Extremely Low Dose of Erythropoiesis-Stimulating Agent May Be Associated with Increased Mortality in Hemodialysis Patients.

INTRODUCTION: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. METHODS: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0-43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. RESULTS: Compared with mean monthly ESA dose of 15,000-25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001-43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000-25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. CONCLUSIONS: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.

Short-Term Effects of a Therapeutic Diet on Biochemical Parameters in Hemodialysis Patients: A Randomized Crossover Trial.

OBJECTIVE: Although unhealthy diets exacerbate nutritional and metabolic derangements in patients with end-stage kidney disease (ESKD), how therapeutic diets that possess a variety of different dietary strategies acutely modify diverse biochemical parameters related to cardiovascular disease remains underexplored. METHODS: Thirty-three adults with end-stage kidney disease undergoing thrice-weekly hemodialysis participated in a randomized crossover trial comparing a therapeutic diet with their usual diets for 7 days, separated by a 4-week washout period. The therapeutic diet was characterized by adequate calorie and protein amounts, natural food ingredients with a low phosphorus-to-protein ratio, higher portions of plant-based food, and high fiber content. The primary outcome measure was the mean difference in the change-from-baseline intact fibroblast growth factor 23 (FGF23) level between the 2 diets. The other outcomes of interest included changes in mineral parameters, uremic toxins, and high-sensitivity C-reactive protein (hs-CRP) levels. RESULTS: Compared with the usual diet, the therapeutic diet lowered intact FGF23 levels (P = .001), decreased serum phosphate levels (P < .001), reduced intact parathyroid hormone (PTH) levels (P = .003), lowered C-terminal FGF23 levels (P = .03), increased serum calcium levels (P = .01), and tended to lower total indoxyl sulfate levels (P = .07) but had no significant effect on hs-CRP levels. Among these changes, reduction in serum phosphate level achieved in 2 days, modifications of intact PTH and calcium levels in 5 days, and reductions in intact and C-terminal FGF23 levels in 7 days of therapeutic diet intervention. CONCLUSION: Within the 1-week intervention period, the dialysis-specific therapeutic diet rapidly reversed mineral abnormalities and tended to decrease total indoxyl sulfate levels in patients undergoing hemodialysis but had no effect on inflammation. Future studies to assess the long-term effects of such therapeutic diets are recommended.

Adverse events following the first, second and third doses of a COVID-19 vaccine in hemodialysis patients.

BACKGROUND: This study aimed to identify adverse events following the first three doses of COVID-19 vaccines in hemodialysis (HD) patients. Risk factors associated with postvaccination adverse events were explored. METHODS: Postvaccination adverse events in 438 HD patients who received 3 doses of COVID-19 vaccines were prospectively assessed. The adverse events among three doses were compared using generalized linear mixed models. Factors associated with adverse events were assessed with multivariate analyses. RESULTS: The vast majority of participants received Oxford/AstraZeneca ChAdOx1 as their first two doses and Moderna mRNA-1273 as their third dose. Overall, 79%, 50% and 84% of the participants experienced at least one adverse event after their first, second, and third doses, respectively. These adverse events were mostly minor, short-lived and less than 5% reported daily activities being affected. Compared with the first dose, the second dose caused a lower rate of adverse events. Compared with the first dose, the third dose elicited a higher rate of injection site reactions and a lower rate of systemic reactions. Multivariate analyses showed that every 10-year increase of age (odds ratio 0.67, 95% confidence intervals 0.57-0.79) was associated with decreased risk of adverse events, while female sex (2.82, 1.90-4.18) and arteriovenous fistula (1.73, 1.05-2.84) were associated with increased risk of adverse events. Compared with Oxford/AstraZeneca ChAdOx1, Moderna mRNA-1273 was associated with an increased risk of injection site reactions. CONCLUSIONS: COVID-19 vaccination was well tolerated in HD patients. Age, sex, dialysis vascular access and vaccine types were associated with postvaccination adverse events.

Altered Monocytic Phenotypes are Associated with Uraemic Pruritus in Patients Receiving Haemodialysis.

Uraemic pruritus is one of the most bothersome symptoms in patients receiving haemodialysis. A total of 175 patients receiving maintenance haemodialysis, with 74 patients experiencing uraemic pruritus, were prospectively recruited to assess the influence of the phenotype of blood monocytes and various cytokines on uraemic pruritus. The phenotype of blood monocytes was determined by flow cytometry as classical (CD14++CD16-) monocytes, non-classical (CD14+CD16++) monocytes, and intermediate (CD14++CD16+) monocytes. Eight cyto-kines, including interleukin (IL)-2, interferon-γ, IL-12p70, IL-4, IL-5, IL-6, tumour necrosis factor-α, and IL-10, were simultaneously detected with a multi-plex bead-based immunoassay. Multivariate linear regression analysis showed that a higher percentage of intermediate monocytes (effect estimate 0.08; 95% confidence interval 0.01-0.16) were independent predictors of a higher visual analogue scale score for pruritus intensity. No differences were noted for all 8 cytokines between patients with and without uraemic pruritus. The results of this study indicate that altered monocytic phenotypes could play a role in uraemic pruritus.

Acute effects of dietary phosphorus intake on markers of mineral metabolism in hemodialysis patients: post hoc analysis of a randomized crossover trial.

BACKGROUND: Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations. METHODS: This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models. RESULTS: Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2-0.4, p < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, -0.11 to -0.01, p = .01), an increase in iPTH of 5.4% (95% CI, 1.4-9.3, p = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0-8.0, p = .001). Dietary phosphorus intake was not related to cFGF23. CONCLUSIONS: Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.

BSA-bounded p-cresyl sulfate potentiates the malignancy of bladder carcinoma by triggering cell migration and EMT through the ROS/Src/FAK signaling pathway.

Para-cresyl sulfate (P-CS), a major uremic toxin derived from the metabolites of tyrosine and phenylalanine through liver, existed in the blood of patients with chronic kidney disease (CKD). CKD increases the malignancy in bladder cancers; however, effects of P-CS on bladder cancers are not fully understood. P-CS is conjugated with BSA physiologically, and this study aims to investigate the effects and possible underlying mechanisms of BSA-bounded P-CS on human bladder cancer cells. With P-CS treatment, the intracellular ROS increased in bladder cancer cells. ROS then triggered epithelial-mesenchymal transition (EMT), stress fiber redistribution, and cell migration. With specific inhibitors, the key signals regulating P-CS-treated migration are Src and FAK. This study provided a clinical clue that patients with higher serum P-CS have a higher risk of malignant urothelial carcinomas, and a regulatory pathway of how P-CS regulates bladder cancer migration.

Prediction of the development of acute kidney injury following cardiac surgery by machine learning.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication that results in increased morbidity and mortality after cardiac surgery. Most established prediction models are limited to the analysis of nonlinear relationships and fail to fully consider intraoperative variables, which represent the acute response to surgery. Therefore, this study utilized an artificial intelligence-based machine learning approach thorough perioperative data-driven learning to predict CSA-AKI. METHODS: A total of 671 patients undergoing cardiac surgery from August 2016 to August 2018 were enrolled. AKI following cardiac surgery was defined according to criteria from Kidney Disease: Improving Global Outcomes (KDIGO). The variables used for analysis included demographic characteristics, clinical condition, preoperative biochemistry data, preoperative medication, and intraoperative variables such as time-series hemodynamic changes. The machine learning methods used included logistic regression, support vector machine (SVM), random forest (RF), extreme gradient boosting (XGboost), and ensemble (RF + XGboost). The performance of these models was evaluated using the area under the receiver operating characteristic curve (AUC). We also utilized SHapley Additive exPlanation (SHAP) values to explain the prediction model. RESULTS: Development of CSA-AKI was noted in 163 patients (24.3%) during the first postoperative week. Regarding the efficacy of the single model that most accurately predicted the outcome, RF exhibited the greatest AUC (0.839, 95% confidence interval [CI] 0.772-0.898), whereas the AUC (0.843, 95% CI 0.778-0.899) of ensemble model (RF + XGboost) was even greater than that of the RF model alone. The top 3 most influential features in the RF importance matrix plot were intraoperative urine output, units of packed red blood cells (pRBCs) transfused during surgery, and preoperative hemoglobin level. The SHAP summary plot was used to illustrate the positive or negative effects of the top 20 features attributed to the RF. We also used the SHAP dependence plot to explain how a single feature affects the output of the RF prediction model. CONCLUSIONS: In this study, machine learning methods were successfully established to predict CSA-AKI, which determines risks following cardiac surgery, enabling the optimization of postoperative treatment strategies to minimize the postoperative complications following cardiac surgeries.

Emergence of T cell immunosenescence in diabetic chronic kidney disease.

BACKGROUND: Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. METHOD: 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. RESULT: Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3+ and CD4+ T cells, but not CD8+ T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8+ T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28-, CD127-, and CD57+ cells among CD8+ T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. CONCLUSION: The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8+ subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8+CD57+ T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.

Interleukin-6 from Adipose-Derived Stem Cells Promotes Tissue Repair by the Increase of Cell Proliferation and Hair Follicles in Ischemia/Reperfusion-Treated Skin Flaps.

The most common postoperative complication after reconstructive surgery is flap necrosis. Adipose-derived stem cells (ADSCs) and their secretomes are reported to mediate skin repair. This study was designed to investigate whether conditioned media from ADSCs (ADSC-CM) protects ischemia/reperfusion- (I/R-) induced injury in skin flaps by promoting cell proliferation and increasing the number of hair follicles. The mouse flap model of ischemia was ligating the long thoracic vessels for 3 h, followed by blood reperfusion. ADSC-CM was administered to the flaps, and their survival was observed on postoperative day 5. ADSC-CM treatment led to a significant increase in cell proliferation and the number of hair follicles. IL-6 levels in the lysate and CM from ADSCs were significantly higher than those from Hs68 fibroblasts. Furthermore, a strong decrease in cell proliferation and the number of hair follicles was observed after treatment with IL-6-neutralizing antibodies or si-IL-6-ADSC. In addition, ADSC transplantation increased flap repair, cell proliferation, and hair follicle number in I/R injury of IL-6-knockout mice. In conclusion, IL-6 secreted from ADSCs promotes the survival of I/R-induced flaps by increasing cell proliferation and the number of hair follicles. ADSCs represent a promising therapy for preventing skin flap necrosis following reconstructive and plastic surgery.

Cognitive impairment in patients with end-stage renal disease: Accelerated brain aging?

BACKGROUND: Chronic kidney disease exhibits a prominent premature aging phenotype in many different organ systems, including the brain. Nevertheless, a comprehensive characterization of brain aging in non-demented patients with end-stage renal disease (ESRD) is lacking and it remains unclear if the collective changes of cognitive functions and brain structures in ESRD is compatible with aging. METHODS: We compared 56 non-demented, independently living dialysis patients (mean age 59.4 ± 11.0 years; mean dialysis vintage of 5.9 years) and 60 non-dialysis controls on a battery of neuropsychological tests, brain MRI T1 imaging and diffusion tensor imaging. Participants with diagnosis of dementia, Mini-Mental State Examination <24, medical history of stroke, or recent hospitalization within 1 month were excluded. RESULTS: Dialysis patients showed significantly worse performance in attention/information processing speed and executive function adjusted for age, sex, education, diabetes and depression. Reduced total brain volume and subcortical volume including hippocampus were found in dialysis patients. Vertex-wise analysis showed cortical thinning in middle frontal, lateral occipital and precuneus region. Furthermore, decreased white matter integrity was found primarily in bilateral anterior thalamic tract, fronto-occipital fasciculus, forceps minor and uncinate tract after correction for multiple comparisons. CONCLUSION: Overall, differences in cognitive functions, cortical volumes/thickness and white matter integrity associated with dialysis are also cognitive domains and brain structure changes associated with normal aging. In other words, non-demented, independently living dialysis patients present an accelerated brain aging phenotype even after taking into account effects of age, diabetes and depression.

Effects of lower versus higher phosphate diets on fibroblast growth factor-23 levels in patients with chronic kidney disease: a systematic review and meta-analysis.

Background: Elevated fibroblast growth factor-23 (FGF23) levels increase the risk of cardiovascular diseases in patients with chronic kidney disease (CKD). We aimed to compare the effects of different dietary interventions, lower versus higher phosphate levels, on FGF23 in patients with CKD. Methods: We conducted electronic literature searches of Medline, PubMed, Embase and the Cochrane Library for publications up to 29 October 2016 for randomized clinical trials that compared lower versus higher phosphate dietary interventions in adults with CKD. The primary outcome was the difference in change-from-baseline FGF23 levels between intervention groups. Considering the difference in measurement units between intact FGF23 and C-terminal FGF23 assays, the treatment effect was analysed as the standardized mean difference (SMD) with the 95% confidence interval (CI). Results: We identified five trials enrolling a total of 94 normophosphataemic patients with Stage 3B CKD. The study duration ranged from 1 to 12 weeks. Compared with higher phosphate diets, lower phosphate diets tended to reduce FGF23 levels (SMD -0.74, 95% CI -1.54 to 0.07, P = 0.07). Subgroup analyses showed a trend (P for interaction = 0.09) towards a better FGF23-lowering effect by lower phosphate diets in studies using the intact FGF23 assay (SMD -1.14, 95% CI -2.24 to -0.04) than those using the C-terminal FGF23 assay (SMD -0.05, 95% CI -0.67 to 0.57). Conclusions: Short-term dietary phosphate restriction tends to reduce FGF23 levels in patients with moderately decreased kidney function, and the FGF23-lowering effects tend to be more prominent when measured with the intact FGF23 assay.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease.

BACKGROUND: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. RESULTS: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. CONCLUSION: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study.

BACKGROUND: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown. RESULTS: Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naïve CD4+ and CD8+ T cell numbers but increase in CD8+ TEMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate. CONCLUSIONS: Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu.

Frequency of Early Predialysis Nephrology Care and Postdialysis Cardiovascular Events.

BACKGROUND: Patients with kidney failure are at a high risk for cardiovascular events. Predialysis nephrology care has been reported to improve postdialysis survival, but its effects on postdialysis major adverse cardiovascular events (MACEs) have not been comprehensively studied. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: We used data from the National Health Insurance Research Database in Taiwan. Adult patients who initiated maintenance dialysis therapy in 1999 to 2010 were enrolled. PREDICTOR: We created 3 subtypes of predialysis nephrology care based on the time between the first nephrology visit and the initiation of dialysis therapy: early frequent (duration ≥ 6 months; at least 1 nephrology visit every 3 months), early infrequent (duration ≥ 6 months, <1 nephrology visit every 3 months), and late (duration < 6 months). OUTCOMES: MACE was defined using the primary diagnosis in hospitalization records of acute myocardial infarction, acute heart failure, acute stroke, or sudden death. MEASUREMENTS: We investigated the associations of different subtypes of nephrology care with postdialysis 1-year MACEs. RESULTS: Among the 60,329 eligible patients, 24,477 (40.6%) had early frequent, 12,763 (21.2%) had early infrequent, and 23,089 (38.3%) had late nephrology care. Compared to the late-nephrology-care group, the early-frequent group was associated with an ∼10% lower risk for 1-year MACEs (HR of 0.89 [95% CI, 0.82-0.96] for first MACE and relative risk of 0.91 [95% CI, 0.84-0.98] for recurrent MACEs). However, the early-infrequent-care group had similar risks for MACEs as the late group (HR of 0.95 [95% CI, 0.86-1.05] for first MACE and relative risk of 0.94 [95% CI, 0.86-1.02] for recurrent MACEs). LIMITATIONS: Lack of physical and biochemical information because of inherent limitations from administrative claims data. CONCLUSIONS: Early frequent nephrology care for 6 or more months before the initiation of long-term dialysis therapy may improve 1-year postdialysis major cardiovascular outcomes.

Additional benefit of dietitian involvement in dialysis staffs-led diet education on uncontrolled hyperphosphatemia in hemodialysis patients.

BACKGROUND: Sustained adherence to dietary phosphorus (P) restriction recommendations among hemodialysis patients is questionable. The aim of this study was to evaluate the effectiveness of additional diet education delivered by a dietitian on the control of hyperphosphatemia. METHODS: We conducted an 8-month prospective observational study in hemodialysis patients who had uncontrolled hyperphosphatemia. In the first half of the study (experimental) period, the dialysis nurses and physicians provided the routine dietetic education with the control group (n = 31), while the experimental group (n = 30) received the routine dietetic education plus an additional diet education delivered by dietitians. Both groups received the routine dietetic education in the rest of the study period to test whether the improvement of serum P level was sustained. The primary outcomes were changes in serum P level. RESULTS: At baseline, there was no significant difference in serum P levels between groups (P = 0.27). In the experimental period, monthly serum P levels decreased significantly in both groups (P < 0.001) and the magnitudes of reduction were 1.81 ± 1.46 and 0.94 ± 1.33 mg/dL in the experimental and control groups, respectively (P = 0.02), at the end. The experimental group maintained such improvement for one more month (P = 0.02), but faded out over time. CONCLUSION: Renal diet education guided either by dietitians plus dialysis staffs or dialysis staffs alone reduces serum P level and dietitian-guided diet education provides an additional benefit on controlling hyperphosphatemia in hemodialysis patients.

Indoxyl sulfate enhances IL-1ß-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway.

Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1ß were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1ß expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1ß-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1ß-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1ß-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1ß-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.

Visceral adiposity index and risks of cardiovascular events and mortality in prevalent hemodialysis patients.

BACKGROUND: The visceral adiposity index (VAI) is a newly-derived measure of visceral adiposity with well-validated predictive power for cardiovascular (CV) outcomes in the general population. However, this predictability has not been investigated in hemodialysis patients, and whether VAI is superior to waist circumference (WC) and waist-to-height ratio (WHtR) in predicting CV outcomes and survival in hemodialysis patients remains unknown. METHODS: We performed a prospective study including 464 prevalent hemodialysis patients. The composite outcome was the occurrence of death and CV events during follow-up. Using multivariate Cox regression analysis, VAI, WC and WHtR were tested for the predictive power of outcomes. To evaluate the predictive performance of the VAI, WC and WHtR, time-dependent receiver operating characteristic curve (ROC) analysis was performed. RESULTS: VAI, WC and WHtR positively correlated with each other. Patients with a higher VAI (tertile 3 vs. tertile 1, adjusted hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.12-2.42; tertile 2 vs. tertile 1, adjusted HR, 1.52; 95% CI, 1.1-2.18) had more composite outcomes. VAI had a similar predictive power of all-cause mortality to WC and WHtR, but superior predictive power of composite and CV outcomes to WC when analyzed by a stepwise forward likelihood ratio test. In time-dependent ROC analysis, VAI, WC and WHtR showed similar predictive performance for outcomes. CONCLUSION: VAI is an optimal method to measure visceral adiposity to assess long-term CV outcomes and all-cause mortality in prevalent hemodialysis patients. VAI may provide a superior predictive power of CV outcomes to WC and WHtR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01457625.

Fetuin A/nutritional status predicts cardiovascular outcomes and survival in hemodialysis patients.

BACKGROUND: Fetuin A - a predictor of cardiovascular (CV) outcomes in dialysis patients - is correlated with over-nutrition in the general population. Whether fetuin A and nutritional status interact with each other to alter CV outcomes and survival in hemodialysis (HD) patients remains unknown. METHODS: We performed a prospective study on 388 prevalent HD patients. We used the geriatric nutritional risk index (GNRI) for the evaluation of nutritional status. Study outcomes included the occurrence of CV event, CV death, and all-cause mortality during follow-up; interactions between parameters for predicting outcomes were assessed by the interaction terms in a Cox regression model. RESULTS: Overall, 131 patients experienced CV events and 92 patients died, with 51 CV deaths. HD patients with higher fetuin A levels had lower numbers of CV events (adjusted hazard ratio [HR], 0.9; 0.81-0.99) and all-cause mortality (adjusted HR, 0.97; 0.91-0.99). However, patients with higher GNRI had lower all-cause mortality (adjusted HR, 0.79; 0.51-0.98, for every 10-unit increase). Fetuin A levels and GNRI showed a significant interaction in the prediction of CV events (adjusted HR, 1.01; 1.008-1.02) but not for all-cause or CV mortality. In patients with poor nutritional status, higher fetuin A levels were associated with fewer CV events; however, in contrast, in subjects with better nutritional status, higher fetuin A levels appeared to lead to a higher number of CV events. CONCLUSIONS: Fetuin A showed a remarkable interaction with nutritional status in evaluating the risks of CV morbidities in prevalent HD patients.

Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis.

BACKGROUND: Interleukin (IL)-31 induces severe pruritus and dermatitis in transgenic mice, and is associated with many itching skin diseases. OBJECTIVE: We sought to investigate the association of serum IL-31 levels with uremic pruritus in patients undergoing hemodialysis. METHODS: Patients receiving maintenance hemodialysis in a referral medical center were recruited. Serum IL-31 levels were determined by the enzyme-linked immunosorbent assay methodology. The various characteristics of pruritus were assessed using an interview questionnaire. RESULTS: Among the 178 study participants, 34.8% had uremic pruritus. The patients with pruritus had higher serum IL-31 levels than those without pruritus symptoms (median 8.68 [first quartile 0.43, third quartile 35.04] vs 4.91 [0, 15.78], P = .04). A multivariate linear regression analysis showed that higher serum levels of IL-31, high-sensitivity C-reactive protein, and alanine transaminase, and a lower dialysis dose assessed by Kt/V, were independent predictors for higher pruritus intensity. The generalized additive model also showed a positive exposure-response relationship between serum levels of IL-31 and visual analog scale scores of pruritus intensity. LIMITATIONS: The cause-effect relationship between IL-31 and uremic pruritus could not be assessed by the cross-sectional study design. CONCLUSION: IL-31 may play an important role in the pathophysiology of uremic pruritus.

Liver fat contents, abdominal adiposity and insulin resistance in non-diabetic prevalent hemodialysis patients.

BACKGROUND: The liver fat contents and abdominal adiposity correlate well with insulin resistance (IR) in the general population. However, the relationship between liver fat content, abdominal adiposity and IR in non-diabetic hemodialysis (HD) patients remains unclear. This study aimed to clarify the associations among these factors. METHODS: This is a cross-sectional, observational study. All patients received abdominal ultrasound for liver fat content. Abdominal adiposity was quantified with the conicity index (Ci) and waist circumference (WC). We checked the homeostasis model assessment for insulin resistance index (HOMA-IR) for IR. RESULTS: A total of 112 patients (60 women) were analyzed. Subjects with higher liver fat contents and WC had higher IR indices. But Ci did not correlate with IR indices. In both the multi-variable linear regression model and the logistic regression model, only higher liver fat content predicted a severe IR status. CONCLUSIONS: Liver fat contents have a remarkable correlation with IR; however, abdominal adiposity, measured either by Ci or WC, dose not independently correlate with IR in non-diabetic prevalent HD patients.