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An 86-year-old Japanese woman was referred to our hospital due to the sudden onset of abdominal pain. Abdominal contrast-enhanced computed tomography (CT) revealed no signs of ischemic bowel; however, laboratory investigations revealed metabolic lactic acidosis, elevation of inflammatory markers, and a remarkable elevation in the serum phosphate level. A prompt surgical evaluation revealed non-occlusive mesenteric ischemia (NOMI). Elevated serum phosphate levels may suggest extensive bowel ischemia or infarction, which can lead to a prompt surgical evaluation, even in the absence of specific radiological findings.

Previous reports have shown that bowel preparation can, in extremely rare circumstances, induce severe acute hyponatremia. Polyethylene glycol plus ascorbic acid as a bowel preparation is considered relatively safe with a smaller amount of free water load and a more pleasant taste with additives. We present the case of an 86-year-old man who developed severe acute hyponatremia presenting with tremor and impaired consciousness after colonoscopy, which is life-threatening. The severe hyponatremia in our case was not caused by free water loads from drinking large amounts of water during bowel preparation or hypovolemia due to bowel preparation-induced nausea, vomiting, and diarrhea, but might have been due to non-osmotic stimuli of antidiuretic hormone (ADH) release (i.e., pre-existing nausea, stress, anxiety, pain, stress, or the colonoscopy itself). Our study indicates that it is important to choose safer bowel preparation solutions, to be aware of ingested water volumes, to assess volume status, and also remain aware of other coexisting risk factors for acute hyponatremia, such as medical history, medication, and ADH release, especially in elderly patients.

Background: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are life-threatening complications of diabetes mellitus. Their clinical profiles have not been fully investigated in the Japanese population. Methods: A multicenter retrospective cohort study was conducted in 21 acute care hospitals in Japan. Patients included were adults aged 18 or older who had been hospitalized from January 1, 2012, to December 31, 2016 due to DKA or HHS. The clinical characteristics and outcomes were extracted from patient medical records. A four-group comparison (mild DKA, moderate DKA, severe DKA, and HHS) was performed to evaluate outcomes. Results: A total of 771 patients including 545 patients with DKA and 226 patients with HHS were identified during the study period. The major precipitating factors of disease episodes were poor medication compliance, infectious diseases, and excessive drinking of sugar-sweetened beverages. The median hospital stay was 16 days [IQR 10-26 days] and was longer in the HHS group (19.5 days) compared to the DKA groups (16 days). The intensive care unit (ICU) admission rate was 44.4% (mean) and the rate at each hospital ranged from 0% to 100%. The median ICU stay was 3 days for all groups. The in-hospital mortality rate was 2.8% in patients with DKA and 7.1% in the HHS group. No significant difference in mortality was seen among the three DKA groups. The most common complication was infection (18%), followed by pulmonary edema (2.7%), stroke (2.1%), ventricular arrhythmia (1.6%), and deep vein thrombosis (1%). Conclusions: The mortality rate of patients with DKA in Japan is similar to other studies, while that of HHS was lower. The ICU admission rate varied among institutions. There was no significant association between the severity of DKA and mortality in the study population. Trial registration: This study is registered in the UMIN clinical trial registration system (UMIN000025393, Registered 23th December 2016)

Background:The worldwide spread of coronavirus disease 2019 (COVID-19) is still not under control and vaccination in Japan started in February 2021, albeit later than in Europe and the USA. The COVID-19 vaccination frequently leads to minor adverse reactions, which may be more intense after the second dose. The number of case reports of myocarditis following COVID-19 vaccination have been recently increased., Case summary:We report a case of a 26-year-old healthy man who presented to our hospital with chest pain on 24 May 2021, 4 days after his second COVID-19 vaccination. The electrocardiogram showed ST elevation with upward concavity in I, II, aVL, aVF, V4 to V6, and small Q wave in II, III, aVF. Laboratory studies revealed elevation of troponin I, creatine kinase, C-reactive protein, and negative viral serologies. Acute aortic dissection and pulmonary thromboembolism were ruled out by contrast-enhanced thoracoabdominal computed tomography. An urgent coronary angiogram was performed because an acute coronary syndrome was suspected, but no significant stenosis was found. Cardiac magnetic resonance imaging demonstrated oedema and late gadolinium enhancement of the left ventricle in a mid-myocardial and epicardial distribution., Discussion:Although the temporal association does not prove causation, the very short span between the second vaccination and the onset of myocarditis suggests that this acute myocarditis seemed to be an adverse reaction to COVID-19 vaccine. To the best of our knowledge, this is the first published case of acute myocarditis following COVID-19 vaccine in Asia.

Aims/Introduction: Although increases in urinary protein excretion generally precede a decline in the glomerular filtration rate, non-proteinuric renal impairment is common in patients with diabetes. In the present study, we examined the relationship between indices of arterial stiffness and renal function in type 2 diabetic patients without proteinuria. Methods: Blood sampling, 24-h urine collection, brachial–ankle pulse wave velocity, and 24-h ambulatory blood pressure monitoring were performed in type 2 diabetic patients without overt proteinuria. The ambulatory arterial stiffness index was calculated as (1 – the regression slope of diastolic/systolic ambulatory blood pressure). Estimated glomerular filtration rate (eGFR)was calculated using the simplified prediction equation proposed by the Japanese Society of Nephrology. Results: Of 213 non-proteinuric patients with type 2 diabetes, 60 (28.2%) had a reduced eGFR (

Free fatty acid (FFA)-bound albumin, which is filtrated through the glomeruli and reabsorbed into proximal tubular cells, is one of the crucial mediators of tubular damage in proteinuric kidney disease. In this study, we examined the role of each kind of FFA on renal tubular damage in vitro and tried to identify its molecular mechanism. In cultured proximal tubular cells, a saturated fatty acid, palmiate, increased the expression of monocyte chemoattractant protein-1 (MCP-1), but this effect was abrogated by co-incubation of monounsaturated fatty acid, oleate, or ω-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). Palmitate led to intracellular accumulation of diacylglycerol (DAG) and subsequent activation of protein kinase C protein family. Among the several PKC inhibitors, rottlerin, a PKCθ inhibitor, prevented palmitate-induced MCP-1 expression via inactivation of NFB pathway. Overexpression of dominant-negative PKCθ also inhibited palmitate-induced activation of MCP-1 promoter. Furthermore, palmitate enhanced PKCθ-dependent mitochondrial apoptosis, which was also prevented by co-incubation with oleate or EPA through restoration of pro-survival Akt pathway. Moreover, oleate and EPA inhibited palmitate-induced PKCθ activation through the conversion of intracellular DAG to triglyceride with the restoration of diacylglycerol acyltransferase 2 expression. These results suggest that oleate and EPA have protective effects against the palmitate-induced renal tubular cell damage by inhibiting PKCθ activation.

OBJECTIVE Cross-sectional studies have reported increased levels of urinary type IV collagen in diabetic patients with progression of diabetic nephropathy. The aim of this study was to determine the role of urinary type IV collagen in predicting development and progression of early diabetic nephropathy and deterioration of renal function in a longitudinal study. RESEARCH DESIGN AND METHODS Japanese patients with type 2 diabetes (n = 254, 185 with normoalbuminuria and 69 with microalbuminuria) were enrolled in an observational follow-up study. The associations of urinary type IV collagen with progression of nephropathy and annual decline in estimated glomerular filtration rate (eGFR) were evaluated. RESULTS At baseline, urinary type IV collagen levels were higher in patients with microalbuminuria than in those with normoalbuminuria and correlated with urinary β2-microglobulin (β = 0.57, P < 0.001), diastolic blood pressure (β = 0.15, P < 0.01), eGFR (β = 0.15, P < 0.01), and urinary albumin excretion rate (β = 0.13, P = 0.01) as determined by multivariate regression analysis. In the follow-up study (median duration 8 years), urinary type IV collagen level at baseline was not associated with progression to a higher stage of diabetic nephropathy. However, the level of urinary type IV collagen inversely correlated with the annual decline in eGFR (γ = −0.34, P < 0.001). Multivariate regression analysis identified urinary type IV collagen, eGFR at baseline, and hypertension as factors associated with the annual decline in eGFR. CONCLUSIONS Our results indicate that high urinary excretion of type IV collagen is associated with deterioration of renal function in type 2 diabetic patients without overt proteinuria.

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.

OBJECTIVE Albuminuria in type 2 diabetic patients is a risk factor for cardiovascular disease. We investigated the correlation between albuminuria and spontaneous microaggregation of platelets (SMAP) formed under shear stress. RESEARCH DESIGN AND METHODS The study subjects were 401 type 2 diabetic individuals (252 with normoalbuminuria and 149 with albuminuria) who were examined for SMAP under conditions of shear stress only (no agonist stimulation) and the reversibility of platelet microaggregation after stimulation with 1 μmol/l ADP, measured by a laser light-cattering method. Active glycoprotein IIb/IIIa (GPIIb/IIIa) and P-selectin expression levels on platelets as an index of platelet activation were measured by whole-blood flow cytometry. RESULTS SMAP formation was noted in 53% of diabetic patients. All patients with SMAP showed an irreversible pattern of platelet microaggregates by a low dose of ADP. SMAP was observed in 75% of diabetic subjects with albuminuria and in 39% of those with normoalbuminuria. Multivariate logistic regression analysis identified urinary albumin excretion rate and brachial-ankle pulse-wave velocity as independent factors associated with SMAP. The degree of SMAP correlated with active GPIIb/IIIa (γ = 0.59, P < 0.001) and P-selectin (γ = 0.55, P < 0.001) expression levels. These early-activated platelet profiles were significantly inhibited in albuminuric patients with aspirin intake, although the effect was incomplete. CONCLUSIONS Our study demonstrated an independent association between albuminuria and early changes in activated platelet profiles of type 2 diabetic patients. Further follow-up and intervention studies are needed to establish whether the inhibition of SMAP affects the course of cardiovascular disease in type 2 diabetic patients.

The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity.

Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat diet (LFD; 10% of total calories from fat) or a HFD (60% fat) for 12 wk. Mice fed a HFD showed significant increases in body weight, systolic blood pressure, plasma insulin, glucose, and triglycerides compared with those on a LFD. Accompanying these systemic changes, mice on a HFD showed albuminuria, an increase in glomerular tuft area, and mesangial expansion. These systemic and renal alterations in mice on a HFD were prevented by body weight control with the dietary restriction of feeding a HFD. Furthermore, mice on a HFD showed renal pathophysiological alterations including renal lipid accumulation, an increased accumulation of type IV collagen in glomeruli, an increase in macrophage infiltration in the renal medulla, an increase in urinary 8-hydroxy-2′-deoxyguanosine excretion, and impaired sodium handling. In conclusion, this study suggests that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight.

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

Legumain/asparaginyl endopeptidase (EC 3.4.22.34) is a novel cysteine protease that is abundantly expressed in the late endosomes and lysosomes of renal proximal tubular cells. Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis. We initially found that purified legumain can directly degrade fibronectin, one of the main components of the extracellular matrix, in vitro. Therefore, we examined the effect of legumain on fibronectin degradation in cultured mouse renal proximal tubular cells. Fibronectin processing can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and can be enhanced by the overexpression of legumain, indicating that fibronectin degradation occurs in the presence of legumain in lysosomes from renal proximal tubular cells. Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced. These findings indicate that legumain might have an important role in extracellular matrix remodeling via the degradation of fibronectin in renal proximal tubular cells.

The early identification of type 2 diabetic patients at risk of developing microalbuminuria-an independent risk factor for renal and cardiovascular diseases-is important to improve the patients' outcomes. We investigated whether serum levels of IL-18, a proinflammatory cytokine, were a predictor of early renal dysfunction.A total of 249 Japanese type 2 diabetic patients without overt proteinuria were enrolled in an observational follow-up study (median follow-up 7 years), and their stage of diabetic nephropathy was classified and their estimated glomerular filtration rate (eGFR) was calculated annually.At baseline, serum levels of IL-18 were higher in subjects with microalbuminuria (n = 76) than in those with normoalbuminuria (n = 173). Elevated serum levels of IL-18 were associated with the progression of nephropathy to a higher stage in normoalbuminuric subjects (118 [interquartile range 91-159] ng/l vs 155 [interquartile range 121-205] ng/l, p = 0.003), but not in microalbuminuric subjects (154 [interquartile range 113-200] ng/l vs 160 [interquartile range 101-190] ng/l, p = 0.50). The adjusted risk for developing microalbuminuria was 3.6 (95% CI 1.2-10.4) in normoalbuminuric subjects with serum IL-18 levels above the median (/=134.6 ng/l), and was significantly enhanced in those urinary AERs at the upper end of the normal range (7.5 mug/min/= AER20 microg/min). Furthermore, the annual rate of decline in eGFR, when examined in the study population as a whole, was significantly greater in subjects with serum IL-18 levels above the median than in other subjects.The results of our observational follow-up study indicate that elevated serum levels of IL-18 may be a predictor of future renal dysfunction in type 2 diabetic patients with normoalbuminuria.

We present a case of a 38-year-old Japanese man with Wegener's granulomatosis complicated with pulmonary-renal syndrome, i.e., diffuse pulmonary hemorrhage and rapidly progressive renal glomerulonephritis. As this is a life-threatening condition, we promptly initiated plasma exchange with intravenous methylprednisolone therapy. Diffuse pulmonary hemorrhage and renal failure were markedly improved. This case merits presentation because there are few clinical studies of the treatment of Wegener's granulomatosis with pulmonary-renal syndrome, particularly with pulmonary hemorrhage.

Oxidative stress-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and the expression of biochemical proapoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMCs) exposed to hydrogen peroxide (H(2)O(2)). H(2)O(2) increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a posttranscriptional modification for p53 activation. H(2)O(2)-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. Although SIRT1 did not affect H(2)O(2)-mediated phosphorylation of mitogen-activated protein (MAP) kinase, it interacted with p53 and inhibited H(2)O(2)-mediated p53 acetylation but not phosphorylation in MMCs. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 deacetylation in mesangial cells. Upregulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases.

A 73-year-old woman was admitted to our hospital because of persistent high fever and cough, generalized myalgia, and renal dysfunction. Laboratory examination revealed severe inflammatory signs, pulmonary fibrosis, progression of renal impairment with active nephritic urinary sediments, and a high titer of myeloperoxidase-antineutrophil cytoplasmic antibody, indicating that she might have microscopic polyangiitis with interstitial pneumonia and rapidly progressive glomerulonephritis. Her renal biopsy, however, showed tubulointerstitial changes with mild glomerular abnormalities, and renal angiography revealed that she had vascular lesions of medium-sized arteries, which were compatible with classical polyarteritis nodosa. Tissue biopsy of the clinically affected organ should be considered in anyone suspected to have vasculitis.

To estimate the frequency of remission/regression of microalbuminuria and to identify factors affecting such outcomes in Japanese patients with type 2 diabetes, we observed 216 patients with type 2 diabetes and microalbuminuria enrolled during an initial 2-year evaluation period for the next 6 years. Remission was defined as shift to normoalbuminuria and regression as a 50% reduction in urinary albumin excretion rate (AER) from one 2-year period to the next. Reduction of urinary AER was frequent, with a 6-year cumulative incidence of 51% (95% CI 42–60) for remission and 54% (45–63) for regression, whereas the frequency of progression to overt proteinuria was 28% (19–37). Microalbuminuria of short duration, the use of renin-angiotensin system-blocking drugs, and lower tertiles for HbA1c (

MAPK/AP-1-dependent regulation of PAI-1 gene expression by TGF-β in rat mesangial cells. Background Receptor-regulated Smads and/or mitogen-activated protein kinases (MAPKs) are involved in transforming growth factor-β (TGF-β)-nduced expression of various genes, including plasminogen activator inhibitor-1 (PAI-1). Because the sequence of the promoter region in rat PAI-1 gene differs from that in the human gene, we examined the mechanisms of TGF-β-induced rat PAI-1 expression in rat mesangial cells. Methods TGF-β1-induced PAI-1 and c-fos mRNA expressions were determined by Northern blot analysis. Activation of MAPKs and Smad proteins was evaluated by an immunoblot analysis. DNA binding activities of nuclear protein were examined by using an electrophoretic mobility shift assay (EMSA). The activities of PAI-1 promoter were measured by a luciferase reporter assay. Results Extracellular-regulated kinase (ERK) and c-Jun NH-terminal kinase (JNK) phosphorylation, c-fos mRNA expression, and activator protein-1 (AP-1) DNA binding activity stimulated by TGF-β1 were completely suppressed by the ERK kinase (MEK) inhibitors. EMSA and reporter analysis revealed that an AP-1-like sequence located in the proximal region of the rat PAI-1 promoter was the target for TGF-β1, and the disruption of this AP-1-like sequence suppressed basal and TGF-β1-induced promoter activation. TGF-β1 also stimulated nuclear translocation of Smads and binding to palindromic Smad binding element (SBE) located in the rat PAI-1 promoter, without being affected by MEK inhibitor. Point mutation and deletion of palindromic SBE did not affect TGF-β1-induced rat PAI-1 promoter activity. Moreover, interferon-γ (IFN-γ) inhibited TGF-β1-induced PAI-1 expression through selectively suppressing the ERK-AP-1 pathway. Conclusion These results suggest that the essential requirement of MAPK/AP-1 activation for TGF-β1-induced PAI-1 expression is unique to rat mesangial cells.

Despite the potentially protective effects of estrogen on bone and cardiovascular tissue as well as against kidney diseases, its effects on diabetic nephropathy are unknown. Here, we examined the therapeutic effectiveness of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, for preventing functional and histological alterations in the kidneys of db/db mice, a model of type 2 diabetes. In the first experiment, ovariectomized female db/db mice were treated with 17beta-estradiol for 8 weeks. The treatment significantly ameliorated albuminuria, attenuated weight gain, and reduced hyperglycemia in diabetic ovariectomized db/db mice. Histologically, the increases in mesangial area and the accumulation of fibronectin were significantly inhibited by 17beta-estradiol. In the second experiment, mice were administered vehicle or raloxifene hydrochloride (3 mg/kg/day) for 8 weeks. Raloxifene significantly reduced mesangial expansion and fibronectin accumulation in db/db mice, but in contrast to 17beta-estradiol, it failed to affect body weight or hyperglycemia. An in vitro experiment further demonstrated that raloxifene inhibited transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity. Thus, our findings suggest that raloxifene, which lacks the harmful effects of estrogen, is useful for the treatment of diabetic nephropathy.

症例は, 53歳女性. 胆石治療の目的にて近医入院中, 発熱とともに血圧低下が出現し, 無尿状態となった. 血液検査にてs-Cre 7.7mg/dL, BUN 67mg/dL, CRP 28.2mg/dLであり, 敗血症に伴った急性腎不全と診断され, 当院に紹介, 集中治療室 (ICU) に入院となった. 入院時, 心電図にて, V1-V3にQSパターンとSTの上昇, 心エコーにて左室壁運動低下, および心筋逸脱酵素の上昇を認めたため, 心筋梗塞の発症を疑い心臓血管カテーテル検査を施行した. 冠動脈には病変なく, 左室造影にて, 心尖部の壁運動低下と心基部の過剰収縮を認めたため, たこつぼ型心筋障害と診断した. 入院後抗菌薬の投与, エンドトキシン吸着, 持続的血液濾過透析による集学的治療に反応し, 全身状態と検査所見の異常は改善し, 入院第7病日にはICUを退室し, 血液透析 (HD) に移行することができた. 第13病日から利尿がみられ, 第25病日にはHDから離脱することができた. 退院前には, 心電図, 心エコー所見は正常化した. 本症例は, 敗血症・急性腎不全がストレスとなり, たこつぼ型心筋障害を発症したと考えられ, 急性腎不全の合併症として, 今後本症候群の発症に注意すべきである.

Persistent proteinuria has been indicated to be a major risk factor for the development of tubulointerstitial damage through a process of proinflammatory molecule expression. Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to recruitment of immune cells into the renal interstitium in acute and chronic renal diseases. However, the molecular mechanisms by which proteinuria causes MCP-1 expression in proximal tubular cells have not been fully clarified. In this study, we examined whether albumin overload-induced MCP-1 expression was regulated by mitogen-activated protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1 expression and MCP-1 promoter/luciferase reporter activity. U-0126 also inhibited an increase in nuclear factor-κB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells. In addition, we found that U-0126 inhibited BSA-induced nuclear factor-κB reporter activity and inhibitory protein degradation in mProx cells. In conclusion, these findings indicate that ERK signaling is involved in BSA-induced MCP-1 expression in mProx cells.

Recent large clinical trials indicate that angiotensin-converting enzyme inhibitors (ACE-I) attenuate the detrimental outcome of progressive renal disease. The hemoregulatory tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP, AcSDKP) is hydrolyzed by ACE, and plasma Ac-SDKP level is increased by fivefold after treatment with ACE-I. Ac-SDKP was found to ameliorate cardiac and renal fibrosis in hypertensive animal models. However, the molecular mechanisms by which Ac-SDKP mediates anti-fibrotic effects remain unclear. This study is an examination of the interaction between Ac-SDKP and transforming growth factor-beta (TGF-beta), one of the key cytokines in the progression of renal disease, in human mesangial cells. Ac-SDKP inhibited TGF-beta1-induced plasminogen activator inhibitor-1 (PAI-1) and alpha2 (I) collagen mRNA. Ac-SDKP suppressed not only TGF-beta1-induced Smad2 phosphorylation at Ser-465/467 in a dose-dependent manner, but also the nuclear accumulation of receptor-regulated Smads (R-Smad), Smad2 and Smad3. As expected, Ac-SDKP inhibited TGF-beta-responsive Smad-dependent luciferase reporters, 3TP-luc and 4xSBE-luc. Immunofluorescence analysis revealed that the inhibitory Smad, Smad7, was exported to the cytoplasm from the nucleus by the treatment with Ac-SDKP. These findings provide novel evidence that Ac-SDKP inhibits TGF-beta signal transduction through the suppression of R-Smad activation via nuclear export of Smad7, highlighting an alternative mechanism involved in the reno-protective efficacy of ACE-I.

15-Deoxy-Δ 12,14 -prostaglandin J 2 inhibits IL-1β–induced cyclooxygenase-2 expression in mesangial cells . Background Cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins, is induced in mesangial cells in response to proinflammatory cytokines. Recently, 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), one of the natural ligands of peroxisome proliferator-activated receptor γ (PPARγ), has been reported to have an anti-inflammatory effect. Therefore, we examined the effect of 15d-PGJ 2 on COX-2 expression in cultured rat mesangial cells. Methods Mesangial cells were incubated with 15d-PGJ 2 for 30 minutes and then exposed to interleukin-1β (IL-1β). The expression of COX-2 mRNA and proteins was determined by Northern blot and immunoblot analyses, respectively. Accumulation of prostaglandin E 2 (PGE 2 ) was measured by an enzyme-linked immunosorbent assay (ELISA). Activities of mitogen-activated protein kinases (MAPKs) were evaluated by an immunoblot analysis. DNA binding activities of activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) were examined by an electrophoretic mobility shift assay (EMSA). The activities of PPAR responsive elements (PPRE) and COX-2 promoter were measured by a luciferase reporter assay. Results 15D-PGJ 2 significantly suppressed IL-1β–induced COX-2 expression and PGE 2 production, but thiazolidinediones, synthetic PPARγ ligands, did not affect COX-2 expression. Moreover, the cells transfected with a PPRE luciferase reporter did not respond to 15d-PGJ 2 . IL-1β rapidly activated extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK), which were involved in the up-regulation of COX-2 induction, but 15d-PGJ 2 inhibited the activation of these kinases. 15d-PGJ 2 inhibited the IL-1β–induced increase in binding activities of nuclear proteins to consensus AP-1 site and AP-1–like site of COX-2 promoter but not of NF-κB. IL-1β was unable to activate the COX-2 promoter when the AP-1–like site was mutated. Conclusions These data suggest that 15d-PGJ 2 inhibits IL-1β–induced COX-2 expression, independent of PPARγ activation, by suppression of ERK and JNK pathways and AP-1 activation in mesangial cells. Thus, 15d-PGJ 2 may play an important role in the negative feedback mechanism of COX-2 expression in renal inflammation and may be useful as an anti-inflammatory agent.

Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with diabetic nephropathy.BackgroundAlthough genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, the definitive gene has not been identified. To identify the genetic marker for diabetic nephropathy, we examined the association between the (A-C)n dinucleotide repeat polymorphism upstream of the matrix metalloproteinase-9 (MMP-9) gene and diabetic nephropathy in a group of Japanese patients with type 2 diabetes.MethodsPatients were divided into three groups based on their urinary albumin excretion rate (AER) and the stage of diabetic retinopathy as follows: uncomplicated group (U), normal albuminuria (AER

Non-ketotic hyperglycaemia is one of the causes of hemiballism.1 2 The involuntary movement is also sometimes referred to as hemichorea. Hyperglycaemic hemiballism has been thought to occur in patients with pooly controlled diabetes. MRI usually shows a hyperintense lesion of the contralateral basal ganglia in T1-weighted image.3 Although there have been a few pathological studies of hyperglycaemic hemiballism, no studies have shown pathological alteration in the subthalamic nucleus (corpus Luysii) which is responsible for the hemiballism resulting from ischaemia.4 Originally, Schwarz and Barrows reported hyperglycaemic hemiballism as ‘hemiballism without involvement of Luys' body.’2 We herein report a case of hyperglycaemic hemiballism in which immunohistochemistry showed the presence of activated microglia in the subthalamic nucleus contralateral to the hemiballism. A 59-year-old man was admitted because of involuntary movement of his right arm that had progressed over 3 days. He had had diabetes mellitus for 19 years treated with insulin injections. Three years prior to admission, he was started on continuous ambulatory peritoneal dialysis (CAPD) due to diabetic nephropathy. One month prior to admission, he began …

Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent glomerular dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway.

Background. Glomerular mesangial cells were found to have a considerable number of receptors for insulin-like growth factor I (IGF-I) and to proliferate in response to IGF-I. However, the mechanism of the metabolic actions of IGF-I in mesangial cells has not yet been fully elucidated. Methods. In order to clarify the effect of IGF-I on glucose metabolism in mesangial cells, we performed a kinetic analysis of 2-deoxyglucose (2-DOG) uptake, the first step of glucose metabolism, and examined the gene and protein expression of glucose transporter 1 (GLUT 1), a major facilitative glucose transporter in mesangial cells. Results. IGF-I was able to increase 2-DOG uptake significantly after 12 h, and the kinetic analysis of 2-DOG uptake revealed that IGF-I increased maximum velocity (Vmax) without changing Michaelis constant (Km). The expression of GLUT 1 mRNA was increased after the exposure to IGF-I and reached the maximal level at 6 h, followed by an increase in its protein expression. Conclusions. These results suggest that IGF-I plays an important role in glucose metabolism in glomerular mesangial cells by enhancing glucose transport through an increase in the expression of GLUT 1.

Although relatively rare, hypothyroidism remains a significant cause of moderate to severe pericardial effusion. Pericardial effusion secondary to hypothyroidism does not usually cause symptoms since it tends to regress slowly and ultimately disappear several months after the patient has reverted to the euthyroid state. Thus, hypothyroidism must be ruled out in patients with an unexplained pericardial effusion, both to improve prognosis and to avoid unnecessary pericardiocentesis. Even when they have a massive pericardial effusion, patients should receive the standard treatment for hypothyroidism. We herein describe a 79-year-old woman with a massive pericardial effusion associated with hypothyroidism who showed a good response to standard levothyroxine replacement therapy after 5 months.

To the editor, Immunosuppressive therapy, including high-dose corticosteroids and other immunosuppressive agents, has markedly improved systemic lupus erythematosus (SLE) patient survival. However, these patients are deemed at increased risk for opportunistic infection because of impaired immunity due to immunosuppressive therapy. We encountered a patient with diVuse lupus nephritis complicated with severe thrombocytopenia and haemolytic anaemia, whose haematological manifestations might have been related to cytomegalovirus (CMV) reactivation. A 23-year-old Japanese man was hospitalized because of urinary abnormalities. Two months prior to admission, proteinuria and haematuria had been detected on a routine health examination. On admission, physical Wndings were unremarkable; however, laboratory testing revealed active nephritic urinary sediments with marked urinary protein excretion (2.6 g per day), low serum complement [C3 (24 mg/dl) and C4 (6 mg/dl)] values, and high titre of antidouble-stranded DNA (ds-DNA) antibody (63.1 IU/ml; reference range < 20). Renal biopsy revealed diVuse mesangial proliferation and capillary wall thickening on light microscopy, “full-house” pattern on immunoXuorescence microscopy, and mesangial/subendothelial electron-dense deposits on electron microscopy. During hospitalization, constitutional manifestations (i.e., fever and general myalgia), arthritis, and lymphopenia developed; thus, we diagnosed him to have SLE associated with diVuse lupus nephritis [International Society of Nephrology (ISN), Class IV]. Intravenous methyl prednisolone (0.5 g, three consecutive days) once every 2 weeks and oral corticosteroid (prednisolone, 55 mg per day) was started. This treatment improved his immunological abnormalities (i.e., hypocomplementaemia and elevated anti-ds-DNA antibody levels); however, his renal function deteriorated and serum creatinine levels were elevated to around 3.0 mg/dl with nephrotic-range proteinuria. On the 60th hospital day, gross haematuria, systemic petechia, melena, and epistaxis suddenly developed. He was afebrile, and physical examination was unremarkable except the bleeding tendency; however, laboratory data revealed marked thrombocytopenia (9,000/ l). Peripheral blood smear showed no morphological abnormalities. Coagulation screening results and serum transaminases were normal, but a haptoglobin level was undetectable. Bone marrow aspiration test showed a normal level and morphology of megakaryocytes, an active erythroid system, and no signs of haemophagocytosis. Abdominal computed tomography revealed no remarkable abnormalities. Platelet-associated IgG (157 ng/10 cells; reference range 5.0–25.0 ng/10 cells) was positive, but direct Coombs’ test, anti-granulocyte antibody, anti-cardiolipin-IgM/IgG antibodies, anti2 glycoprotein I antibody, cryoglobulin, and plasma activity of von Willebrand factorcleaving protease (69.5%) showed negative or normal results. Evaluation for bacterial infection, including blood and urine cultures, yielded negative results. Anti-parvovirus B 19 IgM antibody and Epstein–Barr (EB) virus plasma viremia were also negative, but peripheral blood CMV antigenaemia assay showed an equivocal result (5/34,000 peripheral blood leukocytes) [1]. Platelets transfusion for the marked bleeding symptoms was initiated. Intravenous methyl prednisolone (1.0 g per day, three consecutive days) followed by oral corticosteroid (prednisolone, 55 mg per T. Sugimoto (&) · M. Aoyama · N. Takeda · M. Sakaguchi · Y. Nishio · T. Uzu · A. Kashiwagi Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan e-mail: toshiro@belle.shiga-med.ac.jp

Panniculitis rarely occurs in the course of systemic lupus erythematosus (SLE). When it occurs, it is thought to be mainly lupus erythematosus panniculitis (LEP). Here we describe a 32-year old Japanese woman with chronic SLE, who simultaneously presented facial lymphocytic lobular panniculitis and pancytopenia due to haemophagocytic syndrome. She showed several auto-antibodies against trilineage haematopoetic cells, an anti-cardiolipin antibody, and no evidence of viral infection, indicating that her haemophagocytic syndrome might be autoimmune-associated haemophagocytic syndrome. The panniculitis and haemophagocytic syndrome presented simultaneously, and these manifestations were dramatically improved with corticosteroid therapy; therefore, the lymphocytic lobular panniculitis could be linked to autoimmune-associated haemophagocytic syndrome in this case. Lupus (2007) 16, 363—365.

A middle-aged woman with rheumatoid arthritis was admitted because of cellulitis on the leg. Twenty-four hours after admission haemorrhagic blisters and bullae appeared on the lower extremity. Despite intensive therapy she died due to multiple organ failure at 50 h after admission. Post-mortem examination revealed diffuse necrosis of fascia in her leg. Bacteriological study showed Escherichia coli in her blood cultures and fluid from a bulla, indicating that she had necrotizing fasciitis resulting from Escherichia coli. Necrotizing fasciitis is an uncommon but potentially fatal infection; thus, this disease should be considered in the differential diagnosis of any cutaneous manifestations in patients with rheumatoid arthritis.

The Ras GTPase plays an essential role in many cellular signal transduction events. Activation of the mitogen activated protein (MAP) kinase is a primary consequence of Ras activation and plays a key role in mediating Ras signal transduction. A novel kinase, KSR, has recently been functionally isolated as a positive regulator of Ras signaling in Caenorhabditis elegans vulval induction and Drosophila photoreceptor differentiation. We have examined the effect of KSR on growth factor and Ras-induced MAP kinase signaling in mammalian cells. Surprisingly, we observed that KSR specifically blocks EGF and Ras-induced phosphorylation and activation of ternary complex factors (TCF), physiological substrates of MAP kinases, without affecting the activation of MAP kinase itself. A kinase-deficient mutant of KSR, KSR-RM, appears to function as a dominant interfering mutant which elevates phosphorylation of Elk-1, a member of the TCF family, and Elk-1-dependent transcription. The effect of KSR on Elk-1 was significantly decreased by inhibition of calcineurin, a putative Elk-1 phosphatase. These observations demonstrate that KSR is capable of uncoupling the MAP kinase activation from its target phosphorylation, and thus provide a novel mechanism for modulating the Ras-MAP kinase signaling pathway. This study provides the first evidence that signal output of MAP kinase cascades is subject to regulation at a level independent of MAP kinase activity.

Microscopic polyangiitis, deWned as a necrotizing vasculitis aVecting small vessels (i.e., capillaries, venules, or arterioles), commonly manifests as rapidly progressive glomerulonephritis with necrotizing glomerular tuft, or alveolar hemorrhage or interstitial pneumonia with pulmonary capillaritis. Anti-neutrophil cytoplasmic antibodies (ANCA) are positive in 50–80% of patients with microscopic polyangiitis [1]. Here we describe a patient with myeloperoxidase (MPO)ANCA-related microscopic polyangiitis whose dominant manifestation was sensorineural hearing loss. A 77-year-old Japanese woman was admitted because of progression of renal dysfunction. At age 74 she had developed dyspnea on eVort, and a chest computed tomography (CT) scan revealed bilateral pulmonary Wbrosis in a local hospital. As no marked clinical and laboratory abnormalities (i.e., constitutional symptoms, renal dysfunction, urinary abnormalities, inXammatory signs, or auto-antibodies) had been identiWed, she was diagnosed as having idiopathic interstitial pneumonia and was closely observed without any medication. One month prior to the admission she had started to report constitutional manifestations (i.e., fever, general myalgia, and weight loss). Moreover, a marked increment of serum creatinine levels with active urinary abnormalities, from 0.66 to 1.03 mg/dl during the last 1 month, had been found. As a test for MPO-ANCA was positive (101 EU; normal value

The transcription factor Elk-1 is a component of ternary complex factor and regulates gene expression in response to a wide variety of extracellular stimuli. Phosphorylation of the C-terminal domain of Elk-1, especially at serine 383, is important for its transactivation activity. Recently mitogen-activated protein kinases, such as extracellular signal-regulated kinase, stress-activated protein kinase, and p38 mitogen-activated protein kinase have been demonstrated to be Elk-1 kinases. However, negative regulators of Elk-1, such as protein phosphatases, still remain to be identified. Here we report that COS cell lysates were able to dephosphorylate an extracellular signal-regulated kinase-phosphorylated glutathione S-transferase-Elkc fusion protein, including serine 383. The phosphatase activity was inhibited by cyclosporin A (a calcineurin inhibitor) but not by okadaic acid (a PP1 and PP2A inhibitor). Purified calcineurin also could efficiently dephosphorylate glutathione S-transferase-Elkc in vitro. Pretreatment of COS cells with cyclosporin A significantly enhanced epidermal growth factor-induced serine 383 Elk-1 phosphorylation whereas ionomycin inhibited the Elk-1 phosphorylation. These data provide both in vitro and in vivo evidence that calcineurin is the major Elk-1 phosphatase and plays a critical role in Elk-1 regulation. The identification of calcineurin as the major Elk-1 phosphatase may provide a mechanism for Elk-1 regulation by Ca2+ signals as well as a possible biochemical basis for the neurotoxicity and nephrotoxicity of the immunosuppressant drug cyclosporin A.

To evaluate whether the presence of microalbuminuria can predict cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 297 Japanese NIDDM patients with Albustix-negative urine. Patients were divided into two groups, normoalbuminuric (n = 201) and microalbuminuric (n = 96) and followed until death or the end of 1994 (the mean follow-up period was 6.4 years). During the follow-up period, 28 deaths (14 normoalbuminuric and 14 microalbuminuric patients) were confirmed and only 10 deaths were attributed to cardiovascular disease (6 normoalbuminuric and 4 microalbuminuric patients). Although the age- and sex-adjusted mortality rate from all-causes in the microalbuminuric group was significantly higher than that in the normoalbuminuric group (13.5 vs. 8.2 per 1000 person-years: P0.05), the mortality rate from cardiovascular disease was not significantly different between two groups (3.4 vs. 3.3 per 1000 person-years). On age-adjusted Cox proportional hazards analysis. HbA1c and triglyceride were independent risk factors in mortality from cardiovascular disease, while microalbuminuria was not associated with cardiovascular death. These results indicate that, unlike Caucasians, the presence of microalbuminuria can not predict cardiovascular death in Japanese subjects with NIDDM.

A new type nonflammable large power transformer system is proposed in which the excellent cooling characteristics and insulation properties of nonflammable perfluorocarbon (PFC) liquid is utilized. In the system, transformer windings are put in an insulating cylinder filled with PFC liquid. The core includes cooling panel through the liquid. The space between the insulating cylinder and tank is filled with compressed SF6 gas. This paper describes the insulation characteristics of main insulation and inter-winding insulation models which simulate the transformer. It is found that (1) higher withstand voltage is expected by means of insulation barriers in the main insulation model; (2) partial discharge in inter-winding insulation model is beginning to behave in a constant electric field strength on the point of 0.1 mm liquid gap length.

Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. Because ET-1 was found to stimulate the tyrosine phosphorylation of unidentified cellular proteins in cultured mesangial cells, protein tyrosine kinase might serve as one of the important signals leading to various functions of ET-1. Focal adhesion kinase (p125FAK) is a newly identified cytoplasmic protein tyrosine kinase that is activated by the phosphorylation of its own tyrosine residue. Because p125FAK was found to play a role in the signal transduction of not only integrins but also various neurotransmitters, including bombesin, endothelin, and vasopressin in Swiss 3T3 cells and Rat-1 fibroblasts, whether ET-1 could stimulate the tyrosine phosphorylation of p125FAK in glomerular mesangial cells was examined. ET-1 stimulated the tyrosine phosphorylation of p125FAK by threefold to fourfold in cultured mesangial cells. This effect of ET-1 was detected at 1 min and reached a maximum within 5 min and was blocked by BQ-123, an antagonist for ETA receptor. A23187, a calcium ionophore, failed to stimulate the tyrosine phosphorylation of p125FAK, and ET-1 was able to stimulate the tyrosine phosphorylation of p125FAK, even in a calcium-free medium. The activation of protein kinase C (PKC) by phorbol 12, 13-dibutyrate resulted in a stimulation of the tyrosine phosphorylation of p125FAK, and an inhibition of PKC by calphostin C or staurosporine significantly reduced the effect of ET-1. Furthermore, prolonged treatment of the cells with phorbol 12, 13-dibutyrate markedly inhibited the ET-1-induced tyrosine phosphorylation of p125FAK. These results indicate that p125FAK might play a role in a signal transduction system of ET-1 in glomerular mesangial cells and that the ET-1-induced tyrosine phosphorylation of p125FAK is largely dependent on the PKC pathway.