Carotid hemodynamics is associated with monocyte count determined by serum homocysteine level in patients with essential hypertension.

To examine the association between pulsatility index (PI) in the common carotid artery (CCA) as a marker of vascular resistance and cardiovascular risk factors, including serum homocysteine and inflammation, 67 hypertensive patients were enrolled. PI correlated with homocysteine and interleukin-6, monocyte count, gender, age and BMI, with monocyte count and age being independent determinants for PI. In turn, monocyte count correlated with homocysteine, tumor necrosis factor-alpha, and HDL-cholesterol, BMI, and gender, with HDL-cholesterol and homocysteine being independent determinants for monocyte count. These results indicated monocyte count determined by homocysteine is associated with arterial stiffness in hypertensive patients.

Comparison of the effect of combination therapy with an angiotensin II receptor blocker and either a low-dose diuretic or calcium channel blocker on cardiac hypertrophy in patients with hypertension.

Left ventricular hypertrophy (LVH) regression is an important issue in hypertensive patients. Patients with LVH who had received the angiotensin receptor blocker (ARB) treatment for 8 weeks and had not reached the target blood pressure level were enrolled in the study. Patients were assigned to either losartan (50 mg)/hydrochlorothiazide (HCTZ, 12.5 mg) group or ARB + CCB group (usual dose of ARB and calcium channel blocker, CCB). After 48 weeks, LV mass index was found to be reduced significantly in the losartan/HCTZ group but not in the ARB + CCB group. These results suggest that combination therapy of an ARB and diuretic has greater potential to cause regression compared with an ARB and CCB.

Osteopontin plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic nephropathy.

BACKGROUND/AIMS: Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy. METHODS: Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed. RESULTS: Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistochemistry showed high levels of OPN expression in the proximal tubules of WT-DM mice. Kidney weight and urinary albumin excretion increased to similar levels in the WT-DM and KO-DM mice. Interstitial fibrosis was increased in WT-DM mice compared to KO-DM mice. However, there were no differences in the degree of mesangial expansion or glomerular hypertrophy between the two groups. F4/80-positive cells (macrophages) and FSP-1-positive cells (fibroblasts) showed significantly higher infiltration in WT-DM mice than in KO-DM mice. Renal mRNA expression of NADPH oxidase subunits and urinary 8-isoprostane excretion were also increased in WT-DM mice. CONCLUSIONS: These results indicated that OPN is a key molecule that induces interstitial fibrosis in the diabetic kidney, but does not induce glomerular sclerosis.

Relationship between renal hemodynamics and urinary type IV collagen in patients with essential hypertension.

Urinary type IV collagen excretion (uT4C) in diabetic patients is higher than in normal subjects. In this study, we investigated the relationship between uT4C and renal hemodynamics in 42 patients with essential hypertension. The renal resistive index (RI) is calculated from blood flow velocities measured using pulsed-wave in interlobar arteries. There was a significant correlation between uT4C to creatinine ratio (uT4C/uCr) and age, hemoglobin A1c (HbA1c), and RI. A stepwise regression analysis showed that RI was independently associated with uT4C/uCr. These results indicated that uT4C may be a marker of renovascular stiffness due to glomerulosclerosis in patients with essential hypertension.

[Ultrastructure of glomerular podocyts in the incipient phase of minimal change nephrotic syndrome with thin basement membrane disease].

An 80-year-old woman was referred to the Division of Nephrology at Ehime University Hospital because of leg edema in December 2010. She had been treated with 300 mg of tocopherol for scleroderma since 2007 and treated with 9 mg of prednisolone (PSL) for autoimmune hearing loss since 2010. Due to the occurrence of mild hematuria (5-9/HPF), proteinuria (0.9 g/day) and an increased serum creatinine level (1.31 mg/dL), a renal biopsy was performed. Light microscopy (LM) showed minor abnormality in the glomeruli, and immunohistology showed the absence of deposits of immunoglobulins and complements. Electron microscopy (EM) showed a thin glomerular basement membrane with a limited level of podocyte abnormalities. Due to the findings of intimal thickening of interlobular arteries and subcapsular accumulation of global sclerosis on LM, she was diagnosed with nephrosclerosis and thin basement membrane disease. Four weeks later, her leg edema had increased considerably and urinary protein had increased to 12.4 g/day. The second biopsy showed similar findings in LM and IF as the first biopsy, but EM revealed diffuse foot process effacement. She was diagnosed with minimal change nephrotic syndrome (MCNS) and treated with methylprednisolone pulse therapy followed by 40 mg of oral PSL. Her urinary protein had completely disappeared 6 weeks later. Complete remission with PSL treatment indicates that urinary protein at first renal biopsy was due to MCNS. Our case exhibited podocyte features in the incipient phase of human MCNS.

A patient with myeloperoxidase antineutrophil cytoplasmic antibody-positive polyangiitis who developed sensorineural hearing loss and scleritis.

A 70-year-old woman was admitted to our hospital because of sudden hearing loss. She was treated with intratympanic dexamethasone, but her hearing impairment progressed. After admission, she developed scleritis of her left eye. Laboratory findings included elevated white blood cell count and C-reactive protein level, microhematuria, and proteinuria. Serology was positive for myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA), but negative for proteinase 3 (PR3)-ANCA. Renal biopsy revealed a single glomerulus with extensive glomerular tuft necrosis, indicating necrotizing vasculitis. She was diagnosed with MPO-ANCA-associated polyangiitis. ANCA-related polyangiitis should be considered in the differential diagnosis of sudden deafness or scleritis.

Osteopontin deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney.

Osteopontin (OPN) has been implicated in the pathology of several renal conditions. Recently, we demonstrated in vitro that aldosterone has important roles in collagen synthesis by inducing OPN (Irita J, Okura T, Kurata M, Miyoshi K, Fukuoka T, Higaki J. Hypertension 51: 507-513, 2008). The aim of the present study was to clarify the roles of OPN in aldosterone-mediated renal fibrosis by infusing aldosterone into either wild-type (WT) or OPN knockout mice (OPN(-/-)). We used uninephrectomized mice treated with aldosterone and high salt to exacerbate renal fibrosis. After 4 wk of treatment with aldosterone, we showed similar increases in systolic blood pressure in both strains of mice. Urine albumin excretion was greater in aldosterone-infused WT mice than in aldosterone-infused OPN(-/-) mice. Immunohistochemical analysis showed high levels of OPN expression in aldosterone-infused WT mice. Interstitial fibrosis and inflammatory infiltrations were increased in aldosterone-infused WT mice compared with either vehicle-infused WT or aldosterone-infused OPN(-/-) mice. These changes were ameliorated markedly by eplerenone treatment in aldosterone-infused WT mice. Aldosterone-infused WT mice also had increased expression of NADPH oxidase subunits compared with aldosterone-infused OPN(-/-) mice. We observed a marked increase in oxidative stress markers in aldosterone-infused WT mice compared with aldosterone-infused OPN(-/-) mice. These results indicate that OPN is a promoter of aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney and suggest that inhibition of OPN may be a potential therapeutic target for prevention of renal injury.

The relationship between osteopontin and adiponectin in patients with essential hypertension.

The renin angiotensin aldosterone system (RAAS) induces inflammation and accelerates atherosclerosis, contributes to both pro- and anti-inflammatory cytokines. Osteopontin (OPN) is known as a pro-inflammatory cytokine and adiponectin is known as an anti-inflammatory cytokine. C-reactive protein (CRP) not only reflects an inflammatory state but also leads to inflammation. Previous studies clarified that OPN and adiponectin were regulated by RAAS. In this study, we hypothesized that plasma OPN level relates to serum adiponectin level in patients with essential hypertension (EHT). Sixty-two patients (32 females) with EHT were enrolled in this study. They were evaluated for conventional risk factors for atherosclerosis, further plasma aldosterone, plasma OPN, serum adiponectin, and CRP levels were assayed. There were significant gender differences in creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-denisty lipoprotein(LDL) cholesterol, log transformed (ln) adiponectin and ln CRP. Osteopontin was correlated positively with aldosterone and ln CRP (r = 0.277, p = 0.029, r = 0.278, p = 0.029, respectively), negatively with adiponectin (r = -0.346, p = 0.006). Ln adiponectin was correlated positively with HDL cholesterol (r = 0.373, p = 0.003) and negatively with gender (male as 1), creatinine, triglyceride, aldosterone, and ln CRP (r = -0.55, p < 0.001, r = -0.279, p = 0.028, r = -0.406, p = 0.001, r = -0.307, p < 0.015, r = -0.289, p = 0.023, respectively). Stepwise regression analysis showed that adiponectin was an independent predictor of OPN ß= -0.0339, p = 0.004). Our results suggest that OPN and adiponectin are related to each other underlying the mechanisms of RAAS and inflammation.

Association between cystatin C and inflammation in patients with essential hypertension.

BACKGROUND: Serum cystatin C is not only a marker of renal function but also acts as an independent risk factor for cardiovascular damage, heart failure, and death. It is known that the initiation and progression of these cardiovascular events contributes to renal dysfunction and chronic inflammation. In this study, we investigated the relationship between cystatin C and proinflammatory cytokines. METHODS: Eighty-eight patients with essential hypertension participated in the study, which involved measuring proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP). RESULTS: Positive correlations were detected between cystatin C and estimated glomerular filtration rate (eGFR) (r = -0.503, p < 0.001), systolic blood pressure (r = -0.246, p = 0.034), and pulse pressure (r = -0.295, p = 0.010). In contrast, serum creatinine correlated only with eGFR (r = -0.755, p < 0.001) and eGFR correlated only with age (r = -0.339, p = 0.001) and not with the other clinical parameters, whereas cystatin C also correlated with log natural (ln) IL-6 (r = -0.247, p = 0.033) and ln TNF-α (r = -0.405, p < 0.001) but not with CRP (r = -0.188, p = 0.108). In contrast, plasma creatinine and eGFR did not correlate with any of these proinflammatory cytokines. Stepwise regression analysis showed that ln TNF-α, eGFR and pulse pressure were independent determinants of serum cystatin C concentration. CONCLUSION: This study showed that cystatin C is a marker of inflammation as well as renal function.

Undercarboxylated osteocalcin is a biomarker of carotid calcification in patients with essential hypertension.

The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 gamma-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (-) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (-) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification.

Renal resistance index is a marker of future renal dysfunction in patients with essential hypertension.

AIM: In patients with essential hypertension (EHT), the intrarenal resistance index (RI) has been shown to be related to the severity of target organ damage (TOD). Cystatin C is has been reported to be related to TOD in EHT. The aim of the present study was to clarify whether the RI predicts future renal function assessed by cystatin C levels in EHT. METHODS: One-hundred and twelve patients participated. RI and cystatin C were measured at baseline, and 12 months later, cystatin C was measured again. RESULTS: The patients were divided into 2 groups according to RI value: the low RI group (RI<0.7) and the high RI group (RI> or =0.7). After 12 months, cystatin C levels were significantly elevated in the high RI group, whereas the levels remained unchanged in the low RI group. Stepwise regression analysis using the baseline values of RI, age, pulse pressure, HbA1c, cystatin C, log-transformed (ln) C-reactive protein and ln urinary albumin/creatinine as covariates, showed baseline RI was the only independent determinant of the time-related changes in cystatin C levels. CONCLUSION: This finding suggests that the renal RI may be a marker of future renal dysfunction in EHT.

[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.

Case of membranoproliferative glomerulonephritis due to essential cryoglobulinemia without hepatitis C virus infection.

An 81-year-old man was admitted to our hospital because of leg edema. Serological studies for anti-neutrophil cytoplasmic antibody (ANCA), anti-double stranded DNA antibodies, and antibodies to hepatitis C and B were negative. Severe hypocomplementemia was present and a cryoglobulin was detected with serum immunoelectrophoresis being positive for the immunoglobulin (Ig)M kappa type. The cryoglobulin was characterized by immunoelectrophoresis which showed that the protein was composed of polyclonal IgG and kappa-type monoclonal IgM. A diagnosis of essential type II cryoglobulinemia was made and the patient underwent a renal biopsy. The renal biopsy revealed endocapillary and mesangial cell proliferation with increased matrix. The resultant lobular appearance of the glomerulus and double contours of the basement membrane were indicative of membranoproliferative glomerulonephritis (MPGN). Immunofluorescence studies demonstrated granular staining in the capillary wall for IgG, IgA, IgM and C4 with little C3 deposition but no C1q. He was finally diagnosed with MPGN due to mixed cryoglobulinemia type II. MPGN with essential cryoglobulinemia type II without evidence of hepatitis C virus infection, like that found in the present case, is very rare.

Light chain deposition disease developing 15 years following the diagnosis of monoclonal gammopathy of undetermined significance.

A 64-year-old woman was admitted because of leg edema. Fifteen years previously she had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Urinary immunoelectrophoresis demonstrated positivity for IgA kappa light chains. Bone marrow aspiration revealed a mild plasmacytosis. Her renal biopsy specimen revealed thickened basement membrane, mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed the deposition of kappa light chains in the capillary wall and nodular lesions. These findings confirmed a diagnosis of light chain deposit disease (LCDD) with MGUS. The development of LCDD in patients with MGUS for fifteen years is very rare.

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.