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Arterial calcification is an integral component of active atherosclerosis and is an independent risk factor for cardiovascular disease. Atherosclerosis is a systemic, life-threating disease that may occur at different sites and in various clinical presentations. Intracranial and valvular calcifications are common among dialysis patients and have been associated with poor cardiovascular outcomes. The aim of this study was to assess the clinical impact of valvular and intracranial arterial calcifications on mortality among chronic hemodialysis patients.A blinded neuroradiologist graded intracranial calcifications (ICC) of all hemodialysis patients who underwent brain computerized tomography (CT) from 2015 to 2017 in our institution. Valvular calcifications were assessed by echocardiography. Only hemodialysis patients with available echocardiography and brain CT were included.This study included 119 patients (mean age 70.6 ± 12.6 years, 57.1% men, and mean dialysis vintage 25.8 ± 42.6 months). Among the cohort, 19 (16%) had no cardiac or brain calcifications and 65 (54.6%) had both valvular and intracranial calcifications. Considering the patients with no calcification as the reference group yielded adjusted odds ratios for all-cause mortality of 3.68 (95%CI 1.55-8.75) among patients with any brain calcifications, p = 0.002. While valvular calcifications alone did not increase the 1-year mortality rate, ICC was the most important predictor of all-cause 1-year mortality in the study cohort.We found an independent association between ICC and the risk of death among hemodialysis patients. Assessing ICC may contribute to the risk stratification of hemodialysis patients. These calcifications are no less important than valvular calcifications.

Peritoneal dialysis (PD) causes structural and functional changes in the peritoneal membrane, which are attributed to local inflammatory process. This study assessed the presence of galectin-3 (Gal-3), a known inflammatory modulator, in dialysate effluent and correlated its levels with markers of inflammatory process. Gal-3 levels in serum and dialysate effluent were measured in prevalent PD patients on morning visits (n = 27) or during peritoneal equilibration tests (PET, n = 16), it association with clinical and laboratory parameters, including dialysate/plasma creatinine (D/P creatinine) and interleukin-6 (IL-6) levels was analysed. Gal-3 levels in dialysate effluent correlated with D/P creatinine (0.663, p = 0.005) and dialysate effluent IL-6 levels (0.674, p = 0.002), but not with serum Gal-3 levels or dialysis vintage. Patients who were high transporters had higher Gal-3 levels in dialysate effluent, as compared to lower transporters. In multivariate regression analysis, dialysate IL-6 level was the strongest predictor of dialysate Gal-3 levels. This study found Gal-3 in dialysate effluent correlated with D/P creatinine and dialysate IL-6 levels. These findings may imply that Gal-3 has a role in the intraperitoneal inflammatory process. However, this needs to be investigated further.

Reliable vascular access is a fundamental tool for providing effective hemodialysis. Vascular access dysfunction is associated with increased morbidity and mortality among hemodialysis patients. Current vascular access guidelines strongly recommend creating an arteriovenous fistula (AVF) as the first option; however, a substantial proportion of new AVFs may not be usable.To assess possible predictors of primary and secondary failure of vascular access.This retrospective cohort study included all vascular access sites created at Meir Medical Center from 2006 through 2012. Vascular access site, primary and secondary failure rates, and relevant demographic and clinical data were recorded during 60 months of follow-up.A total of 612 vascular accesses were created and followed for a median of 32 ± 29.4 months. Of these, 490 (80%) were suitable for initiating hemodialysis. Vascular access site was the most important predictor of primary failure but did not predict secondary failure. Co-morbidities such as diabetes mellitus and congestive heart failure, as well as the use of antiplatelet agents did not predict primary or secondary failure. Preoperative vascular mapping using Doppler ultrasonography was performed in 36.4% of cases and was not associated with lower rates of primary or secondary failure.Vascular access site is an important predictor of primary failure. We did not find a benefit of pre-operative vessel mapping or chronic antiplatelet therapy in terms of decreasing primary and secondary failure rates. Physicians should carefully consider the characteristics of the patient and blood vessels before creating vascular access in patients requiring chronic hemodialysis.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are leading causes of perinatal complications, affecting 8-10% of all pregnancies. Inflammasomes are suspected to be one of the mechanisms that lead to the process of term and preterm labors. This study evaluated the inflammasome-dependent inflammation processes in placental tissue of women with PE and IUGR.In this prospective cohort study, 14 women with PE, 15 with placental-related IUGR and 19 with normal pregnancy (NP) were recruited during admission for delivery. Maternal blood was obtained prior to delivery and neonatal cord blood and placental tissue were obtained after delivery.NLRP7 and PYCARD protein expression were higher in placental PE and IUGR samples vs. NP samples. Immunostaining revealed that NLRP7 and PYCARD were upregulated in PE and IUGR placental syncytiotrophoblast, stroma and endothelial cells. PYCARD serum levels were significantly higher in women with PE and IUGR. No significant changes were observed in neonatal cord blood.NLRP7 and PYCARD are key inflammatory proteins that are significantly elevated in PE and IUGR. Better understanding their significance may enable them to become markers of prediction or progression of PE and IUGR. This article is protected by copyright. All rights reserved.

Background and aims Gestational diabetes mellitus (GDM), hyperglycemia diagnosed during pregnancy, is one of the most common medical complications of pregnancy, treated primarily by diet and pharmacotherapy, if indicated. It is well-established that GDM increases the risk of adverse pregnancy outcomes and long-term complications in mothers and infants. Galectin-3 (Gal-3) is important in processes of cell growth, differentiation, inflammation, and fibrosis. We evaluated Gal-3 expression in pregnancies complicated by GDM as a parameter that might explain how GDM influences early onset of future complications. Methods and results Forty-four women with GDM and 40 with normal pregnancy (NP) were recruited during delivery admission. Blood samples were obtained from parturients and umbilical cords blood, as well as placental tissue for analysis. Gal-3 mRNA expression was increased in maternal blood samples and placental tissue of women with GDM compared to NP. In GDM, Gal-3 mRNA was decreased in cord blood compared to maternal blood and placental tissue. Gal-3 GDM placental protein expression was increased compared to NP. Immunostaining revealed that Gal-3 is upregulated in GDM placental extravillous trophoblast. ELISA of Gal-3 maternal serum levels between GDM and NP were similar. Conclusion Gal-3 is strongly expressed at molecular levels (mRNA and protein expression) in GDM maternal blood and placental tissue, and decreased in cord blood. These findings highlight the role of the placenta in protecting the fetus from potential Gal-3 damage. Gal-3 expression at mRNA and protein levels might be influenced by diabetes, even if blood glucose is balanced by medication or diet.

Brain atrophy (BA) is often found in neuroimaging of hemodialysis patients, representing parenchymal cerebral damage. Likely contributing factors to BA are age, chronic hypertension, diabetes mellitus and other cardiovascular risk factors of atherosclerosis that are also common among hemodialysis patients. BA may also occur due to focal ischemia and hypoperfusion during hemodialysis. However, data on optimal blood pressure (BP) in these patients are limited. The goal of this study was to determine whether the prevalence and severity of BA would be higher among hemodialysis patients with lower BP. A blinded neuroradiologist graded BA of all hemodialysis patients who underwent brain non-contrast computerized tomography (CT) from 2015 to 2017 in our institution. Age- and sex-matched patients with normal kidney function who underwent brain CT during the same period and technique served as the control group. A total of 280 patients were included in this retrospective study, with average BP of 140/70 mmHg among hemodialysis patients and 142/75 mmHg in the control group. BA was more common in dialysis patients and its severity increased with age and traditional cardiovascular risk factors. We observed a significant negative correlation between diastolic BP (DBP) at dialysis initiation and BA. Average DBP decreased with increasing severity of BA. These findings were observed in both hemodialysis and non-CKD patients. BA was associated with lower DBP, which may induce cerebral hypoperfusion and ischemia. This finding should discourage over-treatment of hypertension among hemodialysis patients.

Background Chest-pain patients with no evidence of acute coronary syndrome might still be at risk for adverse outcomes. Adding renal function to the classic scoring of CHADS and CHA2DS2 VASC may improve risk stratification of chest-pain patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out. Methods We accessed medical records of patients admitted to internal medicine wards during 2010–2016 and discharged following ACS rule-out. A R2CHA2DS2-VASc score model that included higher scores as kidney function deteriorated was calculated and compared to CHADS and CHA2DS2 VASC scores. The primary endpoint was the composite of 30-day ACS and mortality. One-year ACS and 1-year mortality were the secondary endpoints. The study included 12,449 patients, stratified into three risk groups according to their R2CHA2DS2-VASc score. Results Participants were stratified into 3 groups according to R2CHA2DS2-VASc score. R2CHA2DS2-VASc score predicted better the composite outcome of ACS and 30-day and 1-year mortality after discharge (OR: 4, 95%, CI 2.3–7, p Conclusions The R2CHA2DS2-VASc score is a better predictor of short- and long-term cardiovascular morbidity and mortality after hospital discharge.

Preterm delivery complicates 5-12% of pregnancies and is the primary cause of neonatal morbidity and mortality. The pathophysiology of preterm labor and parturition is not fully known, although it is probably related to inflammation and placental senescence. Telomere shortening is related to senescence and galectin-3 (Gal-3) protein is involved in cell growth, differentiation, inflammation, and fibrosis. This study examined changes in Gal-3 expression and telomere homeostasis (which represent inflammatory and stress markers) in maternal blood and placental tissue of spontaneous preterm births (SPTB) and uncomplicated, spontaneous term pregnancies (NTP) during labor. Participants included 19 women with NTP and 11 with SPTB who were enrolled during admission for delivery. Maternal blood samples were obtained along with placental tissue for Gal-3 analysis and telomere length evaluation. Gal-3 protein expression in placental tissue was increased in SPTB compared to NTP (fold change: 1.89 ± 0.36, P 0.05). Gal-3 immunohistochemistry demonstrated strong staining in placental extravillous trophoblast tissue from SPTB. Maternal blood levels of Gal-3 protein were elevated in SPTB compared to NTP (19.3 ± 1.3 ng/ml vs. 13.6 ± 1.07 ng/ml, P = 0.001). Placental samples from SPTB had a higher percentage of trophoblasts with short telomeres (47.6%) compared to NTP (15.6%, P 0.0001). Aggregate formation was enhanced in SPTB (7.8%) compared to NTP (1.98%, P 0.0001). Maternal blood and placental samples from SPTB had shorter telomeres and increased Gal-3 expression compared to NTP. These findings suggest that increased senescence and inflammation might be factors in the abnormal physiology of spontaneous preterm labor.

Background: Predicting the mortality risk of patients un­dergoing hemodialysis (HD) is challenging. Cell-free DNA (cfDNA) is released into circulation from dying cells, and its elevation is predictive of unfavorable outcome. In a pilot study, we found post-HD cfDNA level to be a predictor of all-cause mortality. Thus, the aim of this study was to confirm the prognostic power of cfDNA in a larger prospective cohort study conducted at 2 medical centers. Methods: CfDNA levels were measured by a rapid fluorometric assay on sera obtained before and after 1 HD session. One hundred fifty-three patients were followed up to 46 months for mortality during which time 47 patients died. We compared the predictive value of cfDNA to age, comorbidities, and standard blood tests. Results: Examining standard blood tests, only post-HD cfDNA levels were elevated in the non-survivor group compared to survivors (959 vs. 803 ng/mL, p = 0.04). Pre- and post-HD cfDNA levels correlated with age and diabetes. Patients with elevated cfDNA (>850 ng/mL) showed lower survival than those with normal levels. A Cox proportional hazard regression model demonstrated a significant hazard ratio of 1.92 for post-HD cfDNA levels. Logistic regression models showed that post-HD cfDNA was a significant predictor of mortality at 1–3 years with odd ratios of 4.61, 4.36, and 6.22, respectively. Conclusions: Post-HD cfDNA level was superior to standard blood tests and could serve as a biomarker to assist in decision-making for HD-treated patients.

To evaluate changes in the inflammatory response of thioredoxin (TXN), thioredoxin interacting protein (TXNIP), transducer and activator of transcription 3, NFƙB-p50 and STAT3 at the level of maternal serum, placenta, and umbilical cord blood of women with gestational diabetes mellitus type 2 (GDMA2) compared to normal pregnancies (NP). Thirty pregnant women (20 with GDMA2 and 10 NP) were recruited during admission for delivery. Blood samples were obtained from the parturients and umbilical cords, as well as placental tissue for mRNA and protein extraction. TXNIP mRNA expression was significantly increased in maternal serum of women with GDMA2 compared to NP women. TXNIP mRNA was significantly decreased in GDMA2 placentas and cord blood compared to NP. TXN/TXNIP mRNA ratio showed significantly high absolute values in placental and cord blood (2.39 and 1.66) respectively, compared to maternal ratio (1.084) (P

Objectives Preeclampsia (PE) is a pregnancy-related syndrome characterized by the onset of hypertension and proteinuria that can lead to end-organ dysfunction. Galectin-3 (Gal-3) is involved in cell growth, differentiation, inflammation and fibrosis. Thioredoxin (TXN) acts as antioxidant enzyme in several cellular processes, regulating inflammation and inhibiting apoptosis. TXNIP is an endogenous inhibitor of TXN. We evaluated changes in the inflammatory response of Gal-3, TXN, and TXNIP at the level of maternal blood, placenta, and umbilical cord blood of women with PE. Study design Ten women with PE and 20 with normal pregnancy (NP) were recruited during admission for delivery. Blood samples were obtained from parturients and umbilical cords, and placental tissue for analysis. Results Gal-3 and TXNIP mRNA expression were higher in maternal plasma in PE group compared to NP and were lower in cord blood plasma and placentas in the PE group. In the PE group, TXN/TXNIP mRNA ratio was higher in cord blood plasma (2.07) compared to maternal plasma (1.09). TXN/TXNIP placental protein ratio was similar between PE (0.89) and NP (0.79). ELISA demonstrated that Gal-3 levels in maternal serum were significantly higher in the PE vs. the NP group. Conclusions Pro-inflammatory changes were expressed by high Gal-3 and TXNIP mRNA in maternal blood of PE women, but not in their placental and cord blood samples. These findings may imply that the placenta has a role in protecting the fetus from the damages of inflammatory response, which is more common in PE than in NP.

Background and Aims Peritoneal dialysis (PD) is a common used method for renal replacement therapy. Prolonged PD treatment causes structural and functional changes in the peritoneal membrane which are attributed to local inflammatory process in the peritoneal cavity. Galectin-3 (Gal-3) is a galactoside-binding lectin with pro-inflammatory and pro-fibrotic effects. The aim of this study was to assess correlation between Gal-3 serum and dialysate effluent levels with peritoneal membrane transport characteristics. Method Gal-3 levels in serum and dialysate effluent were measured simultaneously in prevalent PD patients in morning visit or during peritoneal equilibration test (PET). Gal-3 levels were correlated with clinical and laboratory parameters. Interlukin (IL) -6 levels were measured in dialysate effluent. Gal-3 mRNA and protein expression were evaluated after exposure of primary endothelial cell culture to several dialysate solutions. Results 37 PD patients were included in the study; mean age was 65.7±13.1 years, mean dialysis vintage was 17.5±13 months. Gal-3 levels in dialysate effluent correlated with peritoneal equilibration test (PET) results (0.663, p=0.005) and effluent IL-6 levels (0.674, p=0.002) but not with serum Gal-3 levels or dialysis vintage. Patients with high PET results had higher effluent Gal-3 levels as compared average low PET results. In multivariate regression analysis effluent IL-6 level was the most dominant predictor of effluent Gal-3 levels. Gal-3 mRNA and protein expression in primary endothelial cell culture were not affected by stimulation with dialysate solutions. Conclusion Our study demonstrated presence of Gal-3 within the dialysate effluent in PD patients. Gal-3 levels correlated with peritoneal membrane transport characteristics and effluent IL-6 levels suggesting a role in the inflammatory process within the peritoneal cavity.

Background and Aims Intra-cranial arterial calcification (ICAC) in hemodialysis (HD) patients has a prevalence of about 90%, and its severity is correlated with age, hemodialysis vintage and mineral bone disease. Elevated concentrations of calcium and phosphorus are not sufficient to induce medial calcification because of inhibition by pyrophosphate. Alkaline Phosphatase (ALP) promotes vascular calcification by hydrolyzing pyrophosphate. Epigenetic mechanisms regulation by Apabetalone downregulates pathways involved in vascular calcification. This study assessed the combined impact of ICAC and elevated serum ALP on mortality among chronic HD patients. Method vascular calcifications represented by ICAC were measured simultaneous with mineral bone disease parameters including serum ALP of chronic HD patients who underwent non-contrast brain computerized tomography (CT) from 2015 to 2018 in our institution. Results This retrospective study included 153 hemodialysis patients (mean age 71.3±12.1 years, 60.1% male). Of the total cohort, 12(7.8%) had no brain calcifications and 69 (45.1%) had multiple intracranial calcifications. Considering the patients with normal ALP and no calcification as the reference group yielded adjusted odds ratios for all-cause mortality of 4.6 (95%CI 1.7-12.7) among patients with brain calcifications and normal ALP, p=0.003, and odds ratios for all-cause mortality of 6.1 (95%CI 2.1-17.7) among patients with brain calcifications and increased ALP. Conclusion We founded an independent association between ICAC and the risk of death among hemodialysis patients. The combined effect of ICAC and increased ALP was significantly associated with higher odds-ratio for all-cause mortality in chronic HD patients and may contribute to the risk stratification of these patients.

The incidence of stroke in patients undergoing hemodialysis (HD) is eight-to-ten times greater than that of the general population. However, data on the outcome of stroke in these patients are limited. In this retrospective observational cohort study, electronic medical records of all patients undergoing HD from 1.1.2014 to 31.12.2017 at Meir Medical Center, Israel, were reviewed. Stroke was defined as a focal neurological deficit of cerebrovascular origin, and confirmed as ischemic or hemorrhagic by computed tomography. Age- and sex-matched HD patients who did not experience a stroke (HD-NS) and hospitalized stroke patients with normal kidney function (NRF-S) served as the two control groups. Baseline demographic, clinical, and laboratory data were collected. Thrombolytic therapy, duration of hospital stay, and mortality were recorded. Functional status at discharge was assessed by the Modified Rankin Scale. In the cohort study group (HD-S), 52 strokes occurred during 248.3 patient years, an incidence rate of 8.13%, and a stroke rate of 0.19% patients/month. Most strokes in HD patients were ischemic, and only four patients were administered tissue plasminogen activator. HD-S had longer hospitalization than did NRF-S (10.6 ± 9.9 vs. 5.96 ± 5.3 days, p = 0.004) and lower functional status at discharge (Rankin score 3.75 ± 1.57 vs. 2.29 ± 1.89, p

Evaluate the efficacy of retraining and catheter exit site care in reducing peritonitis rates. This interventional study included all prevalent PD patients from 1/2009 to 12/2017 from a single center. Peritonitis rates and causative organisms were assessed and compared in three periods: (1) Before intervention (01/2009–12/2014), (2) after educational intervention: assessment of training process by infection control nurse and repeat training every 3 months, after each peritonitis episode and after hospitalizations > 2 weeks (01/2015–02/2016), and (3) in addition to the measures in period 2, an exit site care protocol including postoperative care, topical antibacterial therapy and nasal Staph aureus screening and eradication was implemented (03/2016–12/2017). The study included 201 patients (149 men, 52 women), mean age was 65.1 ± 12.6 years. After both interventions, including educational and exit site care strategies, peritonitis decreased significantly from 1.05 episodes per patient-year (n = 113) to 0.67 (n = 54); P = 0.017 between periods 1 and 3. The percentage of peritonitis-free patients increased from 27.4 to 52.4 and 55.6%, respectively (P = 0.001 between period 1 vs. 2 and period 1 vs. 3.). Coagulase-negative staph was the most common pathogen, causing 7.56 peritonitis episodes per year, followed by pseudomonas at 4.33 episodes annually and staph aureus at 3.44 episodes per year. Enforcement of an educational program and strict adherence to an exit site care protocol was associated with a significant decrease in peritonitis rates.

Background and Aims: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF. Galectin 3 (Gal-3) activates a variety of profibrotic processes. Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given ‘on top’ of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitro and in vivo models, in addition to serum samples from patients with IPF. Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following nintedanib treatment (10–100 nM, quantitative polymerase chain reaction), and in a silica-induced fibrosis mouse model with/without nintedanib (0.021–0.21 mg/kg) by immunohistochemistry. In addition, Gal-3 levels were analyzed in serum samples from 41 patients with interstitial lung disease patients with/without nintedanib treatment by ELISA. Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, phospho-signal transducer and activator of transcription 3 (pSTAT3), as well as IL-8 mRNA levels ( p Conclusion: Nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy for patients with IPF.

Background and Aims Brain atrophy (BA) is a common finding in neuroimaging of hemodialysis (HD) patients, representing a parenchymal cerebral damage. Likely contributing factors to BA are age, chronic hypertension, diabetes mellitus and other cardiovascular risk factors of atherosclerosis that are also common among HD patients. BA may also occur due to focal ischemia and hypoperfusion during HD. However, data on optimal blood pressure (BP) in these patients are limited. The goal of this study was to determine whether the prevalence and severity of BA would be higher among HD patients with lower BP. Method A blinded neuroradiologist graded BA of all HD patients who underwent brain non-contrast computerized tomography (CT) from 2015 to 2017 in our institution. Age-and sex-matched patients with normal kidney function who underwent brain CT during the same period and technique served as the control group Results A total of 280 patients were included in this retrospective study, with average BP of 140/70 mmHg among HD patients and 142/75 mmHg in the control group. BA was more common in dialysis patients and its severity increased with age and traditional cardiovascular risk factors. We observed a significant negative correlation between diastolic BP (DBP) at dialysis initiation and BA. Average DBP decreased with increasing severity of BA. These findings were observed in both HD and non-CKD patients. Conclusion Brain atrophy was associated with lower DBP, which may induce cerebral hypoperfusion and ischemia. This finding should discourage over-treatment of hypertension in hemodialysis patients.

Chest-pain patients with no evidence of acute coronary syndrome might still be at risk for adverse outcomes. Adding renal function to the classic scoring of CHADS and CHAWe accessed medical records of patients admitted to internal medicine wards during 2010-2016 and discharged following ACS rule-out. A RParticipants were stratified into 3 groups according to RThe R

Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza vaccination among hemodialysis (HD) patients. In the 2014-2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015-2016 by the hospital dialysis unit staff during an inpatient HD session (P

BACKGROUND The third-generation bio-intact parathyroid hormone (PTH) (1-84) assay was designed to overcome problems associated with the detection of C-terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. METHODS Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1-84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula. RESULTS Serum bio-intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, P

Von Willebrand factor (vWF) is a glycoprotein with a crucial role in the formation of platelet thrombi, and ADAMTS13 is the main enzyme responsible for vWF cleavage. Both are important in the relationship between diabetic nephropathy, hypercoagulability, and cardiovascular disease. This study evaluated a potential relationship between vitamin D (vitD) levels, vWF, ADAMTS13 activity, and inflammation in diabetic patients on chronic hemodialysis (HD). Blood samples from 52 diabetic patients on chronic HD were obtained to determine vitD levels, vWF, and ADAMTS13 activity, and inflammatory markers. HD patients were grouped according to 25-hydroxyvitamin D [25(OH) VitD]25 nmol/L (n=36). vWF antigen and vWF activity were elevated in both groups, with an average of 214.3±82.6% and 175.8±72.6%, respectively. Average ADAMTS13 activity was within the normal range in both groups. Blood samples from the vitD

Background Impaired phagocytic function has been established in uremic patients. Chemotaxis, particle ingestion, and free radical and metabolic activity were all found to be disturbed in dialysis patients. Malnutrition is common among hemodialysis (HD) patients, with an estimated prevalence of 40% to 70%. Malnutrition-Inflammation Score (MIS) appears to be a useful tool for risk stratification of chronic HD patients. We assessed the correlation between MIS and phagocyte function in HD patients. Methods Forty-four chronic HD patients were enrolled from the dialysis unit. The patients were divided into two groups according to the MIS: 1 to 12 (normal-mild) and 13 to 30 (severely malnourished). Hydrogen peroxide release by polymorphonuclear leukocytes was evaluated using the dihydrorhodamine 123 method. Phagocytic activity of neutrophils was evaluated after stimulation with Escherichia coli bacteria and phorbol 12-myristate 13-acetate (PMA) (positive control). Results Neutrophil oxidative activity in all HD patients versus healthy controls was significantly lower in median fluorescence intensity (MdFI)–E. coli and MdFI-PMA. We found significant correlations among MdFI-PMA and calculated MIS and other nutritional parameters in chronic HD patients. Conclusions Impaired phagocytic function was identified in chronic HD patients. The severity of the impairment was associated with nutrition and inflammation parameters, as well as Malnutrition-Inflammation Score.

Background Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that stimulates insulin secretion and may affect the inflammatory pathways involved in diabetes mellitus. Calcitriol, an active form of vitamin D, plays an important role in renal, endothelial and cardiovascular protection. We evaluated the anti-inflammatory and histologic effects of a GLP-1 analogue (liraglutide) and of calcitriol in a db/db mouse diabetes model and in endothelial cells exposed to a diabetes-like environment. Methods Diabetic db/db mice were treated with liraglutide and calcitriol for 14 weeks, after which the kidneys were perfused and removed for mRNA and protein analysis and histology. Endothelial cells were stimulated with advanced glycation end products (AGEs), glucose, liraglutide and calcitriol. Total RNA and protein were extracted and analysed for the expression of selected inflammatory markers. Results Typical histological changes, glomerular enlargement and mesangial expansion were seen in db/db mice compared with control mice. Glomerular hypertrophy was ameliorated with liraglutide, compared with db/db controls. Liraglutide up-regulated endothelial nitric oxide synthase protein expression compared with the db/db control group and down-regulated p65 protein expression. Calcitriol did not further improve the beneficial effect observed on protein expression. In endothelial cells, liraglutide treatment exhibited a dose-dependent ability to prevent an inflammatory response in the selected markers: thioredoxin-interacting protein, p65, IL6 and IL8. In most gene and protein expressions, addition of calcitriol did not enhance the effect of liraglutide. Conclusions The GLP-1 analogue liraglutide prevented the inflammatory response observed in endothelial cells exposed to a diabetes-like environment and in db/db mice at the level of protein expression and significantly ameliorated the glomerular hypertrophy seen in the diabetic control group. Copyright © 2016 John Wiley & Sons, Ltd.

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women with GDMA2 and their fetuses. Methods: Thirty pregnant women were recruited during admission for delivery. The function and expression of HDL, paraoxonase1 (PON1) and apolipoprotein A1 (APOA1) in the blood samples and the placental tissue were evaluated. The effect of HDL on migration of endothelial cells was measured in vitro. Results: Compared to normal pregnancy (NP), APOA1 in the maternal plasma of women with GDMA2 was decreased. More APOA1 and PON1 were released from HDL of women with GDMA2, compared to NP. Placental APOA1 and PON1 were decreased in GDMA2. For endothelial cells stimulated with TNF&alpha, HDL cell migration was decreased when cells were evaluated with NP-HDL, as compared to GDMA2-HDL. Conclusions: GDMA2 affects the composition and function of HDL in plasma. Changes in HDL commonly seen in GDMA2 were observed in maternal and placental samples, but not in cord samples. These results might indicate a placental role in protecting the fetus by preserving the components and functions of HDL and require further investigation.

Emerging evidence demonstrates the involvement of Janus tyrosine kinase/signal transducer and transcription activator (JAK/STAT) proteins in the pathophysiology of diabetic kidney disease (DKD). The JAK/STAT pathway is involved in the inflammatory response and endothelial cell dysfunction observed in DKD. The glucagon-like peptide-1 (GLP-1) analog liraglutide is an effective treatment for type 2 diabetes because it improves the inflammatory changes observed in experimental models of DKD. This study used db/db mice and endothelial cells (ECs) to determine the effect of diabetic environment on the JAK/STAT pathway and to assess the potential effect of liraglutide (200 μg/kg) in both models.Diabetic db/db mice (12 weeks old) were treated with liraglutide for 14 weeks. The kidneys were then perfused with saline and removed for mRNA, protein, and immunohistochemical analyses. Endothelial cells were stimulated advanced glycation end products (AGEs) (200 μg/μL) glucose (200 mg/dL) and liraglutide (100 nM) for 24 hours. Total RNA and protein were extracted and analyzed for expression of JAK/STAT signaling.Phosphorylated (p-) STAT3 was significantly upregulated in db/db mice compared with non-diabetic mice. Liraglutide significantly downregulated p-STAT3 protein expression in db/db mice. In db/db mice, p-STAT3 was primarily expressed in the glomeruli, whereas p-JAK2 was also expressed in kidney tubules. In ECs, liraglutide treatment prevented increased expression of p-STAT3 and p-JAK2. Liraglutide inhibited the target gene suppressor of cytokine signaling 3 (SOCS3) and sirtuin 1 (SIRT1) in db/db mice and in cultured EC.This study suggests that the GLP-1 analog liraglutide inhibits the JAK/STAT pathway, which participates in intracellular processes in experimental models of diabetes.背景: 越来越多的证据表明Janus酪氨酸激酶/信号转导与转录激活因子(Janus tyrosine kinase/signal transducer and transcription activator，JAK/STAT)蛋白参与了糖尿病肾病(diabetic kidney disease，DKD)的病理生理学过程。在DKD中观察到的炎症反应以及内皮细胞功能障碍与JAK/STAT通路有关。胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)类似物利拉鲁肽是一种有效的2型糖尿病治疗药物，因为在DKD实验模型中观察到它可以改善炎症反应。这项研究利用db/db小鼠与内皮细胞(endothelial cells，ECs)来测定糖尿病环境对JAK/STAT通路的影响，并且在这两个模型中评估了利拉鲁肽(200 μg/kg)的潜在影响。 方法: 糖尿病db/db小鼠(12周龄)使用利拉鲁肽治疗14周。然后在肾脏中灌入生理盐水，取出后进行mRNA、蛋白质以及免疫组化分析。使用晚期糖基化终产物(200 μg/μL)、葡萄糖(200 mg/dl)与利拉鲁肽(100 nM)刺激内皮细胞24小时。提取出全部的RNA与蛋白质并且分析了JAK/STAT信号的表达。 结果: 与非糖尿病小鼠相比较，在db/db小鼠中磷酸化STAT(p- STAT3)显著上调了。在db/db小鼠中利拉鲁肽可以显著下调p-STAT3蛋白的表达。在db/db小鼠中，p-STAT3主要在肾小球中表达，而p-JAK2在肾小管中也有表达。在ECs中，使用利拉鲁肽治疗后可以防止p-STAT3与p-JAK2表达增加。在db/db小鼠以及培养的EC中，利拉鲁肽可以抑制细胞因子信号3(suppressor of cytokine signaling，SOCS3)以及sirtuin 1(SIRT1)的靶基因抑制因子。 结论: 这项研究表明，GLP-1类似物利拉鲁肽可以抑制JAK/STAT通路，这个通路与糖尿病实验模型的细胞内进程有关。.

Anemia management strategies among chronic hemodialysis patients with high ferritin levels remains challenging for nephrologists.To compare anemia management in stable hemodialysis patients with high (≥ 500 ng/ml) vs. low (500 ng/ml) ferritin levels.In a single center, record review, cohort study of stable hemodialysis patients who were followed for 24 months, an anemia management policy was amended to discontinue intravenous (IV) iron therapy for stable hemodialysis patients with hemoglobin10 g/dl and ferritin ≥ 500 ng/ml. Erythropoiesis-stimulating-agents (ESA), IV iron doses, and laboratory parameters were compared among patients with high vs. low baseline ferritin levels before and after IV iron cessation.Among 87 patients, 73.6% had baseline ferritin ≥ 500 ng/ml. Weekly ESA dose was greater among patients with high vs. low ferritin (6788.8 ± 4727.8 IU/week vs. 3305.0 ± 2953.9 IU/week, P = 0.001); whereas, cumulative and monthly IV iron doses were significantly lower (1628.2 ± 1491.1 mg vs. 2557.4 ± 1398.9 mg, P = 0.011, and 82.9 ± 85 vs. 140.7 ± 63.9 mg, P = 0.004). Among patients with high ferritin, IV iron was discontinued for more than 3 months in 41 patients (64%) and completely avoided in 6 (9.5%).ESA dose and hemoglobin levels did not change significantly during this period.Iron cessation in chronic hemodialysis patients with high ferritin levels did not affect hemoglobin level or ESA dose and can be considered as a safe policy for attenuating the risk of chronic iron overload.

To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established. Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression. PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL. HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE.

Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza vaccination among hemodialysis (HD) patients. In the 2014-2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015-2016 by the hospital dialysis unit staff during an inpatient HD session (P0.001). A trend toward fewer complications from influenza infection was observed in vaccinated patients. Among HD patients with diabetes (who comprised 56% of the study population), the incidence of influenza was 17% among nonvaccinated patients vs. 6.3% among those who were vaccinated (P =0.026). The inpatient vaccination policy resulted in a greater rate of vaccination. HD patients with diabetes benefit from influenza vaccination, with a significantly lower incidence of influenza infection.

Diabetes mellitus (DM) is the leading cause of end-stage kidney disease. Inflammation, fibrosis, coagulability and oxidative stress exacerbate kidney disease. The glycoprotein, Von Willebrand Factor (VWF) has a crucial role in platelet thrombus formation. The enzyme ADAMTS13 is responsible for VWF cleavage. Both are important in the interface between diabetic nephropathy, hypercoagulability and atherosclerotic cardiovascular disease. Vitamin D inhibits endothelial proliferation, blunts angiogenesis and is a cardioprotective agent. This study evaluated the role of vitamin D on ADAMTS13 activity in human umbilical vein endothelial cells (HUVEC) exposed to a diabetic-like environment.HUVEC were stimulated with 200µg/µl AGE-HSA, 250mg/dl glucose, and 10-10mol/l vitamin D for 24 hours. Western blot and ELISA techniques were used to determine ADAMTS13 protein expression and IL6 and IL8 protein secretion.ADAMTS13 protein expression decreased and IL6 and IL8 protein secretion increased in HUVEC exposed to a diabetic-like environment. The addition of vitamin D significantly down-regulated IL6 and IL8 secretion and up-regulated ADAMST13 expression.Decreased ADAMTS13 expression in HUVEC exposed to a diabetic-like environment may contribute to the pathogenesis of hypercoagulability observed in DM. Normalization of ADAMTS13 by vitamin D may contribute to improvement in hypercoagulability.

Upper respiratory tract infection (URTI) occurs frequently in the general population and is considered a benign self-limited disease. Dialysis patients constitute a high risk population whose morbidity and mortality rate as a result of URTI is unknown.To assess the local incidence, morbidity and mortality of URTI in dialysis patients compared to the general population.In this retrospective cohort study we reviewed the charts of all chronic dialysis patients diagnosed with URTI at Meir Medical Center, Kfar Saba, Israel during the 2014-2015 winter season.Among 185 dialysis patients, 40 were found to be eligible for the study. The average age was 66.1 ± 15.7 years, and the co-morbidity index was high. Influenza A was the most common pathogen found, followed by rhinovirus, respiratory syncytial virus and para-influenza. Of the 40 patients 21 (52.5%) developed complications: pneumonia in 20%, hospitalization in 47.5%, and respiratory failure requiring mechanical ventilation in 12.5%. Overall mortality was 10%. General population data during the same seasonal period showed a peak pneumonia incidence of 4.4% compared to 20% in the study population (P0.0001).The study findings show that compared to the general population, URTI in dialysis patients is a much more severe disease and has a higher complication rate. Influenza A, the most common pathogen, is associated with a worse prognosis.

High blood and tissue concentrations of glucose and advanced glycation end products (AGEs) are thought to play an important role in the development of diabetic vascular complications. Thioredoxin interacting protein (TXNIP) is up-regulated in response to high levels of glucose and is an endogenous inhibitor of thioredoxin (TRX), and may play a contributory role in the occurrence of diabetic-related vascular diseases. Vitamin D inhibits endothelial proliferation and is a cardiovascular protective agent. The present study evaluated the impact of paricalcitol and calcitriol on the endothelial inflammatory and TXNIP pathways in cultured endothelial cells exposed to a diabetic-like environment. Fresh human umbilical vein cord endothelial cells (HUVEC) were treated for 24 h with 200 μg/ml AGE-HSA and 250 mg/dl glucose concentrations, with paricalcitol or calcitriol. IL6, IL8, NFκB (p50/p65), receptor of AGE (RAGE), TXNIP, and TRX expressions were evaluated at the levels of mRNA, protein, and TRX activity. Calcitriol and paricalcitol significantly down-regulated the markers involved in the inflammatory responses. Only paricalcitol induced a significant decrease in TXNIP mRNA and protein expressions. Neither paricalcitol nor calcitriol affected TRX reductase activity or TRX mRNA and protein expressions. Our findings indicate that in an endothelial diabetic-like environment, paricalcitol and calcitriol significantly decreased the expression of genes involved in the inflammatory pathway. In this in vitro study, it seems that the TRX antioxidant system was not involved. The different effects found between paricalcitol and calcitriol might reflect the selectivity of vitamin D receptor (VDR) activation.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that stimulates insulin secretion and may affect the inflammatory pathways involved in diabetes mellitus. Calcitriol, an active form of vitamin D, plays an important role in renal, endothelial and cardiovascular protection. We evaluated the anti-inflammatory and histologic effects of a GLP-1 analogue (liraglutide) and of calcitriol in a db/db mouse diabetes model and in endothelial cells exposed to a diabetes-like environment.Diabetic db/db mice were treated with liraglutide and calcitriol for 14 weeks, after which the kidneys were perfused and removed for mRNA and protein analysis and histology. Endothelial cells were stimulated with advanced glycation end products (AGEs), glucose, liraglutide and calcitriol. Total RNA and protein were extracted and analysed for the expression of selected inflammatory markers.Typical histological changes, glomerular enlargement and mesangial expansion were seen in db/db mice compared with control mice. Glomerular hypertrophy was ameliorated with liraglutide, compared with db/db controls. Liraglutide up-regulated endothelial nitric oxide synthase protein expression compared with the db/db control group and down-regulated p65 protein expression. Calcitriol did not further improve the beneficial effect observed on protein expression. In endothelial cells, liraglutide treatment exhibited a dose-dependent ability to prevent an inflammatory response in the selected markers: thioredoxin-interacting protein, p65, IL6 and IL8. In most gene and protein expressions, addition of calcitriol did not enhance the effect of liraglutide.The GLP-1 analogue liraglutide prevented the inflammatory response observed in endothelial cells exposed to a diabetes-like environment and in db/db mice at the level of protein expression and significantly ameliorated the glomerular hypertrophy seen in the diabetic control group. Copyright © 2016 John WileySons, Ltd.

Background: Diabetes mellitus (DM) is one of the leading causes of chronic vascular disease, which can accelerate the development of cardiovascular and renal disorders. Vascular smooth muscle cells (VSMC) are involved in the occurrence of vascular atherosclerosis and arteriosclerosis. Calcitriol might inhibit endothelial proliferation, blunt angiogenesis, and serve as a cardioprotective agent. We evaluated the impact of a diabetic-like environment and calcitriol on VSMC gene and protein expression. Methods: VSMC were treated for 24 hours using 200 μg/ml AGE-HSA, 250 mg/dl glucose and 10-9 or 10-10 mol/l calcitriol. Microarray gene chip analysis, real time PCR, western blot and ELISA techniques were used to determine gene and protein expression. Results: A total of 2,693 genes were differentially expressed in a diabetic-like environment compared to control, with 1796 up-regulated and 897 down-regulated. These genes are responsible for functions involved in the regulation of metabolic processes, apoptosis and cell adhesion. Addition of calcitriol at physiological concentrations (10-10 mol/l) revealed 1,157 differentially expressed genes, with 673 up-regulated and 484 down-regulated. These genes significantly enriched functions such as regulation of small GTPase and RAS protein signal transduction, cell growth and extracellular matrix part. TXNIP, OPG, RANKL, KLF4, RANK and NFκB p50/p65 mRNA and protein expressions were further investigated. Conclusion: High throughput approach might lead to a better understanding of the pathways involved in the biological adaptation of VSMC exposed to diabetic-like conditions and eventually the possible beneficial effects of calcitriol treatment, which might delay the development of DM-related vascular complications.

BACKGROUND. High blood and tissue concentrations of glucose and advanced glycation end-products (AGEs) are thought to play an important role in the development of vascular diabetic complications. Therefore, the impact of extracellular AGEs and different glucose concentrations was evaluated by studying the gene expressions and the underlying cellular pathways involved in the development of inflammatory pro-atherosclerotic processes observed in cultured endothelial cells. METHODS. Fresh human umbilical vein cord endothelial cells (HUVEC) were treated in the presence of elevated extracellular glucose concentrations (5.5-28 mmol/l) with and without AGE-human serum albumin (HSA). Affymetrix GeneChip(R) Human Gene 1.0 ST arrays were used for gene expression analysis (total 20 chips). Genes of interest were further validated using real-time PCR and western blot techniques. RESULTS. Microarray analysis revealed significant changes in some gene expressions in the presence of the different stimuli, suggesting that different pathways are involved. Six genes were selected for validation as follows: thioredoxin-interacting protein (TXNIP), thioredoxin (TXN), nuclear factor of kappa B (NF-kappaB), interleukin 6 (IL6), interleukin 8 (IL8) and receptor of advanced glycation end-products (RAGE). Interestingly, it was found that the association of AGEs together with the highest pathophysiological concentration of glucose (28 mmol/l) diminished the expression of these specific genes, excluding TXN. CONCLUSIONS. In the present model that mimics a diabetic environment, the relatively short-term experimental conditions used showed an unexpected blunting action of AGEs in the presence of the highest glucose concentration (28 mmol/l). The interactive cellular pathways involved in these processes should be further investigated.