The association between renal elasticity evaluated by Real-time tissue elastography and renal fibrosis.

BACKGROUND: The progression of chronic kidney disease (CKD) depends on the extent of fibrosis in the kidneys; however, a renal biopsy is necessary to evaluate the severity of renal fibrosis. Real-time tissue elastography (RTE), which measures heartbeat-induced tissue displacement, can assess the elasticity of organs. Here, we aimed to investigate the correlation between renal elasticity and the extent of fibrosis in renal biopsy samples. METHODS: We investigated 29 consecutive patients who underwent a renal biopsy at Ehime University Hospital from February 2018 to August 2019. Renal fibrosis was categorized into three grades, mild (< 25%), moderate (25-50%), and severe (> 50%), based on the total affected area within the biopsy sample. The association between renal elasticity assessed by RTE and the grade of renal fibrosis was evaluated, and a receiver operating characteristic curve was used to distinguish the severity of renal fibrosis. RESULTS: The mean age and estimated glomerular filtration rate (eGFR) were 58.8 years and 55.2 mL/min/1.73 m2, respectively. The median urine protein-to-creatinine ratio was 1.24 g/gCr. The mean renal elasticity of mild, moderate, and severe renal fibrosis was 3.40, 3.98, and 4.77, respectively. Renal elasticity of native kidneys was significantly positively correlated with the grade of renal fibrosis (ρ = 0.529, P = 0.003). At the cutoff point of 3.81, the area under the curve, sensitivity, and specificity were 0.778, 68.4%, and 81.8%, respectively. CONCLUSION: Real-time tissue elastography is a promising, non-invasive method for assessing renal fibrosis in patients with CKD.

The association between ear involvement and clinical features and prognosis in ANCA-associated vasculitis.

OBJECTIVE: The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, little is known about the effect of ear involvement on the clinical features and prognosis of AAV. We investigate this issue in this study. METHODS: We retrospectively examined 36 patients diagnosed with OMAAV and 44 patients diagnosed with AAV without ear involvement (non-OMAAV) at Ehime University Hospital from 2013 to 2018. We collected serological findings including ANCA type and titer, C-reactive protein (CRP), serum creatinine level, organ involved at initial diagnosis, treatment, remission, disease relapse, and mortality from medical records. We investigated whether clinical features and outcomes differed between the OMAAV and non-OMAAV groups. RESULTS: Age, ANCA titer, and CRP at initial diagnosis were not significantly different between the two groups, and the rate of intravenous cyclophosphamide (IVCY) use also did not differ. The proportions of patients with concurrent eye involvement, facial palsy (FP), and hypertrophic pachymeningitis (HCP) were significantly higher in the OMAAV than in the non-OMAAV group (p = 0.005, 0.005 and 0.049, respectively), while both renal and peripheral nerve involvement were significantly less common in OMAAV patients (p = 0.04). Among the 30 patients with renal involvement, serum creatinine level at diagnosis was significantly lower in the OMAAV group (p = 0.04). The mortality rate was 8.3% in OMAAV and 6.8% in non-OMAAV cases, but this difference was not significant. The rate of relapse was 33.3% in OMAAV and 13.6% in non-OMAAV cases; this difference was significant (p = 0.04). CONCLUSIONS: Serological measurements of disease activity did not differ between the groups. Eye involvement, FP, and HCP, however, were significantly more common in AAV with ear involvement. In addition, renal involvement was less common and renal impairment was milder in AAV with ear involvement. These findings can be considered clinical features. The relapse rate was significantly higher in AAV with ear involvement.

Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

BACKGROUND: The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-ob/ob mice, a non-alcoholic steatohepatitis mouse model. METHODS: FLS-ob/ob male mice were treated with vehicle (n = 10) and ipragliflozin (n = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels and hepatic mRNA levels related to fibrosis, lipid metabolism and endoplasmic reticulum (ER) stress were compared between the two groups. RESULTS: The body weight and hepatic cholesterol and triglyceride levels were significantly decreased in the ipragliflozin group compared with the control group. Hepatic steatosis and fibrosis were significantly ameliorated by the treatment with ipragliflozin. Hepatic infiltration of macrophage, expression levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and hepatic mRNA levels of ER stress markers were not significantly modulated by the treatment with ipragliflozin. CONCLUSION: Ipragliflozin can be a therapeutic option for patients with NASH. The precise mechanisms of action need to be clarified in future studies.

Pulmonary Hemorrhaging as a Fatal Complication of IgA Vasculitis.

A 64-year-old man was admitted to our hospital for purpuric rash, joint pain, and a fever. He had earlier undergone a follow-up examination for interstitial lung disease. At the current visit, the diagnosis was immunoglobulin A (IgA) vasculitis, based on skin and renal biopsy findings. He developed sudden breathlessness and hemoptysis. Chest computed tomography revealed ground glass opacity in the right lower lung fields, suggesting pulmonary hemorrhaging associated with IgA vasculitis. Despite steroid and cyclophosphamide therapy, and plasma exchange, he died 52 days after admission. Early aggressive therapies may be recommended for old patients with IgA vasculitis who have an additional comorbidities.

Compliance and problems with the surveillance program for HCC diagnosis.

We conducted a multicenter retrospective study for evaluating the background of and diagnostic opportunity for 651 patients with primary hepatocellular carcinoma (HCC). The etiologies were hepatitis B virus (HBV) in 20.0% of patients, hepatitis C virus (HCV) in 36.3%, and non-B non-C (NBNC) in 43.5%. The characteristics of non-alcoholic NBNC HCC patients included low frequency of liver cirrhosis and high frequency of life style-related diseases. The mean diameter of HCC was approximately 4cm. Most patients were diagnosed using ultrasonography and dynamic computed tomography (CT). However, 18.6% of patients were diagnosed using conventional contrast-enhanced CT. Compliance with the surveillance program for HCC diagnosis was 35.4% in HBV carriers and 49.2% in HCV carriers. The main causes of deviation from the program included undiagnosed HBV and HCV carriers, non-compliance with the surveillance program by physicians, and no medical care for HBV and HCV carriers. For an early diagnosis of HCC, it is essential to improve the diagnoses of HBV and HCV carriers, promote the follow-ups of HBV and HCV carriers in hospitals, re-educate physicians, and identify the risk factors of NBNC HCC.

Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice.

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18(-/-) and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.

Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE(-/-)) and ApoE/OPN knockout (ApoE(-/-)/OPN(-/-)) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE(-/-)HD mice, however, significantly suppressed in ApoE(-/-)/OPN(-/-)HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE(-/-)/OPN(-/-)HD mice than ApoE(-/-)HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia.

The Importance of Walking for Control of Blood Pressure: Proof Using a Telemedicine System.

BACKGROUND: Regular physical activity (PA), including daily walking, reduces the risk of many chronic diseases, especially hypertension. Pedometer is a potential motivational aid for increasing PA. In the present study, we used a telemedicine system and analyzed the relationship between daily walking, calculated by pedometers, and blood pressure (BP). METHODS: BP was measured at home twice a day (morning and evening) using an oscillometric automatic device. Body weight (BW) and percent body fat (%BF) were measured after BP measurement. Daily walking steps (DWS) were calculated by a pedometer. These daily parameters were transmitted through the Internet to a central server computer and sent to the Medical Health Center. RESULTS: Sixty-nine (N = 69) hypertensive patients were included in this study. The mean follow-up period was 378 days. Electronic data from a pedometer (DWS) were associated with reduced BW, body mass index, and %BF. Hypertensive patients were divided into two groups based on the DWS. In the high DWS group, morning systolic BP and diastolic BP and evening systolic BP were reduced after induction of the telemedicine system. CONCLUSION: A telemedicine system confirmed the usefulness of walking to control BP in hypertensive patients.

A case of acquired lecithin:cholesterol acyltransferase deficiency with sarcoidosis that remitted spontaneously.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare inherited disorder that causes an extremely low high-density lipoprotein cholesterol concentration in serum. Recently, acquired LCAT deficiency caused by IgG antibodies to LCAT, without any LCAT gene mutation, was reported. Here we describe a case of acquired LCAT deficiency occurring in association with sarcoidosis. The patient was a Japanese female aged 70 years, had no mutation in the LCAT gene exon sequence, but had an LCAT inhibitor factor in her serum, detected using lipoprotein-deficient serum. She was diagnosed with acquired LCAT deficiency. Her abnormalities of serum lipoproteins improved spontaneously during three and a half years. Because they require different treatment strategies, distinction between familial lecithin:cholesterol acyltransferase deficiency (FLD) and acquired LCAT deficiency by gene sequencing is warranted, especially in cases without corneal clouding.

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.

Hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males.

Hyperhomocystemia has been reported to be associated with cardiovascular disease, especially stroke. The resistive index (RI) estimated by carotid ultrasound is an established variable for estimating the risk of cerebral infarction. The aim of this study was to evaluate the relationship between homocysteine concentration and carotid RI, a marker of cerebral vascular resistance in essential hypertensive patients. We measured serum total homocysteine and carotid RI in 261 patients. Multiple linear regression analysis was used to determine the association of homocysteine with carotid RI and intima media thickness (IMT). Age, sex, BMI, systolic blood pressure (SBP), homocysteine, total cholesterol, high density lipoprotein-cholesterol (HDL-C), uric acid, CRP, HbA1c, estimated glomerular filtration rate, and use of antihypertensive agents were included as independent variables. Age, sex, use of antihypertensive agents, HDL-C and homocysteine levels were shown to be significant predictors of carotid RI, but not IMT. Multiple regression analysis in men older than 65 years showed homocysteine and SBP were associated significantly with carotid RI. In elderly male patients, homocysteine was the strongest predictor of carotid RI (B = 0.0068, CI = 0.0017-0.0120, P = 0.011) in the multivariate model. In conclusion, hyperhomocysteinemia is associated with carotid RI, a surrogate marker of cerebral vascular resistance, especially in elderly men.

Kimura's disease associated with membranous nephropathy with IgG4 and phospholipase A2 receptor-positive staining of the glomerular basement membrane.

Kimura's disease is a granulomatous disease of unknown origin that develops in the dermis, subcutaneous tissue and lymph nodes. Kimura's disease is frequently complicated by nephropathy, particularly membranous nephropathy (MN). It has recently been suggested that glomerular immunoglobulin (IgG)4 deposition may play a role in the pathogenesis of idiopathic MN. These IgG4 antibodies are thought to react with antigens, primarily the phospholipase A2 receptor (PLA2R) expressed on the podocyte cell membrane. We herein report a case of Kimura's disease with MN in which a renal biopsy specimen revealed positive staining for anti-IgG4 and anti-PLA2R antibodies.

Effects of dividing amlodipine daily doses on trough drug concentrations and blood pressure control over a 24-hour period.

BACKGROUND: In the treatment of hypertension, once-daily administration of long-acting antihypertensive drugs has been recommended for the improvement of treatment adherence; however, it is unclear whether dividing daily doses has the additional benefit of more ideal blood pressure (BP) control over a 24-hour period. OBJECTIVE: The aim of the study was to investigate whether dividing a 10-mg daily dose of amlodipine, a long-acting calcium channel blocker, is associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, and improved BP control over a 24-hour period. METHODS: Outpatients with essential hypertension were included this open-label, 2-period crossover study. The patients were administered amlodipine 10 mg/d in 2 divided doses for 8 weeks. At week 4, blood was collected just before amlodipine administration for the evaluation of trough plasma amlodipine concentrations. At week 8, 24-hour, daytime, nighttime, and early morning BP, as well as arterial stiffness, were measured using ambulatory BP monitoring (ABPM) and cardio-ankle vascular index (CAVI), respectively. In the subsequent study period, amlodipine 10 mg/d was administered once daily, and the same tests were performed at the same timings as in period 1. RESULTS: Ten patients were enrolled (7 men, 3 women; mean age, 61.0 [15.3] years). Mean 24-hour BP with twice-daily administration was not significantly lower than that with once-daily administration (129.7 [7.3]/80.1 [7.9] mm Hg vs 130.5 [11.8]/80.1 [7.9] mm Hg, respectively). Similarly, there were no significant differences in daytime, nighttime, or early morning BP between twice- and once-daily administration. In addition, the differences in trough plasma amlodipine concentrations (22.37 [7.66] ng/mL vs 20.57 [8.22] ng/mL) and CAVI values (8.2 [1.8] vs 8.5 [1.0]) were not significantly different between twice- and once-daily administration. CONCLUSIONS: Administering amlodipine in 2 divided doses was not associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, or improved BP control over a 24-hour period in patients with essential hypertension.

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.