Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Hyperkalaemia prevalence and dialysis patterns in Chinese patients on haemodialysis: an interim analysis of a prospective cohort study (PRECEDE-K).

BACKGROUND: Hyperkalaemia is a known risk factor for cardiac arrhythmia and mortality in patients on haemodialysis. Despite standard adequate haemodialysis, hyperkalaemia is common in patients with end-stage renal disease (ESRD) at interdialytic intervals. Data on hyperkalaemia burden and its effects on dialysis patterns and serum potassium (sK) fluctuations in patients on haemodialysis in China remain limited. The prospective, observational cohort study (PRECEDE-K; NCT04799067) investigated the prevalence, recurrence, and treatment patterns of hyperkalaemia in Chinese patients with ESRD on haemodialysis. METHODS: Six hundred adult patients were consecutively enrolled from 15 secondary and tertiary hospitals in China. In this interim analysis, we report the baseline characteristics of the cohort, the prevalence of predialysis hyperkalaemia (sK > 5.0 mmol/L), and the trends in serum-dialysate potassium gradient and intradialytic sK shift at Visit 1 (following a long interdialytic interval [LIDI]). RESULTS: At baseline, most patients (85.6%) received three-times weekly dialysis; mean duration was 4.0 h. Mean urea reduction ratio was 68.0% and Kt/V was 1.45; 60.0% of patients had prior hyperkalaemia (previous 6 months). At Visit 1, mean predialysis sK was 4.83 mmol/L, and 39.6% of patients had hyperkalaemia. Most patients (97.7%) received a dialysate potassium concentration of 2.0 mmol/L. The serum-dialysate potassium gradient was greater than 3 mmol/L for over 40% of the cohort (1- < 2, 2- < 3, 3- < 4, and ≥ 4 mmol/L in 13.6%, 45.1%, 35.7%, and 5.2% of patients, respectively; mean: 2.8 mmol/L). The intradialytic sK reduction was 1- < 3 mmol/L for most patients (0- < 1, 1- < 2, 2- < 3, and ≥ 3 mmol/L in 24.2%, 62.2%, 12.8%, and 0.9% of patients, respectively; mean: 1.4 mmol/L). CONCLUSIONS: Hyperkalaemia after a LIDI was common in this real-world cohort of Chinese patients despite standard adequate haemodialysis, and led to large serum-dialysate potassium gradients and intradialytic sK shifts. Previous studies have shown hyperkalaemia and sK fluctuations are highly correlated with poor prognosis. Effective potassium-lowering treatments should be evaluated for the improvement of long-term prognosis through the control of hyperkalaemia and sK fluctuations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04799067.

Mean platelet volume may predict all-cause and cardiovascular mortality among incident peritoneal dialysis patients.

BACKGROUND: The association between mean platelet volume (MPV) and mortality in patients with cardiovascular disease has been demonstrated. However, the association between MPV and mortality in peritoneal dialysis (PD) patients remains unclear. METHODS: Patients catheterized at the First Affiliated Hospital, Nanchang University, between November 1, 2005, and August 31, 2019, were enrolled. The primary endpoints were all-cause and cardiovascular mortality. Patients were divided into two groups according to the cutoff value, which was determined using maximally selected rank statistics. The mortality hazard ratio was evaluated using Cox regression models. RESULTS: Among the 1322 PD patients enrolled, the mean age was 49.3 ± 14.5 years, 57.6% were men, and 18.8% had diabetes. During a median follow-up of 50 months (IQR: 30-80), 360 patients died; among these, 167 deaths were attributed to cardiovascular diseases. Survival analysis revealed that all-cause and cardiovascular mortality rates were lower in the higher-MPV group than in the lower-MPV group (p < .001 and p < .001, respectively). After full adjustment, a higher MPV was significantly associated with a hazard ratio of 0.77 for all-cause mortality (95% CI: 0.60-0.98, p = .036) and 0.75 for cardiovascular mortality (95% CI: 0.51-0.97, p = .041). Subgroup analysis showed that a significant interaction existed between age and MPV (p < .001). Decreased MPV was associated with higher mortality risk only in patients < 60 years old. CONCLUSIONS: Our results showed that lower MPV can be associated with a higher risk of all-cause and cardiovascular mortality in patients with PD.

Changes in the spectrum of kidney diseases: a survey of 2803 patients from 2010 to 2018 at a single center in southeastern China.

Primary glomerular disease was the leading cause of chronic kidney disease (CKD) in China; however, changes in the economy and environment introduce variations in the spectrum of kidney diseases. This study aimed to analyze renal biopsy data to inform disease prevention and public health interventions. In this retrospective cohort study, data from 2,803 consecutive renal biopsies conducted at our center between January 2010 and December 2018 were analyzed. The sample was disaggregated by age and the date of biopsy to facilitate analysis. Primary glomerulonephritis (PGN) is the most frequent (81.84%) finding, followed by secondary glomerulonephritis (SGN; 15.38%), tubulointerstitial nephritis (15.38%), and others (1.57%). IgA nephropathy (IgAN), idiopathic membranous nephropathy (iMN), and minimal change disease were the primary causes of PGN. Among PGN cases, the incidence of iMN arose, especially among those aged ≥ 60 years old, during the observation period. Contrary to the case of iMN, the proportion of IgAN in PGN trended downward, continuously, and at length. Moreover, IgAN mainly affected those aged 25-44 years old and less so those aged ≥ 60 years old. Lupus nephritis, Henoch-Schönlein purpura nephritis, and diabetic nephropathy (DN) were key causes of SGN. A ratio reversal between infectious disease and chronic disease dramatically changed SGN patterns. In the past year, the incidence of hepatitis B-related nephritis has constantly declined; however, the proportion of DN among SGN had steadily increased. The incidence of iMN significantly increased during these years. Among SGN cases, the proportion of DN has increased.

Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study.

OBJECTIVE: To evaluate the efficacy and safety of SHR4640, a highly selective urate transporter 1 inhibitor, in Chinese subjects with hyperuricaemia. METHODS: This was a randomized double-blind dose-ranging phase II study. Subjects whose serum uric acid (sUA) levels were ≥480 µmol/l with gout, ≥480 µmol/l without gout but with comorbidities, or ≥540 µmol/l were enrolled. Subjects were randomly assigned (1:1:1:1:1) to receive once daily 2.5 mg, 5 mg, 10 mg of SHR4640, 50 mg of benzbromarone or placebo, respectively. The primary end point was the proportion of subjects who achieved target sUA level of ≤360 µmol/l at week 5. RESULTS: 99.5% of subjects (n = 197) were male and 95.9% of subjects had gout history. The proportions of subjects who achieved target sUA at week 5 were 32.5%, 72.5% and 61.5% in the 5 mg, 10 mg SHR4640 and benzbromarone groups, respectively, significantly higher than the placebo group (0%; P < 0.05 for 5 mg and 10 mg SHR4640 group). The sUA was reduced by 32.7%, 46.8% and 41.8% at week 5 with 5 mg, 10 mg SHR4640 and benzbromarone, respectively, vs placebo (5.9%; P < 0.001 for each comparison). The incidences of gout flares requiring intervention were similar among all groups. Occurrences of treatment-emergent adverse events (TEAEs) were comparable across all groups, and serious TEAEs were not reported. CONCLUSIONS: The present study indicated a superior sUA-lowering effect and well tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as compared with placebo in Chinese subjects with hyperuricaemia. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03185793.

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

BRAIN FUNCTION ALTERATIONS IN PATIENTS WITH DIABETIC NEPHROPATHY COMPLICATED BY RETINOPATHY UNDER RESTING STATE CONDITIONS ASSESSED BY VOXEL-MIRRORED HOMOTOPIC CONNECTIVITY.

Objective: The voxel-mirrored homologous connection (VHMC) technique was applied to detect resting brain function alterations in patients with diabetic nephropathy and retinopathy (DNR), and their relationships with clinical manifestations in the kidneys and eyes are discussed. Methods: Twenty-two patients with DNR and 22 healthy controls (HCs) similarly matched in age, sex, and educational background were recruited. Resting-state functional magnetic resonance imaging scans were performed for all subjects. Retinal fundus photography and renal biopsy were employed to observe the clinical features of the kidney and retina. Pearson correlation analysis was used to analyze the relationship between clinical manifestations and experimental results. Results: Compared with the HCs, patients with DNR showed decreased mean VMHC values in the bilateral middle temporal gyrus, bilateral middle occipital gyrus (BMOG), and bilateral medial frontal gyrus. The receiver operating characteristic curve analysis of each brain region confirmed that the accuracy of the area under the curve was excellent. The results showed that the average VHMC value of BMOG signals was positively correlated with the urinary protein to creatinine ratio in female subjects (r = 0.626; P<.05). Nonetheless, no such correlation was noted among the male subjects. Conclusion: There were significant changes in brain function in DNR patients compared to the control group. Changes in the central nervous system in patients with DNR were mainly due to the dual negative effects of kidney function and diabetes mellitus. Abbreviations: ACR = albumin/creatinine ratio; BMFG = bilateral medial frontal gyrus; BMOG = bilateral middle occipital gyrus; BMTG = bilateral middle temporal gyrus; DN = diabetic nephropathy; DNR = diabetic nephropathy complicated by retinopathy; DR = diabetic retinopathy; fMRI = functional magnetic resonance imaging; HC = healthy control; MRI = magnetic resonance imaging; PCR = protein to creatinine ratio; ROC = receiver operating characteristic; VHMC = voxel-mirrored homologous connection.

The relationship between neutrophil-to-lymphocyte ratio and the first occurrence of pneumonia in peritoneal dialysis patients.

BACKGROUND: Although neutrophil-to-lymphocyte ratio (NLR) is closely associated with pneumonia in the general population, its relationship is unclear in peritoneal dialysis (PD) patients. METHODS: This is a cohort study consisting of 739 PD patients and dividing into two groups. Kaplan-Meier curves were applied to observe the incidence of the first occurrence of pneumonia, competitive risk analysis was conducted to compare whether there was a significant difference in each NLR group in the presence of other competing events, multivariable COX regression analysis was used to evaluate the hazard ratios (HRs), as well as forest plot was used to analyze the relationship between NLR and the first occurrence of pneumonia in different subgroups. RESULTS: Of all the patients, 116 cases of first-time pneumonia were recorded. The first-time pneumonia incidence rate was 71.67/1000 patient-years in high NLR group, which was markedly higher than that of 45.81/1000 patient-years in low NLR group. Kaplan-Meier curves indicated significant differences in the incidence of the first occurrence of pneumonia between two groups (log-rank test p = 0.015). The competitive risk model suggested a significant difference in the cumulative incidence of first pneumonia between the two groups (p = 0.032). Compared to low NLR group, adjusted Cox model showed that high NLR group was associated with increased risk of pneumonia incidence (HR, 1.51; 95% CI 1.04-2.21; p = 0.031). Forest plot showed no interaction was found in subgroups. CONCLUSIONS: The risk of pneumonia was significantly increasing in PD patients with high NLR, which may have a certain guiding significance for the clinic.

Neutrophil to Lymphocyte Ratio Predicts Adverse Cardiovascular Outcome in Peritoneal Dialysis Patients Younger than 60 Years Old.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is a new inflammatory marker; the relationship between NLR and adverse cardiovascular (CV) prognosis has been gradually emphasized in the general population. However, their association in peritoneal dialysis (PD) patients remains unclear. METHODS: From January 1, 2010, to May 31, 2017, a total of 1652 patients were recruited. NLR was categorized in triplicates: NLR ≤ 2.74, 2.74 < NLR ≤ 3.96, and NLR > 3.96. Kaplan-Meier cumulative incidence curve and multivariable COX regression analysis were used to determine the relationship between NLR and the incidence of adverse CV outcome, while a competitive risk model was applied to assess the effects of other outcomes on adverse CV prognosis. Besides, forest plot was investigated to analyze the adverse CV prognosis in different subgroups. RESULTS: During follow-up, 213 new-onset CV events and 153 CV disease (CVD) deaths were recorded. Multivariable COX regression models showed that the highest tertile of NLR level was associated with increased risk of CV events (HR = 1.39, 95%CI = 1.01-1.93, P = 0.046) and CVD mortality (HR = 1.81, 95%CI = 1.22-2.69, P = 0.003), while compared to the lowest tertile. Competitive risk models showed that the differences in CV event (P < 0.001) and CVD mortality (P = 0.004) among different NLR groups were still significant while excluding the effects of other outcomes. In subgroups, with each 1 increased in the NLR level, adjusted HR of new-onset CV event was 2.02 (95%CI = 1.26 - 3.23, P = 0.003) and CVD mortality was 2.98 (95%CI = 1.58 - 5.62, P = 0.001) in the younger group (age < 60 years). CONCLUSIONS: NLR is an independent risk factor for adverse CV prognosis in PD patients younger than 60 years old.

Novel long non-coding RNA AV310809 promotes TGF-ß1 induced epithelial-mesenchymal transition of human peritoneal mesothelial cells via activation of the Wnt2/ß-catenin signaling pathway.

Peritoneal fibrosis (PF) is a crucial cause of the loss of peritoneal function in patients with peritoneal dialysis. To better understand the underlying mechanism of PF, we selected AV310809, which is one of the most highly upregulated lncRNA in fibrotic peritoneal tissue, for functional analysis. We used co-expression analysis to explore the potential relationship between AV310809 and coding genes. qPCR, WB and IF were applied to evaluate the expression and localization of AV310809, epithelial markers and proteins involved in the Wnt2/ß-catenin signaling pathway. The interaction between AV310809 and ß-catenin was examined using an RNA pulldown assay. The expression level of AV310809 was upregulated in fibrotic peritoneum and TGF-ß1 induced EMT in HPMCs. Ectopic overexpression of AV310809 promoted EMT and activated the Wnt2/ß-catenin signaling pathway. Furthermore, we demonstrated that AV310809 could interact with ß-catenin and blocking ß-catenin inhibited the augmentation of EMT by AV310809. These findings indicated that AV310809 promoted TGF-ß1-induced EMT in HPMCs through the activation of the Wnt2/ß-catenin signaling pathway, possibly by targeting ß-catenin. We suggest that AV310809 may be a new therapeutic target for the management of peritoneal dialysis-associated PF.

Triglyceride to high-density lipoprotein cholesterol ratio is associated with increased mortality in older patients on peritoneal dialysis.

BACKGROUND: The triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been suggested as a simple method to identify unfavorable cardiovascular (CV) outcomes in the general population. The aim of this study was to investigate the association between the TG/HDL-C ratio and all-cause and CV mortality in peritoneal dialysis (PD) patients. METHODS: We retrospectively analyzed patients on PD from November 1, 2005, to February 28, 2017, with a follow-up period lasting until May 31, 2017. The main outcomes were all-cause and CV mortality. RESULTS: Among the 973 PD patients, the mean age was 49.67 ± 14.58 (y). During a median follow-up period of 27.2 months (IQR = 13.4-41.5 months), 229 (23.5%) patients died, with 120 (12.3%) dying as a result of CV diseases. The median serum TG/HDL-C ratio was 1.11 (IQR = 0.71-1.80). In a multivariate Cox regression analysis, patients with higher TG/HDL-C ratio levels (tertile 3) had a higher incidence of CV mortality (adjusted HR = 2.12; 95% CI: 1.21-3.72; P = 0.009) and all-cause mortality (adjusted HR = 2.08; 95% CI: 1.37-3.14; P = 0.001) compared to patients in tertile 1. These associations persisted after excluding the patients who have already taken lipid-lowering medications. For older patients (> 60 years), each 1-unit higher baseline TG/HDL-C level was associated with a 48% (95% CI: 1.06-2.07; P = 0.021) increased risk of all-cause mortality and a 59% (95% CI: 1.03-2.45; P = 0.038) increased risk of CV mortality; however, this association was not observed in patients ≤60 years of age. CONCLUSIONS: A higher serum TG/HDL-C ratio was an independent predictor of all-cause and CV mortality in PD patients. Furthermore, an elevated TG/HDL-C ratio was significantly associated with higher all-cause and CV mortality in older PD patients.

Relationship between serum bilirubin levels and mortality in patients on peritoneal dialysis.

Background: Studies have shown that the serum total bilirubin (TBil) is associated with the mortality of the general population and of hemodialysis patients. However, few studies have examined the associations of the direct bilirubin (DBil) and indirect bilirubin (IBil) with the mortality of peritoneal dialysis (PD) patients. Methods: This was a retrospective cohort study. Clinical and laboratory data were collected from 740 PD patients. The primary endpoint was 5-year all-cause mortality. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. The mortality hazard ratio was evaluated using Cox regression models. Results: Among the 740 PD patients, the mean age was 49.9 ± 15.0 years, 54.9% were men, and 20.3% had diabetes. During the median follow-up period of 28 months (interquartile range, 14-41 months), 178 patients died. Kaplan-Meier analysis revealed that all-cause mortality was higher in the patients in the higher TBil group than in the lower TBil group (25.6% vs. 18.3%, p = .017) and in patients in the higher IBil group than in the lower IBil group (24.3% vs. 19%, p = .026). Multivariate analysis showed that compared with the lower TBil group, the 5-year mortality risk was higher in the higher TBil group (HR = 1.69, 95% CI: 1.11-2.56, p = .014). Similarly, there was a 56% higher risk of 5-year mortality in the higher IBil group than in the lower IBil group (HR = 1.56, 95% CI: 1.04-2.34, p = .032). However, no such associations were observed between the DBil and the mortality risk. Conclusions: The baseline serum TBil and IBil levels were significantly associated with 5-year all-cause mortality among PD patients.

Serum alkaline phosphatase levels correlate with long-term mortality solely in peritoneal dialysis patients with residual renal function.

Introduction: Increased serum alkaline phosphatase (ALP) is predictive of a higher mortality in patients with end-stage renal disease. However, it remains unknown whether residual renal function (RRF) influences the outcome-association of serum ALP among peritoneal dialysis (PD) patients. Methods: A total of 650 incident PD patients receiving PD catheter implantation in an institute between 1 November 2005 and 28 February 2017 were retrospectively enrolled. These patients were divided into groups with and without RRF (RRF and non-RRF groups) and those with serum ALP levels in tertiles. The Kaplan-Meier method and multivariate Cox proportional hazard models were used to analyze their outcomes based on RRF and serum ALP levels. Results: These 650 patients had a mean age of 49.4 ± 14.0 years old, their median ALP level was 74 U/L (interquartile range (IQR): 59-98). After 28-month (IQR: 14-41) follow-up, 80 patients in RRF group and 40 patients in non-RRF group died. PD patients with the highest serum ALP tertile had significant lower survival (p = .014), when compared to other patients in the RRF group. However, this relationship was not observed in patients in the non-RRF group. After multivariate adjustment, in the RRF group, patients with the highest ALP tertile had a significantly higher risk of mortality (hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.06-4.82, p = .034). Each 10-U/L increase in ALP level was associated with a 4% (HR: 1.04, 95% CI: 1.00-1.08, p = .045) higher mortality risk. Conclusions: Higher serum ALP level is associated with increased mortality solely in PD patients with RRF.

MiR-200a negatively regulates TGF-ß1-induced epithelial-mesenchymal transition of peritoneal mesothelial cells by targeting ZEB1/2 expression.

Although epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells was recognized as the key process of peritoneal fibrosis, which is a major cause of peritoneal failure related to peritoneal dialysis (PD), mechanisms underlying these processes remain largely unknown. In this study, we found that miR-200a was significantly downregulated in peritoneal tissues with fibrosis in a rat model of PD. In vitro, transforming growth factor (TGF)-ß1-induced EMT, identified by de novo expression of α-smooth muscle actin and a loss of E-cadherin in human peritoneal mesothelial cells (HPMCs), was associated with downregulation of miR-200a but upregulation of zinc finger E-box-binding homeobox 1/2 (ZEB1/2), suggesting a close link between miR-200a and ZEB1/2 in TGF-ß1-induced EMT. It was further demonstrated that miR-200a was able to bind to the 3'UTR of ZEB1/2, and overexpression of miR-200a blocked TGF-ß1-induced upregulation of ZEB1/2 and, therefore, inhibited EMT and collagen expression. In contrast, overexpression ZEB1/2 blocked miR-200a inhibition of EMT and collagen expression in HMPCs. In conclusion, miR-200a could negatively regulate TGF-ß1-induced EMT by targeting ZEB1/2 in peritoneal mesothelial cells. Blockade of EMT in HPMCS indicates the therapeutic potential of miR-200a as a treatment for peritoneal fibrosis associated with PD.

Apolipoprotein B/apolipoprotein A1 ratio and mortality among incident peritoneal dialysis patients.

BACKGROUND: To investigate the association between the ratio of apolipoprotein B (apo B) / apolipoprotein A1 (apo A1) with all-cause mortality and cardiovascular events in peritoneal dialysis (PD) patients. METHODS: Eight hundred and sixty incident PD patients were enrolled from November 1, 2005, to February 28, 2017, and followed until May 31, 2017. Outcomes were all-cause mortality and cardiovascular events. Associations between the apo B/apo A1 ratio with all-cause mortality and cardiovascular events were evaluated using multivariable-adjusted Cox models. RESULTS: Of the 860 patients, the mean age was 49.9 ± 14.5 years, 57.6% were men, and 19.3% were diabetic patients. The median apo B/apo A1 ratio was 0.65 (range: 0.22-2.24). During a median follow-up period of 27 months (interquartile range, 13 - 41 months), 202 deaths, and 145 cardiovascular events were recorded. After adjustment for age, sex, body mass index, diabetes, cardiovascular disease, systolic blood pressure, total Kt/V, estimated glomerular filtration rate, hemoglobin level, neutrophil to lymphocyte ratio and albumin, triglyceride, and cholesterol, as well as the use of lipid-lowering agents, the highest apo B/apo A1 ratio tertile was significantly associated with a hazard ratio for all-cause mortality of 1.60 (95% CI: 1.02 to 2.49, P = 0.040) and for cardiovascular events of 2.04 (95% CI: 1.21 to 3.44, P = 0.008). CONCLUSION: An increased apo B/apo A1 ratio was independently associated with all-cause mortality and cardiovascular events in PD patients.

A meta-analysis of the association between diabetic patients and AVF failure in dialysis.

PURPOSE: The most preferable vascular access for patients with end-stage renal failure needing hemodialysis is native arteriovenous fistula (AVF) on account of its access longevity, patient morbidity, hospitalization costs, lower risks of infection and fewer incidence of thrombotic complications. Meanwhile, according to National Kidney Foundation (NKF)̸Dialysis Out-comes Quality Initiative (DOQI) guidelines, AVF is more used than before. However, a significant percentage of AVF fails to support dialysis therapy due to lack of adequate maturity. Among all factors, the presence of diabetes mellitus was shown to be one of the risk factors for the development of vascular access failure by some authors. Therefore, this review evaluates the current evidence concerning the correlation of diabetes and AVF failure. METHODS: A search was conducted using MEDLINE, SCIENCE DIRECT, SPRINGER, WILEY-BLACKWELL, KARGER, EMbase, CNKI and WanFang Data from the establishment time of databases to January 2016. The analysis involved studies that contained subgroups of diabetic patients and compared their outcomes with those of non-diabetic adults. In total, 23 articles were retrieved and included in the review. RESULTS: The meta-analysis revealed a statistically significantly higher rate of AVF failure in diabetic patients compared with non-diabetic patients (OR = 1.682; 95% CI, 1.429-1.981, Test of OR = 1: z = 6.25, p <.001). CONCLUSIONS: This review found an increased risk of AVF failure in diabetes patients. If confirmed by further prospective studies, preventive measure should be considered when planning AVF in diabetic patients.

Cross-talk between angiotensin-II and toll-like receptor 4 triggers a synergetic inflammatory response in rat mesangial cells under high glucose conditions.

Toll-like Receptor 4 (TLR4) may play an important role in the pathogenesis of diabetic nephropathy (DN). In this study, We observed the TLR4 signal and the release of inflammation factors after angiotensin II (Ang II) stimulation in rat mesangial cells (MCs) under high glucose conditions, this revealed the innate immune mechanism of injury by Ang II in DN. Our data showed that TLR4 and MyD88 were up-regulated significantly in high glucose and AngII-induced MCs; meanwhile, NF-κB as well as MCP-1, IL-6 were also highly expressed. In cells that were transfected with TLR4 SiRNA，the parameters were greatly inhibited; similar effects were detected in cells that were treated with Irbesartan. We concluded that Ang II synergized with high glucose in the release of pro-inflammatory factors mainly through the upregulation of TLR4 signaling in MCs, Cross-talk between Ang II and TLR4 contributed to the MC inflammatory injury under high glucose conditions.

Octopus-Inspired Soft Robot for Slow Drug Release.

Octopus tentacles are equipped with numerous suckers, wherein the muscles contract and expel air, creating a pressure difference. Subsequently, when the muscular tension is released, objects can be securely adhered to. This mechanism has been widely employed in the development of adhesive systems. However, most existing octopus-inspired structures are passive and static, lacking dynamic and controllable adhesive switching capabilities and excellent locomotion performance. Here, we present an octopus-inspired soft robot (OISR). Attracted by the magnetic gradient field, the suction cup structure inside the OISR can generate a strong adsorption force, producing dynamically controllable adsorption and separation in the gastrointestinal (GI) tract. The experimental results show that the OISR has a variety of controllable locomotion behaviors, including quick scrolling and rolling motions, generating fast locomotion responses, rolling over gastric folds, and tumbling and swimming inside liquids. By carrying drugs that are absorbable by GI epithelial cells to target areas, the OISR enables continuous drug delivery at lesions or inflamed regions of the GI tract. This research may be a potential approach for achieving localized slow drug release within the GI tract.

Microgripper Robot with End Electropermanent Magnet Collaborative Actuation.

Magnetic microgrippers, with their miniaturized size, flexible movement, untethered actuation, and programmable deformation, can perform tasks such as cell manipulation, targeted drug delivery, biopsy, and minimally invasive surgery in hard-to-reach regions. However, common external magnetic-field-driving devices suffer from low efficiency and utilization due to the significant size disparity with magnetic microgrippers. Here, we introduce a microgripper robot (MGR) driven by end electromagnetic and permanent magnet collaboration. The magnetic field generated by the microcoils can be amplified by the permanent magnets and the direction can be controlled by changing the current, allowing for precise control over the opening and closing of the magnetic microgripper and enhancing its operational range. Experimental results demonstrate that the MGR can be flexibly controlled in complex constrained environments and is highly adaptable for manipulating objects. Furthermore, the MGR can achieve planar and antigravity object grasping and transportation within complex simulated human cavity pathways. The MGR's grasping capabilities can also be extended to specialized tasks, such as circuit connection in confined spaces. The MGR combines the required safety and controllability for in vivo operations, making it suitable for potential clinical applications such as tumor or abnormal tissue sampling and surgical assistance.

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study.

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80 µg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80 µg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80 µg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 µg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80 µg/kg in hemodialysis patients. HSK21542-0.3 µg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.