocytoma and Cushing's syndrome are related to an excessive production of catecholamines and cortisol, respectively. Hypo-/hyperthyroidism, hyperparathyroidism and acromegaly are also etiologically involved in hypertension. In vascular hypertension, angiitis syndrome, such as aortitis syndrome, polyarteritis nodosa (PN) and systemic scleroderma, aortic coarctation and aortic insufficiency have been reported. Compression of the rostral ventrolateral medulla by brainstem blood vessels causes hypertension through hyperactivity of the sympathetic nerves. Furthermore, hypertension is also observed in patients with brain tumors or cerebrovascular disease. In addition, hereditary or drug-induced hypertension has been reported.
It has been recognized that secondary hypertension accounts for ∼10% of hypertensive patients,982,983 but a study indicated that the incidence of PA was higher than previously reported; at least 10% of hypertensive patients may have secondary hypertension. As secondary hypertension is often resistant to treatment, the incidence of secondary hypertension in patients with a resistance-resistant hypertension may be higher. According to several studies, PA accounts for approximately 5–10% of hypertensive patients,984,985 and it is the most frequent in endocrine hypertension. In addition, frequent etiological factors for secondary hypertension include renal parenchymal hypertension and renovascular hypertension. A study reported that sleep apnea syndrome was the most frequent factor for secondary hypertension.517 The number of patients with secondary hypertension may further increase with the widespread diagnosis of sleep apnea syndrome.
Generally, the presence of severe or resistant hypertension, juvenile hypertension and the rapid onset of hypertension suggest the possibility of secondary hypertension. In such hypertensive patients, a close inquiry on medical history, medical examination and adequate examinations must be performed, considering the possibility of secondary hypertension. Table 13-1 shows findings suggestive of major types of secondary hypertension and tests necessary for their differential diagnosis. The possibility of secondary hypertension should be considered in the diagnosis and treatment of all hypertensive patients. It is important to conduct appropriate examinations without overlooking findings of secondary hypertension.
1. RENAL PARENCHYMAL HYPERTENSION
Renal parenchymal hypertension is caused by renal parenchymal disorders and is the most common form of secondary hypertension, accounting for 2–5% of all hypertensive patients.982,986–991 In the Hisayama Study, which followed up a general population aged over 40 years, autopsy was performed on 131 hypertensive patients during the 20 years after 1961, and the incidence of secondary hypertension was 3.8%. Renal parenchymal hypertension was observed in 3.1% of hypertensive patients, accounting for ∼80% of patients with secondary hypertension.991
The incidence of end-stage renal failure has increased despite advances in antihypertensive treatment, but has recently decreased slightly. In 38 613 patients in whom hemodialysis was initiated in 2011, the most frequent underlying disease was diabetic nephropathy (n=16 803, 44.3%), with chronic glomerulonephritis being the second most frequent (n=7670, 20.2%) and nephrosclerosis being the third (n=4475, 11.8%). Together with PKD, which was the fourth most frequent underlying disease (n=957, 2.5%), these four diseases accounted for ∼80%.992 Most of these chronic kidney diseases (CKDs) induce hypertension, but hypertension promotes the progression of kidney damage and establishes a vicious circle leading to end-stage renal failure.993,994 As there is no radical treatment for CKD at present, blood pressure control by antihypertensive drug therapy primarily using RA system inhibitors (angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors) is extremely important for the prevention of end-stage renal failure.995 In Japan, there are marked regional differences in the incidence of end-stage renal failure.996,997 As a negative correlation exists between its incidence and the prescribed amount of RA system inhibitors,998,999 RA system inhibitors may actually suppress the progression to renal failure. Recently, however, an increase in the incidence of renal failure has been more markedly inhibited in regions in which its incidence had been higher. The regional differences in the incidence of end-stage renal failure have almost disappeared.1000
As there is a close relationship between CKD and hypertension, it is often difficult to determine which came first, CKD or hypertension, if they are concurrent. If abnormal findings have been obtained on urinalysis, or renal dysfunction has appeared before hypertension, or if the presence of hypertension, proteinuria or renal dysfunction from an early phase of pregnancy (superimposed pre-eclampsia) can be confirmed, hypertension is likely to be caused by CKD. Also, if hypertension is mild relative to abnormal urinary findings or kidney damage, or if there are few hypertensive cardiovascular complications concurrent with the kidney disorders, CKD is considered to underlie the hypertension. Urinalysis and measurement of the serum creatinine concentration should be performed in all hypertensive patients, and, if an abnormality persists, kidney morphology must be evaluated using abdominal ultrasonography or CT.
As the prognosis of CKD, especially renal parenchymal disease, may be improved by early treatment, it is strongly recommended to promptly refer patients suspected of having renal parenchymal disorders to nephrologists.439 Hypertensive nephrosclerosis, which causes renal dysfunction on the basis of essential hypertension, and diabetic nephropathy are discussed in Section 3 of Chapter 6, KIDNEY DISEASE.
1) Chronic glomerulonephritis
Patients with chronic glomerulonephritis frequently develop hypertension from an early stage. Blood pressure is elevated further with the progression of renal dysfunction, and hypertension occurs in nearly all patients with end-stage renal failure.1001 Hypertension is observed more often in patients with marked tissue damage on kidney biopsy. It may be caused by body fluid expansion due to Na retention (increased salt sensitivity), inappropriate activation of the RA system and due to an involvement of the sympathetic nervous system.993,994,1002,1003
Therapeutic strategies for hypertension related to chronic glomerulonephritis should be basically determined in accordance with those for CKD complications (see Section 3 of Chapter 6, KIDNEY DISEASE).
2) Polycystic kidney disease
PKD is a disease in which a large number of cysts develop in the bilateral kidneys. Confirmation of the presence of many cysts in the bilateral kidneys by abdominal ultrasonography or CT is necessary for diagnosis.1004 The genes responsible for PKD are mostly autosomal dominant PKD1 (short arm of chromosome 16) and PKD2 (long arm of chromosome 4), and the disease is transmitted rarely by autosomal recessive inheritance. PKD1 accounts for 80–90% of the disease, with PKD2 accounting for the rest.1005 The number of patients treated for PKD at medical institutions accounts for 1 in 2000–4000 of the population.1006 The disease is progressive, and renal function reduces gradually, resulting in end-stage renal failure in about 40% of patients in their 50s.1006
Hypertension is observed in about 60% of patients at an early stage, when renal function remains normal,1001,1007 and it occurs in all patients with end-stage renal failure.1008 Cysts displace blood vessels, causing ischemia in local kidney tissues, and the resultant increases in renin section and sympathetic activity are involved in the genesis of hypertension.1009 Therapeutic strategies should be determined in accordance with those for CKD complications (see Section 3 of Chapter 6, KIDNEY DISEASE).
3) Ischemic nephropathy
Ischemic nephropathy is a disease in which atherosclerosis-based bilateral renal artery stenosis causes renal dysfunction. It is not necessarily a renal parenchymal disease in a narrow sense, but the condition resembles bilateral renovascular hypertension. Although its incidence is increasing in Europe and the United States,1010,1011 this disease name is absent in Japan, and this disease may be overlooked as nephrosclerosis. According to data, the incidence of end-stage renal failure associated with nephrosclerosis has steadily increased,992 possibly because the number of patients with ischemic nephropathy is increasing, as reported in foreign countries (for antihypertensive treatment, see Section 2 of Chapter 13, RENOVASCULAR HYPERTENSION).
2. RENOVASCULAR HYPERTENSION POINT 13a
Renovascular hypertension (RVHT) is hypertension caused by stenosis or obstruction of the renal artery and is observed in about 1% of all hypertensive patients. Its primary cause is atherosclerosis in middle-aged and elderly patients and fibromuscular dysplasia in younger patients. Atherosclerotic RVHT is often complicated by other vascular diseases such as peripheral and coronary artery diseases. Significant unilateral or bilateral renal artery stenosis and renal dysfunction cause progressive renal failure called ischemic nephropathy (Evidence level: II).
In patients with juvenile hypertension, severe or resistant hypertension, exacerbating hypertension, abdominal vascular bruit, a lateral difference in kidney size or deterioration of renal dysfunction after the administration of an RA system inhibitor, RVHT should be suspected (Recommendation: Grade C1, Evidence level: IVa).
A diagnosis of RVHT should be made on the basis of morphological evaluation involving diagnostic imaging. If necessary, functional assessment should be performed as an auxiliary procedure. Initially, renal artery ultrasonography, which is useful for morphological and functional screening, must be considered. In addition, magnetic resonance angiography (MRA) and CT angiography (CTA) should be considered in accordance with renal function (Recommendation Grade: C1, Evidence level: IVa).
RVHT treatment is started with antihypertensive drugs in many cases. Combination therapy with RA system inhibitors, Ca channel blockers, diuretics and β-blockers should be administered until a target blood pressure is achieved (Recommendation Grade C1, Evidence level: IVa).
The use of RA system inhibitors should be considered because they are useful for reducing blood pressure, maintaining renal function and improving the prognosis in patients with unilateral RVHT (Recommendation Grade C1, Evidence level: IVa).
In patients with bilateral RVHT, RA system inhibitors may rapidly induce renal dysfunction, and are contraindicated as a general rule (Recommendation Grade C2, Evidence level: IVa).
A combination of percutaneous transluminal renal angioplasty (PTRA) and antihypertensive drug therapy is useful for reducing blood pressure, but evidence regarding renoprotective effects is not sufficient. Although PTRA should be carefully indicated, it may be considered in accordance with individual patients (Recommendation Grade B, Evidence level: II).
However, in patients with fibromuscular dysplasia, potent hypotensive effects are achieved, and the long-term prognosis is relatively favorable. Therefore, PTRA should be performed (Recommendation Grade C1, Evidence level: IVa).
Renovascular hypertension is caused by stenosis or obstruction of the renal artery and is observed in about 1% of hypertensive patients. The most frequent cause of renal artery stenosis is atherosclerosis, which is common in middle-aged and elderly people, followed by fibromuscular dysplasia, which occurs more frequently in young people. Aortitis syndrome (Takayasu's arteritis), which frequently affects young women, is also rarely noted. RVHT may also be caused by congenital malformations, aortic dissection, compression of the renal artery by extrarenal masses and thromboembolism. Stenosis is either unilateral or bilateral. Atherosclerosis usually occurs at the origin of the renal artery, whereas fibromuscular dysplasia occurs more often in the middle to distal parts.1012
Atherosclerosis of the renal artery suggests advanced systemic arteriosclerosis and is often complicated by peripheral/coronary artery diseases, renal hypofunction and proteinuria. According to reports in Japan, 50% or greater stenosis of the renal artery was observed in 10% of patients who underwent coronary angiography, in 18% of hypertensive patients, in 25% of patients with peripheral artery disease, in 33% of those with abdominal aortic aneurysms1013 and in 27% of those with marked carotid stenosis.1014 Fibromuscular dysplasia has subtypes, such as intimal and medial thickening, and may be accompanied by other lesions of vascular stenosis. Aortitis syndrome is accompanied by findings of inflammation, stenosis or dilation of other large vessels, and lateral or vertical differences in blood pressure are often noted.
In many patients with renovascular hypertension, renal function is normal. On the other hand, hemodynamically significant unilateral or bilateral renal artery stenosis and renal dysfunction cause progressive renal failure called ischemic nephropathy. Ischemic nephropathy accounts for about 10% of underlying diseases of end-stage renal failure.1015
1) Diagnostic clues
Table 13-2 shows histories and clinical signs that suggest RVHT and ischemic nephropathy. However, these histories or signs are not observed in all patients.
2) Examinations for a definitive diagnosis
For the diagnosis of renovascular hypertension, it is necessary to demonstrate the presence of hypertension and involvement of renovascular stenosis as its etiological factor (Figure 13-1). Examinations include functional diagnosis based on plasma renin activity (PRA), renal scintigraphy findings (renograms) and captopril-loaded PRA and morphological diagnosis by renal artery ultrasonography, MRA and CTA.
Renal artery ultrasonography is inexpensive and noninvasive and facilitates a morphological and functional diagnosis. This procedure should be first considered due to its accuracy.1016 In particular, a high-level accuracy can be obtained using the peak systolic velocity as an index (sensitivity: 84–98%, specificity: 62–99%).1017,1018 However, this examination has limitations: obesity or intestinal gas makes it difficult to visualize the renal artery, and, when the unilateral renal artery consists of multiple vessels, its visualization is affected. Furthermore, this procedure depends on operators, and there are regional or facility-related differences in special technician skills.1019
MRA and CTA should be considered if renal artery ultrasonography is impossible or if the above screening does not reach a conclusion. If renal artery ultrasonography suggests stenosis, its presence should also be morphologically confirmed using MRA or CTA. Contrast-enhanced MRA is highly accurate,1020 but may cause renal systemic fibrosis; therefore, as a rule, it should be avoided in patients with an eGFR of <30 ml min−1 per 1.73 m2.1021 According to a recent study, the sensitivity and specificity of non-contrast-enhanced MRA without contrast medium have become similar to those of contrast-enhanced MRA,1022 and this procedure should be predominantly used. However, it must be considered that both the sensitivity and specificity markedly depend on devices and examiner skills. CTA is also highly accurate.1020 In particular, its spatial/temporal resolution is more favorable than that of MRA or arteriography, and clearer, high-quality images can be obtained. Contrast medium must be carefully used in accordance with renal function.1023 On the other hand, stenosis may be overestimated in the presence of calcified lesions on CT. On MRI, it is difficult to evaluate intra-stent stenosis due to metallic artifacts. If noninvasive examinations do not lead to a definitive diagnosis and whether or not indications for percutaneous angioplasty is examined, aortic angiography with a catheter or left and right selective renal arteriography should be finally considered. Although PRA can be simply measured, it is not high in some patients with bilateral renal artery stenosis.
Moreover, PRA is normal in 20–37% of patients with renovascular hypertension, and there is also an increase in PRA in some patients with essential hypertension.1024,1025 The sensitivity and specificity of captopril-loaded PRA and captopril-loaded renography are slightly lower than those of MRA and CTA.1020 On the other hand, captopril-loaded renography is useful for evaluating a split renal function and lateral difference in the renal blood flow. Currently, most international guidelines claim that the above functional diagnosis, which has been conducted, is not appropriate for screening in comparison with morphological diagnosis primarily using images; it should be used as an auxiliary procedure.1018
A diagnosis of renovascular hypertension is predicted on the basis of medical history, supported by laboratory data, and confirmed by imaging procedures. Considering the characteristics of individual patients and the facility's examination capacity, it is important to review the merits and limitations of morphological and functional diagnoses.
(1) Antihypertensive drug therapy
The treatment of renovascular hypertension is started with antihypertensive drugs in many cases. Several large-scale clinical studies compared antihypertensive drug therapy with a combination of antihypertensive drug therapy and PTRA, and indicated that the hypotensive and renoprotective effects of the former were similar to those of the later.
According to some studies, ACE inhibitors contributed to improvement in the prognosis and renal function in both the antihypertensive drug therapy and PTRA-combined groups in comparison with other antihypertensive drugs.1026,1027 A study reported that, in patients taking ACE inhibitors or ARBs, the risk of heart failure-related admission, that of dialysis introduction, and mortality rate were lower than in those taking other antihypertensive drugs.1028 In patients with unilateral renal artery stenosis-related hypertension, the use of RA system inhibitors should be considered. However, a study indicated that the use of these drugs increased the risk of acute renal failure-related admission.1028 As there is always a risk of the rapid progression of renal dysfunction or an excessive decrease in blood pressure in a specific percentage of patients, caution is needed for the use of RA system inhibitors.
In patients with bilateral renal artery stenosis, RA system inhibitors may induce the rapid exacerbation of renal function1029 and are contraindicated as a general rule. When using ARBs and ACE inhibitors, they should be started at a low dose, and the dose should be adjusted by paying attention to excessive decreases in blood pressure, hyperkalemia and renal function. If the renal function deteriorates rapidly, administration should be discontinued, and the drugs should be substituted for other antihypertensive agents. Combination therapy with Ca channel blockers, diuretics and β-blockers should be performed until a target blood pressure level is achieved.
(2) Vascular reconstruction
For vascular reconstruction, PTRA is initially considered because of its low-level invasiveness. In patients with fibromuscular dysplasia, the initial success rate of PTRA is high,1030 and PTRA may be a first-choice procedure unless it is technically difficult. The long-term prognosis of fibromuscular dysplasia after PTRA is also relatively favorable, but restenosis may occur.1031 On the other hand, in patients with atherosclerotic renal artery stenosis, the initial response rate to PTRA using a balloon alone was slightly low, and the restenosis rate was high; the results of treatment were not always satisfactory.1032 Since the introduction of a stent, the results of treatment have improved, with marked improvement in renal function and blood pressure.1033
The results of previous clinical studies have not demonstrated any marked difference between antihypertensive drug therapy alone and a combination of antihypertensive drug therapy and PTRA.1034–1039 In 2009, two large-scale randomized clinical trials (RCTs) were reported. The results of the two trials did not show any further prognosis improving the effects of PTRA in combination with antihypertensive drug therapy with respect to the hypotensive effects, renal function and prevention of complications such as chronic kidney disease, supporting antihypertensive drug therapy alone from the perspective of the risk of PTRA-related complications.1040,1041 These trials, however, had methodological limitations. The latest randomized trial (CORAL study) also failed to show a clear benefit for PTRA except for a slight improvement in blood pressure with stenting.1042 At present, PTRA may be considered for (I) patients with hemodynamically significant renal artery stenosis and <1> resistant hypertension in whom the target of blood pressure control is not achieved despite the use of three or more antihypertensive drugs including a diuretic, <2> exacerbating hypertension, <3> malignant hypertension, <4> hypertension with idiopathic unilateral kidney atrophy, <5> idiopathic pulmonary edema that suddenly develops, <6> repeated heart failure, <7> unstable angina or <8> fibromuscular dysplasia, as well as (II) patients with bilateral renal artery stenosis and (III) progressive chronic kidney disease patients with renal artery stenosis of a single kidney that functions.1018
In some patients in whom vascular reconstruction by PTRA is difficult or hypertension is resistant to drug therapy, surgery may also be an option. Several studies compared PTRA with surgery, and reported that the patency rate and prognosis in the surgery group were similar to or more favorable than those in the PTRA group,1043,1044 whereas another study indicated a high mortality rate.1045 Internationally, the number of patients for whom surgical procedures such as nephrectomy and bypass are indicated has decreased, and PTRA should be initially considered.
For antihypertensive drug therapy alone or a combination of antihypertensive drug therapy and PTRA, serial changes in the serum creatinine level, the kidney size on ultrasonography and peak systolic velocity must be carefully examined.
3. ENDOCRINE HYPERTENSION POINT 13b
As appropriate diagnosis and treatment of endocrine hypertension are essential, patients in whom endocrine hypertension is suspected should be referred without delay to the specialists of The Japanese Society of Hypertension and/or the Japan Endocrine Society (Recommendation Grade: B, Consensus).
The incidence of PA is high. The disease can be cured, but often causes organ damage. Early diagnosis and treatment are therefore important. In hypertensive patients, especially in those at a high risk of PA, screening should be positively performed, and a definitive diagnosis should be made based on the results of confirmatory tests and localization diagnosis (Recommendation Grade: B, Consensus, Evidence level: IVa).
For the diagnosis of Cushing's syndrome, attention should be paid first to characteristic physical findings, followed by measurement of blood cortisol and adrenocorticotropic hormone (ACTH) levels and the dexamethasone suppression test. In cases of adrenal incidentaloma, subclinical Cushing's syndrome should be differentiated (Recommendation Grade: B, Consensus, Evidence level: IVa).
Pheochromocytoma/paraganglioma should be suspected on the basis of symptoms such as headache and paroxysmal hypertension. Diagnosis should be made on the basis of the measurement of catecholamines and their metabolites and imaging examinations. As about 10% of pheochromocytomas/paragangliomas are malignant, follow-up should be carefully continued after initial surgery (Recommendation Grade: B, Consensus, Evidence level: IVa).
Characteristic physical findings are clues to the diagnosis of acromegaly, hyperthyroidism and hypothyroidism. Hypercalcemia suggests primary hyperparathyroidism (Evidence level: IVa).
Endocrine hypertension is a group of diseases in which hypertension is caused by excessive hormone secretion from the endocrine organs, represented by PA, Cushing's syndrome and pheochromocytoma. Although endocrine hypertension can be cured by the treatment of the primary disease, a delay in diagnosis is involved in the progression of target organ damage. Early diagnosis and treatment are therefore important. Patients in whom endocrine hypertension is suspected should be referred without delay to the specialists of The Japanese Society of Hypertension and/or the Japan Endocrine Society.
1) Primary aldosteronism
In typical PA patients, hypertension, hypokalemia and hypomagnesemia are observed. The major disease subtypes of PA are aldosterone-producing adenoma and idiopathic aldosteronism. The incidence of PA in hypertensive patients is reported to be ∼5% (1.6–11.2%)984,1046 and that in hypertensive patients with various complications is ∼20% (11.3–31%), being higher than previously estimated. As PA is often associated with target organ damage including the brain, cardiovascular system and kidneys,1047,1048 it is the most important cause of endocrine hypertension. Guidelines for PA treatment were also published by the Endocrine Society (USA)1049 and the Japan Endocrine Society.1050
(1) Diagnostic clues
A recent study indicated that many patients with PA showed normal K levels.1051 As PA is difficult to differentiate from essential hypertension, screening should be performed in all hypertensive patients. However, evidence regarding cost-effectiveness has not been established, and screening should be performed particularly in hypertensive patients at a high risk of PA. These patients include those with hypokalemia (including those with diuretic-induced hypokalemia), young patients with hypertension, patients with grade II or severer hypertension (7%),1052 those with resistant hypertension (11.3–20%),1053,1054 those with adrenal incidentaloma (4%)1055 and those, aged under 40 years, with cerebrovascular diseases (Table 13-3). A recent study reported that the incidence of PA was high in patients with sleep apnea syndrome.1056 Although extremely rare, screening for familial hyperaldosteronism should be performed, if there is a family history of PA. Even when there is a family history of hypertension, PA cannot be ruled out. A study reported that the urinary K/Na ratio increased in patients with PA.1057
(2) Screening tests
A plasma aldosterone concentration (PAC) to plasma renin activity (PRA) (or plasma active renin concentration:ARC) ratio (ARR)1058,1059 of >200 (PAC/ARC >40) is used for screening. However, considering that it is necessary to prevent false-positive findings evaluated on the basis of a low PRA alone, and that there are many PA patients with a PAC of <150 pg ml−1, patients with a PAC of >120 pg ml−1 are regarded as screening-positive. Values are influenced by conditions for blood collection, but, initially, measurement should be taken after sitting for 15–30 min. If a positive reaction is detected, an additional examination under stricter conditions (after fasting, early in the morning, after a 30-min rest)1060 or referral to specialists should be considered. As antihypertensive medication can cause a false-positive or false-negative result (Table 13-4), measurement is preferably taken in an untreated condition or after a 2-week medication-free period. If discontinuation is difficult due to the necessity of blood pressure control, measurement should be taken after switching the drugs to Ca channel blockers, α-blockers or hydralazine, which have less marked effects on the PRA or PAC. As spironolactone has marked effects, it should be withdrawn for 2 months or more. For blood pressure control, antihypertensive drugs should be discontinued or switched, considering their advantages and risks.1061 As a rule, evaluation is performed on a single session of measurement, but an additional examination should be conducted if necessary, considering changes related to various factors.1062 As PAC is expressed in pg ml−1 or ng dl−1, caution is needed.
(3) Confirmatory tests
If a positive reaction is detected on screening, it must be confirmed on at least one of the confirmatory tests presented in Table 13-5 to demonstrate the autonomous secretion of aldosterone.1063 The confirmatory tests should be performed after correcting hypokalemia using K preparations. Captopril challenge and oral salt-loading tests can be performed at the outpatient clinic. The furosemide-upright test is physically stressful. The saline infusion test has been reported to have excellent specificity, but requires a long duration; it is not appropriate for patients with heart/renal hypofunction. If the ARR and PAC are high (ARR >1000, PAC >250 pg ml−1), the confirmatory tests can be spared.1064
(4) Localization of the lesion site
In patients with positive reactions on confirmatory tests, the localization of the lesion site should be evaluated. Initially, adrenal CT (1- to 3-mm slices, contrast-enhanced CT) should be performed to investigate the presence or absence of a tumor. The tumor detection rate is higher than that of MRI. If a tumor is detected in the unilateral adrenal gland, aldosterone-producing adenoma should be suspected. However, the possibility that the tumor may be a nonfunctional lesion cannot be ruled out. Microadenoma measuring 5 mm or smaller, which cannot be confirmed on CT, has also been reported. 131I-adosterol adrenal scintigraphy should be performed under dexamethasone suppression, but the proportion of patients with positive reactions is low in those with microadenoma or nonfunctional lesions. When selecting surgery, it is necessary to accurately evaluate the localization of the lesion site, and adrenal venous sampling should be performed.1065,1066 The concomitant use of ACTH loading is useful for successfully achieving catheterization and evaluating the localization of the lesion site. On the other hand, this procedure is invasive, and has the following limitations: no localization-evaluating method (parameter, cutoff) has been standardized,1067,1068 and the success rate for the right adrenal vein is low, raising technical issues. Therefore, whether or not adrenal venous sampling is indicated should be determined, considering the presence or absence of indications for surgery and the patient's wishes. In addition, adrenal venous sampling is recommended to be performed in a skilled, special facility.1069,1070
In patients with unilateral lesions, laparoscopic adrenalectomy is a first-choice procedure. After surgery, improvement in hypertension, electrolyte abnormalities and organ damage is achieved. The postoperative blood pressure normalization rate depends on the duration and severity of hypertension and the presence or absence of essential hypertension. In patients with no indication or wish for surgery, those with bilateral lesions, or those before surgery, hypertension and hypokalemia must be treated using aldosterone antagonists and other antihypertensive drugs. The preoperative administration of an aldosterone antagonist reduces rapid postoperative changes in hemodynamics through the activation of the RA system, preventing electrolyte abnormalities and renal hypofunction.1071 Eplerenone less frequently causes adverse effects such as gynecomastia, compared with spironolactone.1072 However, this drug is contraindicated for diabetics with proteinuria and for patients taking K preparations. Ca channel blockers suppress aldosterone secretion. It remains to be clarified whether aldosterone antagonists are more useful than other antihypertensive drugs for improving the prognosis even in patients with normal serum K levels.
(6) Timing of referral to specialists
Figure 13-2 shows the procedure for the diagnosis of PA in clinical practice. In hypertensive patients, particularly those at a higher risk for PA, screening should be positively performed. If a positive reaction is detected, the patient must be referred to a specialist.
2) Other conditions associated with mineralocorticoid excess
Congenital adrenocortical hyperplasia (17α- and 11β-hydroxylase deficiency) and deoxycorticosterone (DOC)-producing tumors cause hypertension and hypokalemia. Usually, the PRA and aldosterone levels are low to normal.
3) Cushing's syndrome
Cushing's signs, hypertension and diabetes mellitus are caused by the autonomous and excessive secretion of cortisol. The disease conditions are classified into ACTH-dependent and ACTH-independent types. The former includes Cushing's syndrome due to adrenal adenoma, whereas the latter includes Cushing's disease due to ACTH-producing pituitary tumors and ectopic ACTH-producing tumors. Cardiovascular complications such as heart failure influence the prognosis.1073
(1) Diagnostic clues
Attention must be paid to central obesity, moon face, buffalo humps, red striae, skin thinning, polytrichosis and acne. Nonspecific findings include hypertension, diabetes mellitus, dyslipidemia, osteoporosis, urolithiasis and nail trichophytia. On general laboratory tests, considerable attention should be paid to eosinopenia and hypokalemia. Cushing's syndrome accounts for ∼8% of patients with adrenal incidentaloma.1074 Adrenal subclinical Cushing's syndrome does not show any characteristic physical findings. Therefore, a differential diagnosis should be carefully made if adrenal incidentaloma is detected.
Increases in the plasma and urinary free cortisol levels, the absence of cortisol suppression on the dexamethasone suppression test (overnight method) (cortisol after dexamethasone administration at 1 mg: >5 μg dl−1) and the disappearance of diurnal changes in the plasma cortisol level must be confirmed. Subsequently, whether the condition is dependent on or independent of ACTH must be differentiated through blood ACTH and corticotropin-releasing hormone challenge tests, and adrenal and pituitary lesions should be investigated using adrenal CT and pituitary MRI, respectively. Subclinical Cushing's syndrome should be diagnosed in accordance with the diagnostic criteria established by the Study Group of the Ministry of Health, Labour and Welfare.1075
First-choice procedures for adrenal adenoma, Cushing's disease and ectopic ACTH-producing tumors are laparoscopic adrenalectomy, trans-sphenoidal hypophysectomy and resection of the causative mass, respectively. If the tumor diameter is 4 cm or larger or there is a slight increase in its size in patients with subclinical Cushing's syndrome, resection should be performed, considering the possibility of malignancy. In subclinical Cushing's syndrome patients with hypertension, obesity or impaired glucose tolerance, surgery should also be considered.1076
(4) Timing of referral to specialists
If Cushing's signs, the concurrence of resistant hypertension and diabetes mellitus, or adrenal incidentaloma is detected, patients should be referred to specialists.
Adrenal medulla-derived pheochromocytoma and paraganglion-derived paraganglioma have been reported. These lesions are associated with hypertension and impaired glucose tolerance due to catecholamine excess. Extra-adrenal, bilateral, multiple and malignant pheochromocytoma accounts for ∼10% of cases, respectively. Diagnosis and treatment should be performed in accordance with the treatment guidelines established by the Study Group of the Ministry of Health, Labour and Welfare.1077 Malignant pheochromocytoma is the most important issue. Recently, various etiological gene mutations have been reported in patients with malignant pheochromocytoma/paraganglioma.1078
(1) Diagnostic clues
Symptoms including headache, palpitation, sweating and pallor, as well as paroxysmal hypertension, are suggestive of pheochromocytoma/paraganglioma. Hypertensive crisis is induced by exercise, stress or excretion. It may also be induced by intravenous metoclopramide injection. The disease may be found as adrenal incidentaloma.
Increases (threefold the upper limit of the normal range or greater) in the plasma catecholamine level, 24-h urinary catecholamine excretion and urinary excretions of its metabolites, metanephrine and normetanephrine, must be confirmed. Provocation (glucagon, metoclopramide) and phentolamine tests are not recommended because of problems with specificity and safety. The localization of the tumor is determined by CT. However, as the use of contrast medium is essentially contraindicated because of possible induction of hypertensive crisis, phentolamine and propranolol must be prepared if contrast enhancement is indicated. On MRI, a low signal intensity on T1-weighted and a high signal intensity on T2-weighted images are characteristic findings. If the localization of the tumor is unclear, the whole body should be scanned by iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy, whole-trunk CT and/or 18F-FDG-PET.
Resection of the tumor is the treatment of choice. For preoperative blood pressure management, correction of the circulating plasma volume and prevention of intraoperative crises, α1-blockers, such as doxazosin, should be administered. Beta-blockers are concomitantly used for the treatment of tachycardia and arrhythmia. However, the administration of β-blockers alone is contraindicated because it enhances α-actions. Malignant pheochromocytoma is the most important issue. As it is difficult to differentiate benign from malignant diseases based on histopathological findings, long-term postoperative follow-up is recommended. Pheochromocytoma crises should be treated by the intravenous injection or drip infusion of phentolamine, followed by the administration of α1-blockers.
(4) Timing of referral to specialists
If paroxysmal hypertension or adrenal tumors suggest pheochromocytoma/paraganglioma, patients should be referred to specialists.
5) Other endocrine hypertension
Hypertension is noted in about 40% of patients with acromegaly. The diagnosis is suggested by characteristic physical findings, including enlargement of the peripheral parts of limbs, and is established by high blood growth hormone and insulin-like growth factor-1 levels, the absence of growth hormone suppression on the 75-g oral glucose tolerance test, paradoxical responses on the thyroid-releasing hormone test and the presence of a pituitary tumor. Trans-sphenoidal hypophysectomy is the treatment of choice.
Systolic hypertension with an increased pulse pressure is characteristic. Palpitation, finger tremor, increased appetite, weight loss, goiter and exophthalmos suggest the disease. A diagnosis of hyperthyroidism is made by measuring the fT3, fT4, thyrotropin-releasing hormone and thyroid autoantibody (TSAb or TRAb) levels. The disease is treated by the administration of antithyroid drugs. Patients should be referred to specialists for the differentiation of the disease from other thyrotoxic disorders such as painless thyroiditis.
Hashimoto's disease is the major cause of hypothyroidism. Although the concomitant development of hypertension is known, hypothyroidism is rarely diagnosed due to hypertension. Nonspecific symptoms such as malaise, goiter and dyslipidemia are clues to the diagnosis. For treatment, Levothyroxine replacement therapy should be performed.
(4) Primary hyperparathyroidism
Hypertension is observed in about 20% of patients with primary hyperparathyroidism, but it rarely leads to diagnosis. Hypercalcemia and/or urolithiasis are clues to the diagnosis. Resection of the morbid parathyroid gland should be performed.
4. VASCULAR HYPERTENSION POINT 13c
Diseases that cause vascular hypertension include aortitis syndrome (Takayasu's arteritis), other forms of vasculitis syndrome (PN, progressive systemic scleroderma), aortic coarctation and diseases with an increase in cardiac output (aortic valve insufficiency, patent ductus arteriosus and arteriovenous fistula). Treatment should be performed in accordance with the condition of each disease for blood pressure control (Recommendation Grade: C1, Evidence level: IVa).
1) Aortitis syndrome (Takayasu's arteritis)
Aortitis syndrome (Takayasu's arteritis) refers to idiopathic, nonspecific large-vessel arteritis that induces obstructive or dilating lesions in the aorta, its major branches or pulmonary/coronary arteries.1079 In Japan, this disease is observed more frequently in women.1080 This disease is relatively rare, and sometimes requires a long period until a definitive diagnosis can be made. Therefore, common complaints on the initial consultation include vertigo, syncope, vision disorder, numbness of the hands and hypertension, which suggest the progression of vascular lesions. It is important to prevent the progression of vascular lesions by starting the administration of adrenocorticosteroids or immunosuppressive drugs early, for improving the patient's prognosis/QOL. Even when nonspecific symptoms such as fever and malaise are present, this disease should be considered. Its primary findings are lateralities in the pulse and blood pressure, neck or abdominal bruit and an enhanced carotid sinus reflex. An aortitis syndrome is an important etiological factor for secondary hypertension, and hypertension is observed in about 40% of patients with this disease, and markedly affects the prognosis of this disease.1081 In patients with bilateral subclavian artery stenosis, the upper limb blood pressure is lower than the aortic pressure, leading to underestimation. Advances in noninvasive diagnostic procedures such as diagnostic imaging and medical treatment have facilitated early therapeutic intervention. In patients who developed aortitis syndrome after 2000, the incidences of hypertension and aortic valve insufficiency have decreased.1082 The pathogenesis of hypertension in the presence of this disease varies: (1) renovascular hypertension, (2) hypertension due to aortic coarctation (atypical aortic coarctation), (3) hypertension due to aortic valve insufficiency and (4) hypertension due to aortic wall sclerosis.1079,1080
Renovascular hypertension is observed in about 20% of patients with aortitis syndrome.1083 Revascularization is indicated for aortic coarctation and RVHT when (1) antihypertensive drugs have become ineffective for the sufficient control of blood pressure, (2) antihypertensive treatment causes renal dysfunction, (3) congestive heart failure has occurred and (4) the renal artery has narrowed bilaterally.1079 PTRA for RVHT is mildly invasive and is performed as a first-choice procedure. Its postoperative hypotensive effects and decreases in the doses of antihypertensive drugs have been reported, but the long-term patency rate is lower than that after bypass.1084 Moreover, aortic valve insufficiency is an important complication that influences the prognosis of this disease; hence, under appropriate antihypertensive treatment, aortic valve replacement (including Bentall's operation) should be indicated in accordance with indication criteria for aortic valve insufficiency in general.1085
Surgical treatment for this disease should be performed after the complete resolution of active inflammation or control of inflammation with corticosteroids. Although the long-term prognosis of Japanese patients with this disease undergoing surgery is generally good, attention must be paid to the occurrence of anastomotic aneurysms and dilation of the rest of the ascending aorta.1086 Hypertension due to renal artery stenosis or aortic coarctation, congestive heart failure due to aortic valve insufficiency, coronary artery disease, dissecting aortic aneurysms and aortic aneurysm rupture are considered to be important clinical conditions that influence the prognosis. Therefore, early, appropriate medical treatment (steroid therapy, antihypertensive therapy) and appropriate surgery for severe cases may improve the long-term prognosis.1084
Antihypertensive treatment for this disease is basically the same as that for renovascular or essential hypertension. However, as cerebral blood flow may be reduced in patients with stenotic lesions in the carotid artery, sufficient evaluation and attention for the cerebral blood flow is necessary for conducting antihypertensive treatment.
2) Other forms of vasculitis
Vasculitis syndrome, other than aortitis syndrome, such as PN and progressive systemic scleroderma, contributes to hypertension.1087 Necrotic arteritis of systemic small- and medium-sized muscular arteries, including the renal artery in PN patients1088 and spasms of the renal vessels in PSS patients, is involved in the etiology of hypertension. PN is complicated by hypertension (⩾160/95 mm Hg) in about 30% of patients,1089 and some patients develop rapidly progressing nephritis. Patients with PSS often show renal crisis (malignant hypertension, renal failure). Other than PSS, causes of death in the acute phase are cerebral hemorrhage, myocardial infarction, heart failure and renal failure, all of which are closely related to the hypertension they complicate; therefore, the importance of blood pressure control must be recognized. For conditions other than PSS, steroid pulse and immunosuppressive therapies are performed in combination in the acute phase. The strategy for blood pressure control is the same as that for renal parenchymal or essential hypertension. In PSS patients, a treatment basically the same as that for malignant hypertension is indicated, and ACE inhibitors and Ca channel blockers are markedly effective.1090
3) Coarctation of the aorta
Coarctation of the aorta is suspected, based on vascular bruit ranging from precordium to back along the descending aorta, a reduction in lower-limb vascular pulsation and differences in blood pressure between the upper and lower limbs. In this condition, blood pressure is increased in the upper limb proximal to the site of stenosis and reduced in the lower limb distal to the site of stenosis, with a systolic blood pressure difference between the upper and lower limbs of 20–30 mm Hg or greater. In patients with this disease, the progression of systemic vascular remodeling,1092 RA/sympathetic nervous systems1093 and mechanical factors, such as an increase in the arterial reflection waves from the site of aortic coarctation,1091 an increase in the peripheral vascular resistance in the upper body and weakening of the Windkessel effect of the aorta, are involved in the etiology of hypertension. As a rule, the surgical relief of stenosis or angioplasty using a balloon catheter is indicated in childhood, and a better outcome has been reported on earlier treatment.1094 Postoperative recrudescence of hypertension is observed in ∼33% of patients,1095 and in this case antihypertensive treatment should be performed in accordance with the condition. Some studies suggest that not only an increase in blood pressure at rest but also that on ABPM or exercise loading is a prognostic factor for recrudescence of hypertension in the postoperative chronic phase.1096,1097
4) Vascular hypertension accompanied by an increase in cardiac output
In patients with aortic valve insufficiency, patent ductus arteriosus or arteriovenous fistula, systolic hypertension may be caused primarily by an increase in stroke volume. Antihypertensive treatment should be performed in accordance with individual conditions. However, radical treatment for the primary disease may reduce hypertension.
5. HYPERTENSION RELATED TO DISEASES OF THE BRAIN OR CENTRAL NERVOUS SYSTEM POINT 13d
In patients with hypertension related to an increase in intracranial pressure (Cushing's response) due to cerebrovascular disorders, brain tumors, encephalitis (myelitis) or brain injury, treatment for each cause should be performed first (Recommendation Grade: C1, Evidence level: VI).
Compression by arteries around the rostral ventrolateral medulla induces an increase in blood pressure through the enhancement of sympathetic activities (neurovascular compression syndrome). In patients with neurological symptoms, surgical decompression may also be considered (Recommendation Grade: C1, Evidence level: V).
Hypertension associated with stroke is described in detail in another chapter. In patients with central nervous diseases such as brain tumors (particularly those in the posterior cranial fossa), encephalitis (myelitis) and brain injury, sympathetic activities are increased through ischemia related to increased intracranial pressure at the brainstem, possibly causing hypertension (Cushing's response). Furthermore, the pathogenesis of neurovascular compression syndrome, in which compression of the rostral ventrolateral medulla, which is the vasomotor center of sympathetic activities, by surrounding arteries causes an increase in blood pressure or hypertension through the enhancement of sympathetic activities, and a surgical decompression-related decrease in blood pressure, was reported in the 1980s.1098
Thereafter, it was reported that this syndrome was an etiological factor for hypertension with the enhancement of sympathetic activities, and that it was related to blood pressure changes and the functional prognosis after the onset of ischemic stroke.1098–1102 In patients with neurological symptoms such as unilateral facial spasm and trigeminal neuralgia, surgical decompression should be considered. In Japan, four patients in whom decompression reduced blood pressure and sympathetic activities have also been reported.1103 On the other hand, neither the efficacy nor safety of decompression in patients without concomitant neurological symptoms has been established. In nonresponders to treatment with antihypertensive drugs, whether this procedure should be indicated must be carefully examined. As antihypertensive drugs, α-blockers, β-blockers and centrally acting sympatholytic drugs are effective from the perspective of their pressor mechanisms. RA system inhibitors and Ca channel blockers, especially drugs with sympatholytic actions, are useful.1104,1105
6. HEREDITARY HYPERTENSION POINT 13e
Essential hypertension is a multifactorial disorder in which genetic and environmental factors are involved. Approximately 30–70% of interindividual differences are influenced by genetic factors. For genetic factors, many common variants have been identified.
The influence of individual variants on blood pressure in the general population is not marked (∼1 mm Hg). Despite the potential racial diversity, salt sensitivity candidate gene variants are frequently observed in the Japanese population.
On the other hand, genetic variants that markedly influence blood pressure have also been reported, although they are rare.
Hereditary blood pressure abnormalities caused by single-gene disorder exist, but are rare.
Essential hypertension is a multifactorial disease in which many genetic and environmental factors are involved. The morbidity of hypertension is reported to be ∼3.5 times higher in pairs of hypertensive siblings than in the general population,1106 and the contribution of genetic factors is estimated to be approximately 30–70%.1107 Common interindividual variations in the nucleotide sequence of the genome observed in the general population are called ‘genetic polymorphisms or variants’, showing a wide range of frequency, from common to rare. Among the genetic factors, common variants have been identified through a genome-wide association study. However, the influence of individual common variants on blood pressure in the general population is only slight (∼1 mm Hg),1108 and it may be difficult to make a diagnosis of essential hypertension solely on the basis of information on these variants alone. In a genome-wide association study involving different racial groups, while some genetic factors have been identified across the populations, there should be marked racial differences in the frequency of variants and their influence on blood pressure.1109 In the Millennium Genome Project conducted in Japan, hypertension-associated gene loci such as ATP2B1 were identified.1110 In a large-scale meta-analysis of a genome-wide association study in East Asians, gene loci were comprehensively investigated/verified.1111 Furthermore, a study reported that the frequency of candidate gene polymorphisms for salt sensitivity was relatively high in the Japanese population.1112 Therefore, information on gene polymorphisms may be useful for recommending lifestyle modifications, including salt reduction,1113 and for selecting antihypertensive drugs.1114
On the other hand, among the genetic factors, some rare variants markedly influence blood pressure,1115 and diagnosis and treatment may be determined/changed primarily based on such variant information, although it is rare, in a group of individuals. In contrast, rare heritable blood pressure abnormalities caused by single-gene mutation and diagnosed by gene analysis have been reported.1116 In particular, many such blood pressure abnormalities result from gene mutations of ion channels or cotransporters regulating water and electrolyte balance at the renal tubular level. Recently, two genes causing Gordon syndrome1117 have been newly identified, and a gene causing type III familial aldosteronism1118 has also been clarified. Table 13-6 shows the genes responsible for and clinical characteristics of hereditary blood pressure abnormalities. In the setting of clinical practice, there may be few cases in which gene analysis is required. However, if patients with early-onset hypertension do not respond to treatment and have a low PRA value, an abnormal serum potassium level and acid–base balance disturbance, the possibility of hereditary hypertension must be considered. When suspecting hereditary hypertension based on family history or clinical characteristics and wishing to perform a detailed analysis, the attending physician should consult a specialist in hypertension, because analytical facilities differ depending on the gene abnormalities. In such cases, currently, the purpose of gene analysis is limited to research, and it is essential to conduct gene analyses in accordance with the Ethics Guidelines for Human Genome/Gene Analysis Research1119 from the timing of informed consent regarding blood collection.
7. DRUG-INDUCED HYPERTENSION POINT 13f
Nonsteroidal anti-inflammatory drugs (NSAIDs) raise the blood pressure and antagonize the antihypertensive effects of diuretics, β-blockers, ACE inhibitors and ARBs. Their effects tend to be more marked in elderly people (Evidence level: E-II).
The use of kampo drugs containing glycyrrhizin, a major active component of glycyrrhiza, drugs for liver/gastrointestinal diseases, or health foods may induce hypertension accompanied by hypokalemia (pseudoaldosteronism). Attention is necessary particularly when using kampo drugs. If there is an increase in blood pressure, the discontinuation of these drugs must be considered (Recommendation Grade: C2, Evidence level: VI). If the discontinuation of administration is difficult, an aldosterone antagonist should be used (Recommendation Grade: C1, Evidence level: V).
Massive therapy with glucocorticoids induces an increase in blood pressure. If their administration is unavoidable, Ca channel blockers, ACE inhibitors, ARBs, β-blockers, diuretics or aldosterone antagonists should be used (Recommendation Grade: C1, Evidence level: V).
The use of cyclosporine or tacrolimus may cause an increase in blood pressure. For antihypertensive treatment, Ca channel blockers, ACE inhibitors, ARBs or diuretics should be used (Recommendation Grade: C1, Evidence level: V).
The use of erythropoietin, estrogen or drugs with sympathomimetic actions may cause an increase in blood pressure. If blood pressure increases during the use of these drugs, a reduction in the dose or discontinuation of administration should be considered (Recommendation Grade: C2, Evidence level: VI). If they cannot be discontinued, Ca channel blockers, ACE inhibitors, ARBs or α-blockers should be used (Recommendation Grade: C1, Evidence level: V).
Molecule-targeting drugs, primarily anti-VEGF antibody preparations, induce hypertension. Its incidence depends on the type of drug or tumor. However, when using these drugs, changes in blood pressure must be monitored. Treatment with routine antihypertensive drugs should be performed (Recommendation Grade: C1, Evidence level: V).
Drugs such as NSAIDs, glycyrrhizin preparations, glucocorticoids, cyclosporine, erythropoietin, oral contraceptives and sympathomimetic drugs are suggested to have hypertensive effects, to induce hypertension and attenuate the blood pressure-lowering effects of antihypertensive drugs if used concomitantly. Recently, hypertension induced by molecule-targeting drugs has been reported (Table 13-7). Many hypertensive patients also have other diseases and consult multiple medical organizations. Therefore, if the blood pressure management used to be adequate but has become difficult, or in cases of poorly controlled hypertension, the possibility of drug-induced hypertension should be considered. Also, if these drugs are used, attention must be paid to blood pressure control, and their administration simply as routine must be avoided.
1) Nonsteroidal anti-inflammatory drugs
NSAIDs cause water and Na retention and suppress vasodilation by inhibiting cyclooxygenase (COX) in the process of prostaglandin production from arachidonic acid in the kidney.1120 In elderly patients and patients with renal dysfunction, renal prostaglandins maintain the renal function as a compensatory mechanism and contribute to the prevention of an increase in blood pressure. However, NSAIDs inhibit prostaglandin production and increase blood pressure by suppressing the renal function. COX has two isoforms, COX-1 and COX-2, which is induced in the presence of inflammation. Although classic NSAIDs nonselectively inhibit both, there are also selective inhibitors of COX-2. The harmful effects of nonselective and selective COX-2 inhibitors on the cardiovascular system are related to the suppression ratio between COX-1 and COX-2 and tissue-specific COX distribution, rather than the selectivity. Therefore, similar caution is necessary when using NSAIDs that are nonselective as well as for selective COX-2 inhibitors.1121–1123
In elderly people, NSAIDs often cause acute renal dysfunction, which further aggravates the rise in blood pressure, and they also increase the risk of heart failure if used concomitantly with diuretics compared with diuretics alone. Therefore, if NSAIDs are administered to elderly hypertensive patients, they should be used at a low dose for a limited period with careful observation and examination of the renal function. If renal hypofunction is observed and the drug cannot be discontinued, switching to acetaminophen should be considered.
Diuretics simultaneously inhibit the reabsorption of NaCl and stimulate prostacyclin production in the renal tubules. Therefore, the antihypertensive effects of diuretics are reduced when they are used with NSAIDs. The antihypertensive effects of ACE inhibitors and β-blockers are also reduced by their concomitant use with NSAIDs. The effects of their concomitant use with ARBs have not been evaluated sufficiently, but ARBs appear to be affected similarly as ACE inhibitors.1124 The effects of NSAIDs on the antihypertensive effects of Ca channel blockers are considered to be minor.
2) Glycyrrhiza (licorice), glycyrrhizin
Glycyrrhiza is contained in drugs for liver and gastrointestinal diseases, in many other kampo drugs, in supplements and in cosmetics. Glycyrrhizin, a major active component of glycyrrhiza, inhibits 11β-hydroxylated steroid dehydrogenase, which metabolizes cortisol into inactive cortisone, enhances the actions of endogenous steroids by prolonging the half-life of cortisol1125 and enhances Na and water retention and reduces the potassium level, causing pseudoaldosteronism. The glycyrrhizin dose, administration period and age (⩾60 years) are considered to be risk factors for glycyrrhizin-induced hypertension.1126 Glycyrrhizin-induced hypertension should be suspected if hypokalemia is concurrent with hypertension, and if the renin activity and plasma aldosterone level are reduced (pseudoaldosteronism). As the use of kampo drugs or supplements is rarely reported by patients themselves, the possibility of their use must be carefully evaluated. Clinically, glycyrrhizin-induced hypertension is resolved by the withdrawal of glycyrrhiza for a few weeks (maximum: 4 months) or by concomitant administration of an anti-aldosterone drug.
Glucocorticoids rarely cause hypertension at low doses even in the long-term treatment of asthma or rheumatoid arthritis. However, the long-term administration of glucocorticoids at intermediate doses frequently induces hypertension.1127 As with other drugs, blood pressure increased more notably in elderly patients with increases in the dose of prednisolone, and marked increases were observed when the dose was 20 mg per day or higher. Hypertension was observed in 37.1% of these elderly patients, and hypertensive patients more often had a familial history of hypertension compared with nonhypertensives.1128 The mechanism of a glucocorticoid-induced increase in blood pressure remains to be clarified, although an increase in the angiotensin II level due to elevated renin substrate production,1129 vasoconstriction due to an increase in erythropoietin production,1130 vascular endothelial dysfunction through impairment of nitric oxide (NO) use related to the inhibition of NO production1131 or excess production of superoxides,1132 and stimulation of mineral corticoid receptors have been suggested.
Treatment is primarily a decrease in dose or withdrawal of the glucocorticoid. If this is difficult, blood pressure should be controlled with Ca channel blockers, ACE inhibitors, ARBs, β-blockers, diuretics or aldosterone antagonists.
Cyclosporine and tacrolimus are used for immunosuppression after organ or bone marrow transplantation. Both of them frequently cause hypertension, although frequency varies with dose, treatment period and pathological conditions. Although the mechanism of the occurrence of hypertension has not been sufficiently clarified, the involvement of nephrotoxicity,1133 stimulation of the sympathetic nervous system,1134 inhibition of calcineurin1135 and vascular endothelial cell dysfunction1136 are suspected. Ca channel blockers are effective in the treatment of hypertension due to immunosuppressants, and their combination with ACE inhibitors has been reported to be even more effective.1137 Although diuretics are also effective, caution regarding uric acid metabolism is necessary in patients after kidney transplantation. As Ca channel blockers may increase the blood concentrations of cyclosporine and tacrolimus, measurement of the blood concentrations of these immunosuppressants should be considered if necessary.
Although erythropoietin alleviates renal anemia, it increases the blood pressure. In Japan, an increase in blood pressure was reported in 29% of patients surveyed in postmarketing research.1138 Its possible mechanism involves increases in the hematocrit and blood viscosity associated with recovery from anemia by erythropoietin treatment and a resultant increase in peripheral vascular resistance, but this possibility has been refuted by one report.1139 An increase in the intracellular Na concentration,1140 vascular endothelial dysfunction1141 and genetic predispositions1142 may also be involved. There is also a report that no increase in blood pressure due to erythropoietin was observed before hemodialysis.1143 The dose of erythropoietin should be reduced or administration should be discontinued if hypertension develops or if blood pressure increases. However, if the increase is mild, antihypertensive drugs are also useful.1144 On the other hand, a study indicated that blood pressure control was insufficient despite the administration of antihypertensive drugs in chronic dialysis patients (patients registered at the Japanese Society for Dialysis Therapy), of whom 82% were taking erythropoietin.722
Estrogen is used as an oral contraceptive and drug for climacteric disturbance, but has been considered to cause an increase in blood pressure or thromboembolism at a high dose. The details of the mechanism of estrogen-induced hypertension have not been clarified, although an increased renin substrate production in the liver has been proposed. An investigation of the relationship between the use of oral contraceptives and health showed that, although the blood pressure and lipid levels in users were slightly higher than in age-matched nonusers, the former's satisfaction with health and QOL was more favorable, suggesting the safety of oral contraceptives.1145 Although the rate of increase in blood pressure was dose-dependent, caution is necessary even at a low dose. A sufficient analysis of the relationship between oral contraceptives and hypertension has not been made in Japan. When using oral contraceptives, blood pressure should be measured periodically, their use should be discontinued if an increase in blood pressure is observed and other contraceptive measures should be selected. If they cannot be discontinued, the administration of ACE inhibitors or ARBs should be considered. Concerning hormone replacement therapy, see Section 2 of Chapter 10, POSTMENOPAUSAL BLOOD PRESSURE.
Drugs with sympathomimetic actions may increase the blood pressure. An overdose of phenylpropanolamine, which is contained in drugs for the common cold, may increase the blood pressure. Caution is needed in its concomitant use during treatment with a β-blocker alone, because it may induce a state of dominant α-receptor stimulation and cause a marked increase in blood pressure. Tri- or tetracyclic antidepressants may also inhibit the antihypertensive effects of peripheral sympatholytic drugs by inhibiting catecholamine reuptake at the sympathetic nerve terminals and induce hypertensive crisis1146 or hypertensive emergencies.1147 Monoamine oxidase inhibitors, which are used for the treatment of Parkinson's disease, also cause an increase in blood pressure or orthostatic dysregulation.
A monoamine oxidase inhibitor and a tricyclic antidepressant must not be used simultaneously. The concomitant use of a monoamine oxidase inhibitor with ephedrine or methylephedrine may also cause an elevation in blood pressure and tachycardia. If hypertension is induced by these drugs, a reduction in the dose or discontinuation of administration is necessary, but if discontinuation is impossible α-blockers or central sympatholytic agents should be administered.
As metoclopramide, a dopamine (D2) receptor antagonist used for the treatment of gastrointestinal disorders, β-blockers and tricyclic antidepressants may cause clinical activation of pheochromocytoma as well as hypertensive crisis,1148 caution is needed in their use.
Molecule-targeting drugs inhibiting angiogenesis, which are used for the treatment of malignant tumors or age-related macular degeneration, primarily anti-VEGF antibody preparations, may cause hypertension, myocardial infarction and cerebral infarction.1149,1150 The incidence of hypertension is reportedly approximately from 2–3% to 90%, although it depends on the type of drug or tumor and race. The pathogenesis of hypertension remains to be clarified, but an increase in peripheral vascular resistance associated with a decrease in the microvascular floor or a VEGF inhibition-related reduction in NO production, as well as renal dysfunction, is suggested.1151,1152 If hypertension is present before the start of treatment with anti-VEGF antibody preparations, strict blood pressure control should be performed. If hypertension develops, a reduction in the dose of the drug or discontinuation must be considered, and treatment with standard antihypertensive drugs should be conducted.1152
We recommend that any citations to information in the Guidelines are presented in the following format:
The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res 2014; 37: 253–392.
Please refer to the title page for the full list of authors.
Pickering TG, Eguchi K, Kario K . Masked hypertension: a review . Hypertens Res 2007 ; 30 : 479 – 488 . VI
Japanese Society of Nephrology . Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease 2012 (in Japanese) . Japanese Society of Nephrology: Tokyo, 2012 . GL
Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, Amodeo C, Bortolotto LA, Krieger EM, Bradley TD, Lorenzi-Filho G . Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension . Hypertension 2011 ; 58 : 811 – 817 . IVb
Iseki K, Nakai S, Shinzato T, Morita O, Shinoda T, Kikuchi K, Wada A, Kimata N, Akiba T . Prevalence and determinants of hypertension in chronic hemodialysis patients in Japan . Ther Apher Dial 2007 ; 11 : 183 – 188 . E-II
Whaley-Connell AT, Sowers JR, Stevens LA, McFarlane SI, Shlipak MG, Norris KC, Chen SC, Qiu Y, Wang C, Li S, Vassalotti JA, Collins AJ Kidney Early Evaluation Program Investigators . CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999–2004 . Am J Kidney Dis 2008 ; 51 : S13 – S20 . IVb
Sinclair AM, Isles CG, Brown I, Cameron H, Murray GD, Robertson JW . Secondary hypertension in a blood pressure clinic . Arch Intern Med 1987 ; 147 : 1289 – 1293 . IVb
Anderson Jr GH, Blakeman N, Streeten DH . The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients . J Hypertens 1994 ; 12 : 609 – 615 . IVb
Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F PAPY Study Investigators . A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients . J Am Coll Cardiol 2006 ; 48 : 2293 – 2300 . IVb
Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T . Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan . Hypertens Res 2004 ; 27 : 193 – 202 . IVb
Gifford RW . Evaluation of the hypertensive patients with emphasis on detecting curable causes . Milbank Mem Fund Q 1969 ; 47 : 170 – 186 . V
Bech K, Hilden T . The frequency of secondary hypertension . Acta Med Scand 1975 ; 197 : 65 – 69 . IVb
Ferguson RK . Cost and yield of the hypertensive evaluation. Experience of a community-based referral clinic . Ann Intern Med 1975 ; 82 : 761 – 765 . V
Berglund G, Andersson O, Wilhelmsen L . Prevalence of primary and secondary hypertension: studies in a random population sample . Br Med J 1976 ; 2 : 554 – 556 . E-II
Danielson M, Dammström B . The prevalence of secondary and curable hypertension . Acta Med Scand 1981 ; 209 : 451 – 455 . E-II
Omae T . Pathogenesis and prognosis of hypertension . J Jpn Soc Intern Med 1985 ; 74 : 401 – 405 . Japanese. VI
Japan Dialysis Medical Science Association Statistics Investigation Committee . An overview of regular dialysis treatment in Japan . J Jpn Soc Dial Ther 2013 ; 46 : 1 – 76 . Japanese. E-II
Kimura G, Brenner BM . The renal basis for salt sensitivity in hypertension . In: Laragh JH, Brenner BM (eds), Hypertension: Pathophysiology, Diagnosis and Management 2nd edn. pp 1569 – 1588 Raven Press: New York, 1995 . VI
Kimura G . Glomerular function reserve and sodium sensitivity . Clin Exp Nephrol 2005 ; 9 : 102 – 113 . VI
Kimura G . Clinical pathology and treatment of renin–angiotensin system 2. Chronic kidney disease and the renin–angiotensin system . Intern Med 2007 ; 46 : 1295 – 1298 . VI
Usami T, Koyama K, Takeuchi O, Morozumi K, Kimura G . Regional variations in the incidence of end-stage renal failure in Japan . JAMA 2000 ; 284 : 2622 – 2624 . E-III
Usami T, Sato R, Yoshida A, Kimura G . Regional variation in end-stage renal disease . Curr Opin Nephrol Hypertens 2002 ; 11 : 343 – 346 . VI
Usami T, Nakao N, Fukuda M, Takeuchi O, Kamiya Y, Yoshida A, Kimura G . Maps of end-stage renal disease and amounts of angiotensin-converting enzyme inhibitors prescribed in Japan . Kidney Int 2003 ; 64 : 1445 – 1449 . E-II
Usami T, Kimura G . Proposal for mapping renal failure in Japan and its application for strategy to arrest endstage renal disease . Clin Exp Nephrol 2006 ; 10 : 8 – 12 . VI
Wakamatsu-Yamanaka T, Fukuda M, Sato R, Naito T, Togawa H, Tomonari T, Kato Y, Miura T, Mizuno M, Ichikawa T, Miyagi S, Shirasawa Y, Ito A, Yoshida A, Kimura G . Geographic differences in the increasing ESRD rate have disappeared in Japan . Clin Exp Nephrol 2011 ; 15 : 708 – 713 . E-III
Blythe WB . Natural history of hypertension in renal parenchymal disease . Am J Kidney Dis 1985 ; 5 : A50 – A56 . VI
Konishi Y, Imanishi M, Okamura M, Yoshioka K, Okumura M, Okada N, Tanaka S, Fujii S, Kimura G . Relationship of renal histological damage to glomerular hypertension in patients with immunoglobulin A nephropathy . J Hypertens 2000 ; 18 : 103 – 109 . E-II
Preston RA, Singer I, Epstein M . Renal Parenchymal Hypertension: current concepts of pathogenesis and management . Arch Intern Med 1996 ; 156 : 602 – 611 . VI
Progressive Kidney Damage Study Group (Chairman: Tomino Y, Director of the Multiple Cystic Kidney Working Group: Higashihara E), Research Business for Specific Disease Control, Ministry of Health, Labour and Welfare . Guidelines for the Treatment of Autosomal Dominant Multiple Cystic Kidney (2nd version)] . In: Higashihara E (ed), Multiple cystic kidney . Intermedica: Tokyo, 2006 . pp 294 – 313 . Japanese. GL
Mizoguchi M, Tamura T, Yamaki A, Higashihara E, Shimizu Y . Genotypes of autosomal dominant polycystic kidney disease in Japanese . J Hum Genet 2002 ; 47 : 51 – 54 . E-II
Higashihara E, Nutahara K, Kojima M, Tamakoshi A, Yoshiyuki O, Sakai H, Kurokawa K . Prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease in Japan . Nephron 1998 ; 80 : 421 – 427 . E-II
Higashihara E, Aso Y, Shimazaki J, Ito H, Koiso K, Sakai O . Clinical aspects of polycystic kidney disease . J Urol 1992 ; 147 : 329 – 332 . E-II
Kelleher CL, McFann KK, Johnson AM, Schrier RW . Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population . Am J Hypertens 2004 ; 17 : 1029 – 1034 . E-II
Chapman AB, Johnson A, Gabow PA, Schrier RW . The renin–angiotensin-aldosterone system and autosomal dominant polycystic kidney disease . New Engl J Med 1990 ; 323 : 1091 – 1096 . E-II
Gansevoort RT, van der Heij B, Stegeman CA, de Charro FT, Nieuwenhuizen MG, de Zeeuw D, de Jong PE . Trends in the incidence of treated end-stage renal failure in The Netherlands: hope for the future? Kidney Int Suppl 2004 ; S7 – S10
Sørensen VR, Hansen PM, Heaf J, Feldt-Rasmussen B . Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark . Kidney Int 2006 ; 70 : 187 – 191 . E-II
Safian RD, Textor SC . Renal-artery stenosis . New Engl J Med 2001 ; 344 : 431 – 442 . VI
de Mast Q, Beutler JJ . The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review . J Hypertens 2009 ; 27 : 1333 – 1340 . I
Nakamura S, Iihara K, Matayoshi T, Yasuda H, Yoshihara F, Kamide K, Horio T, Miyamoto S, Kawano Y . The incidence and risk factors of renal artery stenosis in patients with severe carotid artery stenosis . Hypertens Res 2007 ; 30 : 839 – 844 . IVb
Preston RA, Epstein M . Ischemic renal disease: an emerging cause of chronic renal failure and end-stage renal disease . J Hypertens 1997 ; 15 : 1365 – 1377 . VI
Olin JW, Piedmonte MR, Young JR, DeAnna S, Grubb M, Childs MB . The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis . Ann Intern Med 1995 ; 122 : 833 – 838 . IVb
Williams GJ, Macaskill P, Chan SF, Karplus TE, Yung W, Hodson EM, Craig JC . Comparative accuracy of renal duplex sonographic parameters in the diagnosis of renal artery stenosis: paired and unpaired analysis . AJR Am J Roentgenol 2007 ; 188 : 798 – 811 . IVa
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor Jr LM, White CJ, White J, White RA, Antman EM, Smith Jr SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B, American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease, American Association of Cardiovascular and Pulmonary Rehabilitation, National Heart, Lung, and Blood Institute, Society for Vascular Nursing, TransAtlantic Inter-Society Consensus, Vascular Disease Foundation . ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation . Circulation 2006 ; 113 : e463 – e654 . GL
Postma CT, van Aalen J, de Boo T, Rosenbusch G, Thien T . Doppler ultrasound scanning in the detection of renal artery stenosis in hypertensive patients . Br J Radiol 1992 ; 65 : 857 – 860 . IVb
Vasbinder GB, Nelemans PJ, Kessels AG, Kroon AA, de Leeuw PW, van Engelshoven JM . Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: a meta-analysis . Ann Intern Med 2001 ; 135 : 401 – 411 . IVa
Joint committee for NSF and use of gadolinium-based contrast agents (Japan Radiological Society/Japanese Society of Nephrology) . Guidelines for Administering Gadolinium-Based Contrast Agents to Patients with Renal Dysfunction : Second edition (in Japanese) . Tokyo Igakusha: Tokyo. 2009 . GL
Khoo MM, Deeab D, Gedroyc WM, Duncan N, Taube D, Dick EA . Renal artery stenosis: comparative assessment by unenhanced renal artery MRA versus contrast-enhanced MRA . Eur Radiol 2011 ; 21 : 1470 – 1476 . IVb
Japanese Society of Nephrology/Japan Radiological Society/The Japanese Circulation Society . Guidelines for iodinated contrast in patient with CKD 2012 . Tokyo Igakusha: Tokyo 2012 . Japanese, GL
Wilcox CS . Use of angiotensin-converting-enzyme inhibitors for diagnosing renovascular hypertension . Kidney Int 1993 ; 44 : 1379 – 1390 . IVb
Rossi GP, Pavan E, Chiesura-Corona M, Bader M, Paganini G, Cesari M, De Toni R, Feltrin GP, Ganten D, Pessina AC . Renovascular hypertension with low-to-normal plasma renin: clinical and angiographic features . Clin Sci (Lond) 1997 ; 93 : 435 – 443 . E-II
Hackam DG, Spence JD, Garg AX, Textor SC . Role of renin–angiotensin system blockade in atherosclerotic renal artery stenosis and renovascular hypertension . Hypertension 2007 ; 50 : 998 – 1003 . VI
Losito A, Errico R, Santirosi P, Lupattelli T, Scalera GB, Lupattelli L . Long-term follow-up of atherosclerotic renovascular disease. Beneficial effect of ACE inhibition . Nephrol Dial Transplant 2005 ; 20 : 1604 – 1609 . IVa
Hackam DG, Duong-Hua ML, Mamdani M, Li P, Tobe SW, Spence JD, Garg AX . Angiotensin inhibition in renovascular disease: a population-based cohort study . Am Heart J 2008 ; 156 : 549 – 555 . IVa
van de Ven PJ, Beutler JJ, Kaatee R, Beek FJ, Mali WP, Koomans HA . Angiotensin converting enzyme inhibitor-induced renal dysfunction in atherosclerotic renovascular disease . Kidney Int 1998 ; 53 : 986 – 993 . E-II
Tegtmeyer CJ, Selby JB, Hartwell GD, Ayers C, Tegtmeyer V . Results and complications of angioplasty in fibromuscular disease . Circulation 1991 ; 83 : I155 – I161 . E-III
Alhadad A, Mattiasson I, Ivancev K, Gottsäter A, Lindblad B . Revascularisation of renal artery stenosis caused by fibromuscular dysplasia: effects on blood pressure during 7-year follow-up are influenced by duration of hypertension and branch artery stenosis . J Hum Hypertens 2005 ; 19 : 761 – 767 . E-III
Bonelli FS, McKusick MA, Textor SC, Kos PB, Stanson AW, Johnson CM, Sheedy 2nd PF, Welch TJ, Schirger A . Renal artery angioplasty: technical results and clinical outcome in 320 patients . Mayo Clin Proc 1995 ; 70 : 1041 – 1052 . III
Zeller T, Frank U, Müller C, Bürgelin K, Sinn L, Bestehorn HP, Cook-Bruns N, Neumann FJ . Predictors of improved renal function after percutaneous stent-supported angioplasty of severe atherosclerotic ostial renal artery stenosis . Circulation 2003 ; 108 : 2244 – 2249 . III
Plouin PF, Chatellier G, Darn B, Raynaud A . Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group . Hypertension 1998 ; 31 : 823 – 829 . II
Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, Loose H, Main J, Padfield P, Russell IT, Walker B, Watson M, Wilkinson R, Scottish Newcastle Renal Artery Stenosis Collaborative Group . Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis . J Hum Hypertens 1998 ; 12 : 329 – 335 . II
van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in ‘t Veld AJ, Schalekamp MA, Dutch Renal Artery Stenosis Intervention Cooperative Study Group . The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis . New Engl J Med 2000 ; 342 : 1007 – 1014 . II
Ives NJ, Wheatley K, Stowe RL, Krijnen P, Plouin PF, van Jaarsveld BC, Gray R . Continuing uncertainty about the value of percutaneous revascularization in atherosclerotic renovascular disease: a meta-analysis of randomized trials . Nephrol Dial Transplant 2003 ; 18 : 298 – 304 . I
Nordmann AJ, Woo K, Parkes R, Logan AG . Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials . Am J Med 2003 ; 114 : 44 – 50 . I
Balk E, Raman G, Chung M, Ip S, Tatsioni A, Alonso A, Chew P, Gilbert SJ, Lau J . Effectiveness of management strategies for renal artery stenosis: a systematic review . Ann Intern Med 2006 ; 145 : 901 – 912 . I
Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, Braam B, Huysmans FT, Schultze Kool LJ, Rutten MJ, Doorenbos CJ, Aarts JC, Rabelink TJ, Plouin PF, Raynaud A, van Montfrans GA, Reekers JA, van den Meiracker AH, Pattynama PM, van de Ven PJ, Vroegindeweij D, Kroon AA, de Haan MW, Postma CT, Beutler JJ . Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial . Ann Intern Med 2009 ; 150 : 840 – 848, W150–1. II
Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, Carr S, Chalmers N, Eadington D, Hamilton G, Lipkin G, Nicholson AScoble J, ASTRAL Investigators . Revascularization versus medical therapy for renal-artery stenosis . New Engl J Med 2009 ; 361 : 1953 – 1962 . II
Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KR, Shapiro JI, Rundback JH, Massaro JM, D’Agostino Sr RB, Dworkin LD, CORAL Investigators . Stenting and medical therapy for atherosclerotic renal-artery stenosis . New Engl J Med 2014 ; 370 : 13 – 22 . II
II Galaria, Surowiec SM, Rhodes JM, Illig KA, Shortell CK, Sternbach Y, Green RM, Davies MG . Percutaneous and open renal revascularizations have equivalent long-term functional outcomes . Ann Vasc Surg 2005 ; 19 : 218 – 228 . IVa
Cherr GS, Hansen KJ, Craven TE, Edwards MS, Ligush Jr J, Levy PJ, Freedman BI, Dean RH . Surgical management of atherosclerotic renovascular disease . J Vasc Surg 2002 ; 35 : 236 – 245 . III
Modrall JG, Rosero EB, Smith ST, Arko 3rd FR, Valentine RJ, Clagett GP, Timaran CH . Operative mortality for renal artery bypass in the United States: Results from the National Inpatient Sample . J Vasc Surg 2008 ; 48 : 317 – 322 . IVb
Volpe C, Wahrenberg H, Hamberger B, Thorén M . Screening for primary aldosteronism in a primary care unit . J Renin Angiotensin Aldosterone Syst 2013 ; 14 : 212 – 219 . IVa
Quinkler M, Born-Frontsberg E, Fourkiotis VG . Comorbidities in primary aldosteronism . Horm Metab Res 2010 ; 42 : 429 – 434 . VI
Viera AJ, Hinderliter AL . Evaluation and management of the patient with difficult-to-control or resistant hypertension . Am Fam Physician 2009 ; 79 : 863 – 869 . VI
Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr WF, Montori VM, Endocrine Society . Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline . J Clin Endocrinol Metab 2008 ; 93 : 3266 – 3281 . GL
Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A, Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society . Guidelines for the diagnosis and treatment of primary aldosteronism—the Japan Endocrine Society 2009 . Endocr J 2011 ; 58 : 711 – 721 . GL
Gordon RD . Primary aldosteronism . J Endocrinol Invest 1995 ; 18 : 495 – 511 . VI
Hannemann A, Bidlingmaier M, Friedrich N, Manolopoulou J, Spyroglou A, Völzke H, Beuschlein F, Seissler J, Rettig R, Felix SB, Biffar R, Döring A, Meisinger C, Peters A, Wichmann HE, Nauck M, Wallaschofski H, Reincke M . Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies . Eur J Endocrinol 2012 ; 167 : 7 – 15 . IVb
Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C . Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study . Lancet 2008 ; 371 : 1921 – 1926 . IVa
Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P . Hyperaldosteronism among black and white subjects with resistant hypertension . Hypertension 2002 ; 40 : 892 – 896 . IVa
Vierhapper H . Determination of the aldosterone/renin ratio in 269 patients with adrenal incidentaloma . Exp Clin Endocrinol Diabetes 2007 ; 115 : 518 – 521 . IVa
Di Murro A, Petramala L, Cotesta D, Zinnamosca L, Crescenzi E, Marinelli C, Saponara M, Letizia C . Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism . J Renin Angiotensin Aldosterone Syst 2010 ; 11 : 165 – 172 . IVa
Suzuki S, Ito S . Aldosterone and Na metabolism on the renin stimulation test . Jpn J Nephrol 1978 ; 20 : 1 – 10 . Japanese. VI
Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara M, Nagata H, Izumiyama T . A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients . Arch Intern Med 1981 ; 141 : 1589 – 1593 . IVb
Stowasser M, Taylor PJ, Pimenta E, Ahmed AH, Gordon RD . Laboratory investigation of primary aldosteronism . Clin Biochem Rev 2010 ; 31 : 39 – 56 . VI]
Stowasser M . Update in primary aldosteronism . J Clin Endocrinol Metab 2009 ; 94 : 3623 – 3330 . VI
Fischer E, Beuschlein F, Bidlingmaier M, Reincke M . Commentary on the Endocrine Society Practice Guidelines: Consequences of adjustment of antihypertensive medication in screening of primary aldosteronism . Rev Endocr Metab Disord 2011 ; 12 : 43 – 48 . IVb
Tanabe A, Naruse M, Takagi S, Tsuchiya K, Imaki T, Takano K . Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism . J Clin Endocrinol Metab 2003 ; 88 : 2489 – 2494 . V
Arlt W . A detour guide to the Endocrine Society Clinical Practice Guideline on case detection, diagnosis and treatment of patients with primary aldosteronism . Eur J Endocrinol 2010 ; 162 : 435 – 438 . VI
Nanba K, Tamanaha T, Nakao K, Kawashima ST, Usui T, Tagami T, Okuno H, Shimatsu A, Suzuki T, Naruse M . Confirmatory testing in primary aldosteronism . J Clin Endocrinol Metab 2012 ; 97 : 1688 – 1694 . IVb
Nishikawa T, Omura M . Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital . Biomed Pharmacother 2000 ; 54 (Suppl 1) ; 83s – 85s . IVb
Ishidoya S, Kaiho Y, Ito A, Morimoto R, Satoh F, Ito S, Ishibashi T, Nakamura Y, Sasano H, Arai Y . Single-center outcome of laparoscopic unilateral adrenalectomy for patients with primary aldosteronism: lateralizing disease using results of adrenal venous sampling . Urology 2011 ; 78 : 68 – 73 . V
Mulatero P, Bertello C, Sukor N, Gordon R, Rossato D, Daunt N, Leggett D, Mengozzi G, Veglio F, Stowasser M . Impact of different diagnostic criteria during adrenal vein sampling on reproducibility of subtype diagnosis in patients with primary aldosteronism . Hypertension 2010 ; 55 : 667 – 673 . IVb
Rossi GP, Barisa M, Allolio B, Auchus RJ, Amar L, Cohen D, Degenhart C, Deinum J, Fischer E, Gordon R, Kickuth R, Kline G, Lacroix A, Magill S, Miotto D, Naruse M, Nishikawa T, Omura M, Pimenta E, Plouin PF, Quinkler M, Reincke M, Rossi E, Rump LC, Satoh F, Schultze Kool L, Seccia TM, Stowasser M, Tanabe A, Trerotola S, Vonend O, Widimsky Jr J, Wu KD, Wu VC, Pessina AC . The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism . J Clin Endocrinol Metab 2012 ; 97 : 1606 – 1614 . IVb
Stewart PM, Allolio B . Adrenal vein sampling for Primary Aldosteronism: time for a reality check . Clin Endocrinol (Oxf) 2010 ; 72 : 146 – 148 . VI
Vonend O, Ockenfels N, Gao X, Allolio B, Lang K, Mai K, Quack I, Saleh A, Degenhart C, Seufert J, Seiler L, Beuschlein F, Quinkler M, Podrabsky P, Bidlingmaier M, Lorenz R, Reincke M, Rump LC, German Conn's Registry . Adrenal venous sampling: evaluation of the German Conn's registry . Hypertension 2011 ; 57 : 990 – 995 . IVb
Morimoto S, Takeda R, Murakami M . Does prolonged pretreatment with large doses of spironolactone hasten a recovery from juxtaglomerular-adrenal suppression in primary aldosteronism? J Clin Endocrinol Metab 1970 ; 31 : 659 – 664 . IVb
Parthasarathy HK, Ménard J, White WB, Young Jr WF, Williams GH, Williams B, Ruilope LM, McInnes GT, Connell JM, MacDonald TM . A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism . J Hypertens 2011 ; 29 : 980 – 990 . II
Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G . High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines . Clin Endocrinol(Oxf) 2004 ; 61 : 768 – 777 . E-III
Miyachi Y . Study report in 2001 by the ‘Study Group on Abnormalities in Adrenal Hormone Production’, Research Business for Specific Disease Control by a scientific grant/subsidy from the Ministry of Health and Welfare . Japanese. IVB
Nawada H, Demura H, Suda T, Takayanagi R . Adrenal preclinical Cushing's syndrome] (in Japanese) . Study report in 1995 by the Working Group for Investigating ‘Abnormalities in Adrenal Hormone Production’, Specific Disease/Endocrine Disease Study Group, Ministry of Health and Welfare, 1999, pp 223 – 226 . VI
Tsuiki M, Tanabe A, Takagi S, Naruse M, Takano K . Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing's syndrome . Endocr J 2008 ; 55 : 737 – 745 . E-II
Study Group on the Promotion of Pheochromocytoma Diagnosis and Treatment, Research Business for Refractory Disease Control, Ministry of Health, Labour and Welfare . Clinical Guide to the Management of Pheochromocytoma 2012 . (In Japanese). 2012. GL
Gimenez-Roqueplo AP, Dahia PL, Robledo M . An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes . Horm Metab Res 2012 ; 44 : 328 – 333 . VI
Kobayashi Y, Hashimoto H . [Guidelines for the diagnosis and treatment of aortitis syndrome (Takayasu's arteritis)] (in Japanese) . Scientific grant/subsidy from the Ministry of Health and Welfare: Research Business for Specific Disease Control, Investigational study regarding refractory angiitis, Study report in 1999 to 2001, 2002, pp 41 – 63 . VI
Ishikawa K . Takayasu's disease hypertension] (in Japanese) . Syndrome series with respect to regions, 12 cardiovascular syndromes (special version of the Nihon Rinsho) . 1996, pp 18 – 121 . VI
Hashimoto H . Study report in 2001 by the ‘Working Group for Refractory Angiitis’, Specific Disease/Immunological Disease Study Group, Ministry of Health and Welfare (in Japanese), 2002, pp 21 – 25 . VI
Ohigashi H, Haraguchi G, Konishi M, Tezuka D, Kamiishi T, Ishihara T, Isobe M . Improved prognosis of Takayasu arteritis over the past decade: comprehensive analysis of 106 patients . Circ J 2012 ; 76 : 1004 – 1011 . IVb
Kobayashi K . Epidemiological study of aortitis syndrome : On the number of new crisis patient and complications . Study report in 1994 by the Specific Disease/Refractory Angiitis Study Group, Ministry of Health and Welfare, 1994, pp 7 – 10 . VI
Ogino H, Matsuda H, Minatoya K, Sasaki H, Tanaka H, Matsumura Y, Ishibashi-Ueda H, Kobayashi J, Yagihara T, Kitamura S . Overview of late outcome of medical and surgical treatment for Takayasu arteritis . Circulation 2008 ; 118 : 2738 – 2747 . VI
Machida M, Sakuma M, Aoki H, Yasuda Y . Long-term results of cardiac macrovascular lesions accompanying Takayasu's arteritis] (in Japanese) . Study report in 1993 by the Specific Disease/Immunological Disease Study Group, Ministry of Health and Welfare, 1993, pp 192 – 195 . VI
Miyata T, Sato O, Koyama H, Shigematsu H, Tada Y . Long-term survival after surgical treatment of patients with Takayasu's arteritis . Circulation 2003 ; 108 : 1474 – 1480 . V
Disease Control Section, Health and Medical Bureau, Ministry of Health and Welfare. [Nodular periarteritis] . Guidelines for the diagnosis and treatment of refractory diseases (in Japanese), Roppo Publishing Company: Aichi 1997 . pp 107 – 115 . GL
Blaustein DA, Kumbar L, Srivastava M, Avram MM . Polyarteritis nodosa presenting as isolated malignant hypertension . Am J Hypertens 2004 ; 17 : 380 – 381 . V
Kurosawa M, Inaba Y, Kobayashi S, Ozaki S, Nagai M . Analysis of personal sheet-based electronic data on a clinical survey in 2004 regarding refractory angiitis (nodular periarteritis)] (in Japanese) . Scientific grant/subsidy from the Ministry of Health, Labour and Welfare: Study report in 2005 by the ‘Clinical Research Working Group for Intermediate/Micro Angiitis’, Study Group on Refractory Angiitis, 2006, pp 137 – 150 . VI
Bussone G, Bérezn A, Pestre V, Guillevin L, Mouthon L . The scleroderma kidney: progress in risk factors, therapy, and prevention . Curr Rheumatol Rep 2011 ; 13 : 37 – 43 . VI
Murakami T, Ueno M, Takeda A, Yakuwa S . Pressure wave reflection after successful balloon dilatation of aortic coarctation . Circ J 2007 ; 71 : 1821 – 1822 . V
Trojnarska O, Szczepaniak-Chiche L, Mizia-Stec K, Gabriel M, Bartczak A, Grajek S, Ga˛sior Z, Kramer L, Tykarski A . Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery . Clin Res Cardiol 2011 ; 100 : 447 – 455 . IVb
Ross RD, Clapp SK, Gunther S, Paridon SM, Humes RA, Farooki ZQ, Pinsky WW . Augmented norepinephrine and renin output in response to maximal exercise in hypertensive coarctectomy patients . Am Heart J 1992 ; 123 : 1293 – 1299 . IVb
Toro-Salazar OH, Steinberger J, Thomas W, Rocchini AP, Carpenter B, Moller JH . Long-term follow-up of patients after coarctation of the aorta repair . Am J Cardiol 2002 ; 89 : 541 – 547 . V
Canniffe C, Ou P, Walsh K, Bonnet D, Celermajer D . Hypertension after repair of aortic coarctation- A systematic review . Int J Cardiol 2013 ; 167 : 2456 – 2461 . IVa
Lee MG, Kowalski R, Galati JC, Cheung MM, Jones B, Koleff J, d’Udekem Y . Twenty-four-hour ambulatory blood pressure monitoring detects a high prevalence of hypertension late after coarctation repair in patients with hypoplastic arches . J Thorac Cardiovasc Surg 2012 ; 144 : 1110 – 1116 . V
Luijendijk P, Bouma BJ, Vriend JW, Vliegen HW, Groenink M, Mulder BJ . Usefulness of exercise-induced hypertension as predictor of chronic hypertension in adults after operative therapy for aortic isthmic coarctation in childhood . Am J Cardiol 2011 ; 108 : 435 – 439 . IVa
Jannetta PJ, Segal R, Wolfson SK Jr . Neurogenic hypertension: etiology and surgical treatment. I. Observations in 53 patients . Ann Surg 1985 ; 201 : 391 – 398 . IVb
Makino Y, Kawano Y, Okuda N, Horio T, Iwashima Y, Yamada N, Takamiya M, Takishita S . Autonomic function in hypertensive patients with neurovascular compression of the ventrolateral medulla oblongata . J Hypertens 1999 ; 17 : 1257 – 1263 . IVb
Schobel HP, Frank H, Naraghi R, Geiger H, Titz E, Heusser K . Hypertension in patients with neurovascular compression is associated with increased central sympathetic outflow . J Am Soc Nephrol 2002 ; 13 : 35 – 41 . IVb
Smith PA, Meaney JF, Graham LN, Stoker JB, Mackintosh AF, Mary DA, Ball SG . Relationship of neurovascular compression to central sympathetic discharge and essential hypertension . J Am Coll Cardiol 2004 ; 43 : 1453 – 1458 . IVb
Aoki S, Ohtsuki T, Hosomi N, Sueda Y, Kono T, Yamawaki T, Matsumoto M . Blood pressure variability and prognosis in acute ischemic stroke with vascular compression on the rostral ventrolateral medulla (RVLM) . Hypertens Res 2011 ; 34 : 617 – 622 . IVa
Sasaki S, Tanda S, Hatta T, Morimoto S, Takeda K, Kizu O, Tamaki S, Saito M, Tamura Y, Kondo A . Neurovascular decompression of the rostral ventrolateral medulla decreases blood pressure and sympathetic nerve activity in patients with refractory hypertension . J Clin Hypertens (Greenwich) 2011 ; 13 : 818 – 820 . V
Sakuma T, Morimoto S, Aota Y, Takahashi N, Toyoda N, Kosaki A, Maehara M, Tanigawa N, Ikeda K, Sawada S, Iwasaka T . Efficacy of clonidine in patients with essential hypertension with neurovascular contact of the rostral ventrolateral medulla . Hypertens Res 2010 ; 33 : 633 – 637 . IVa
Aota Y, Morimoto S, Sakuma T, Morita T, Jo F, Takahashi N, Maehara M, Ikeda K, Sawada S, Iwasaka T . Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla . Hypertens Res 2009 ; 32 : 700 – 705 . IVa
Brown MJ . The causes of essential hypertension . Br J Clin Pharmacol 1996 ; 42 : 21 – 27 . VI
Kupper N, Willemsen G, Riese H, Posthuma D, Boomsma DI, de Geus EJ . Heritability of daytime ambulatory blood pressure in an extended twin design . Hypertension 2005 ; 45 : 80 – 85 . IVb
International Consortium for Blood Pressure Genome-Wide Association Studies . Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk . Nature 2011 ; 478 : 103 – 109 . IVb
Kato N . Ethnic differences in genetic predisposition to hypertension . Hypertens Res 2012 ; 35 : 574 – 581 . VI
Tabara Y, Kohara K, Kita Y, Hirawa N, Katsuya T, Ohkubo T, Hiura Y, Tajima A, Morisaki T, Miyata T, Nakayama T, Takashima N, Nakura J, Kawamoto R, Takahashi N, Hata A, Soma M, Imai Y, Kokubo Y, Okamura T, Tomoike H, Iwai N, Ogihara T, Inoue I, Tokunaga K, Johnson T, Caulfield M, Munroe P, Umemura S, Ueshima H, Miki T . Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project . Hypertension 2010 ; 56 : 973 – 980 . IVb
Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, Tay WT, Chen CH, Zhang Y, Yamamoto K, Katsuya T, Yokota M, Kim YJ, Ong RT, Nabika T, Gu D, Chang LC, Kokubo Y, Huang W, Ohnaka K, Yamori Y, Nakashima E, Jaquish CE, Lee JY, Seielstad M, Isono M, Hixson JE, Chen YT, Miki T, Zhou X, Sugiyama T, Jeon JP, Liu JJ, Takayanagi R, Kim SS, Aung T, Sung YJ, Zhang X, Wong TY, Han BG, Kobayashi S, Ogihara T, Zhu D, Iwai N, Wu JY, Teo YY, Tai ES, Cho YS, He J . Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians . Nat Genet 2011 ; 43 : 531 – 538 . IVb
Katsuya T, Ishikawa K, Sugimoto K, Rakugi H, Ogihara T . Salt sensitivity of Japanese from the viewpoint of gene polymorphism . Hypertens Res 2003 ; 26 : 521 – 525 . VI
Hunt SC, Cook NR, Oberman A, Cutler JA, Hennekens CH, Allender PS, Walker WG, Whelton PK, Williams RR . Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II . Hypertension 1998 ; 32 : 393 – 401 . II
Arnett DK, Baird AE, Barkley RA, Basson CT, Boerwinkle E, Ganesh SK, Herrington DM, Hong Y, Jaquish C, McDermott DA, O’Donnell CJ American Heart Association Council on Epidemiology and Prevention; American Heart Association Stroke Council; Functional Genomics and Translational Biology Interdisciplinary Working Group . Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Counci l on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group . Circulation 2007 ; 115 : 2878 – 2901 . VI
Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP . Rare independent mutations in renal salt handling genes contribute to blood pressure variation . Nat Genet 2008 ; 40 : 592 – 599 . IVb
Lifton RP, Gharavi AG, Geller DS . Molecular mechanisms of human hypertension . Cell 2001 ; 104 : 545 – 556 . VI
Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP . Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities . Nature 2012 ; 482 : 98 – 102 . IVb
Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, kerström G, Wang W, Carling T, Lifton RP . K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension . Science 2011 ; 331 : 768 – 772 . IVb
Ministry of Health, Labor, and Welfare . Ethical Guidelines for Human Genome/Gene Analysis Research. Revised on February 8, 2013 . http://www.mhlw.go.jp/seisakunitsuite/bunya/hokabunya/kenkyujigyou/i-kenkyu/index.html . Japanese. VI
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA American Heart Association . Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association . Circulation 2007 ; 115 : 1634 – 1642 . GL
Layton D, Souverein PC, Heerdink ER, Shakir SA, Egberts AC . Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in The Netherlands . Drug Saf 2008 ; 31 : 143 – 158 . E-II
Strand V . Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet 2007 ; 370 : 2138 – 2151 . VI
Arellano FM, Yood MU, Wentworth CE, Oliveria SA, Rivero E, Verma A, Rothman KJ . Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile . Pharmacoepidemiol Drug Saf 2006 ; 15 : 861 – 872 . E-II
Fogari R, Zoppi A, Carretta R, Veglio F, Salvetti A Italian Collaborative Study Group . Effect of indomethacin on the antihypertensive efficacy of valsartan and lisinopril: a multicentre study . J Hypertens 2002 ; 20 : 1007 – 1014 . II
Cosmetic Ingredient Review Expert Panel . Final repo rt on the safety assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhi zate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate . Int J Toxicol 2007 ; 26 : (Suppl 2) 79 – 112 . VI
Homma M, Ishihara M, Qian W, Kohda Y . Effects of Long Term Administration of Shakuyaku-kanzo-To and Shosaiko-To on Serum Potassium Levels . Yakugaku Zasshi 2006 ; 126 : 973 – 978 . Japanese. V
Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, Metsios GS, Nightingale P, Kita MD, Elisaf MS, Kitas GD . Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis . Rheumatology (Oxford) 2008 ; 47 : 72 – 75 . E-II
Sato A, Funder JW, Okubo M, Kubota E, Saruta T . Glucocorticoid-induced hypertension in the elderly. Relation to serum calcium and family history of essential hypertension . Am J Hypertens 1995 ; 8 : 823 – 828 . E-II
Saruta T . Mechanism of glucocorticoid-induced hypertension . Hypertens Res 1996 ; 19 : 1 – 8 . VI
Kelly JJ, Martin A, Whitworth JA . Role of erythropoietin in cortisol-induced hypertension . J Hum Hypertens 2000 ; 14 : 195 – 198 . II
Whitworth JA, Schyvens CG, Zhang Y, Andrews MC, Mangos GJ, Kelly JJ . The nitric oxide system in glucocorticoid-induced hypertension . J Hypertens 2002 ; 20 : 1035 – 1043 . VI
Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H, Matsumoto T . Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction . Circ Res 2003 ; 92 : 81 – 87 . VI
Andoh TF, Johnson RJ, Sander M, Lyson T, Thomas GD, Victor RG . Sympathetic neural mechanisms of cyclosporine-induced hypertension . Am J Hypertens 1996 ; 9 : 121S – 138S . VI
Sander M, Lyson T, Thomas GD, Victor RG . Sympathetic neural mechanisms of cyclosporine-induced hypertension . Am J Hypertens 1996 ; 9 : 121S – 138S . VI
Zhang W, Victor RG . Calcineurin inhibitors cause renal afferent activation in rats: a novel mechanism of cyclosporine-induced hypertension . Am J Hypertens 2000 ; 13 : 999 – 1004
Lungu AO, Jin ZG, Yamawaki H, Tanimoto T, Wong C, Berk BC . Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae . J Biol Chem 2004 ; 279 : 48794 – 48800
Halimi JM, Giraudeau B, Buchler M, Al-Najjar A, Etienne I, Laouad I, Bruyère F, Lebranchu Y . Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial . Clin Transplant 2007 ; 21 : 277 – 284 . II
Suzuki M, Goya T . Survey regarding the preparation of guidelines for the use of EPO . Study report in 1992 by the Medical Research Business for Renal Failure by a scientific grant from the Ministry of Health and Welfare, 1993, pp 165 – 172 . Japanese. VI
Sasagawa I, Nakada T, Hashimoto T, Kubota Y, Suzuki H, Sawamura T . Change in haemoglobin concentration, haematocrit and vasoactive hormones in haemodialysis patients with erythropoietin-associated hypertension . Int Urol Nephrol 1994 ; 26 : 237 – 243 . III
Okura Y, Oshima T, Yasunobu Y, Amano K, Mori M, Shinozaki K, Kajiyama G . Effect of erythropoietin treatment on blood pressure and intracellular cation concentrations in maintenance hemodialysis patients . Hypertens Res 1996 ; 19 : 91 – 95 . III
Shimada N, Saka S, Sekizuka K, Tanaka A, Takahashi Y, Nakamura T, Ebihara I, Koide H . Increased endothelin: nitric oxide ratio is associated with erythropoietin-induced hypertension in hemodialysis patients . Ren Fail 2003 ; 25 : 569 – 578 . III
Ishimitsu T, Tsukada H, Ogawa Y, Numabe A, Yagi S . Genetic predisposition to hypertension facilitates blood pressure elevation in hemodialysis patients treated with erythropoietin . Am J Med 1993 ; 94 : 401 – 406 . E-Ib
Miyashita K, Tojo A, Kimura K, Goto A, Omata M, Nishiyama K, Fujita T . Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients . Hypertens Res 2004 ; 27 : 79 – 84 . III
Ohkubo M, Ishimitsu T, Kawaguchi T, Abe M, Yagi S . Efficacy and safety of long-term erythropoietin therapy in chronic hemodialysis patients with renal anemia . Jpn J Nephrol Nihon Jinzo Gakkai Shi 1993 ; 35 : 171 – 177 . Japanese. V
Du Y, Melchert HU, Schäfer-Korting M . Use of oral contraceptives in Germany: prevalence, determinants and use-associated health correlates. Results of National Health Surveys from 1984 to 1999 . Eur J Obstet Gynecol Reprod Biol 2007 ; 134 : 57 – 66 . E-II
Hui KK . Hypertensive crisis induced by interaction of clonidine with imipramine . J Am Geriatr Soc 1983 ; 31 : 164 – 165 . V
Abo-Zena RA, Bobek MB, Dweik RA . Hypertensive urgency induced by an interaction of mirtazapine and clonidine . Pharmacotherapy 2000 ; 20 : 476 – 478 . V
Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K . Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management . Drug Saf 2007 ; 30 : 1031 – 1062 . VI
Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S, Motzer RJ . PhaseI trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma . J Clin Oncol 2009 ; 27 : 1432 – 1439 . IVa
Dienstmann R, Braña I, Rodon J, Tabernero J . Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs . Oncologist 2011 ; 16 : 1729 – 1740 . VI
Sane DC, Anton L, Brosnihan KB . Angiogenic growth factors and hypertension . Angiogenesis 2004 ; 7 : 193 – 201 . VI
Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP . Management of hypertension in angiogenesis inhibitor-treated patients . Ann Oncol 2009 ; 20 : 807 – 815 . VI
About this article
Fundamental & Clinical Pharmacology (2017)
Circulation Journal (2015)