Renal impairment is closely associated with plasma aldosterone concentration in patients with primary aldosteronism.

OBJECTIVE: Several clinical studies have reported that renal impairments are sometimes observed in patients with primary aldosteronism (PA). We analyzed the prevalence of renal impairments in PA patients and identified parameters that increase the risk for them. DESIGN: This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan PA study (JPAS). Data were also collected from patients with essential hypertension (EHT). METHODS: We compared the prevalences of proteinuria and lowered estimated glomerular filtration rate (eGFR) between patients with PA and age, sex, blood pressure and duration of hypertension-matched patients with EHT. We also performed logistic regression analysis to identify parameters that increase the risk for these renal impairments. RESULTS: Among 2366 PA patients, the prevalences of proteinuria and lowered eGFR were 10.3 and 11.6%, respectively. The prevalence of proteinuria was significantly higher in PA patients than matched-EHT patients (16.8 vs 4.4%), whereas there was no significant difference in the prevalence of lowered eGFR (17.2 vs 15.0%). The logistic regression analysis also showed that the plasma aldosterone concentration (PAC) significantly increases the risk of proteinuria and lowered eGFR, independent of other known risk factors. CONCLUSION: Plasma aldosterone levels are closely associated with renal impairment in patients with PA. This is contrast to our earlier finding that the PAC was not itself linearly associated with cardiovascular events such as stroke or ischemic heart disease. The mechanism underlying the kidney damage in patients with PA may differ from that affecting the cardiovascular system.

Latent Autonomous Cortisol Secretion From Apparently Nonfunctioning Adrenal Tumor in Nonlateralized Hyperaldosteronism.

CONTEXT: Adrenal tumors (ATs), even those diagnosed as nonfunctioning, may cause metabolic disorders. Some primary aldosteronism (PA) patients with ATs are diagnosed with bilateral PA based on adrenal venous sampling (AVS), and their ATs are apparently nonfunctioning. OBJECTIVE: To clarify the influence of apparently nonfunctioning ATs, we compared hormone levels and clinical complications between bilateral PA cases with and without ATs. DESIGN, SETTING, AND PARTICIPANTS: After retrospectively assessing 2814 patients with PA in the multicenter Japan PA study, bilateral PA cases on AVS were divided into cases with and without ATs by computed tomography findings. Importantly, patients with cortisol levels >1.8 µg/dL after the 1-mg dexamethasone suppression test (DST) were excluded. Clinical characteristics and biochemical data were compared between them. The correlation between AT size and hormone levels was also analyzed. MAIN OUTCOME MEASURES: Analyzed were 196 bilateral PA patients with ATs and 331 those without ATs. Although basal cortisol and aldosterone levels were similar between them, cortisol levels after the 1-mg DST and the prevalences of diabetes mellitus and proteinuria were significantly higher and ACTH levels and plasma renin activity were significantly lower in cases with ATs than in those without. After adjusting for patients' backgrounds, cortisol levels after the 1-mg DST and plasma renin activity remained significantly different between them. Moreover, cortisol levels after the 1-mg DST and ACTH levels correlated with AT size. CONCLUSIONS: Apparently nonfunctioning ATs in bilateral PA cases may cause latent autonomous cortisol secretion, inducing diabetes and proteinuria.

High Prevalence of Diabetes in Patients With Primary Aldosteronism (PA) Associated With Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA: A Large, Multicenter Cohort Study in Japan.

OBJECTIVE: To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. RESEARCH DESIGN AND METHODS: The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ≥6.5% [≥48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ≥1.8 µg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% ≤ HbA1c <6.5% [39 mmol/mol ≤ HbA1c <48 mmol/mol]) were examined. RESULTS: Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30-69 years. Logistic regression or χ2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS: Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

Obesity as a Key Factor Underlying Idiopathic Hyperaldosteronism.

Context: Recently, the relationship between primary aldosteronism (PA) and various metabolic disorders, including obesity, diabetes mellitus, and dyslipidemia, has been discussed. However, in PA, aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) have different etiologies. Objective: Our objectives were to clarify differences in obesity and metabolic disorders between APA and IHA and to gain insight in the pathogenesis of IHA. Design, Setting, and Participants: This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan Primary Aldosteronism Study. For comparative analysis, data were also collected from 274 patients with essential hypertension (EHT). Main Outcome Measures: We compared prevalences of obesity and metabolic disorders between patients with APA and patients with IHA. Comparisons with sex-, age-, and blood pressure-matched patients with EHT were also performed. Correlations between metabolic parameters and plasma aldosterone concentrations (PACs) in each subtype were analyzed. Results: Analysis of 516 patients with APA and 1015 patients with IHA revealed PACs were significantly higher in patients with APA than patients with IHA. By contrast, after we adjusted for clinical backgrounds, the prevalence of obesity was significantly higher in patients with IHA than in patients with APA or EHT. Although the prevalences of diabetes mellitus and dyslipidemia did not significantly differ between patients with IHA and patients with APA, triglyceride and HbA1c were significantly higher in patients with IHA than in patients with APA. There was no significant correlation between metabolic parameters and PACs in either subtype. Conclusions: Patients with IHA tend to be obese despite lower PACs than in patients with APA. The present results suggest that obesity-related factors contribute to the pathogenesis of IHA.

Correlation Between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism.

OBJECTIVES: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. PATIENTS AND METHODS: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. MAIN OUTCOME MEASURES: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. RESULTS: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). CONCLUSIONS: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism: A Multicenter Study in Japan.

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K+ ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

Subtype prediction of primary aldosteronism by combining aldosterone concentrations in the left adrenal vein and inferior vena cava: a multicenter collaborative study on adrenal venous sampling.

Subtype diagnosis of primary aldosteronism (PA) by adrenal vein sampling (AVS) is recommended as a mandatory step for indicating adrenal surgery. It is a technically demanding procedure, especially in the right adrenal vein. The aim of the study was to predict the subtype diagnosis in the absence of values from the right AVS. From the databases of nine centers (WAVES-J), 308 patients with PA who underwent successful AVS were studied. Based on the ipsilateral ratio (IR) (aldosterone/cortisol ratio of the left adrenal vein [A/Cleft AV] / aldosterone/cortisol ratio of the inferior vena cava [A/CIVC]), the patients were divided into two groups: the patients with IR ≥ 1.0 (n = 262) and those with IR < 1.0 (n = 46). In patients with IR > 1.0, the A/Cleft AV was significantly higher in patients with the left unilateral subtype than in patients with the bilateral subtype. Receiver operating characteristic (ROC) curve analysis revealed that an A/Cleft AV cutoff >68 showed 70.8% sensitivity and 93.5% specificity for the left unilateral subtype. On the other hand, in patients with IR < 1.0, the A/Cleft AV was significantly lower in patients with the right unilateral subtype. ROC analysis revealed that an A/Cleft AV cutoff <9 showed 86.7% sensitivity and 75.0% specificity for the right unilateral subtype. Hence, the combination of the IR and A/C ratio in the left adrenal vein is useful for predicting the subtype. The present results provide important information for patients with PA in whom AVS was unsuccessful in the right adrenal vein.

Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism.

OBJECTIVE: Although corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA. DESIGN, SETTING AND PATIENTS: In this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve. RESULTS: Of 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 0·01) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes. CONCLUSIONS: C-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT.

Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study.

CONTEXT: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). OBJECTIVES: To investigate the prevalence of BAS in AVS and how to resolve this condition. DESIGN AND SETTING: Retrospective study involving nine referral centres. PATIENTS: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. MEASUREMENTS: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. RESULTS: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. CONCLUSIONS: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure.

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism.

Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per µg/dL;P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism.

CONTEXT: Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized. OBJECTIVE: To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients. DESIGN AND SETTING: Retrospective study in nine referral centres. PARTICIPANTS: Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included. MAIN OUTCOME MEASURES: Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results. RESULTS: Subtype diagnosis using common trunk and central vein was discordant in 10 (4·6%) of the 217 patients (κ = 0·87, P < 0·05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data. CONCLUSION: In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required.

Hypercalcemic crisis due to primary hyperparathyroidism occurring concomitantly with Graves' disease.

We herein describe a case of hypercalcemic crisis in a 52-year-old Japanese woman. She suffered from thirst and fatigue for one month. Her serum calcium (a) levels were 19.0 mg/dL, and she was diagnosed with hypercalcemic crisis. Circulating levels of parathyroid and thyroid hormones were elevated. She was diagnosed with primary hyperparathyroidism accompanied by Graves' disease. Thyroparathyroidectomy was performed after circulating levels of Ca and thyroid hormones were normalized. Both of primary hyperparathyroidism and Graves' disease can contribute and accelerate hypercalcemia, resulting in a state of crisis. The possibility of their coexistence should therefore be taken into consideration in cases of hypercalcemia.

Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism.

OBJECTIVES: Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy. AIM: The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS. DESIGN AND PATIENTS: A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia. RESULTS: The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0·2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0·004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0·01). CONCLUSIONS: In patients with PA, where the LI is <4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management.

Effect of renal impairment on the pharmacokinetics of memantine.

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.

[Case of 131I-meta-iodobenzylguanidine (MIBG) scintigraphy-negative and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)-positive pheochromocytoma].

A 53-year-old man was admitted to Ehime University Hospital because of a left adrenal tumor, which was detected by a routine medical examination. Blood pressure was 124/74 mmHg and the pulse rate was 80/min and regular. Computed tomography showed the tumor consisting mainly of low-density areas and partly of heterogeneous density areas. Magnetic resonance imaging demonstrated that the tumor consisted mainly of low intensity areas, partly of heterogeneous intensity areas determined by T1-weighted images; T2-weighted images showed that the tumor consisted mainly of high intensity areas and partly of heterogeneous intensity areas. These images suggested that the left adrenal tumor was a pheochromocytoma. The concentrations of serum adrenaline and noradrenaline were slightly elevated (adrenaline 0.11 ng/mL (normal: < 0.1) and noradrenaline 1.11 ng/mL (normal 0.1 - 0.5)). Although 131I-meta-iodobenzylguanidine (MIBG) scintigraphy did not show an accumulation of the tracer, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) showed an increased accumulation of the tracer in the left adrenal tumor. These results were suggestive of the diagnosis of pheochromocytoma, and left adrenalectomy was performed by endoscopy. He was finally diagnosed with pheochromocytoma. The detection rate of pheochromocytoma by FDG-PET is not very high and has been reported to be about 70 %. However, FDG-PET may be useful for detecting local recurrence or distant metastasis, in patients with MIBG-negative pheochromocytoma.

Long-term effects of angiotensin II receptor blockade with valsartan on carotid arterial stiffness and hemodynamic alterations in patients with essential hypertension.

Increased arterial stiffness and intima media thickness (IMT) in the common carotid artery (CCA) are related to cardiovascular risk in essential hypertension. Angiotensin II plays an important role in structural and functional changes in the vasculature. In this study, we evaluated the long-term effect of the angiotensin II receptor blocker, valsartan, on IMT, arterial stiffness, and hemodynamics in the CCA in patients with essential hypertension. A prospective 24 month study of treatment with valsartan (80-160 mg/day) was performed in 24 hypertensive patients. An ultrasound of the CCA was carried out to determine IMT, the cross-sectional distensibility coefficient (CSDC), the carotid arterial stiffness index beta, and diastolic flow velocity to systolic flow velocity ratio (Vd/Vs). Treatment with valsartan for 24 months reduced systolic and diastolic blood pressure significantly. Compared to baseline, the decrease in pulse pressure was greater after 24 months treatment than after 12 months treatment. Valsartan did not influence IMT; however, after 24 months, it caused a significant increase in CSDC and a decrease in stiffness index beta compared to baseline. These changes were not observed after 12 months of treatment. In addition, Vd/Vs, a sensitive marker of relative diastolic blood flow, increased after 24 months' treatment with valsartan. These results suggest that long-term treatment with valsartan improves vascular wall function and hemodynamics in patients with essential hypertension.

A case of hyperreninemic hypertension with bilateral positive captopril renography but without renovascular stenosis.

A 34-year-old woman was admitted to our hospital because of hypertension with hypokalemia. Her past medical history revealed that at age 24 she had been diagnosed with left renal lithiasis and had undergone extracorporeal shock-wave lithotripsy (ESWL). Physical examination showed that her peripheral pulses were intact and no peripheral edema or audible bruits were detected. Her serum potassium concentration was 2.7 mEq/mL, her plasma aldosterone concentration (PAC) was 96.7 ng/dL, and her plasma renin activity (PRA) was 28.1 ng/mL/h. Intrarenal lobar artery flow pattern assessed by Doppler ultrasound showed no abnormality. A renogram demonstrated a normal symmetrical tracing pattern. However, administration of 50 mg captopril induced delayed transit of tracer in both kidneys. Selective angiographic studies showed no stenotic lesions in the proximal to distal renal arteries. Blood sampling from each renal vein showed no laterality of PRA. While the possibility of the Page kidney phenomenon resulting from ESWL could not be excluded completely, the patient was diagnosed as a very rare case of hyperreninemic essential hypertension with positive captopril renography in both kidneys.

Osteopontin in rat renal fibroblasts: functional properties and transcriptional regulation by aldosterone.

Osteopontin (OPN), a proinflammatory cytokine, plays an important role in renal fibrosis. We reported that plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. However, the regulatory mechanism of OPN by aldosterone remains unclear. Here, we report the transcriptional regulation of OPN expression by aldosterone and the functional effects of aldosterone-mediated OPN transcription in renal fibroblasts. Aldosterone induced OPN expression in a dose-dependent manner with significant responses at 10 nmol/L (1.6+/-0.2-fold of controls, P<0.05, n=5) and elicited maximal effects at 10 micromol/L (3.5+/-0.4-fold of controls, P<0.01, n=5). Aldosterone increased OPN expression in a time-dependent manner with a maximal effect after 48 hours (2.7+/-0.3-fold of controls, P<0.01, n=5). This effect was abolished by the mineralocorticoid receptor (MR) antagonist spironolactone. Luciferase promoter deletion assays identified a novel cis regulatory element (-2153 to -1758) in the OPN promoter that is responsive to aldosterone. This element contains an activator protein-1 (AP-1) and nuclear factor kappa B (NF kappaB) site. Electrophoretic mobility shift assays, supershift assays, and chromatin immunoprecipitation assays identified both AP-1 and NF kappaB as the DNA binding proteins induced by aldosterone with spironolactone inhibiting aldosterone-induced AP-1 or NF kappaB activity. OPN-siRNA inhibited completely the induction of cell proliferation, type I, III, and IV collagen synthesis by aldosterone. These results indicate that aldosterone induced MR-mediated OPN expression through AP-1 and NF kappaB activation and suggest that aldosterone plays an important role in renal fibrosis through the induction of OPN.

Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study.

BACKGROUND: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness. OBJECTIVES: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness. METHODS: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5-10 mg/d) or candesartan (8-12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment. RESULTS: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (-7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect. CONCLUSION: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT.

Relationship between cardio-ankle vascular index (CAVI) and carotid atherosclerosis in patients with essential hypertension.

Aortic stiffness measured by aorta-iliac or carotid-femoral pulse wave velocity (PWV) predicts all-cause and cardiovascular mortality. Brachial-ankle PWV (baPWV) has been developed as a more convenient assessment of arterial stiffness. However, the problem with clinical use of baPWV is that the index itself is closely dependent on blood pressure. Recently, a new method, termed the cardio-ankle vascular index (CAVI), has been proposed in Japan to overcome the disadvantages associated with measuring PWV. However, its clinical usefulness has not yet been fully clarified. In the present study, we compared the usefulness of CAVI with that of ultrasound for evaluating atherosclerosis in patients with essential hypertension. CAVI was measured in 70 hypertensive patients. The intima-media thickness (IMT), cross-sectional distensibility coefficient (CSDC), stiffness parameter beta, and mean diastolic (V(d)) and systolic (V(s)) flow velocities were evaluated by carotid ultrasound. The V(d)/V(s) ratio, an index of peripheral arterial resistance, was also calculated. CAVI was positively correlated with IMT (r=0.360, p=0.0022) and stiffness beta (r=0.270, p=0.0239) and negatively correlated with V(d)/V(s) (r=-0.471, p<0.0001) and CSDC (r=-0.315, p=0.0079). Stepwise regression analysis revealed that age (r=0.475, p<0.0001) and pulse pressure (r=0.492, r<0.0001) were independent determinants of CAVI. These results suggest that CAVI is a useful clinical marker for evaluating atherosclerosis and arteriolosclerosis in patients with essential hypertension.