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Abstract Background Serum albumin level is a crucial nutritional indicator for patients on dialysis. Approximately one-third of patients on hemodialysis (HD) have protein malnutrition. Therefore, the serum albumin level of patients on HD is strongly correlated with mortality. Methods In study, the data sets were obtained from the longitudinal electronic health records of the largest HD center in Taiwan from July 2011 to December 2015, included 1,567 new patients on HD who met the inclusion criteria. Multivariate logistic regression was performed to evaluate the association of clinical factors with low serum albumin, and the grasshopper optimization algorithm (GOA) was used for feature selection. The quantile g-computation method was used to calculate the weight ratio of each factor. Machine learning and deep learning (DL) methods were used to predict the low serum albumin. The area under the curve (AUC) and accuracy were calculated to determine the model performance. Results Age, gender, hypertension, hemoglobin, iron, ferritin, sodium, potassium, calcium, creatinine, alkaline phosphatase, and triglyceride levels were significantly associated with low serum albumin. The AUC and accuracy of the GOA quantile g-computation weight model combined with the Bi-LSTM method were 98% and 95%, respectively. Conclusion The GOA method was able to rapidly identify the optimal combination of factors associated with serum albumin in patients on HD, and the quantile g-computation with DL methods could determine the most effective GOA quantile g-computation weight prediction model. The serum albumin status of patients on HD can be predicted by the proposed model and accordingly provide patients with better a prognostic care and treatment.

Objective To investigate the different impacts on clinical outcomes between regular recall and non-regular recall among incident peritoneal dialysis (PD) patients.Methods A two-center cohort of 216 new PD patients from 1January 2013, to 31 December 2014, was studied. Informative clinical data were collected from baseline until two years after PD initiation, including demographics, laboratory and PD-related parameters, PD-related peritonitis rates, and frequency of hospitalization. Regular in-person recall (RPR) was defined as having a one-month interval and non-regular in-person recall (NRPR) as an interval ranging from more than one month to less than three months.Results Percentage of patients with peritonitis was significantly higher among patients in the NRPR group than among those in the RPR group (27.7% vs. 16.5%, p = .049). PD-related peritonitis rate was higher in the NRPR vs. RPR cohorts (0.16 vs. 0.09 person/year, p = .019). PD-related hospitalization frequency was also higher in the NRPR cohort (0.8 ± 1.0 vs. 0.5 ± 0.9, p = .039) over two years. Kt/V values in the NRPR cohort gradually decreased over two years and were at lower levels than in the RPR cohort.Conclusions New PD patients with NRPR showed higher rates of PD-related peritonitis and hospitalization frequency than patients with RPR.

Objective: To find changes in voice quality, airway invasion during swallowing, pharyngeal residue after swallowing, acoustic and aerodynamic measurements and pulmonary function tests after total parathyroidectomy plus auto-transplantation for secondary hyperparathyroidism. Methods: We recruited 38 patients who underwent successful surgery for secondary hyperparathyroidism in this study. Voice quality was evaluated using voice handicap index (VHI-10), eating assessment tool (EAT-10), voice impairment, and the grade, roughness, breathiness, asthenia, strain (GRBAS) scale. Acoustic and aerodynamic measurements included fundamental frequency (F0), maximal phonation time, high pitch, jitter, s/z, shimmer and noise-to-harmonic ratio. Vocal cord mobility, vocal cord closure, premature spillage, the penetration–aspiration scale and the Yale pharyngeal residue severity rating scale (PRSRS) after swallowing were examined using fiber-optic endoscopy. Pulmonary function tests included forced vital capacity, forced expiratory volume in 1 s, bronchodilator test, total lung capacity, diffusion capacity of the lung for carbon monoxide, alveolar volume, and distance and O2 desaturation of the 6 min walking test (6MWT). Results: Four months after successful parathyroidectomy, VHI-10 improved significantly (p

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032–3.005) per log μg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065–3.086) per log μg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228–0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937–0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants.

Introduction: Mortality is a major primary endpoint for long-term hemodialysis (HD) patients. The clinical status of HD patients generally relies on longitudinal clinical observations such as monthly laboratory examinations and physical examinations. Methods: A total of 829 HD patients who met the inclusion criteria were analyzed. All patients were tracked from January 2009 to December 2013. Taken together, this study performed full-adjusted-Cox proportional hazards (CoxPH), stepwise-CoxPH, random survival forest (RSF)-CoxPH, and whale optimization algorithm (WOA)-CoxPH model for the all-cause mortality risk assessment in HD patients. The model performance between proposed selections of CoxPH models were evaluated using concordance index. Results: The WOA-CoxPH model obtained the highest concordance index compared with RSF-CoxPH and typical selection CoxPH model. The eight significant parameters obtained from the WOA-CoxPH model, including age, diabetes mellitus (DM), hemoglobin (Hb), albumin, creatinine (Cr), potassium (K), Kt/V, and cardiothoracic ratio, have also showed significant survival difference between low- and high-risk characteristics in single-factor analysis. By integrating the risk characteristics of each single factor, patients who obtained seven or more risk characteristics of eight selected parameters were dichotomized as high-risk subgroup, and remaining is considered as low-risk subgroup. The integrated low- and high-risk subgroup showed greater discrepancy compared with each single risk factor selected by WOA-CoxPH model. Conclusion: The study findings revealed WOA-CoxPH model could provide better risk assessment performance compared with RSF-CoxPH and typical selection CoxPH model in the HD patients. In summary, patients who had seven or more risk characteristics of eight selected parameters were at potentially increased risk of all-cause mortality in HD population.

Both osteoporosis and cardiovascular disease (CVD) share similar pathways in pathophysiology and are intercorrelated with increased morbidity and mortality in elderly women. Although denosumab and raloxifene are the current guideline-based pharmacological treatments, their impacts on cardiovascular protection are yet to be examined. This study aimed to compare mortality rate and cardiovascular events between denosumab and raloxifene in osteoporotic women. Risks of CVD development and all-cause mortality were estimated using Cox proportional hazard regression. A total of 7972 (3986 in each group) women were recruited between January 2003 and December 2018. No significant difference between denosumab and raloxifene was observed in composite CVDs, myocardial infarction, or congestive heart failure. However, comparison of the propensity score matched cohorts revealed that patients with proportion of days covered (PDC) ≥60% had lower incidence of ischemic stroke in the denosumab group than that in the raloxifene group (aHR 0.68; 95% CI 0.47–0.98; p = 0.0399). In addition, all-cause mortality was lower in the denosumab group than in the raloxifene group (aHR 0.59; 95% CI 0.48–0.72; p = 0.001), except in patients aged

Abstract Altered high-density lipoprotein cholesterol (HDL-C) subclass distribution in hemodialysis (HD) patients is well documented. Aim of this study is to investigate the relationship between HDL-C subclass distribution and macrovascular events in patients undergoing HD. A total of 164 prevalent HD patients and 71 healthy individuals in one hospital-facilitated clinic were enrolled from May 2019 to July 2019 and individual HD patients was follow-up for one year. Macrovascular events (cerebral stroke, coronary heart disease) were recorded in the study period. The HDL-2b, HDL-3 proportions and biochemical parameters were measured. Pearson correlation test and logistic regression analysis were used to examine correlation and odds ratio (OR). 144 HD patients completed one-year follow-up. Cohort with macrovascular events revealed significantly lower HDL-2b and higher HDL-3 subclass proportions compared to those without events. By multivariable adjustment, HDL-3 subclass proportion revealed significantly increase risk for these events (OR 1.17, 95% CI 1.02–1.41, P = 0.044). HDL-2b subclass was significantly higher and HDL-3 subclass was significantly lower in the HD cohort under the hs-CRP level of

Purpose This study aimed to investigate the association between clinical factors and temporary changes in functional performance in patients undergoing hemodialysis. Methods This was a retrospective, longitudinal observational study conducted from 2015 to 2017. Eight-two patients undergoing hemodialysis in the outpatient clinic were enrolled. Functional performance was measured using the Karnofsky Performance Status (KPS) scale. Collected data for analysis included demographics, laboratory parameters, and KPS scale scores. All participants were grouped into a high KPS cluster and a low KPS cluster based on dynamic changes in KPS scales from 2015 to 2017. Results Participants in the high KPS cluster demonstrated an approximate trend, and those in the low KPS cluster demonstrated a low pattern. By stepwise selection model analysis, age (OR 1.12, 95% CI 1.03–1.23, p = 0.011), serum BUN (OR 1.08, 95% CI 1.02–1.16, p = 0.015), calcium levels (OR 3.24, 95% CI 1.2–8.73, p = 0.02), and beta-2-microglobulin (OR > 1.0, CI >1.00-

Purpose In this prospective study, we aimed to examine the sociodemographic factors and clinical factors associated with psychological disorders in chronic kidney disease (CKD) patients receiving unplanned hemodialysis (HD). Methods We prospectively enrolled 187 CKD stage 5 patients receiving unplanned HD at a tertiary hospital from January 2015 to December 2016. We used structured questionnaires to gather data about participants’ anxiety, depression, and sleep disturbance. Generalized linear regression analysis was used to examine the relationships between sociodemographic and laboratory parameters, and severity of psychological distress. Results The mean age of the participants was 60 years, and the number of men and women was 97 and 90, respectively. We did not find a significant association between anxiety, depression, and sleep disturbance scores and gender, age, marital status, religion status, education levels, and employment status and number of comorbidities. Generalized linear regression analysis showed that a multidisciplinary CKD care program in outpatient clinic disclosed a significant negative association with psychological disorders in participants. Conclusions CKD patients exhibited psychological distress when receiving unplanned HD, not closely associated with sociodemographic profiles.

Intradialytic hypotension is a common problem during hemodialysis treatment. Despite several clinical variables have been authenticated for associations during dialysis session, the interaction effects between variables has not yet been presented. Our study aimed to investigate clinical factors associated with intradialytic hypotension by deep learning. A total of 279 participants with 780 hemodialysis sessions on an outpatient in a hospital-facilitated hemodialysis center were enrolled in March 2018. Associations between clinical factors and intradialytic hypotension were determined using linear regression method and deep neural network. A full-adjusted model indicated that intradialytic hypotension is positively associated with body mass index (Beta = 0.17, p = 0.028), hypertension comorbidity (Beta = 0.17, p = 0.008), and ultrafiltration amount (Beta = 0.31, p

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults without diabetes. Primary MN has been associated with circulating antibodies against native podocyte antigens, including phospholipase A2 receptor (PLA2R); however, precision therapy targeting the signaling cascade of PLA2R activation is lacking. Both PLA2R and the mammalian target of rapamycin (mTOR) exist in podocytes, but the interplay between these two proteins and their roles in MN warrants further exploration. This study aimed to investigate the crosstalk between PLA2R activation and mTOR signaling in a human podocyte cell line. We demonstrated that podocyte apoptosis was induced by Group IB secretory phospholipase A2 (sPLA2IB) in a concentration- and time-dependent manner via upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mTOR, and inhibited by rapamycin or LY294002. Furthermore, aberrant activation of the PI3K/AKT/mTOR pathway triggers both extrinsic (caspase-8 and caspase-3) and intrinsic (Bcl-2-associated X protein [BAX], B-cell lymphoma 2 [BCL-2], cytochrome c, caspase-9, and caspase-3) apoptotic cascades in podocytes. The therapeutic implications of our findings are that strategies to reduce PLA2R activation and PI3K/AKT/mTOR pathway inhibition in PLA2R-activated podocytes help protect podocytes from apoptosis. The therapeutic potential of rapamycin shown in this study provides cellular evidence supporting the repurposing of rapamycin for MN treatment.

Panax notoginseng (PN) exerts cardiovascular-disease-protective effects, but the effect of PN on reducing vascular calcification (VC) is unknown. Under the VC process, however, endothelial bone morphogenetic protein-2 (BMP-2) signals connect endothelial and smooth muscle cells. To investigate the effects of PN water extract (PNWE) on BMP-2 expression, human EA.hy926 endothelial cells were pretreated with PNWE for 48 h, and BMP-2 expression was then induced using warfarin/β-glycerophosphate (W/BGP) for another 24 h. The expression of BMP-2, the degrees of oxidative stress and inflammation, and the activation of noncanonical NF-κB and Wnt/β-catenin signaling were analyzed. The results showed that the BMP-2 levels in EA.hy926 cells were reduced in the groups treated with 10, 50, or 100 μg/mL PNWE combined with W/BGP. PNWE combined with W/BGP significantly reduced thiobarbituric-acid-reactive substrate and reactive oxygen species levels as well as prostaglandin E2, IL-1β, IL-6, and TNF-α. PNWE (10, 50, and 100 μg/mL) reduced the p52 levels and p52/p100 protein ratio. Wnt and β-catenin protein expression was decreased in the groups treated with PNWE combined with W/BGP. These results showed that PNWE reduced BMP-2 expression in EA.hy926 cells by inhibiting the noncanonical NF-κB and Wnt/β-catenin signaling pathways.

Abstract Background In this study, we investigated the association of time-varying serum albumin levels with mortality over a 5-year period in one cohort of patients undergoing long-term peritoneal dialysis (PD) therapy. Methods The participants in this study enrolled 302 patients who underwent long-term PD at a single PD center in Taiwan. We reviewed medical records from 2011 to 2015 retrospectively. Time-averaged albumin level and serum albumin reach rate (defined as the percentage of serum albumin measurements that reached ≥3.5 g/dL) were applied as the predictor variables in the first 2 years (2011–2012). All-cause mortality was used as the outcome variable in the subsequent 3 years (2013–2015). Hazard function of all-cause mortality in the study participants was examined by using Cox proportional hazard regression models . Results Patients with different albumin reach rates (75–

Background/Aims: Studies on the long-term clinical benefits of hemodiafiltration (HDF) and high-flux hemodialysis (HFHD) are very limited. This study aimed to investigate the hospitalization rate and aortic arch calcification (AAC) of these two dialysis modalities over 6 years. Methods: Participants who received regular HDF and HFHD in one hospital-facilitated hemodialysis center were prospectively enrolled after matching for age, sex, and diabetes between January 2009 and December 2014. Medical records were reviewed retrospectively on demographics, laboratory variables, calcified scores in aortic arch measured by chest radiography, and rates of hospital admission. Cox proportional hazard regression and linear regression were used to obtain the outcome results. Results: The HDF and HFHD groups consisted of 108 and 102 participants, respectively. Levels of laboratory variables including small soluble solutes and Kt/V were not statistically different over the 6-year period between the HDF and HFHD groups. Calcified scores of the aortic arch increased over 6 years in both groups. The changes in the mean calcified scores were significant when compared between the two groups (0.44–1.82 in HFHD, 0.79–1.8 in HDF, respectively, p = 0.008). Hospitalization rates were 735 per 1,000 patients in the HDF group and 852 per 1,000 patients in the HFHD group, respectively. No significant difference was observed in frequency and days of hospitalization between HDF and HFHD. Conclusion: Hospitalization rates and AAC were observed to be equal for HDF and HFHD.

Purpose: We examined the association between catheter use for maintenance hemodialysis (HD) and mortality/hospitalization in a cohort of patients with prevalent HD. Methods: In this study, 70 HD patients with tunneled cuffed central venous catheters (TCVCs) from a Taiwanese HD center during 2014–2016 were enrolled and compared with 70 matched HD patients with native arteriovenous fistulae (AVF). The compared variables included demographic parameters and laboratory and dialysis-related indices. Cox regression analysis was used to assess the risk of mortality/hospitalization within a year. Results: Low baseline serum albumin levels were found in patients with TCVCs (3.64 g/dL vs 3.79 g/dL, p = 0.030). The mortality rates of patients with AVF and TCVCs were 14 per 1000 patients and 171 per 1000 patients, respectively. Infection was the leading cause of mortality/hospitalization in patients with TCVCs. Using multivariate analyses, the risk of death was found to be significantly higher in patients with TCVCs than in those with AVF (Hazard ratio [HR] 12.15, 95% CI 1.16–127.17; p = 0.037). Patients with TCVC also had a higher hospitalization rate (HR 1.33, 95% CI 0.71–2.49; p = 0.369) (not statistically significant). Conclusion: Catheter use for maintenance HD was associated with increased all-cause mortality. Keywords: Tunneled catheter, Arteriovenous fistula, Mortality, Hemodialysis

Introduction: Kidney renal clear cell carcinoma (KIRCC) is a highly heterogeneous and lethal cancer that can arise in patients with renal disease. DeepSurv combines a deep feed-forward neural network with a Cox proportional hazards function and could provide optimized survival results compared with convenient survival analysis. Methods: This study used an improved DeepSurv algorithm to identify the candidate genes to be targeted for treatment on the basis of the overall mortality status of KIRCC subjects. All the somatic mutation missense variants of KIRCC subjects were abstracted from TCGA-KIRC database. Results: The improved DeepSurv model (95.1%) achieved greater balanced accuracy compared with the DeepSurv model (75%), and identified 610 high-risk variants associated with overall mortality. The results of gene differential expression analysis also indicated nine KIRCC mortality-risk-related pathways, namely the tRNA charging pathway, the D-myo-inositol-5-phosphate metabolism pathway, the DNA double-strand break repair by nonhomologous end-joining pathway, the superpathway of inositol phosphate compounds, the 3-phosphoinositide degradation pathway, the production of nitric oxide and reactive oxygen species in macrophages pathway, the synaptic long-term depression pathway, the sperm motility pathway, and the role of JAK2 in hormone-like cytokine signaling pathway. The biological findings in this study indicate the KIRCC mortality-risk-related pathways were more likely to be associated with cancer cell growth, cancer cell differentiation, and immune response inhibition. Conclusion: The results proved that the improved DeepSurv model effectively classified mortality-related high-risk variants and identified the candidate genes. In the context of KIRCC overall mortality, the proposed model effectively recognized mortality-related high-risk variants for KIRCC.

Time-averaged serum albumin (TSA) is commonly associated with clinical outcomes in hemodialysis (HD) patients and considered as a surrogate indicator of nutritional status. The whale optimization algorithm-based feature selection (WOFS) model could address the complex association between the clinical factors, and could further combine with regression models for application. The present study aimed to demonstrate an optimal multifactor TSA-associated model, in order to interpret the complex association between TSA and clinical factors among HD patients. A total of 829 HD patients who met the inclusion criteria were selected for analysis. Monthly serum albumin data tracked from January 2009 to December 2013 were converted into TSA categories based on a critical value of 3.5 g/dL. Multivariate logistic regression was used to analyze the association between TSA categories and multiple clinical factors using three types of feature selection models, namely the fully adjusted, stepwise, and WOFS models. Five features, albumin, age, creatinine, potassium, and HD adequacy index (Kt/V level), were selected from fifteen clinical factors by the WOFS model, which is the minimum number of selected features required in multivariate regression models for optimal multifactor model construction. The WOFS model yielded the lowest Akaike information criterion (AIC) value, which indicated that the WOFS model could achieve superior performance in the multifactor analysis of TSA for HD patients. In conclusion, the application of the optimal multifactor TSA-associated model could facilitate nutritional status monitoring in HD patients.

Background and Aims: In Taiwan, approximately 90% of patients with end-stage renal disease receive maintenance hemodialysis. Although studies have reported the survival predictability of multiclinical factors, the higher-order interactions among these factors have rarely been discussed. Conventional statistical approaches such as regression analysis are inadequate for detecting higher-order interactions. Therefore, this study integrated receiver operating characteristic, logistic regression, and balancing functions for adjusting the ratio in risk classes and classification errors for imbalanced cases and controls using multifactor-dimensionality reduction (MDR-ER) analyses to examine the impact of interaction effects between multiclinical factors on overall mortality in patients on maintenance hemodialysis. Meterials and Methods: In total, 781 patients who received outpatient hemodialysis dialysis three times per week before 1 January 2009 were included; their baseline clinical factor and mortality outcome data were retrospectively collected using an approved data protocol (201800595B0). Results: Consistent with conventional statistical approaches, the higher-order interaction model could indicate the impact of potential risk combination unique to patients on maintenance hemodialysis on the survival outcome, as described previously. Moreover, the MDR-based higher-order interaction model facilitated higher-order interaction effect detection among multiclinical factors and could determine more detailed mortality risk characteristics combinations. Conclusion: Therefore, higher-order clinical risk interaction analysis is a reasonable strategy for detecting non-traditional risk factor interaction effects on survival outcome unique to patients on maintenance hemodialysis and thus clinically achieving whole-scale patient care.

Abstract Background The clinical course of Viridans streptococci (VS) peritonitis in patients undergoing peritoneal dialysis (PD) is rarely reported. This study examined the association of clinical factors with VS peritonitis. Methods We retrospectively reviewed clinical data from patients with VS peritonitis from March 1990 to February 2016 in a PD center in Taiwan and evaluated clinical profiles and treatment outcomes. Results A total of 109 episodes of VS peritonitis in 71 patients identified. Among these patients, 57 had mono-VS peritonitis and 14 had concurrent polymicrobial infections. The median time interval from PD initiation to the first VS peritonitis episode was 18 months (range, 0.6–144 months). Among clinical outcomes, most VS peritonitis episodes were completely cured regardless of a history of peritonitis. All episodes with catheter removal occurred in those without a history of recent antibiotic use. Conclusion VS peritonitis in patients undergoing PD typically has favorable treatment outcomes. Antibiotic therapy should be started promptly.

Abstract Background This study aimed to evaluate the longitudinal changes in cardiac structure and function in incident-automated peritoneal dialysis (APD) patients. Methods We conducted a 2-year prospective, randomized, open-label, parallel-group study to compare the efficacy of icodextrin solution versus glucose-based solution. Echocardiography was performed at baseline, 1 and 2 years. Echocardiographic parameters over 2 years were evaluated for each group, using the Friedman test. Generalized linear regression analysis was used to test the associations between baseline clinical variables and echocardiographic changes, and a multivariate model was used to analyze cardiac function between the two groups. Results A total of 43 APD patients were enrolled in the beginning of this study. Twenty patients in the icodextrin group (ICO) and 18 patients in the glucose group (GLU) completed the study. In left ventricular (LV) systolic function measurements, ejection fraction (EF) increased significantly in the GLU group. Measurements of LV diastolic function and septal early mitral annulus velocity (EMV) increased significantly from baseline to 24-months in the ICO group (5.43–5.51 ms). The GLU group showed a significant decrease in peak early diastolic velocity (EDV) (70.67–68.25 cm/s), but a significant increase in septal EMV (5.94–7.57 ms) from baseline to 24-months. No significant association was found between the baseline clinical variables and echocardiographic changes within 24 months in the generalized linear regression analysis. Multivariate models were used to investigate changes in the four primary endpoints, namely, myocardial performance index (MPI), left ventricular ejection fraction (LVEF), deceleration time (DT), and E/e′ ratio. These primary endpoints show no significant association with the baseline values in both the ICO and GLU groups. Conclusion The present study demonstrates that long-dwell icodextrin solution can maintain reasonable cardiac structure and function in incident-APD patients. Trial registration ISRCTN14931270 (retrospectively registered on 23/03/2018).

Pre-germinated brown rice (PGBR) could ameliorate metabolic syndrome, however, not much research estimates the effect of PGBR extract on insulin resistance. The aim of this study is to examine the effects of PGBR extract in TNF-α induced insulin resistance. HepG2 cells, hepatocytes, were cultured in DMEM medium and added with 5 μM insulin or with insulin and 30 ng/ml TNF-α or with insulin, TNF-α and PGBR extract (50, 100, 300 μg/ml). The glucose levels of the medium were decreased by insulin, demonstrating insulin promoted glucose uptake into cell. However, TNF-α inhibited glucose uptake into cells treated with insulin. Moreover, insulin increased the protein expressions of AMP-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase-α (PI3K-α), serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB), glucose transporter-2 (GLUT-2), glucokinase (GCK), peroxisome proliferator activated receptor-α (PPAR-α) and PPAR-γ. TNF-α activated p65 and MAPKs (JNK1/2 and ERK1/2) which worsened the expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, glycogen synthase kinase-3 (GSK-3), PPAR-α and PPAR-γ. Once this relationship was established, we added PGBR extract to cell with insulin and TNF-α. We found glucose levels of medium were lowered and that the protein expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, GSK-3, PPAR-α, PPAR-γ and p65, JNK1/2 were also recovered. In conclusion, this study found that TNF-α inhibited insulin stimulated glucose uptake and aggravated related proteins expressions, suggesting that it might cause insulin resistance. PGBR extract was found to ameliorate this TNF-α induced insulin resistance, suggesting that it might be used in the future to help control insulin resistance.

High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.

Abstract Objectives To survey by measuring patient’s functional status which is crucial when end-stage renal disease patients begin a dialysis program. The influence of the disease on patients can be examined by the measurement of Karnofsky Performance Status (KPS) scores, together with a quality of life survey, and clinical variables. Methods The details for the dataset in the study were collected from patients receiving regular hemodialysis (HD) in one hospital, which were available retrospectively for 1166 patients during the 5-year study period. KPS scores were applied for quantifying functional status. To identify risk factors for functional status, clinical factors including demographics, laboratory data, and HD vintage were selected. This study applied a classification and regression tree approach (CART) and logistic regression to determine risk factors on functional impairment among HD patients. Results Ten risk factors were identified by CART and regression model (age, primary kidney disease subclass, treatment years, hemoglobin, albumin, creatinine, phosphorus, intact parathyroid hormone, ferritin, and cardiothoracic ratio). The results of logistic regression with selected interaction models showed older age or higher hematocrit, blood urea nitrogen, and glucose levels could significantly increase the log-odds of obtaining low KPS scores at in-person visits. Conclusions In interaction results, the combination of older age with higher albumin level and higher creatinine level with longer HD treatment years could significantly decrease the log-odds of a low KPS score assessment during in-person visits. Age, hemoglobin, albumin, urea, creatinine levels, primary kidney disease subclass, and HD duration are the major determinants for functional status in HD patients.

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immunohistochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astrocytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.

Current strategies targeting serum cholesterol bring limited benefits to mortality and macrovascular events prevention among hemodialysis patients. Direct measurements and analysis on circulating markers of cholesterol homeostasis could be promising solutions to this bottleneck. We prospectively enrolled 90 maintenance hemodialysis patients and 9 healthy controls in 2019 for 1 year. We measured circulating desmosterol and lathosterol as markers for cholesterol synthesis and campesterol and sitosterol for cholesterol absorption. At baseline, hemodialysis patients showed higher levels of campesterol (p = 0.023) compared to healthy controls. During follow-up, we identified 14 (15.4%) patients who experienced macrovascular events. Comparisons of cholesterol homeostasis markers between cohorts with and without macrovascular events showed no significant differences in markers of cholesterol synthesis or absorption. Using logistic regression analysis, the odds ratio was not statistically significant for the prediction of macrovascular events after full-adjusting for age, sex, diabetes, serum albumin, cholesterol, and triglyceride. We concluded that hemodialysis patients demonstrated higher level of cholesterols absorption, indicated by circulating campesterol compared to healthy subjects. Markers for cholesterol homeostasis were not significantly associated with macrovascular events during a 1-year follow-up. Our results shed light on the novel therapeutic target of modulating cholesterol absorption in HD patients.

Background/Aims: Abnormal potassium profiles are common in peritoneal dialysis (PD) patients. We studied the factors associated with serum potassium profiles in incident PD patients. Methods: Patients were enrolled from two hospital-facilitated PD centers from May 2013 to May 2016 and January 2009 to December 2015. A total of 319 incident PD patients were examined for factors associated with serum potassium profile. Average serum potassium levels were obtained for analysis during the first 3 months after PD initiation. Clinically factors and parameters associated with PD were assessed by logistic regression. Results: There were 168 men and 151 women (mean age, 50.8 years). Blood urea nitrogen (BUN), creatinine (Cr), and intact parathyroid hormone levels were significantly increased in patients in the higher serum potassium group. There were no significant risk factors for hypokalemia, including sex, age, diabetes, blood examination parameters, medication use, or PD-related parameters by multivariate logistic regression analysis. BUN (adjusted odds ratio [OR] 1.02, 95% CI 1.01-1.03, p = 0.001) and Cr (adjusted OR 1.08, 95% CI 1.01-1.16, p = 0.029) levels were significant risk factors for hyperkalemia by multivariate logistic regression analysis. Conclusion: Hyperkalemia and blood BUN and Cr levels were significantly associated in incident PD patients.

Background/Aims: Although high serum alkaline phosphatase (ALP) levels were reported as predictive factors for death risk in dialysis patients on the basis of large databank analyses, the real scenario in a single hemodialysis (HD) center is unknown. Methods: In this study, a 5-year cohort of 1126 prevalent HD patients in the largest HD center in Taiwan was studied. The associations of ALP levels expressed as baseline, time-average, and time-dependent with all-cause mortality and cardiovascular mortality were evaluated by using adjusted Cox regression models. Results: At baseline, levels of serum parathyroid hormone, calcium, and liver enzymes are increased in parallel with ALP quartiles. The hazard ratio (HR) for all-cause mortality was significantly increased in time-average and time-dependent ALP quartile in the unadjusted Cox analysis. The significance disappeared when multivariate adjusted Cox analysis was used. Similarly, HR was not significantly increased for cardiovascular mortality with ALP quartile expressed as baseline, time-average, and time-dependent in three models of Cox analyses. Conclusion: Our study demonstrated that serum ALP levels were not associated with increased death risk in prevalent HD patients over a 5-year interval.

Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients (mean age, 59.1 years); CDR > 0.5 included 33 patients (mean age, 64.0 years). On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest (0.897, 95% confidence interval 0.806–0.988). Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis.

Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of long-term peritoneal dialysis (PD). However, previous studies reported large variations in its mortality rates that may associate with a different degree of EPS severity. This study reports the incidence and outcomes of EPS and identifies the risk factors associated with severe EPS.We retrospectively analyzed clinical data of EPS patients from 3 medical centers in Taiwan from January 1982 to September 2015, and classified patients as having mild/moderate or severe EPS. Patients with intractable intestinal obstruction/gut-related sepsis that needed surgical intervention or resulted in mortality were in severe EPS group. Follow-up for outcome was through December 31, 2015. Clinical characteristics, peritoneal dialysis (PD)-related parameters, biochemical and imaging results were analyzed and compared between groups.Fifty-eight of 3202 patients undergoing PD during the study period had EPS (prevalence 1.8%). The incidence of EPS increased for patients on PD for >6-8 years (≤6 yrs. vs. >6-8 yrs., 0.0% vs. 1.8%, p = 0.001). Relative to those on PD for >6-8 years, the risk of EPS significantly increased with PD duration longer than 10 years (>10-12 years vs. >6-8 years: OR: 5.5, 95% CI: 1.7-17.1, p < 0.01). Twenty-three patients fulfilled the criteria for severe EPS. The overall mortality rate of EPS was 35% (20/58), and was 74% (17/23) in the severe EPS group. The average serum levels of C-reactive protein (CRP) and intact-parathyroid hormone (i-PTH), which were checked every 3~6 months within one year before diagnosis of EPS, were higher in severe EPS group than in mild/moderate group (p = 0.02, p = 0.08, respectively). Multivariate analysis revealed severe EPS was independently associated with bowel tethering (based on CT), presentation with bloody ascites, diagnosis of EPS after withdrawal from PD, and i-PTH ≥ 384 pg/mL. Receiver operating characteristic analysis indicated that presentation with 2 or more of the 5 risk factors (EPS diagnosis after PD withdrawal, bloody ascites, bowel tethering, CRP ≥ 29 mg/L, and i-PTH ≥ 384 pg/mL) had a good accuracy (AUC = 0.80, p = 0.001) for prediction of severe EPS.The incidence of EPS increases with PD duration. Severe EPS has high mortality rate and is associated with bowel tethering, presentation of bloody ascites, diagnosis after PD withdrawal, and higher serum levels of i-PTH before EPS diagnosis. Having 2 or more of the 5 risk factors can provide a good accuracy for prediction of severe EPS.

Background: In the face of increasing treatment options for extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-Kp) hemodialysis (HD) access-related bacteremia, the difference in clinical effectiveness between ertapenem and flomoxef remains unclear. We conducted this retrospective study to determine their efficacies and treatment outcomes. Methods: Patients on maintenance HD with fistula-, graft-, or catheter-related ESBL-Kp bacteremia were enrolled. Data related to clinical features and antibiotic treatments were collected. Outcome was determined by mortality resulting from bacteremia during the 14-day period after the collection of the first positive blood culture for flomoxef-susceptible ESBL-Kp. Results: The 64 patients studied had severe septicemia as determined by the Pitt bacteremia score; 50% (32/64) were in the intensive care unit (ICU) at the time of bacteremia. Old age (>65 years; 57.8%), malnutrition (albumin 30 days; 75%) were also highly prevalent. The study population comprised nine fistula-, 10 graft-, and 45 HD catheter-related bacteremia cases, and the mortality rate was high (38/64, 59.4%). The mortality rate was significantly higher in the flomoxef treatment group than in the ertapenem treatment group (22/30, 73% vs. 16/34, 47%, p

Controlled attenuation parameter (CAP) is a non-invasive method for measuring hepatic steatosis (HS). Non-alcoholic fatty liver disease (NAFLD) is closely related to cardiovascular diseases (CVDs). CVDs are the leading cause of morbidity and mortality in hemodialysis patients. The aim of this study was to investigate the prevalence of NAFLD in hemodialysis patients.We prospectively enrolled patients undergoing chronic hemodialysis, as well as patients with normal renal function who served as controls. The control group patients were referred by an endocrinologist to be tested for NAFLD; most of these patients had diabetes, hypertension, or dyslipidemia. We excluded those with excess alcohol intake, use of drugs known to induce HS, chronic viral hepatitis, or CAP failure. CAP ≥ 238 dB/m was used as a cutoff suggesting HS. An increased liver kidney contrast, as defined by ultrasound, was used to make the diagnosis of HS.Three hundred and forty-three hemodialysis patients and 252 control group patients were enrolled. Among the hemodialysis patients, 192 (56.0%) had CAP- or ultrasound-identified HS compared with 91 (26.5%) who only had ultrasound-identified HS (P

The relationships between all-cause mortality and serum intact parathyroid hormone (iPTH), calcium, and phosphate are fairly diverse in patients on maintenance hemodialysis according to prior studies. This study evaluated the association of chronic kidney disease-mineral and bone disorder (CKD-MBD) markers with all-cause mortality in prevalent hemodialysis patients from 2007 to 2012 in Beijing, China. A cohort, involving 8530 prevalent hemodialysis patients who had undergone a 6-70 months follow-up program (with median as 40 months) was formed. Related data was recorded from the database in 120 hemodialysis centers of Beijing Health Bureau (2007 to 2012). Information regarding baseline demographics, blood CKD-MBD markers and all-cause mortality was retrospectively reviewed. By using multivariate Cox regression model analysis, patients with a low iPTH level at baseline were found to have greater risk of mortality (

Antrodia camphorata is a fungus that is endemic to Taiwan, and its fruiting body has been used as a folk medicine for the prevention or treatment of diverse diseases. The present study is aimed at investigating the antimelanogenesis and antioxidation effect of the ethanolic extract of Antrodia camphorata fruiting body (EE-AC), as well as its antiproliferation effects in B16-F0 melanoma cells. Regarding antimelanogenic effects, EE-AC had effective cupric ions reducing capacity and expressed more potent inhibitory effect than kojic acid on mushroom tyrosinase activity. Moreover, EE-AC significantly inhibited cellular tyrosinase activity and the melanin content in B16-F0 cells at 12.5 μg/mL concentration without cell toxicities. Regarding antioxidant effects, EE-AC exhibited potent DPPH radical- and SOD-like-scavenging activities. Regarding antiproliferative effects, EE-AC exhibited a selective cytotoxic effect and markedly inhibited the migration ability of B16-F0 cells. EE-AC increased the population of B16-F0 cells at sub-G1 phase of the cell cycle. EE-AC also caused the increase of early apoptotic cells and chromatin condensation, which indicated the apoptotic effects in B16-F0 cells. We demonstrated that EE-AC possessed antimelanogenic, antioxidant and anti-skin cancer actions. The results would contribute to the development and application of cosmetics, healthy food and pharmaceuticals.

Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. Autophagic dysfunction may hasten the progression of neuronal degeneration. In this study, resveratrol promoted autophagic flux and protected dopaminergic neurons against rotenone-induced apoptosis. In an in vivo PD model, rotenone induced loss of dopaminergic neurons, increased oxidation of mitochondrial proteins and promoted autophagic vesicle development in brain tissue. The natural phytoalexin resveratrol prevented rotenone-induced neuronal apoptosis in vitro, and this pro-survival effect was abolished by an autophagic inhibitor. Although both rotenone and resveratrol promoted LC3-II accumulation, autophagic flux was inhibited by rotenone and augmented by resveratrol. Further, rotenone reduced heme oxygenase-1 (HO-1) expression, whereas resveratrol increased HO-1 expression. Pharmacological inhibition of HO-1 abolished resveratrol-mediated autophagy and neuroprotection. Notably, the effects of a pharmacological inducer of HO-1 were similar to those of resveratrol, and protected against rotenone-induced cell death in an autophagy-dependent manner, validating the hypothesis of HO-1 dependent autophagy in preventing neuronal death in the in vitro PD model. Collectively, our findings suggest that resveratrol induces HO-1 expression and prevents dopaminergic cell death by regulating autophagic flux; thus protecting against rotenone-induced neuronal apoptosis.

Empagliflozin is known to retard the progression of kidney disease in diabetic patients. However, the underlying mechanism is incompletely understood. High glucose induces oxidative stress in renal tubules, eventually leading to mitochondrial damage. Here, we investigated whether empagliflozin exhibits protective functions in renal tubules via a mitochondrial mechanism. We used human proximal tubular cell (PTC) line HK-2 and employed western blotting, terminal deoxynucleotidyl transferase dUTP nick end labelling assay, fluorescence staining, flow cytometry, and enzyme-linked immunosorbent assay to investigate the impact of high glucose and empagliflozin on cellular apoptosis, mitochondrial morphology, and functions including mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, and adenosine triphosphate (ATP) generation. We found that PTCs were susceptible to high glucose-induced mitochondrial fragmentation, and empagliflozin ameliorated this effect via the regulation of mitochondrial fission (FIS1 and DRP1) and fusion (MFN1 and MFN2) proteins. Empagliflozin reduced the high glucose-induced cellular apoptosis and improved mitochondrial functions by restoring mitochondrial ROS production, MMP, and ATP generation. Our results suggest that empagliflozin may protect renal PTCs from high glucose-mediated injuries through a mitochondrial mechanism. This could be one of the novel mechanisms explaining the benefits demonstrated in EMPA-REG OUTCOME trial.

Background: Real-time ultrasound-guided techniques allow for improved cannulation of the internal jugular vein and femoral vein for hemodialysis; however, these techniques require extra sterilization procedures, specialized probes, or needle guides. A simpler ultrasound vessel localization method was performed to investigate whether this alternative approach would aid in the cannulation of the femoral vein for patients in whom temporary angioaccess was required for hemodialysis. Methods: Patients requiring temporary femoral vein catheters for hemodialysis were divided into 2 groups on alternating days of the week during a 6-month period. One group underwent ultrasound localization of the femoral vein before cannulation and the second group received conventional landmark localization. Data regarding the strength of the femoral arterial pulse, number of attempts, failures, and complications were recorded. Results: Ultrasound localization resulted in significantly improved first-attempt success rates, reduced attempts, and reduced failure and complication rates overall (p < 0.001, p < 0.001, p = 0.002 and p = 0.004 respectively) as well as in the group of patients with a clearly discernible arterial pulse (p < 0.001, p = 0.001, p = 0.004 and p = 0.011 respectively). The same trend was observed among patients with faintly palpable or non-palpable femoral arterial pulses, although the differences were not statistically significant. Conclusion: Cannulation of the femoral vein for hemodialysis should be performed with the aid of ultrasound. If real-time ultrasound-guided cannulation is not available, the vessel localization method is a good alternative, given its known limitations and the fact that it is simpler. It remains to be determined whether 1 - dimensional localization or localization including vessel depth information can improve outcomes in patients with faintly palpable or non-palpable femoral arterial pulses.

Indoxyl sulfate (IS) contributes to oxidative stress and endothelial dysfunction in chronic kidney disease patients. However, the role of mitochondria in IS-induced oxidative stress is not very clear. In this study, we examined whether mitochondria play a pivotal role in modulating the effects of antioxidants during IS treatment. In the context of human umbilical vein endothelial cells, we found that IS had a dose-dependent antiproliferative effect. In addition, we used flow cytometry to demonstrate that the level of reactive oxygen species increased in a dose-dependent manner after treatment with IS. High doses of IS also corresponded to increased mitochondrial depolarization and decreased mitochondrial DNA copy number and mitochondrial mass. However, these effects could be reversed by the addition of antioxidants, namely, vitamin C and N-acetylcysteine. Thus, our results suggest that IS-induced oxidative stress and antiproliferative effect can be attributed to mitochondrial dysfunction and impaired biogenesis and that these processes can be protected by treatment with antioxidants.

BACKGROUND: Determining the complex relationship between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has proven capable of effectively detecting statistical patterns of epistasis. However, MDR has its weakness in accurately assigning multi-locus genotypes to either high-risk and low-risk groups, and does generally not provide accurate error rates when the case and control data sets are imbalanced. Consequently, results for classification error rates and odds ratios (OR) may provide surprising values in that the true positive (TP) value is often small. METHODOLOGY/PRINCIPAL FINDINGS: To address this problem, we introduce a classifier function based on the ratio between the percentage of cases in case data and the percentage of controls in control data to improve MDR (MDR-ER) for multi-locus genotypes to be classified correctly into high-risk and low-risk groups. In this study, a real data set with different ratios of cases to controls (1:4) was obtained from the mitochondrial D-loop of chronic dialysis patients in order to test MDR-ER. The TP and TN values were collected from all tests to analyze to what degree MDR-ER performed better than MDR. CONCLUSIONS/SIGNIFICANCE: Results showed that MDR-ER can be successfully used to detect the complex associations in imbalanced data sets.

Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (ρ(0) cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups.

Purpose: It has been documented that a low protein diet (LPD) with ketoacid analogues (one ketosteril® /5kg) can postpone dialysis therapy in chronic kidney disease. The purpose of the study was to compare the effects of residual renal function preservation between low dose (one ketosteril® /10kg) and standard dose (one ketosteril® /5kg) ketoacid analogues. Methods: The study was a prospective, open-label, group-comparison design. The duration was 6 months. Patients were enrolled in two hospitals when the serum Cr more than 6 mg/dL (CKD stage 4,5). Then the enrolled patients were randomized to three groups, LPD, LPDK1 (LPD + standard dose ketosteril®), LPDK2 (LPD + low dose ketosteril®). The definition of LPD was 0.6-0.8gm of protein/kg body weight/day. The comparable variables were routine hemogram, bio-chemistry data, iPTH, reciprocal Cr (1/Cr), (eGFR), UN/Cr levels in 24-hr urine (UUN/UCr). The measurements were performed in baseline and 6th month. Results: Demographics of patients were LPD: 22 (M/F:10/12), 49.5y/o, BMI 21.5±3.3; LPDK1:21 (8/13), 53.6y/o, BMI 22.7±3.5; LPDK2:37 (15/22), 62y/o (p:

BACKGROUND: The mitochondrial (mt) displacement loop (D-loop) is known to accumulate structural alterations and mutations. The aim of this study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) within the D-loop among chronic dialysis patients and healthy controls. METHODOLOGY AND PRINCIPAL FINDINGS: We enrolled 193 chronic dialysis patients and 704 healthy controls. SNPs were identified by large scale D-loop sequencing and bioinformatic analysis. Chronic dialysis patients had lower body mass index, blood thiols, and cholesterol levels than controls. A total of 77 SNPs matched with the positions in reference of the Revised Cambridge Reference Sequence (CRS) were found in the study population. Chronic dialysis patients had a significantly higher incidence of 9 SNPs compared to controls. These include SNP5 (16108Y), SNP17 (16172Y), SNP21 (16223Y), SNP34 (16274R), SNP35 (16278Y), SNP55 (16463R), SNP56 (16519Y), SNP64 (185R), and SNP65 (189R) in D-loop of CRS. Among these SNPs with genotypes, SNP55-G, SNP56-C, and SNP64-A were 4.78, 1.47, and 5.15 times more frequent in dialysis patients compared to controls (P

High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo-N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy. [ABSTRACT FROM AUTHOR]

The aim of this studywas to examine the effect ofmitochondrialmorphogenesis changes on apoptosis and autophagy of high-glucose-treated proximal tubular epithelial cells (HK2). Cell viability, apoptosis, and mitochondrial morphogenesis were examined using crystal violet, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and mitotracker staining, respectively.High glucose inhibited cell viability and induced mitochondrial fission in HK2 cells. After depleting mitofusin 1 (MFN1), the MFN1(-) HK2 cells (fission type) became more susceptible to high-glucose-induced apoptosis and mitochondrial fragmentation observed by TUNEL and mitotracker assays. In siMFN2 HK2 cells (fission type), mitochondria were highly fragmented (>80% fission rate) with or without high-glucose treatment; however, siFIS1 (mitochondrial fission protein 1) HK2 cells (fusion type) exhibited little fragmentation (<13%). High-glucose treatment induced autophagy, characterized by the formation of autophagosome andmicrotubule-associated protein light chain 3 (LC3) B-II, as observed by transmission electron microscopy and western blotting, respectively. LC3B-II levels decreased in both MFN1(-) and siMFN2 HK2 cells, but increased in siFIS1 HK2 cells. Moreover, autophagy displays a protective role against high-glucoseinduced cell death based on cotreatment with autophagy inhibitors (3-methyladenine and chloroquine). Mitochondrial fission may increase apoptosis and decrease autophagy of high-glucose-treated HK2 cells. [ABSTRACT FROM AUTHOR]

Background: Until now, no long-term studies relating serum albumin level to mortality rate in prevalent haemodialysis (HD) patients have been conducted. We aimed to examine the association between serum albumin level and mortality over a 5-year period.Methods: This study included 781 patients who received maintenance HD in a large, hospital-facilitated HD centre. Five-year medical records (2009-2013) were retrospectively reviewed, and the cut-off level for serum albumin level was set at 3.5 g/dL. The analysed albumin levels were expressed as time-averaged levels (first 24-month data) and albumin target reach rate over the first 2-year interval. Univariate and multivariate Cox proportional hazard regression models were used to examine the hazard function of the all-cause and cardiovascular mortality of the study participants in the subsequent 3-year period (2011-2013).Results: Compared to those with a 100 % albumin reach rate (3.5 g/dL), the participants with 75- < 100, 50- < 75, and 1- < 50 % albumin reach rates exhibited significantly increased risk for all-cause mortality (HR 1.72, 95 % CI 1.19-2.47; HR 3.14, 95 % CI 1.91-5.16; HR 3.66, 95 % CI 2.18-6.16, respectively). A similar trend for all-cause mortality was demonstrated in participants with time-averaged albumin levels <4 g/dL (HR 1.57, 95 % CI 1.00-2.46 for 3.5-4.0 g/dL; HR 3.66, 95 % CI 2.11-6.32 for <3.5 g/dL). Compared to a 100 % albumin reach rate, the 50- < 75 and 1- < 50 % groups (HR 4.28, 95 % CI 1.82-10.01; HR 3.23, 95 % CI 1.22-8.54 respectively) showed significantly higher cardiovascular mortality rates. Similarly, participants with a time-averaged serum albumin level <3.5 g/dL exhibited a higher risk for cardiovascular mortality (HR 3.24, 95 % CI: 1.23-8.56).Conclusions: This long-term study demonstrated that higher reach rates of serum albumin levels and higher time-averaged serum albumin levels are associated with a lower mortality rate in patients undergoing maintenance HD. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate whether a high baseline level of high-sensitivity C-reactive protein (hs-CRP) or changes in the level predicts the risk of peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD). Methods: A prospective, cross-sectional, case-control study was conducted in a single hospital-based PD unit. A total of 327 patients were included in the study. Serum hs-CRP was measured annually for 2 years. Patients were divided into 4 groups according to the changes in annual hs-CRP levels (at baseline and at 1 year intervals): group 1 (from <5 mg/L to <5 mg/L, n = 171), group 2 (from <5 mg/L to ⩾5 mg/L, n = 45), group 3 (from ⩾5 mg/L to <5 mg/L, n = 45), and group 4 (from ⩾5 mg/L to ⩾5 mg/L, n = 80). Demographics, biochemistry results, PD adequacy indices, and peritonitis risk were compared between the groups. Results: The initial serum albumin level was similar in the 4 groups (p = 0.12). There was a negative linear correlation between the serial albumin change (Δalb) and serial hs-CRP change (Δhs-CRP; r = -0.154, p = 0.005). The hazard ratio (HR) for peritonitis was significantly higher in group 2 (HR = 1, reference) than in group 4 (HR = 0.401, 95% CI 0.209 - 0.769). Group 2 had a greater serum albumin decline rate (Δalb: -3% ± 9%) and hs-CRP elevation rate (Δhs-CRP: 835% ± 1232%) compared to those for the other groups. Conclusions: A progressive increase in the hs-CRP level was associated with a corresponding decline in the serum albumin level. Progressive rather than persistently high levels of serum hs-CRP predicted peritonitis risk in CAPD patients. [ABSTRACT FROM AUTHOR]

Myeloid differentiation factor 88 (MyD88) and NF-κB play central roles in mediating signal transduction of the Toll-like receptor (TLR) superfamily in human macrophages. The feedback regulation of LDL receptor (LDLR) and 3-hydroxy- 3-methylglutaryl-CoA reductase (HMG-CoAR) are mediated by the sterol regulatory element-binding protein (SREBP) cleavageactivating protein (SCAP)-SREBP2 pathway and are key regulatory elements for cholesterol homeostasis in human cells. This study was designed to investigate cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways in macrophage foam cell formation phorbol 12-myristate 13-acetate-activated THP-1 macrophages were transfected with negative control or MyD88 small interfering (si)RNA. Transfected cells were incubated with LPS in the absence or presence of LDL or IκB kinase (IKK) inhibitor (BMS-345541). Intracellular cholesterol content was assessed mRNA and protein expression of LDLR, HMG-CoAR, SCAP, and SREBP2 were examined by real-time RT-PCR and Western blot analysis. Intracellular translocation of SCAP in the organelles was detected by immunofluorecence and confocal microscopy. We demonstrated that LPS-induced cholesterol accumulation was attenuated by applying siRNA against MyD88 in the absence or presence of LDL. LPS increased both gene and protein expression of LDLR and HMG-CoAR by increasing expression and abnormal translocation of SCAP from the endoplasmic reticulum to the Golgi. These effects were blocked by knockdown of MyD88 or blockade of IKK or by knockdown of SCAP, suggesting that the cross-talk between NF-κB and SCAP plays an important role in macrophage foam cell formation and that interfering with the cross-talk might be a potential approach in preventing LPS-induced macrophage foam cell formation. [ABSTRACT FROM AUTHOR]

Both the coding and control regions of mitochondrial DNA (mtDNA) play roles in the generation of diabetes; however, no studies have thoroughly reported on the combined diabetogenic effects of variants in the two regions. We determined the mitochondrial haplogroup and the mtDNA sequence of the control region in 859 subjects with diabetes and 1,151 normoglycemic control subjects. Full-length mtDNA sequences were conducted in 40 subjects harboring speci c diabetes-related haplogroups. Multivariate logistic regression analysis with adjustment for age, sex, and BMI revealed that subjects harboring the mitochondrial haplogroup B4 have significant association with diabetes (DM) (odds ratio [OR], 1.54 [95% CI 1.18-2.02]; P , 0.001), whereas subjects harboring D4 have borderline resistance against DM generation (0.68 [0.49-0.94]; P = 0.02). Upon further study, we identified an mtDNA composite group susceptible to DM generation consisting of a 10398A allele at the coding region and a polycytosine variant at nucleotide pair 16184-16193 of the control region, as well as a resistant group consisting of C5178A, A10398G, and T152C variants. The OR for susceptible group is 1.31 (95% CI 1.04-1.67; P = 0.024) and for the resistant group is 0.48 (0.31-0.75; P = 0.001). Our study found that mtDNA variants in the coding and control regions can have combined effects influencing diabetes generation. [ABSTRACT FROM AUTHOR]

Background: The mitochondrial (mt) displacement loop (D-loop) is known to accumulate structural alterations and mutations. The aim of this study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) within the Dloop among chronic dialysis patients and healthy controls. Methodology and Principal Findings: We enrolled 193 chronic dialysis patients and 704 healthy controls. SNPs were identified by large scale D-loop sequencing and bioinformatic analysis. Chronic dialysis patients had lower body mass index, blood thiols, and cholesterol levels than controls. A total of 77 SNPs matched with the positions in reference of the Revised Cambridge Reference Sequence (CRS) were found in the study population. Chronic dialysis patients had a significantly higher incidence of 9 SNPs compared to controls. These include SNP5 (16108Y), SNP17 (16172Y), SNP21 (16223Y), SNP34 (16274R), SNP35 (16278Y), SNP55 (16463R), SNP56 (16519Y), SNP64 (185R), and SNP65 (189R) in D-loop of CRS. Among these SNPs with genotypes, SNP55-G, SNP56-C, and SNP64-A were 4.78, 1.47, and 5.15 times more frequent in dialysis patients compared to controls (P<0.05), respectively. When adjusting the covariates of demographics and comorbidities, SNP64-A was 5.13 times more frequent in dialysis patients compared to controls (P<0.01). Furthermore, SNP64-A was found to be 35.80, 3.48, 4.69, 5,55, and 4.67 times higher in female patients and in patients without diabetes, coronary artery disease, smoking, and hypertension in an independent significance manner (P<0.05), respectively. In patients older than 50 years or with hypertension, SNP34-A and SNP17-C were found to be 7.97 and 3.71 times more frequent (P<0.05) compared to patients younger than 50 years or those without hypertension, respectively. Conclusions and Significance: The results of large-scale sequencing suggest that specific SNPs in the mtDNA D-loop are significantly associated with chronic dialysis. These SNPs can be considered as potential predictors for chronic dialysis. [ABSTRACT FROM AUTHOR]