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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Clinical Significance of Fronto-Temporal Gray Matter Atrophy in Executive Dysfunction in Patients with Chronic Kidney Disease: The VCOHP Study.

BACKGROUND & OBJECTIVES: It is well known that cognitive impairment in patients with chronic kidney disease (CKD) is characterized by executive dysfunction, rather than memory dysfunction, although the precise mechanism of this remains to be elucidated. The purpose of the present study is to examine the correlation between gray matter volume (GMV) and executive function in CKD patients. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: This cross-sectional study recruited 95 patients with non-dialysis-dependent CKD (NDD-CKD) with no history of cerebrovascular disease, who underwent brain magnetic resonance imaging (MRI) and Trail Making Test (TMT) in the VCOHP Study. The subjects underwent brain MRI and TMT part A (TMT-A) and part B (TMT-B). The segmentation algorithm from Statistical Parametric Mapping 8 software was applied to every T1-weighted MRI scan to extract tissue maps corresponding to gray matter, white matter, and cerebrospinal fluid. GMV was normalized by dividing by the total intracranial volume, calculated by adding GMV, white matter volume, and cerebrospinal fluid space volume. Then, normalized whole-brain GMV was divided into four categories of brain lobes; frontal, parietal, temporal, and occipital. We assessed the correlation between normalized GMV and TMT using multivariable regression analysis. RESULTS: Normalized whole-brain GMV was significantly inversely correlated to the scores of TMT-A, TMT-B, and ΔTMT (TMT-B minus TMT-A). These correlations remained significant even after adjusting for relevant confounding factors. Normalized frontal and temporal GMV, but not parietal and occipital GMV, were significantly inversely correlated with TMT-A, TMT-B, and ΔTMT using multivariable regression analysis. CONCLUSIONS: The present study demonstrates the correlation between normalized GMV, especially in the frontal and temporal lobes, and executive function, suggesting that fronto-temporal gray matter atrophy might contribute to executive dysfunction in NDD-CKD.

De novo myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis 31 years after living-donor kidney transplantation.

A 61-year-old woman was admitted to our hospital because of an unexpected rise in serum creatinine (sCr) level with proteinuria and microhematuria. She had undergone living-donor kidney transplantation 31 years before for end-stage renal disease caused by chronic glomerulonephritis (GN). On admission, her sCr was 1.27 mg/dL which was increased from 0.6 mg/dL, urinary protein/creatinine ratio was 1.39 g/gCr, and urinary red blood cell count was more than 100 per high power field. The allograft biopsy revealed crescentic glomerulonephritis with moderate to severe tubulointerstitial inflammation. Immunofluorescence staining yielded only a minimal staining for immunoglobulin A, and negative C4d in peritubular capillary. Since increased myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) titer of 45.5 U/mL was detected, we made the diagnosis of post-transplant MPO-ANCA-associated GN. She was treated with three doses of bolus methylprednisolone (500 mg) followed by oral prednisolone therapy. Her sCr was stable at 1.20 mg/dL thereafter. ANCA-associated GN should be considered in older kidney transplant patients with new-onset urinary abnormalities because typical systemic symptoms and vasculitis in other organs might be masked by maintenance immunosuppression.

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.

Improvement in spatial memory dysfunction by telmisartan through reduction of brain angiotensin II and oxidative stress in experimental uremic mice.

AIMS: We previously reported that chronic uremia induces spatial working memory dysfunction in mice, and that it is attributed to cerebral oxidative stress. The source of oxidative stress was considered to be uremic toxins, but this remains unclear. In the present study, we examined whether the brain renin-angiotensin system was activated in the CKD mouse model, and whether it contributed to cognitive impairment. MAIN METHODS: CKD was induced in 8-week-old male mice by 5/6 nephrectomy. Mice were divided into four groups: control mice administered tap water (Cont-V), control mice treated with 0.5mg/kg/day telmisartan, an angiotensin II (AII) receptor blocker, for 8 weeks (Cont-T), CKD mice administered tap water (CKD-V), and CKD mice treated with 0.5 mg/kg/day telmisartan for 8 weeks (CKD-T). After the treatment period, a radial arm water maze (RAWM) test was performed, and angiotensin II (AII) concentrations and markers of oxidative stress were measured in the brains of mice. KEY FINDINGS: Errors in the RAWM test were more frequent in the CKD-V group than in the Cont-V group. In addition, errors in the CKD-T group were comparable to control mice. Tissue brain AII concentrations were greater in the CKD-V group compared with the other groups. Oxidative DNA damage and lipid peroxidation in the brain were also greater in the CKD-V group compared with the other groups. SIGNIFICANCE: Our results suggest that brain AII levels were exaggerated in CKD mice, and that this contributes to cognitive impairment through oxidative stress.