History of fragility fracture is associated with cardiovascular mortality in hemodialysis patients: the Q-Cohort study.

INTRODUCTION: In patients undergoing dialysis, major bone fracture is associated with a high risk of mortality, including death of cardiovascular (CV) origin. In the present study, we aimed to determine whether a history of fragility fracture is a predictor of CV death in patients undergoing hemodialysis with long-term follow-up. MATERIALS AND METHODS: In total, 3499 patients undergoing hemodialysis were analyzed for 10 years. We evaluated the history of fragility fracture in each patient at enrollment. The primary outcome was CV death. A Cox proportional hazard model and a competing risk approach were applied to determine the association between a history of fragility fracture and CV death. RESULTS: A total of 346 patients had a history of fragility fracture at enrollment. During a median follow-up of 8.8 years, 1730 (49.4%) patients died. Among them, 621 patients experienced CV death. Multivariable Cox analyses after adjustment for confounding variables showed that a history of fragility fracture was associated with CV death (hazard ratio, 1.47; 95% confidence interval, 1.16-1.85). In the Fine-Gray regression model, a history of fragility fracture was an independent risk factor for CV death (subdistribution hazard ratio, 1.36; 95% confidence interval, 1.07-1.72). CONCLUSION: In a large cohort of patients undergoing hemodialysis, a history of fragility fracture was an independent predictor of CV death.

Sex differences in the association between urate metabolism and kidney outcomes in patients with chronic kidney disease.

BACKGROUND: The association between serum uric acid (SUA) concentration and kidney outcomes in patients with chronic kidney disease (CKD) is controversial. Furthermore, there are no reports regarding the association of clearance of uric acid (CUA) with kidney outcomes. We aimed to determine whether SUA or CUA was associated with kidney outcomes in patients with CKD stratified by sex. METHODS: The present prospective study was conducted in 815 patients (523 men and 292 women) with CKD. The participants were divided into quartiles (Q1-Q4) of SUA or CUA for each sex. Endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage kidney disease (ESKD), or death (outcome 1) and a composite of doubling of SCr or ESKD (outcome 2). RESULTS: During a median follow-up of 2.5 years, outcomes 1 and 2 occurred in 363 and 321 patients, respectively. Multivariable-adjusted Cox analyses showed that in men, the hazard ratios (95% confidence intervals) for outcome 1 of Q1, Q2, and Q3 of CUA were 2.08 (1.18-3.70), 2.03 (1.22-3.39), and 1.85 (1.17-2.95), respectively, compared with Q4. Additionally, there were similar associations between lower CUA quartiles and outcome 2 in men. However, no associations between SUA and either outcome were observed in men. Conversely, in women, neither SUA nor CUA was associated with an outcome. CONCLUSION: In CKD, lower CUA was independently associated with poor kidney outcomes only in men, and in both sexes, there was no association of SUA with kidney outcomes.

Low plasma renin activity is independently associated with kidney disease progression in patients with type 2 diabetes and overt nephropathy, including those with impaired kidney function: a 2-year prospective study.

Plasma renin activity (PRA) is lower in patients with diabetic nephropathy (DN) than in healthy individuals. However, the association, if any, between PRA and renal outcomes in patients with DN remains uncertain. In a 2-year prospective observational study, we aimed to investigate the association of PRA with the decline in kidney function in patients with DN. We studied 97 patients with DN who were categorized according to tertile (T1-T3) of PRA. The annual changes in estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2/year) were determined from the slope of the linear regression curve for eGFR. The secondary endpoint was defined as a composite of the doubling of serum creatinine or end-stage renal disease. Results showed that kidney function rapidly declined with lower tertiles of PRA (median value [interquartile range] of the annual eGFR changes: -8.8 [-18.5 to -4.2] for T1, -8.0 [-14.3 to -3.2] for T2, and -3.1 [-6.3 to -2.0] for T3; p for trend <0.01). Multivariable linear regression analyses showed that, compared with T3, T1 was associated with a larger annual change in eGFR (coefficient, -4.410; 95% confidence interval [CI], -7.910 to -0.909 for T1). Composite renal events occurred in 46 participants. In multivariable Cox analysis, the lower tertiles of PRA (T1 and T2) were associated with higher incidences of the composite renal outcome (T2: hazard ratio [HR], 4.78; 95% CI, 1.64-13.89; T1: HR, 4.85; 95% CI 1.61-14.65) than T3. In conclusion, low PRA is independently associated with poor renal outcomes in patients with DN.

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction.

Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-ß1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

Renal denervation has blood pressure-independent protective effects on kidney and heart in a rat model of chronic kidney disease.

We elucidate the underlying mechanisms of bidirectional cardiorenal interaction, focusing on the sympathetic nerve driving disruption of the local renin-angiotensin system (RAS). A rat model of N(ω)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) administration was used to induce damage in the heart and kidney, similar to cardiorenal syndrome. L-NAME induced sympathetic nerve-RAS overactivity and cardiorenal injury accompanied by local RAS elevations. These were suppressed by bilateral renal denervation, but not by hydralazine treatment, despite the blood pressure being kept the same between the two groups. Although L-NAME induced angiotensinogen (AGT) protein augmentation in both organs, AGT mRNA decreased in the kidney and increased in the heart in a contradictory manner. Immunostaining for AGT suggested that renal denervation suppressed AGT onsite generation from activated resident macrophages of the heart and circulating AGT excretion from glomeruli of the kidney. We also examined rats treated with L-NAME plus unilateral denervation to confirm direct sympathetic regulation of intrarenal RAS. The levels of urinary AGT and renal angiotensin II content and the degrees of renal injury from denervated kidneys were less than those from contralateral innervated kidneys within the same rats. Thus, renal denervation has blood pressure-independent beneficial effects associated with local RAS inhibition.

A Novel Kidney Failure Prediction Model in Individuals with CKD: Impact of Serum Bilirubin Levels.

CONTEXT: Predicting the progression of chronic kidney disease (CKD) to end-stage kidney disease (ESKD) is crucial for improving patient outcomes. OBJECTIVE: To reveal the highly predictive activity of serum bilirubin levels for the progression of CKD to ESKD, and to develop and validate a novel ESKD prediction model incorporating serum bilirubin levels. METHODS: We assessed the relative importance of 20 candidate predictors for ESKD, including serum bilirubin levels, in a CKD cohort (15< eGFR <60 mL/min/1.73 m2), and subsequently developed a prediction model using the selected variables. The development cohort comprised 4,103 individuals with CKD who underwent follow-up at Kyushu University Hospital, Japan, from 2008 to 2018. The primary outcome was incident ESKD, defined as an eGFR <15 mL/min/1.73 m2, chronic dialysis, or renal transplantation. RESULTS: The mean follow-up time was 7.0 ± 4.2 years, during which 489 individuals (11.9%) progressed to ESKD. The Cox proportional hazard model selected eGFR, serum bilirubin, proteinuria, age, diabetes, gender, hypertension, serum albumin, and hemoglobin in order of their importance. The predictive performance of the model was optimized by incorporating these 9 variables in discrimination evaluated by time-dependent area under the curve (AUC). This model also demonstrated excellent calibration. Additionally, this model exhibited excellent predictive performance in both discrimination (2-year AUC: 0.943, 5-year AUC: 0.935) and calibration in a validation cohort (n=2,799). CONCLUSION: Serum bilirubin levels were strong predictors for the progression of CKD to ESKD. Our novel model that incorporates serum bilirubin levels could accurately predict ESKD in individuals with CKD.

Association between Hemoglobin A1c and Renal Arteriolar Sclerosis in Subjects Presenting without any Apparent Kidney Dysfunction.

AIMS: Diabetic kidney disease is a major vascular complication in patients with diabetes mellitus (DM). However, the association between the hemoglobin (Hb)A1c levels, notably the prediabetic levels, and renal pathological changes remains unclear. We investigated the association between the HbA1c levels and renal arteriolar lesions in subjects without any apparent kidney dysfunction using a living kidney donor cohort. METHODS: Between January 2006 and May 2016, 393 living kidney donors underwent a "zero-time" biopsy at Kyushu University Hospital. The patients were divided into four groups (HbA1c levels ＜5.6%, 5.6%-5.7%, 5.8%-6.4%, and ≥ 6.5%, or diagnosed with DM [DM group]). Renal arteriolar hyalinization and wall thickening were assessed using semi-quantitative grading. We then investigated the association between the HbA1c levels and renal pathological changes. RESULTS: 158 (40.2%) patients had arteriolar hyalinization and 148 (37.6%) showed wall thickening. A significant correlation was observed between the HbA1c levels and wall thickening (p for trend ＜0.001). An elevated HbA1c level was significantly associated with wall thickening according to a multivariable logistic analysis in subjects with HbA1c levels of 5.6%-5.7% and 5.8%-6.4%, and the DM group, compared with those with HbA1c levels of ＜5.6% (odds ratio [OR], 1.91; 95% confidence interval [CI]: [1.03-3.54] for 5.6%-5.7%, OR, 1.96; 95% CI: [1.09-3.53] for 5.8%-6.4%, and OR, 2.86; 95% CI: [0.91-9.01] for the DM group), whereas arteriolar hyalinization did not increase within the nondiabetic HbA1c levels. CONCLUSIONS: Elevated high-normal HbA1c levels are considered to be independent risk factors for arteriolar wall thickening. Subclinical renal arteriolar sclerosis may develop in patients with prediabetic HbA1c levels.

More rapid progression of brain atrophy in patients on peritoneal dialysis compared with hemodialysis: The VCOHP Study.

We previously reported that brain atrophy was more severe and progressed more rapidly in patients with end-stage kidney disease on peritoneal dialysis (PD) than those with non-dialysis-dependent chronic kidney disease. However, it remains unknown whether there is a difference between patients on PD and hemodialysis (HD). In total, 73 PD and 34 HD patients who underwent brain magnetic resonance imaging (MRI) were recruited for a cross-sectional analysis. Among them, 42 PD and 25 HD patients who underwent a second brain MRI after 2 years were recruited for a longitudinal analysis. T1-weighted MRI images were analyzed. Total gray matter volume (GMV), total white matter volume, and cerebrospinal fluid volume were segmented, and each volume was quantified using statistical parametric mapping software. The ratio of GMV (GMR) was calculated by dividing GMV by intracranial volume, to adjust for variations in head size. We compared GMR between PD and HD patients in the cross-sectional analysis and the annual change in GMR (AC-GMR) in the longitudinal analysis. In the cross-sectional analysis, age- and sex-adjusted GMR was significantly lower in PD than HD patients [least square mean (LSM): 39.2% vs. 40.0%, P = 0.018]. AC-GMR was significantly greater in PD than HD patients and this difference remained significant even after adjustment for potential confounding factors (LSM: -0.68 vs. -0.28 percentage-points/year, P = 0.011). In conclusion, the present study demonstrated a more rapid progression of brain atrophy in PD patients compared with HD patients. We demonstrated that decline in GMR progressed significantly more rapidly in PD than HD patients independent of potential confounding factors. GMR gray matter volume ratio, HD hemodialysis, PD peritoneal dialysis.

The clinical utility of serum tartrate-resistant acid phosphatase 5b in the assessment of bone resorption in patients on peritoneal dialysis.

OBJECTIVES: Serum tartrate-resistant acid phosphatase 5b (TRACP5b) is a bone resorption marker used in the assessment of bone metabolic status. The present study was designed to determine the clinical characteristics and utility of measuring serum TRACP5b levels in peritoneal dialysis (PD) patients. DESIGN: Cross-sectional study. PATIENTS: Forty-one patients receiving PD treatment in a single centre. MEASUREMENT: Serum levels of the bone turnover markers TRACP5b, N-terminal cross-linking telopeptide of type 1 collagen (NTX), bone-specific alkaline phosphatase (BAP), and parathyroid hormone (PTH) were simultaneously measured. The correlation of serum TRACP5b with other established bone markers was analysed after logarithmic transformation. Multivariate linear regression analysis was performed to examine the effects of both renal and peritoneal Kt/V (an index for solute clearance) for urea on bone markers using age, sex, body mass index, and PTH as covariates. Bone markers were also measured in three patients before and after treatment with cinacalcet hydrochloride, alphacalcidol, and raloxifene hydrochloride. RESULTS: Log TRACP5b was significantly correlated with log NTX, log BAP and log PTH. In the multivariate analysis, peritoneal Kt/V was not correlated with log NTX, log BAP or log TRACP5b. In contrast, renal Kt/V was significantly correlated with log NTX only. Responses to drug treatment were more accurately determined from serum TRACP5b and BAP than from serum NTX. CONCLUSIONS: Serum TRACP5b and BAP are potentially useful biomarkers for the evaluation of bone turnover in PD patients because they correlate well with other established bone markers and they are not influenced by renal and peritoneal clearances.

Renal interstitial fibrosis in 0-hour biopsy as a predictor of post-transplant anemia.

BACKGROUND/AIMS: Anemia is common in kidney transplant patients and may cause adverse cardiovascular events. Several studies have reported some predictors of post-transplant anemia. However, associations between the pathological findings in the 0-hour biopsy and anemia have not been well described. METHODS: 258 consecutive kidney transplant patients were enrolled in this retrospective study. The patients were divided into two groups, according to the presence or absence of interstitial fibrosis and tubular atrophy (IF/TA) in the 0-hour biopsy: the IF/TA group with fibrotic area ≥5% (n = 131) and the non-IF/TA group with fibrotic area <5% (n = 127). We examined the association between IF/TA and post-transplant anemia. RESULTS: Serial changes in hemoglobin levels in the IF/TA group were lower than in the non-IF/TA group (p = 0.007). Anemia at 12 months was found in 53% of the IF/TA group, and 35% of the non-IF/TA group (p = 0.004). Even after adjustment for several confounders including graft function, the presence of IF/TA was independently associated with post-transplant anemia at 12 months (odds ratio 1.88, 95% confidence interval 1.06-3.36, p = 0.031). This association was still significant in a subgroup with normal graft function. CONCLUSIONS: IF/TA in the 0-hour biopsy specimen is one of the predictors for post-transplant anemia and can be used to identify patients who need the treatment with erythropoiesis-stimulating agents.

Association between iron status markers and kidney outcome in patients with chronic kidney disease.

Several studies conducted in patients with various stages of chronic kidney disease (CKD) have investigated the association of iron status markers, such as transferrin saturation (TSAT) and serum ferritin, with kidney outcomes. However, the associations were inconsistent and remain strongly debated. Therefore, we aimed to investigate whether TSAT and serum ferritin levels were associated with kidney outcome in such a population. In this study, 890 patients who were admitted for the evaluation of and education for CKD were prospectively followed. Primary kidney outcome was a composite of doubling of serum creatinine, end-stage kidney disease, or death due to kidney failure. Participants were divided into quartiles (Q1-Q4) according to TSAT or serum ferritin levels. During a median follow-up period of 2.8 years, kidney events occurred in 358 patients. In the multivariable Cox analyses, compared with Q3 of TSAT, the hazard ratios (95% confidence intervals) for Q1, Q2, and Q4 were 1.20 (0.87, 1.66), 1.38 (1.01, 1.87), and 1.14 (0.82, 1.59), respectively. Compared with Q2 of serum ferritin, lower and higher quartiles had a significantly increased risk for kidney outcome; hazard ratios (95% confidence intervals) for Q1, Q3, and Q4 were 1.64 (1.18, 2.27), 1.71 (1.24, 2.37), and 1.52 (1.10, 2.10), respectively. A Fine-Gray model with death before kidney events as a competing risk showed results similar to the above. In CKD, lower and higher ferritin levels were independent risk factors for kidney disease progression.

The Association of Controlling Nutritional Status Score and Prognostic Nutritional Index with Cardiovascular Diseases: the Fukuoka Kidney Disease Registry Study.

AIM: The Controlling Nutritional Status (CONUT) score and the Prognostic Nutritional Index (PNI) reflect the immunonutritional status of patients. However, the associations of these two indices with cardiovascular disease (CVD) have not been characterized in patients with chronic kidney disease (CKD). Therefore, the current study aimed to determine whether the CONUT score or PNI was associated with prior CVD in patients with CKD. METHODS: A cross-sectional study of 2,751 patients with CKD who were not on dialysis was performed. The patients were grouped into tertiles (T1-T3) of PNI and placed into three groups following their CONUT score: low- (CONUT score, 0), mild- (CONUT score, 1-2), and moderate-to-high- (CONUT score, ≥ 3) risk groups. RESULTS: Prior CVD was present in 655 (24%) of the participants. Multivariable logistic regression analyses, with adjustment for potential confounders, showed that high CONUT score was associated with prior CVD than the low score (mild-risk group: odds ratio [OR]=1.35, 95% confidence interval [CI]=1.04-1.76; moderate-to-high-risk group: OR=1.66, 95% CI=1.19-2.30). In addition, the lower PNI tertiles were independently associated with prior CVD compared with T3 of PNI (T1: OR=1.45, 95% CI=1.09-1.92; T2: OR=1.32, 95% CI=1.01-1.72). CONCLUSIONS: Both CONUT score and PNI were found to be independently associated with prior CVD in patients with CKD in the present cross-sectional study. A longitudinal study is needed to elucidate whether these two indices are associated with subsequent cardiovascular events.

Subclinical hypothyroidism is independently associated with poor renal outcomes in patients with chronic kidney disease.

PURPOSE: It remains unclear whether subclinical hypothyroidism (SCH) is associated with renal prognosis in patients with chronic kidney disease (CKD). Therefore, we prospectively investigated the association of SCH with renal outcomes in CKD. METHODS: We conducted a prospective observational study of 480 euthyroid patients and 89 patients with SCH. The endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage renal disease (ESRD), or death, and a composite of doubling of SCr or ESRD was added as an alternative outcome. Logistic regression analyses were used to identify the factors associated with SCH. In addition, a Cox proportional hazards model was performed to determine whether SCH was associated with poor renal outcomes. RESULTS: During a median follow-up period of 26.1 months, doubling of SCr, ESRD, or death and doubling of SCr or ESRD occurred in 244 and 213 patients, respectively. In univariable logistic regression analyses, SCH was significantly associated with older age, lower hemoglobin, higher proteinuria, lower estimated glomerular filtration rate (eGFR), and higher log B-type natriuretic peptide (BNP). Multivariable Cox analyses showed that SCH was associated with poorer renal outcomes after adjustment for covariates, including eGFR and log BNP [doubling of SCr, ESRD, or death: hazard ratio (HR) 1.61, 95% confidence interval (CI), 1.16-2.23; doubling of SCr or ESRD: HR 1.53, 95% CI 1.07-2.20], compared with euthyroidism. CONCLUSIONS: In CKD, SCH is independently associated with poor renal outcomes, suggesting that screening for SCH might be needed to accurately predict renal prognosis.

A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the AppNL-F/NL-F knock-in mouse model.

Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock-in mouse model, AppNL-F/NL-F , which accumulates Aß plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male AppNL-F/NL-F and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and AppNL-F/NL-F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aß deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed AppNL-F/NL-F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aß binding protein transthyretin (TTR) in AppNL-F/NL-F mice, suggesting that the depletion of TTR underlies the increased Aß deposition in the hippocampus of HFD-fed AppNL-F/NL-F mice.

Severe anasarca due to beriberi heart disease and diabetic nephropathy.

A 40-year-old man was transferred to our hospital because of severe anasarca. He was a heavy drinker for more than 20 years, and diagnosed with diabetes mellitus 8 years earlier and treated with retinal photocoagulation 8 months earlier. He reported loss of appetite after divorce 10 months prior to admission. On admission, he presented with systemic edema and dyspnea. Chest radiography showed massive pleural effusion and cardiomegaly. Serum total protein was 5.6 g/dl, albumin 2.6 g/dl, and urinary protein excretion was 5.3 g/day. Glucose tolerance test showed normal pattern. Ultrafiltration and continuous hemofiltration resulted in loss of 40 kg body weight in 5 days. Echocardiography revealed high-output heart failure and blood tests showed low serum thiamine level of 12 ng/ml (normal, >28 ng/ml). Accordingly, the diagnosis was established as beriberi heart disease complicated with nephrotic syndrome. Treatment with 50 mg/day thiamine intravenously and 80 mg/day furosemide resulted in increase in urine output, decrease in cardiac output, resolution of pulmonary effusion, and about 70 kg body weight loss. Percutaneous renal biopsy showed nodular glomerulosclerosis, mesangial matrix expansion, and thickening of glomerular basement membrane (GBM). Immunofluorescence study showed no glomerular deposition of immunoglobulin or complement. Electron microscopy showed GBM thickening and mesangial matrix deposition without electron-dense deposits or fibrils. These findings were compatible with diabetic glomerulosclerosis. In this patient, extreme malnutrition altered glucose tolerance but, on the other hand, nephrotic syndrome associated with diabetic nephropathy made the diagnosis of beriberi heart disease difficult.

8-Oxoguanine accumulation in aged female brain impairs neurogenesis in the dentate gyrus and major island of Calleja, causing sexually dimorphic phenotypes.

In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoguanine DNA glycosylase minimize 8-oxoguanine accumulation in genomic DNA. We investigated age-related alterations in behavior, 8-oxoguanine levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-Oxoguanine accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoguanine accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that newborn neurons from SVZ maintain ICjM in the adult brain, and increased accumulation of 8-oxoguanine in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age.

Association between serum uric acid level and renal arteriolar hyalinization in individuals without chronic kidney disease.

BACKGROUND AND AIMS: Recent studies have reported an association between serum uric acid (SUA) and renal arteriolar changes in patients with chronic kidney disease (CKD). However, the association in individuals without CKD remains unclear. In this study, we investigated the relationship between SUA and renal arteriolar lesions in individuals without CKD from our living kidney donor cohort. METHODS: Between January 2006 and May 2016, 393 living kidney donors underwent "time-zero" biopsy at Kyushu University Hospital. Patients were divided into sex-specific quartiles of SUA before donation: Q1, Q2, Q3, and Q4 (male: <5.2,5.2-5.8,5.9-6.4, and ≥6.5 mg/dL, female: <3.8,3.8-4.3,4.4-5.0, and ≥5.1 mg/dL). Renal arteriolar hyalinization and wall thickening were assessed using a semiquantitative grading system. Predictive performance was compared between models with and without SUA by calculating the net reclassification improvement (NRI). RESULTS: In total, 158 (40.2%) patients had arteriolar hyalinization, and 148 (37.6%) had wall thickening. High SUA was significantly associated with arteriolar hyalinization in multivariable logistic analysis (odds ratio [OR] per 1-mg/dL increase in SUA, 1.24; 95% confidence interval [CI], 1.00-1.53; p = 0.048. OR for Q4 vs. Q2, 2.22; 95% CI, 1.17-4.21; p = 0.01). We found no association between SUA and wall thickening. When SUA was incorporated into a predictive model with conventional atherosclerotic factors, the NRI was 0.21 (p = 0.04). CONCLUSIONS: High SUA was an independent risk factor for arteriolar hyalinization in individuals without CKD. SUA provided additional predictive value beyond conventional atherosclerotic factors in predicting arteriolar hyalinization.

Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation.

Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid ß (Aß) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aß pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G-F cortex as Aß amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aß amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

Subacute pulmonary embolism in a hemodialysis patient, successfully treated with surgical thrombectomy.

A 53-year-old woman was admitted to our hospital with a 1-month history of gradually progressive resting dyspnea and lumbar backache. For the preceding 6 years, she had received regular hemodialysis for end-stage renal disease caused by autosomal dominant polycystic kidney disease and had taken tamoxifen for 3 years as post-operative chemotherapy for breast cancer. Before admission, the patient's symptoms had been attributed to volume overload, based on right thoracic fluid and leg edema. However, despite volume correction by dialysis therapy, her symptoms had not improved. The patient was transferred to our hospital, where she was diagnosed with subacute pulmonary embolism (PE). Emergent pulmonary thrombectomy was performed using cardio-pulmonary bypass. The patient was discharged from our hospital on post-operative day 23. Recent reports have shown that hemodialysis patients have a relatively higher risk of PE compared with the general population. Our case had additional risk factors for PE: female sex, decreased protein C level, tamoxifen use, and autosomal dominant polycystic kidney disease. These factors may have had a synergistic effect on the onset of PE.

Extended Swan-Neck Catheter With Upper Abdominal Exit-Site Reduces Peritoneal Dialysis-Related Infections.

Extended catheters with an upper abdominal exit-site (UAE) are reportedly associated with a lower incidence of peritoneal dialysis (PD)-related infections. However, little information about the optimal peritoneal catheter configuration for UAE is available. In this nonrandomized multicenter trial, 147 consecutive cases of a UAE involving either a conventional straight (CS; 80 cases) or extended swan-neck catheter (SN; 67 cases) were analyzed to compare exit-site and tunnel infections (ESTI), peritonitis, and catheter survival. The ESTI-free and catheter survival rates were significantly lower in the SN than in the CS group (P <0.01). However, the peritonitis-free survival rate was not different (P = 0.26). In terms of analyses for infection rates, fewer episodes of ESTI (1.284 vs 0.608 episodes/patient-year; P <0.01) and peritonitis (0.345 vs 0.152 episodes/patient-year; P = 0.06) were observed in the SN than CS group. Recurrence analyses showed that the mean number of cumulative episodes of ESTI and peritonitis between two groups were significantly different.