Diminishing dry weight is strongly associated with all-cause mortality among long-term maintenance prevalent dialysis patients.

OBJECTIVES: To investigate the relationship between dry weight (DW) change and survival in long-term maintenance prevalent dialysis patients. METHODS: We conducted a prospective data collection study with retrospective analysis of the registered data. Patients were followed up for 5 years (1-year observation of DW changes and subsequent 4-year follow-up). The outcome was all-cause mortality. The predictors were 1-year DW change rates. The hazard ratios (HRs) for all-cause mortality were calculated using multivariable Cox regression analysis, fully adjusted for age, sex, basal kidney disease, dialysis vintage, current smoking, past cardiovascular events, serum albumin, DW at enrollment, serum creatinine, mean predialysis systolic blood pressure, and cardiothoracic ratio or 1-year cardiothoracic ratio change rate. Propensity score (PS) analysis was also conducted using the same covariates of Cox regression analysis. RESULTS: In total, 899 dialysis patients (mean dialysis vintage: 101.2 months) were followed up, and 180 deaths were recorded, of which 90 were of cardiovascular origin. Each 2% decrement of DW showed adjusted HR, and the 95% confidence interval was 1.24 [1.16-1.33]. According to the 1-year DW change rate, participants were divided into five groups (group A, ≥+3%; group B, +1 to +2.9%; group C, -0.9 to +0.9%; group D, -2.9 to -1.0%; and group E, ≤-3%). For survival curves based on grouping, group B had the best and group E had the worst survival rate (p<0.01, log-rank test). Therefore, we set group B as a reference; adjusted risks for death of groups D and E were 2.16 [1.23-3.79] and 2.66 [1.54-4.58], respectively. However, this relation was blunted in patients of heavier DW. The PS-matched cohort showed a poorer prognosis in patients with diminishing DW divided by DW change rate at -0.635% (mean value of DW change rate). CONCLUSION: In the long-term maintenance hemodialysis cohort, 1-year DW decrement, especially ≤-3.0%, was significantly associated with all-cause mortality, and cardiovascular disease-related death was prominent in these patients.

Asymptomatic Plaques of Lower Peripheral Arteries and Their Association with Cardiovascular Disease: An Autopsy Study.

AIM: Patients with peripheral artery disease (PAD) have a high prevalence of cardiovascular morbidity and mortality; however, majority of patients with PAD are asymptomatic. This study aimed to histologically evaluate whether asymptomatic, lower extremity artery plaques are associated with systemic atherosclerosis and the onset of cardiovascular disease (CVD) events using autopsy cases. METHODS: We histologically investigated the atherosclerotic plaques of the common iliac, common carotid, coronary, and renal arteries from 121 autopsy cases without symptoms of PAD (mean age:67.6 years; 63% men; 83% non-CVD death). We evaluated the relationship between the degree of iliac artery atherosclerosis and that of other arteries, and also the presence of any CVD, myocardial infarction, stroke, and renal failure. RESULTS: Advanced atherosclerotic plaques (American Heart Association ≥4) were present in 86 (72%) common iliac arteries in these cases. These arteries also showed high frequencies of calcification (66%), intraplaque hemorrhage (42%), and plaque disruption (24%). These advanced lesions were associated with age (≥60 years), sex (male), hypertension, diabetes, and smoking habit (all P＜0.05). Additionally, it was significantly associated with CVD (odds ratio, 95% confidence interval; 6.2, 2.2-22), myocardial infarction (6.4, 1.2-19), stroke (8.7, 1.7-16), and renal failure/hemodialysis (5.8, 1.1-11). Cases with advanced iliac artery plaques had advanced coronary and carotid atherosclerosis. CONCLUSION: These results indicate that asymptomatic advanced plaques are frequently observed in common iliac arteries, and are associated with generalized atherosclerosis and CVD events.

Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits.

Diabetes mellitus accelerates atherosclerosis that causes most cardiovascular events. Several metabolic pathways are considered to contribute to the development of atherosclerosis, but comprehensive metabolic alterations to atherosclerotic arterial cells remain unknown. The present study investigated metabolic changes and their relationship to vascular histopathological changes in the atherosclerotic arteries of rabbits with alloxan-induced diabetes. Diabetic atherosclerosis was induced in rabbit ilio-femoral arteries by injecting alloxan (100 mg/kg), injuring the arteries using a balloon, and feeding with a 0.5% cholesterol diet. We histologically assessed the atherosclerotic lesion development, cellular content, pimonidazole positive-hypoxic area, the nuclear localization of hypoxia-inducible factor-1α, and apoptosis. We evaluated comprehensive arterial metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using 18F-fluorodeoxyglucose and pimonidazole. Plaque burden, macrophage content, and hypoxic areas were more prevalent in arteries with diabetic, than non-diabetic atherosclerosis. Metabolomic analyses highlighted 12 metabolites that were significantly altered between diabetic and non-diabetic atherosclerosis. A half of them were associated with glycolysis metabolites, and their levels were decreased in diabetic atherosclerosis. The uptake of glucose evaluated as 18F-fluorodeoxyglucose in atherosclerotic lesions increased according to increased macrophage content or hypoxic areas in non-diabetic, but not diabetic rabbits. Despite profound hypoxic areas, the nuclear localization of hypoxia-inducible factor-1α decreased and the number of apoptotic cells increased in diabetic atherosclerotic lesions. Altered glycolysis metabolism and an impaired response to hypoxia in atherosclerotic lesions under conditions of insulin-dependent diabetes might be involved in the development of diabetic atherosclerosis.

Urinary podocyte and TGF-ß1 mRNA as markers for disease activity and progression in anti-glomerular basement membrane nephritis.

BACKGROUND: Podocyte depletion causes glomerulosclerosis, with persistent podocyte loss being a major factor driving disease progression. Urinary podocyte mRNA is potentially useful for monitoring disease progression in both animal models and in humans. To determine whether the same principles apply to crescentic glomerular injury, a rat model of anti-glomerular basement membrane (anti-GBM) nephritis was studied in parallel with a patient with anti-GBM nephritis. METHODS: Podocyte loss was measured by Wilms' Tumor 1-positive podocyte nuclear counting and density, glomerular epithelial protein 1 or synaptopodin-positive podocyte tuft area and urinary podocyte mRNA excretion rate. Glomerulosclerosis was evaluated by Azan staining and urinary transforming growth factor (TGF)-ß1 mRNA excretion rate. RESULTS: In the rat model, sequential kidney biopsies revealed that after a threshold of 30% podocyte loss, the degree of glomerulosclerosis was linearly associated with the degree of podocyte depletion, compatible with podocyte depletion driving the sclerotic process. Urinary podocyte mRNA correlated with the rate of glomerular podocyte loss. In treatment studies, steroids prevented glomerulosclerosis in the anti-GBM model in contrast to angiotensin II inhibition, which lacked a protective effect, and urinary podocyte and TGF-ß1 mRNA markers more accurately reflected both the amount of podocyte depletion and the degree of glomerulosclerosis compared with proteinuria under both scenarios. In a patient successfully treated for anti-GBM nephritis, urinary podocyte and TGB-ß1 mRNA reflected treatment efficacy. CONCLUSION: These results emphasize the role of podocyte depletion in anti-GBM nephritis and suggest that urinary podocyte and TGF-ß1 mRNA could serve as markers of disease progression and treatment efficacy.

Relationship between Hemoglobin Levels Corrected by Interdialytic Weight Gain and Mortality in Japanese Hemodialysis Patients: Miyazaki Dialysis Cohort Study.

BACKGROUND: Although hemoglobin (Hb) levels are affected by a change in the body fluid status, the relationship between Hb levels and mortality while taking interdialytic weight gain (IDWG) at blood sampling into account has not yet been examined in hemodialysis patients. STUDY DESIGN: Cohort study. SETTING, PARTICIPANTS: Data from the Miyazaki Dialysis cohort study, including 1375 prevalent hemodialysis patients (median age (interquartile range), 69 (60-77) years, 42.3% female). PREDICTOR: Patients were divided into 5 categories according to baseline Hb levels and two groups based on the median value of IDWG rates at blood sampling at pre-HD on the first dialysis session of the week. OUTCOMES: All-cause and cardiovascular mortalities during a 3-year follow-up. MEASUREMENTS: Hazard ratios were estimated using a Cox model for the relationship between Hb categories and mortality, and adjusted for potential confounders such as age, sex, dialysis duration, erythropoiesis-stimulating agent dosage, Kt/V, comorbid conditions, anti-hypertensive drug use, serum albumin, serum C-reactive protein, serum ferritin, and serum intact parathyroid hormone. Patients with Hb levels of 9-9.9 g/dL were set as our reference category. RESULTS: A total of 246 patients (18%) died of all-cause mortality, including 112 cardiovascular deaths. Lower Hb levels (<9.0g/dL) were associated with all-cause mortality (adjusted HRs 2.043 [95% CI, 1.347-3.009]), while Hb levels were not associated with cardiovascular mortality. When patients were divided into two groups using the median value of IDWG rates (high IDWG, ≥5.4% and low IDWG, <5.4%), the correlation between lower Hb levels and all-cause mortality disappeared in high IDWG patients, but was maintained in low IDWG patients (adjusted HRs 3.058 [95% CI,1.575-5.934]). On the other hand, higher Hb levels (≥12g/dL) were associated with cardiovascular mortality in high IDWG patients (adjusted HRs 2.724 [95% CI, 1.010-7.349]), but not in low IDWG patients. CONCLUSION: In hemodialysis patients, target Hb levels may need to be selected in consideration of IDWG at blood sampling.

Apoprotein B/Apoprotein A-1 Ratio and Mortality among Prevalent Dialysis Patients.

BACKGROUND AND OBJECTIVES: In dialysis patients, the associations between apoprotein profile and all-cause or cardiovascular disease (CVD)-related mortality are not well known. We, therefore, investigated whether apoprotein levels are associated with these events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We undertook a prospective observational cohort study of prevalent hemodialysis patients aged ≥18 years (n=1081), who were followed for 4 years (2011-2014). Outcomes were all-cause and CVD-related mortality. Predictors used were baseline apoprotein levels, particularly the apoprotein B (apo B)/ apoprotein A-1 (apo A-1) ratio. A Cox regression analysis was used to calculate the hazard ratios (HRs) for mortality. Apo A-1, apo B, and apo B/ apo A-1 ratio were analyzed with adjustments in three models: model 1, basic adjustment for age and sex; model 2, basic adjustments plus dialysis conditions (dialysis vintage, mean predialysis systolic blood pressure, dry weight, and mean intradialytic weight gain); and model 3, model 2 plus metabolic and inflammatory conditions (basal kidney disease, serum albumin, C-reactive protein level, and statin use). RESULTS: Of the 1081 patients included in the study, 203 deaths were recorded, 92 of which were related to CVD. The apo B/ apo A-1 ratio was significantly associated with all-cause and CVD-related mortality when analyzed by 1-SD increments or quartile IV versus I in all models. In model 3, HRs and 95% confidence intervals (95% CIs) for 1-SD increments of apo B/ apo A-1 ratio for all-cause mortality or CVD-related mortality were: HR, 1.16 (95% CI, 1.00 to 1.35), or HR, 1.38 (95% CI, 1.11 to 1.71), respectively, and for quartile IV versus I: HR, 1.65 (95% CI, 1.05 to 2.57), or HR, 2.56 (95% CI, 1.21 to 5.40), respectively. Apo A-1 was significantly associated with both mortalities in models 1 and 2. However, apo B was only significantly associated with CVD-related mortality in model 3. CONCLUSIONS: Apoprotein measurement, especially the apo B/ apo A-1 ratio, was significantly associated with all-cause and CVD-related mortality in prevalent dialysis patients.

Human coronary thrombus formation is associated with degree of plaque disruption and expression of tissue factor and hexokinase II.

BACKGROUND: Atherosclerotic plaque thrombogenicity is a critical factor that affects thrombus formation and the onset of acute myocardial infarction (AMI). The aim of this study was to identify the vascular factors involved in thrombus formation and AMI onset. METHODS AND RESULTS: Culprit lesions in 40 coronary arteries with thrombi at autopsy after lethal AMI and non-cardiac death (asymptomatic plaque disruption) were analyzed on histology. Thrombus size, ratio of thrombus to lumen area, length of plaque disruption, and immunopositive areas for tissue factor (TF) and hexokinase (HK)-II were significantly larger in coronary arteries with AMI than with asymptomatic plaque disruption. The size of coronary thrombus positively correlated with the length of plaque disruption (r=0.80) and with immunopositive areas for TF (r=0.38) and HK-II (r=0.40). Because both M1 and M2 macrophages express TF and HK-II in symptomatic plaques, we assessed TF and HK-II expression in M1- and M2-polarized macrophages. The expression of TF was increased and that of HK-II was decreased in M2-, compared with M1-polarized THP-1 macrophages. Inhibiting glycolysis enhanced TF expression in the macrophages partly via hypoxia inducible factor-1α. CONCLUSIONS: The degree of plaque disruption and expression of TF and HK-II appear to be important vascular factors for AMI onset, and polarized macrophages make a distinct contribution to thrombogenicity and glucose metabolism.

Urine podocyte mRNAs mark disease activity in IgA nephropathy.

BACKGROUND: Podocyte depletion is a major mechanism driving glomerulosclerosis. We and others have previously projected from model systems that podocyte-specific mRNAs in the urine pellet might serve as glomerular disease markers. We evaluated IgA nephropathy (IgAN) to test this concept. METHODS: From 2009 to 2013, early morning voided urine samples and kidney biopsies from IgAN patients (n = 67) were evaluated in comparison with urine samples from healthy age-matched volunteers (n = 28). Urine podocyte (podocin) mRNA expressed in relation to either urine creatinine concentration or a kidney tubular marker (aquaporin 2) was tested as markers. RESULTS: Urine podocyte mRNAs were correlated with the severity of active glomerular lesions (segmental glomerulosclerosis and acute extracapillary proliferation), but not with non-glomerular lesions (tubular atrophy/interstitial fibrosis) or with clinical parameters of kidney injury (serum creatinine and estimated glomerular filtration rate), or with degree of accumulated podocyte loss at the time of biopsy. In contrast, proteinuria correlated with all histological and clinical markers. Glomerular tuft podocyte nuclear density (a measure of cumulative podocyte loss) correlated with tubular atrophy/interstitial fibrosis, estimated-glomerular filtration rate and proteinuria, but not with urine podocyte markers. In a subset of the IgA cohort (n = 19, median follow-up period = 37 months), urine podocyte mRNAs were significantly decreased after treatment, in contrast to proteinuria which was not significantly changed. CONCLUSIONS: Urine podocyte mRNAs reflect active glomerular injury at a given point in time, and therefore provide both different and additional clinical information that can complement proteinuria in the IgAN decision-making paradigm.

Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity.

Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %-cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immunopositive nuclei was positively correlated with that of NF-κB-immunopositive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.

Increased metabolite levels of glycolysis and pentose phosphate pathway in rabbit atherosclerotic arteries and hypoxic macrophage.

AIMS: Inflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages. METHODS: Macrophage-rich or smooth muscle cell (SMC)-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS) and interferon-γ (INFγ) were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using (18)F-fluorodeoxyglucose ((18)F-FDG) and pimonidazole, a marker of hypoxia. RESULTS: The levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20). The uptake of (18)F-FDG in arterial walls measured by autoradiography positively correlated with macrophage- and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p<0.0001). Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor-1α and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8) and pentose phosphate pathway (4 of 6) metabolites increased in LPS and INFγ stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely associated with metabolic pathways in the macrophages. CONCLUSION: Infiltrative macrophages in atherosclerotic arteries might affect metabolic systems, and hypoxia but not classical activation might augment glycolytic and pentose phosphate pathways in macrophages.

[Clinical characteristics of patients with IgA nephropathy and long-term survival after dialysis therapy].

BACKGROUND AND OBJECTIVES: Little is known about the treatment and clinical status of patients with biopsy-proven IgA nephropathy (IgAN) during long-term maintenance dialysis. METHODS: Fifty-two of 433 patients with IgAN who had favorable survival rates of 93.3% and 65.1% at 10 and 20 years, respectively, in a previous study and had reached end-stage kidney disease were followed up for 11.1 ± 6.2 years. Forty of the 52 patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) at the final observation in February 2012 were eligible for entry in this study. Laboratory findings, treatments and complications during the long-term follow-up were analyzed. RESULTS: Mean age at starting dialysis (HD, n = 39; PD, n = 1) was 44.2 ± 13.1 years. Vascular access was achieved through an arteriovenous fistula in 95% of the 39 patients. Prescription rates of anti-hypertensive agents (68%), anti-platelet agents (35%), and statins (15%) were relatively low. The cardiothoracic ratio was well-controlled (< 50%) in about 60% of all patients and mean values for hemoglobin (10.6 ± 1.31 g/dL), adjusted calcium (9.56 ± 0.81 mg/dL), phosphate(5.89 ± 1.64 mg/dL), and intact-PTH (186 ± 221 pg/mL) were within the treatment goals recommended by Japanese guidelines. Complications during follow-up comprised cardiovascular events (n = 11), malignancy (n = 4), diabetes (n = 2), and arterial fibrillation (n = 2). Patients who remained on dialysis for > 10 years (n = 22) had started dialysis when they were significantly younger, and had a higher rate of onset of malignancy and of intact PTH values than those who were on dialysis for < 10 years (n = 18). CONCLUSIONS: Patients with IgAN who remain on dialysis over the long-term can maintain stable and favorable clinical findings although the occurrence of malignant complications and bone mineral metabolic disorder should be monitored.

Association between renal vasculature changes and generalized atherosclerosis: an autopsy survey.

AIM: To examine the association between renal vasculature changes and generalized atherosclerosis using autopsy cases. METHODS: We histologically examined 107 autopsy patients(mean age, 68.4 years; 64% men; 81% non-CVD) to investigate the association between renal vasculature changes and generalized atherosclerosis. We measured the intima/media(I/M) ratio for the renal, intrarenal and systemic arteries(coronary, cerebral, common carotid and common iliac), calculated the rates of arteriolar hyalinization and global glomerulosclerosis and evaluated the frequency of advanced lesions(AHA classification ≥IV) in the systemic arteries. RESULTS: The I/M ratios of the renal and intrarenal arteries and the rate of global glomerulosclerosis increased with age, while the rates of arteriolar hyalinization and global glomerulosclerosis were associated with diabetes and hypertension(all p＜0.05). The I/M ratio of the coronary artery was independently associated with the rate of global glomerulosclerosis(p＜0.05). The frequency of advanced atherosclerotic lesions in the coronary and cerebral arteries was also correlated with the I/M ratio of the renal artery and rates of arteriolar hyalinization and global glomerulosclerosis(all p＜0.05). The frequency of advanced lesions in the cerebral and common carotid arteries was independently associated with the I/M ratio of the renal artery and the rate of renal arteriolar hyalinization(odds ratio(OR) with [95% confidence interval]; 5.09 [1.15-27.9] and 4.11 [1.38-13.9], respectively). CONCLUSIONS: The results of this study demonstrated that pathological changes in four portions of the renal vasculature differ. Renal vasculature changes except the intrarenal arteries were significantly associated with those observed in the cerebral, common carotid and coronary arteries.

Long-term survival of patients with IgA nephropathy after dialysis therapy.

BACKGROUND/AIMS: How dialysis affects the survival of patients with biopsy-proven IgA nephropathy (IgAN) is not fully understood. The present long-term cohort study quantifies the survival rates and incidence of cardio-cerebrovascular diseases (CCVDs) among such patients in Japan. METHODS: Fifty-two of 433 patients with IgAN who had reached end-stage kidney disease underwent renal replacement therapy (RRT) between 1981 and 2010. The overall survival rate and incidence of CCVDs in these patients were evaluated during follow-up for 11.3 ± 6.4 years. RESULTS: The mean age at starting RRT was 42.8 ± 13.3 years. Only seven patients died during follow-up (mortality rate, 1.2/100 person-years) and Kaplan-Meier analysis revealed favorable survival rates of 93.3% and 65.1% at 10 and 20 years, respectively, compared with that of patients with glomerulonephritis in the registry of the Japanese Society for Dialysis Therapy who required RRT. Malignancy and CCVDs were causes of death at 13.6 ± 4.8 and 3.9 ± 1.3 years, respectively, after starting RRT. Fatal and non-fatal CCVDs developed in 15 (incidence, 2.7/100 person-years) patients and acute coronary syndrome and cerebral hemorrhage developed relatively soon after starting RRT. Cox proportional hazards models revealed that age at the time of starting RRT was a significant factor affecting the onset of CCVDs. Meanwhile, a history of having had corticosteroid as an initial treatment did not affect the onset of events. CONCLUSION: Although the survival of patients with IgAN is favorable after dialysis, the onset of CCVDs during the early phase of dialysis should be carefully monitored.

Arterial (18)F-fluorodeoxyglucose uptake reflects balloon catheter-induced thrombus formation and tissue factor expression via nuclear factor-κB in rabbit atherosclerotic lesions.

BACKGROUND: Imaging modalities to assess atherosclerotic plaque thrombogenicity have not been established, so in this study the relationship between [(18)F]-fluorodeoxyglucose ((18)F-FDG) uptake and thrombus formation was investigated in rabbit atherosclerotic arteries. METHODS AND RESULTS: Atherosclerotic plaque was induced in the iliacofemoral artery by balloon injury and a 0.5% cholesterol diet. At 3 weeks after the first balloon injury, the arteries were visualized by (18)F-FDG positron emission tomography (PET) imaging 2h after an (18)F-FDG infusion, and then arterial thrombus was induced by a second balloon injury of both iliacofemoral arteries. Imaging with (18)F-FDG-PET revealed significantly more radioactivity along the injured (0.63 ± 0.12 SUVmax), than the contralateral non-injured artery (0.34 ± 0.08 SUV max, n=17, P<0.0001). Arterial radioactivity measured by autoradiography positively correlated with macrophage area, the number of nuclei that were immunopositive for nuclear factor κ B (NF-κB), and tissue factor (TF) expression. The immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly larger in the atherosclerotic than in the contralateral arteries, and significantly correlated with radioactivity in PET (r=0.92, P<0.001, n=10) and autoradiography (r=0.73, P<0.0001, n=50) in the arteries. Inhibition of NF-κB significantly reduced TF expression in cultured atherosclerotic plaque. CONCLUSIONS: Arterial (18)F-FDG uptake reflects the thrombogenicity of atherosclerotic plaque following balloon injury.

Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: A new histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis was recently proposed. We evaluated the predictive value of this classification for renal outcome in Japanese patients. METHODS: We enrolled 122 patients with ANCA-associated glomerulonephritis diagnosed at several institutions in Japan between January 2000 and March 2010. Twenty patients were excluded because of observation durations of <1 year, and/or because their biopsy specimens contained <10 glomeruli. Renal biopsy specimens were categorized into four classes according to the proposed classification. We evaluated the predictive value of immunohistochemical staining for α-smooth muscle actin (SMA), Wilm's tumor 1 (WT1), CD68, and cytokeratin for end-stage renal disease (ESRD). RESULTS: The study population included 54 men and 48 women. Age, estimated glomerular filtration rate (eGFR), and proteinuria were 66.3 ± 11.3 years, 21.6 ml/min. and 1.10 g/24 h, respectively. Eighty-six patients were positive for myeloperoxidase-ANCA, five were positive for proteinase 3-ANCA, and 11 were negative for both antibodies. Median follow-up time was 41.0 months. Twenty-three patients (22.5%) developed ESRD during the follow-up period. Twelve patients died during follow up; 7/12 patients developed ESRD before death, and 5/12 patients died without ESRD. The incidence of ESRD increased with sequential categories: focal, 2/46 (4.3%); crescentic, 9/32 (28%); mixed, 8/18 (44%); and sclerotic, 4/6 (67%). The focal class had the best renal survival and the sclerotic class had the worst renal survival (p < 0.001). Kaplan-Meier renal survival analysis was similar to that of the new classification system proposal. In the multivariate analysis, the classification system tended to be a prognostic factor for ESRD (p = 0.0686, crescentic, mixed and sclerotic vs. focal, hazard ratio (HR) [95% confidence interval, CI]; 2.99 [0.61-22.7], 5.04 [1.11-36.4] and 9.93 [1.53-85.7], respectively). α-SMA-positivity also tended to be associated with ESRD (p = 0.1074). CONCLUSION: The new histopathological classification was associated with eGFR at 1 year and tended to be associated with ESRD in our Japanese cohort with ANCA-associated glomerulonephritis. α-SMA positivity might be an additional prognostic factor for ESRD.

Elevated plasma factor VIII enhances venous thrombus formation in rabbits: contribution of factor XI, von Willebrand factor and tissue factor.

Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.

Usefulness of carotid intima-media thickness measurement as an indicator of generalized atherosclerosis: findings from autopsy analysis.

BACKGROUND: Ultrasound-determined carotid intima-media thickness (IMT) is widely used as an indicator of generalized atherosclerotic burden, but there are limited autopsy findings in support of the association, directly. METHODS: We performed an autopsy analysis (n = 111, mean 68.8 years; 65.0% men; 86% non-cardiovascular disease death) to examine the associations of microscopy-determined carotid IMT including plaque thickness with the severity of atherosclerosis in the generalized arteries. RESULTS: Microscopy-determined carotid IMT was associated with the extent of intima/media layer ratio of the vasculature, a marker of atherosclerosis, in each structure examined, i.e., coronary artery, cerebrovasculature, thoracic aorta, abdominal aorta, and iliac artery (R = 0.31-0.42; all P < 0.01). The prevalence of a necrotic core in the coronary artery, cerebrovasculature, thoracic aorta, abdominal aorta, and iliac artery increased in accordance with increasing microscopy-determined carotid IMT (all P < 0.05). CONCLUSION: Our autopsy analysis confirms the validity of carotid IMT including plaque thickness as an indicator of generalized atherosclerosis.

A huge intraventricular congenital anaplastic astrocytoma: case report with histopathological and genetic consideration.

Congenital malignant gliomas are rare brain tumors about which few reports have been published. We present the clinical course and genetic alterations in an infant with a congenital malignant glioma detected incidentally by ultrasonography at 36 weeks. The tumor occupied the right temporoparietal region, extended to the posterior fossa, and significantly compressed surrounding structures. The female infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally resected by two-stage surgery; pathological diagnosis was anaplastic astrocytoma. Immunohistochemical staining was positive for p53 and negative for epidermal growth factor receptor. There was no O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, no 1p/19q loss of heterozygosity, and no isocitrate dehydrogenase 1 (IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery.