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.

Antioxidative effects of azelnidipine on mesangial cell proliferation induced by highly concentrated insulin.

Insulin resistance combined with hyperinsulinemia is involved in the generation of oxidative stress. There is known to be a relationship between increased production of reactive oxygen species and the diverse pathogenic mechanisms involved in diabetic vascular complications including nephropathy. The present study found that high doses of insulin affect mesangial cell proliferation through the generation of intracellular reactive oxygen species and the activation of cell signaling pathways. We also examined whether azelnidipine, a dihydropyridine-based calcium antagonist with established antioxidant activity, has the potential to inhibit mesangial cell proliferation. Cell proliferation was increased in a dose-dependent manner by high doses of insulin (0.1-10 microM), but was inhibited by 0.1 microM azelnidipine. Phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 was found to be increased by insulin in a dose-dependent manner (0.1-10 microM). This increased phosphorylation of ERK-1/2 was inhibited by treatment with 0.1 microM azelnidipine. Intracellular oxidative stress was also increased by insulin stimulation in a dose-dependent manner (0.01-10 microM), and 0.1 microM azelnidipine was found to block intracellular reactive oxygen species production more effectively than 0.1 microM nifedipine. The NAD(P)H oxidase inhibitor, apocynin (0.01-0.1 microM), prevented insulin-induced mesangial cell proliferation. Taken together, these results suggest that azelnidipine inhibits insulin-induced mesangial cell proliferation by inhibiting the production of reactive oxygen species. Given these pharmacological characteristics, azelnidipine may have the potential to protect against the onset of diabetic nephropathy and slow its progression.

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.

The effect of losartan and amlodipine on serum adiponectin in Japanese adults with essential hypertension.

BACKGROUND: Adiponectin, an adipocyte-derived protein, is reduced in patients with hypertension and insulin resistance (IR). Angiotensin II receptor blockers (ARBs) have been reported to improve IR and reduce albuminuria. The purpose of this study was to evaluate the influence of an ARB and a calcium channel blocker on serum adiponectin levels in Japanese patients with hypertension who were treated with losartan or amlodipine for 3 months. METHODS: Patients with essential hypertension (EHT) were randomized to treatment prospectively with losartan (50-100 mg/d) or amlodipine (5-10 mg/d) for 3 months. Patients with renal damage and/or macroproteinuria were excluded. The urine albumin/creatinine ratio, homeostasis model assessment (HOMA) index, adiponectin concentration, and tumor necrosis factor-alpha (TNF-alpha) concentration of each patient were evaluated before and after 3 months of treatment. When the HOMA index exceeded 1.73, a patient was considered to have IR. RESULTS: All 40 participants completed both 3-month treatment periods. Study patients were primarily male (52.5%) with a mean (SD) age of 63.8 (10.6) years and a mean body weight of 60.7 (10.8) kg. Patients with EHT and diabetes mellitus (n = 9) and IR (n = 12) had significantly lower adiponectin concentrations than patients who had EHT without diabetes or IR (n = 19; mean [SD], 7.84 [5.54] vs 12.81 [7.36] microg/mL, P = 0.034; and 6.12 [3.04] vs 12.81 [7.36] microg/mL, P = 0.004, respectively). Adiponectin concentrations correlated negatively with body mass index (r = -0.393; P = 0.012) and HOMA index (r = -0.440; P = 0.005) and positively with high-density lipoprotein cholesterol (r = 0.441; P = 0.004) before treatment. Systolic blood pressure was significantly decreased in patients treated with losartan (n = 20; mean [SD], 166 [19] to 140 [15] mm Hg; P < 0.001) or amlodipine (n = 20; 164 [15] to 136 [15] mmHg; P < 0.001), and diastolic blood pressure also was significantly decreased with losartan (93 [14] to 83 [10] mm Hg; P = 0.031) or amlodipine (96 [12] to 82 [10] mm Hg; P < 0.001). Losartan increased adiponectin concentrations (9.56 [6.75] to 10.36 [6.94] microg/mL; P = 0.038), whereas amlodipine had no significant effect (9.67 [6.62] to 10.01 [6.79] microg/mL). The difference in TNF-alpha concentration before and after treatment with losartan and amlodipine did not reach statistical significance (mean [SD], 15.2 [1.4] to 14.8 [1.5] pg/mL; and 14.3 [1.4] to 14.5 [1.7] pg/mL, respectively). CONCLUSION: In this study, Japanese adults with EHT had significant increases in adiponectin after 3 months of treatment with 50 to 100 mg/d of losartan, but not with 5 to 10 mg/d of amlodipine.

Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension.

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.

Coexistence of three distinct adrenal tumors in the same adrenal gland in a patient with primary aldosteronism and preclinical Cushing's syndrome.

A 62-year-old woman was admitted to our hospital because of hypokalemia. Physical examination revealed no signs of excessive adrenocortical steroid production, as are found in Cushing's syndrome. Her plasma renin activity (PRA) was suppressed (0.10 ng/ml per h), and her serum aldosterone level was high (30.0 ng/dl). PRA was not increased after a renin-releasing test. Her plasma adrenocorticotropic hormone (ACTH) level was low (<5 pg/ml), but her serum cortisol level was normal (21.0 microg/dl). Administration of 8 mg dexamethasone did not suppress her plasma cortisol level. Finally, she was diagnosed with clinical primary aldosteronism associated with preclinical Cushing's syndrome. Magnetic resonance image revealed three sequential nodular masses (each 15 mm x 15 mm) in the right adrenal gland. A right adrenalectomy was performed by endoscopy. The three removed tumors appeared to have different characteristics. Microscopic examination revealed that the upper and lower tumors were adrenocortical adenomas, and the middle tumor was a black adenoma. Immunohistochemical staining for the enzymes involved in cortisol biosynthesis suggested that the upper tumor secreted aldosterone, whereas either or both of the two other tumors secreted cortisol. Surprisingly, at 33 years of age, she had been diagnosed with Cushing's syndrome, due to a cortisol-producing adrenocortical adenoma, and she had received a left adrenalectomy. Clinically and pathophysiologically, this was a very rare case.

Plasma osteopontin levels are higher in patients with primary aldosteronism than in patients with essential hypertension.

BACKGROUND: The incidence of cardiovascular events is higher in patients with primary aldosteronism (PA) than in patients with essential hypertension (EHT). Aldosterone has been shown to play an important role in the development of vascular inflammation and myocardial fibrosis in animal models. Elevated serum inflammatory cytokine is an independent cardiovascular risk factor in patients with EHT. In the present study, we compared levels of inflammatory cytokines between patients with PA and EHT. METHODS: The study subjects were 15 patients with PA and 15 age-matched patients with EHT. Serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), high sensitive C-reactive protein (hsCRP), and plasma osteopontin (OPN) levels were measured by enzyme-linked immunosorbent assays. RESULTS: Systolic and diastolic blood pressure (BP) did not differ between the PA and EHT patient groups. Levels of serum IL-6 (P = .563), TNF-alpha (P = .480), and hsCRP (P = .870) did not differ between the two groups. In contrast, plasma OPN levels in patients with PA were significantly higher than those in patients with EHT (P < .0001). There was no relationship between BP and plasma OPN levels in patients with PA. CONCLUSIONS: The present study showed that plasma OPN levels were higher in patients with PA than in patients with EHT.

Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension.

Chronic inflammation is common in hypertension and acts as an independent determinant of arterial blood pressure. Hypertensive patients are reported to have high circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Recently, angiotensin II receptor blockers (ARBs) have been shown to possess benefits in addition to their ability to lower blood pressure, including anti-inflammatory and antioxidative properties within the vasculature. We evaluated the effects of the angiotensin II receptor blocker, valsartan, on these inflammatory cytokines. Thirty-nine patients with essential hypertension participated. These subjects received valsartan, 40 to 80 mg/day. Serum TNF-alpha, IL-6, CRP, and serum amyloid A (SAA) were measured before and after 3 months of treatment with valsartan. Valsartan significantly decreased systolic and diastolic blood pressure (160 +/- 16/92 +/- 11 mm Hg to 147 +/- 21/84 +/- 11 mm Hg, P = 0.001/P = 0.001, respectively). Serum TNF-alpha (9.1 +/- 8.6 pg/mL to 6.1 +/- 1.0 pg/mL, P = 0.006) and IL-6 (9.3 +/- 1.7 pg/mL to 8.9 +/- 1.4 pg/mL, P = 0.005) were significantly reduced after treatment with valsartan. However, C-reactive protein and serum amyloid A did not change. The angiotensin II receptor blocker, valsartan, may inhibit the development of atherosclerosis by lowering serum pro-inflammatory cytokines.

Fibrillary glomerulonephritis associated with monoclonal gammopathy of undetermined significance showing lambda-type Bence Jones protein.

A 79-year-old woman was admitted to our hospital because of leg edema due to a nephrotic syndrome. Urinary and serum immunoelectrophoresis showed positive for the lambda type of Bence Jones protein. A bone marrow aspiration test revealed mild plasmacytosis (6.4% of the total cells). These findings confirmed her diagnosis of monoclonal gammopathy of undetermined significance (MGUS). Her renal biopsy specimen revealed mild mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed positive staining for IgG, IgA, C3, and kappa and lambda light chains in the capillary wall and mesangium area. Electron microscopy showed that the electron deposits in the thickened basement membrane were formed by randomly arranged 16- to 18-nm nonbranching fibrils. A Congo red stain for amyloid was negative. These findings corresponded with the diagnosis of fibrillary glomerulonephritis. Therefore, this case showed a rare combination of fibrillary glomerulonephritis and MGUS.

Granulomatous interstitial nephritis due to isolated renal sarcoidosis.

An 81-year-old woman was admitted to our hospital because of acute exacerbation of chronic renal failure. Her 24-h urine protein value was 0.37 g, but neither hematuria nor leukocyturia was seen. Renal biopsy specimens showed noncaseating granulomas with giant cells in the interstitium. A clinical examination revealed no evidence of tuberculosis, fungus, or malignancy. All of the drugs she had been taking were discontinued, but her renal function continued to deteriorate. No uveitis, erythema nodosum, or common macular skin lesion was seen. A computed tomography scan of the thorax and a total-body gallium-67 scan showed no abnormalities. The serum lysozyme level was greater than four times above normal. Finally, a diagnosis was made, of granulomatous interstitial nephritis due to isolated renal sarcoidosis. Treatment was started with 60 mg/day of prednisolone, and she had an excellent response. Her serum creatinine level decreased to the level shown before the acute exacerbation. It is important to consider renal sarcoidosis as a differential diagnosis in patients with severely progressive renal failure, because corticosteroid therapy is very effective.

Humidifier lung: possible contribution of endotoxin-induced lung injury.

A 56-year-old man was admitted with cough, fever, myalgia, and arthralgia. Chest computed tomography demonstrated bilateral diffuse ground-glass opacities predominantly in the upper lungs. Subpleural non-segmental consolidation was observed in the late phase. Hypersensitivity pneumonitis was suspected, and an environmental provocation test with the incidental use of a home ultrasonic humidifier was positive. Unlike typical hypersensitivity pneumonitis, serum KL-6 levels were normal. Although several microorganisms were isolated from the humidifier water, there was no evidence for immune sensitization. We detected high amounts of endotoxin in the humidifier water, which may have contributed to the lung injury of this patient.