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Abstract Background The target blood pressure (BP) value is unclear for diabetic kidney disease (DKD). Therefore, we aimed to evaluate the effect of strict BP control or ‘on treatment’ BP on clinical outcomes in patients with DKD. Methods A post-hoc analysis of the prespecified secondary outcomes of the FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC) trial, a randomized multicenter double-blind phase III trial. Eligible patients were aged ≥ 19 years with DKD. We assigned 341 participants with DKD to BP control strategy (standard-systolic BP [SBP]

Background Whether advanced age is associated with poor outcomes of elderly patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is controversial. This study aimed to evaluate age effect and predictors for mortality in elderly AKI patients undergoing CRRT. Methods Data of 480 elderly AKI patients who underwent CRRT were retrospectively analyzed. Subjects were stratified into two groups according to age: younger-old (age, 65–74 years; n = 205) and older-old (age, ≥75 years; n = 275). Predictors for 28-day and 90-day mortality and age effects were analyzed using multivariable Cox regression analysis and propensity score matching. Results Urine output at the start of CRRT (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.99–1.00; p = 0.04), operation (aHR, 0.53; 95% CI, 0.30–0.93; p = 0.03), and use of an intra-aortic balloon pump (aHR, 3.60; 95% CI, 1.18–10.96; p = 0.02) were predictors for 28-day mortality. Ischemic heart disease (aHR, 1.74; 95% CI, 1.02–2.98; p = 0.04) and use of a ventilator (aHR, 0.56; 95% CI, 0.36–0.89; p = 0.01) were predictors for 90-day mortality. The older-old group did not exhibit a higher risk for 28-day or 90-day mortality than the younger-old group in multivariable or propensity score-matched models. Conclusion Advanced age was not a risk factor for mortality among elderly AKI patients undergoing CRRT, suggesting that advanced age should not be considered for therapeutic decisions in critically ill elderly patients with AKI requiring CRRT.

Background Little is known about how the interaction between red blood cell distribution width (RDW) and vascular calcification (VC) affects cardiovascular (CV) events and mortality in end-stage kidney disease (ESKD) patients. This study investigated the combined prognostic effect of RDW and VC in ESKD patients starting dialysis. Methods A retrospective single-center study of 582 ESKD patients was conducted. VC was assessed by calculating the aortic calcification index (ACI) using computed tomography. Patients were divided into low ACI-low RDW, low ACI-high RDW, high ACI-low RDW, and high ACI-high RDW groups based on median ACI (17.12) and RDW (14.3) values. The association between RDW and VC and the composite endpoint of CV events and death was analyzed. Results During a median follow-up of 3.1 years (range, 1.5–5.5 years), 165 CV events (28.4%) and 124 deaths (21.4%) occurred. Cox regression showed that the low ACI-high RDW (adjusted hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.04–2.66; p = 0.03) and high ACI-low RDW (adjusted HR, 1.95; 95% CI, 1.21–3.14; p = 0.006) groups had a greater risk of CV events and death than the low ACI-low RDW group. The high ACI-high RDW group had the greatest risk (adjusted HR, 2.23; 95% CI, 1.42–3.52; p = 0.001). The effect of the interaction between ACI and RDW on CV events and mortality was statistically significant (p = 0.005). Conclusion High RDW and VC interact to increase the risk of CV events and death in ESKD patients.

Background Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. Results Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. Conclusion These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.

Background : : Vascular calcification (VC) is a major component of mineral bone disorders in patients with endstage renal disease (ESRD). Bone metabolism is affected by various factors, including sex hormones. This study investigated whether there was a sex-specific relationship between VC and incident fracture in patients with ESRD. Methods : : This was a retrospective cohort study of dialysis patients from a single center. VC was assessed by the aortic calcification index (ACI) using abdominal computed tomography. Patients were grouped by sex and stratified into low or high ACI groups, according to the median ACI value. The association between ACI and incident fracture was analyzed. Results : : Data from 593 patients (male: n = 328, median ACI, 14.57; female: n = 265, median ACI, 19.44) were included. During a median follow-up of 36.7 months, 71 patients (12.0%) developed fractures. The fracturefree survival rate was significantly lower in the high ACI group versus the low ACI group, both in males (P = 0.021) and females (P = 0.001). In males, multivariate analysis showed that the high ACI group and ACI per se were not significant risks for fracture. However, in females, both the high ACI group (adjusted hazard ratio, 2.720; P = 0.003) and ACI per se (adjusted hazard ratio, 1.768; P = 0.035) were independently associated with fracture after adjustment for confounding variables. Conclusion : : VC was independently associated with incident fracture in female patients with ESRD. There may be a sex-specific relationship between VC and fracture in patients with ESRD.

Objective High monocyte to high-density lipoprotein cholesterol ratio (MHR) is known to be a risk factor for cardiovascular (CV) complications. We aimed to evaluate the relationship between MHR and CV outcomes in patients commencing dialysis. Methods The medical records of patients who started maintenance dialysis between January 2006 and July 2017 were reviewed. The primary outcomes were all-cause mortality and overall CV mortality and the secondary outcomes were CV event-free survival and the incidence of CV complications. Results Five hundred ninety-seven patients were enrolled and allocated to low- or high-MHR groups. All-cause mortality did not differ between the groups during a mean follow-up period of 3.9 years. In addition, overall CV mortality did not differ between the groups. However, CV event-free survival was significantly lower in the high-MHR group than in the low-MHR group (47.5% vs . 59.0%). Multivariate Cox regression analysis showed that high MHR was an independent predictor of CV events (HR 1.886, 95% CI 1.015–3.505). Conclusion High MHR at the time of initiation of dialysis may represent a useful predictor of CV complications.

ObjectivesContrast-enhanced ultrasound (CEUS) enables the assessment of real-time renal microcirculation. This study investigated CEUS-driven parameters as hemodynamic predictors for renal outcomes in patients with acute kidney injury (AKI).MethodsForty-eight patients who were diagnosed with AKI were prospectively enrolled and underwent CEUS at the occurrence of AKI. Parameters measured were the wash-in slope (WIS), time to peak intensity, peak intensity (PI), area under the time-intensity curve (AUC), mean transit time (MTT), time for full width at half maximum, and rise time (RT). The predictive performance of the CEUS-driven parameters for Kidney Disease Improving Global Outcomes (KDIGO) AKI stage, initiation of renal replacement therapy (RRT), AKI recovery, and chronic kidney disease (CKD) progression was assessed. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of CEUS.ResultsCortical RT (Odds ratio [OR] = 1.21) predicted the KDIGO stage 3 AKI. Cortical MTT (OR = 1.07) and RT (OR = 1.20) predicted the initiation of RRT. Cortical WIS (OR = 76.23) and medullary PI (OR = 1.25) predicted AKI recovery. Medullary PI (OR = 0.78) and AUC (OR = 1.00) predicted CKD progression. The areas under the ROC curves showed reasonable performance for predicting the initiation of RRT and AKI recovery. The sensitivity and specificity of the quantitative CEUS parameters were 60-83% and 62-77%, respectively, with an area under the curve of 0.69-0.75.ConclusionCEUS may be a supplemental tool in diagnosing the severity of AKI and predicting renal prognosis in patients with AKI.

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys.

[This corrects the article DOI: 10.1371/journal.pone.0181757.].

The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.

Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes.Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue.After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05).Dapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

Objective: Brain-derived neurotrophic factor (BDNF) is a neurotrophin which modulates neuronal survival and proliferation. Recently, plasma BDNF is associated with inflammatory conditions. The present study was to investigate the changes of the plasma BDNF level in hemodialysis patients and to evaluate the relationship between the plasma BDNF and uremic inflammation.Method: We measured the plasma BDNF, serum IL-2, IL-4, IFN-γ and TNF-α in hemodialysis patients and control subjects. In addition, we investigated the associations of the plasma BDNF with clinical or biochemical parameters.Results: The plasma BDNF level was significantly higher in hemodialysis patients than in the control subjects (median, 312.3 vs. 630.3 pg/ml, p < 0.05). In subgroup analysis, hemodialysis patients with diabetes showed higher values of the plasma BDNF than the patients without diabetes. However, there were no significant differences in age and gender subgroups of the hemodialysis patients. The logBDNF was positively correlated with hs-CRP and IFN-γ, and negatively correlated with serum albumin. In multivariate regression analysis, the logBDNF was independently associated with the presence of diabetes (β-coefficient = 0.399, p = 0.041) and IFN-γ (β-coefficient = 0.538, p = 0.003).Conclusion: The plasma BDNF may increase in hemodialysis patients, and more prominently in the patients with diabetes. Furthermore, the plasma BDNF might reflect inflammatory condition in hemodialysis patients.

Pasteurella multocida is a zoonotic pathogen found in the oral cavities of both domestic and wild animals. Although P. multocida has been involved in a wide range of human diseases, only a limited number of studies on P. multocida peritonitis in patients undergoing peritoneal dialysis (PD) had been carried out. We herein present the case of P. multocida peritonitis in a patient undergoing continuous ambulatory PD, which is believed to have resulted from contact with cats. We suggest that patients undergoing PD and having domestic animals at home should be educated about the possible transmission of the infection from the animals; in addition, these patients should also maintain a high level of personal hygiene.

Red blood cell distribution width (RDW) is a robust marker of adverse clinical outcomes in various populations. However, the clinical significance of a progressive rise in RDW is undetermined in end-stage renal disease (ESRD) patients. The purpose of this study was to determine the prognostic importance of a change in RDW in ESRD patients. Three hundred twenty-six incident dialysis patients were retrospectively analyzed. Temporal changes in RDW during 12 months after dialysis initiation were assessed by calculating the coefficients by linear regression. Patients were divided into two groups: an RDW-decreased group who had negative coefficient values (n = 177) and an RDW-increased group who had positive values (n = 149). The associations between rising RDW and mortality and cardiovascular (CV) events were investigated. During a median follow-up of 2.7 years (range, 1.0-7.7 years), 75 deaths (24.0%) and 60 non-fatal CV events (18.4%) occurred. The event-free survival rate for the composite of end-points was lower in the RDW-increased group (P = 0.004). After categorizing patients according to baseline RDW, the event-free survival rate was lowest in patients with a baseline RDW >14.9% and increased RDW, and highest in patients with a baseline RDW ≤14.9% and decreased RDW (P = 0.02). In multivariate analysis, rising RDW was independently associated with the composite of end-points (hazard ratio = 1.75, P = 0.007), whereas the baseline RDW was not. This study shows that a progressive rise in RDW independently predicted mortality and CV events in ESRD patients. Rising RDW could be an additive predictor for adverse CV outcomes ESRD patients.

The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice. While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high-glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP-activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling. In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy.

Vascular changes characterized by calcification of either intima or media result in arterial stiffness and cardiac hypertrophy, especially in hemodialyais patients with secondary hyperparathyroidism. The purpose of this study is to evaluate the effects of cinacalcet on arterial compliance and cardiac hypertrophy. We studied 14 patients with ESRD who had high levels of intact PTH (iPTH, >300 pg/mL) and of corrected serum calcium (cCa, >9.0 mg/dL) with cinacalcet over 20-week period prospectively. After 20 weeks treatment, we performed flow-mediated dialation (FMD), cadio-ankle vascular index (CAVI) and echocardiographic analyses. Twenty weeks cinaclacet treatment significantly decreased blood levels of iPTH (628.2±250.8 vs. 251.7±237.4 pg/ml, p

Recent studies have shown that brain-derived neurotrophic factor (BDNF) is associated with neurotoxic, inflammatory and nutritional status . The pulpose of this study is to investigate the changes in plasma BDNF concentration that were induced by chronic uremic condition. Using an enzyme-linked immunosorbent assay (ELISA), we measured peripheral BDNF levels in pre-hemodialysis (pre-HD), peritoneal dialysis (PD) patients and in a control group. The plasma BDNF concentrations of pre-HD, PD patients were significantly higher compared with those of controls (856.3 ± 879.1, 1167.9 ± 647.5 versus 403.1 ± 288.9 pg/ml, respectively). The plasma BDNF in dialysis patients was positively correlated with high-sensitivity C reactive protein (hs-CRP) and with serum albumin negatively. Plasma BDNF hs-CRP Albumin r p r p Pre-HD 0.321 0.025 -0.298 0.021 PD 0.414 0.070 -0.527 0.008 Pre-HD + PD 0.446 0.001 -0.453 0.001 In conclusion, BDNF might plays some role in the neurotoxicity of uremia and associated with inflammation and malnutrition in dialysis patients.

Recent studies have shown that brain-derived neurotrophic factor (BDNF) is associated with neurotoxic, inflammatory and nutritional status. The purpose of this study is to investigate the changes in plasma BDNF concentration that were induced by chronic uremic condition. Using an enzyme-linked immunosorbent assay (ELISA), we measured peripheral BDNF levels in pre-hemodialysis (pre-HD), peritoneal dialysis (PD) patients and in a control group. The plasma BDNF concentrations of pre-HD, PD patients were significantly higher compared with those of controls (856.3±879.1, 1167.9±647.5 versus 403.1±288.9 pg/ml, respectively). The plasma BDNF in dialysis patients was positively correlated with high-sensitivity C reactive protein (hs-CRP) and with serum albumin negatively. Plasma BDNF hs-CRP Albumin r p r p Pre-HD 0.321 0.025 -0.298 0.021 PD 0.414 0.070 -0.527 0.008 Pre-HD + PD 0.446 0.001 -0.453 0.001 In conclusion, BDNF might plays some role in the neurotoxicity of uremia and associated with inflammation and malnutrition in dialysis patients.