Integrative ATAC-seq and RNA-seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin.

Dapagliflozin (DAPA) are clinically effective in improving diabetic nephropathy (DN). However, whether and how chromatin accessibility changed by DN responds to DAPA treatment is unclear. Therefore, we performed ATAC-seq, RNA-seq, and weighted gene correlation network analysis to identify the chromatin accessibility, the messenger RNA (mRNA) expression, and the correlation between clinical phenotypes and mRNA expression using kidney from three mouse groups: db/m mice (Controls), db/db mice (case group), and those treated with DAPA (treatment group). RNA-Seq and ATAC-seq conjoint analysis revealed many overlapping pathways and networks suggesting that the transcriptional changes of DN and DAPA intervention largely occured dependently on chromatin remodeling. Specifically, the results showed that some key signal transduction pathways, such as immune dysfunction, glucolipid metabolism, oxidative stress and xenobiotic and endobiotic metabolism, were repeatedly enriched in the analysis of the RNA-seq data alone, as well as combined analysis with ATAC-seq data. Furthermore, we identified some candidate genes (UDP glucuronosyltransferase 1 family, Dock2, Tbc1d10c, etc.) and transcriptional regulators (KLF6 and GFI1) that might be associated with DN and DAPA restoration. These reversed genes and regulators confirmed that pathways related to immune response and metabolism pathways were critically involved in DN progression.

Fractal Analysis of Left Ventricular Trabeculae in Patients with End-Stage Renal Disease: A Random Survival Tree Analysis.

BACKGROUND: The complexity of left ventricular (LV) trabeculae is related to the prognosis of several cardiovascular diseases. PURPOSE: To evaluate the prognostic value of LV trabecular complexity in patients with end-stage renal disease (ESRD). STUDY TYPE: Prospective outcome study. POPULATION: 207 participants on maintenance dialysis, divided into development (160 patients from 2 centers) and external validation (47 patients from a third center) cohorts, and 72 healthy controls. FIELD STRENGTH: 3.0T, steady-state free precession (SSFP) and modified Look-Locker imaging sequences. ASSESSMENT: All participants had their trabecular complexity quantified by fractal analysis using cine SSFP images. Patients were followed up every 2 weeks until April 2023, or endpoint events happened. Random Forest (RF) and Cox regression models including age, diabetes, LV mass index, mean basal fractal dimension (FD), and left atrial volume index, were developed to predict major adverse cardiac events (MACE). Patients were divided into low- and high-risk groups based on scores derived from the RF model and survival compared. STATISTICAL TESTS: Receiver operating characteristic curve analysis; Kaplan-Meier survival analysis with log rank tests; Harrel's C-index to assess model performance. A P value <0.05 was considered statistically significant. RESULTS: Fifty-five patients (26.57%) experienced MACE during a median follow-up time of 21.83 months. An increased mean basal FD (≥1.324) was associated with a significantly higher risk of MACE. The RF model (C-index: 0.81) had significantly better discrimination than the Cox regression model (C-index: 0.74). Participants of the external validation dataset classified into the high-risk group had a hazard of experiencing MACE increased by 12.29 times compared to those in the low-risk group. DATA CONCLUSION: LV basal FD was an independent predictor for MACE in patients with ESRD. Reliable risk stratification models could be generated based on LV basal FD and other MRI variables using RF analysis. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Left Ventricular Vertical Run-Length Nonuniformity MRI Adds Prognostic Value to MACE in Patients with End-Stage Renal Disease.

BACKGROUND: Vertical run-length nonuniformity (VRLN) is a texture feature representing heterogeneity within native T1 images and reflects the extent of cardiac fibrosis. In uremic cardiomyopathy, interstitial fibrosis was the major histological alteration. The prognostic value of VRLN in patients with end-stage renal disease (ESRD) remains unclear. PURPOSE: To evaluate the prognostic value of VRLN MRI in patients with ESRD. STUDY TYPE: Prospective. POPULATION: A total of 127 ESRD patients (30 participants in the major adverse cardiac events, MACE group). FIELD STRENGTH/SEQUENCE: 3.0 T/steady-state free precession sequence, modified Look-Locker imaging. ASSESSMENT: MRI image qualities were assessed by three independent radiologists. VRLN values were measured in the myocardium on the mid-ventricular short-axis slice of T1 mapping. Left ventricular (LV) mass, LV end-diastolic and end-systolic volume, as well as LV global strain cardiac parameters were measured. STATISTICAL TESTS: The primary endpoint was the incident of MACE from enrollment time to January 2023. MACE is a composite endpoint consisting of all-cause mortality, acute myocardial infarction, stroke, heart failure hospitalization, and life-threatening arrhythmia. Cox proportional-hazards regression was performed to test whether VRLN independently correlated with MACE. The intraclass correlation coefficients of VRLN were calculated to evaluate intraobserver and interobserver reproducibility. The C-index was computed to examine the prognostic value of VRLN. P-value <0.05 were considered statistically significant. RESULTS: Participants were followed for a median of 26 months. VRLN, age, LV end-systolic volume index, and global longitudinal strain remained significantly associated with MACE in the multivariable model. Adding VRLN to a baseline model containing clinical and conventional cardiac MRI parameters significantly improved the accuracy of the predictive model (C-index of the baseline model: 0.781 vs. the model added VRLN: 0.814). DATA CONCLUSION: VRLN is a novel marker for risk stratification toward MACE in patients with ESRD, superior to native T1 mapping and LV ejection fraction. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 2.

Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels.

Introduction: Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Therefore, efforts to understand DKD pathophysiology and prevent its development at the early phase are highly warranted. Methods: Here, we analyzed kidneys from healthy mice, diabetic mice, and diabetic mice treated with the sodium-glucose cotransporter 2 inhibitor dapagliflozin using ATAC and RNA sequencing. The findings were verified at the protein levels and in cultured cells. Results: Our combined method of ATAC and RNA sequencing revealed Csf2rb, Btla, and Isg15 as the key candidate genes associated with hyperglycemia, azotemia, and albuminuria. Their protein levels were altered together with multiple other inflammatory cytokines in the diabetic kidney, which was alleviated by dapagliflozin treatment. Cell culture of immortalized renal tubular cells and macrophages unraveled that dapagliflozin could directly effect on these cells in vitro as an anti-inflammatory agent independent of glucose concentrations. We further proved that dapagliflozin attenuated ischemia/reperfusion-induced chronic kidney injury and renal inflammation in mice. Discussion: Overall, our data emphasize the importance of inflammatory factors to the pathogenesis of DKD, and provide valuable mechanistic insights into the renoprotective role of dapagliflozin.

Assessment of the Prognostic Value of MRI Left Ventricular Global Function Index (LVGFI) in Patients With End-Stage Renal Disease Under Maintenance Dialysis.

BACKGROUND: Left ventricular global function index (LVGFI) integrates LV volumetric and functional parameters. In patients with end-stage renal disease (ESRD), cardiac injury manifests as LV hypertrophy and dysfunction. However, the prognostic value of LVGFI in this population remains unclear. PURPOSE: To investigate the association of LVGFI with major adverse cardiac events (MACE) in patients with ESRD. STUDY TYPE: Prospective. POPULATION: One hundred fifty-eight ESRD patients (mean age: 54.1 ± 14.4 years; 105 male) on maintenance dialysis. FILED STRENGTH/SEQUENCE: 3.0 T, balanced steady-state free precession (bSSFP) cine and modified Look-Locker inversion recovery (MOLLI) sequences. ASSESSMENT: LV volumetric and functional parameters were determined from bSSFP images. LVGFI was calculated as the ratio of stroke volume to global volume and native T1 was determined from MOLLI T1 maps. MACE was recorded on follow up. Models were developed to predict MACE from conventional risk factors combined with LVGFI, GLS, native T1, and LV mass index (LVMI), respectively. Subgroup analyses were further performed in participants with LVEF above median. STATISTICAL TESTS: Cox proportional hazard regression and log-rank test were used to investigate the association between LVGFI and MACE. The predictive models were evaluated and compared using Harrell's C-statistics and DeLong tests. A P value <0.05 was considered statistically significant. RESULTS: Thirty-four MACE occurred during the median follow-up period of 26 months. The hazard of MACE increased by 114% for each 10% decrease in LVGFI in univariable analysis. The predictive model consisting of LVGFI (C-statistic: 0.724) had significantly better predictive performance than the others (all P < 0.001). These results were consistent in patients (N = 79) with LVEF > median (63.54%). DATA CONCLUSION: LVGFI is a novel marker for MACE risk stratification in patients with ESRD and was better able to predict MACE than native T1 mapping and GLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice.

Background: The intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear. Methods: To investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks. Results: We found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks. Conclusion: We firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

The initial attempt at home hemodialysis in mainland China.

BACKGROUND: Observational studies have shown home hemodialysis (HHD) to be associated with better survival than facility hemodialysis (HD) and peritoneal dialysis (PD). Patients on HHD have reported higher quality of life and independence. HHD is considered to be an economical way to manage end-stage kidney disease (ESKD). The coronavirus disease 2019 pandemic has had a significant impact on patients with ESKD. Patients on HHD may have an advantage over in-center HD patients because of a lower risk of exposure to infection. PARTICIPANTS AND METHODS: We enrolled HD patients from our dialysis center. We first established the HHD training center. The training center was approved by the Chinese government. Doctors, nurses and engineers train and assess patients separately. There are three forms of patient monitoring: home visits, internet remote monitoring, and outpatient services. Demographic and medical data included age, sex, blood pressure, and dialysis-related data. Laboratory tests were conducted in our central testing laboratory, including hemoglobin (Hgb), serum creatinine (Cr), urea nitrogen (BUN), uric acid (UA), albumin (Alb), calcium (Ca), phosphorus (P), parathyroid hormone (PTH), and brain natriuretic peptide (BNP) levels. RESULTS: Six patients who underwent regular dialysis in the HD center of our hospital were selected for HHD training. We enrolled 6 patients, including 4 males and 2 females. The mean age of the patients was 47.5 (34.7-55.7) years, and the mean dialysis age was 33.5 (11.2-41.5) months. After an average of 16.0 (11.2-25.5) months of training, Alb, P and BNP levels were improved compared with the baseline values. After training, three patients returned home to begin independent HD. During the follow-up, there were no serious adverse events leading to hospitalization or death, but there were several adverse events. They were solved quickly by extra home visits of the technicians or online by remote monitoring. During the follow-up time, the laboratory indicators of all the patients, including Hgb, Alb, Ca, P, PTH, BNP, and ß2-MG levels, remained stable before and after HHD treatment. CONCLUSION: HHD is feasible and safe for ESKD in China, but larger-scale and longer-term studies are needed for further confirmation.

Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerulonephritis, and a major cause of end-stage renal disease; however, its pathogenesis requires elucidation. Here, a hub gene, FABP1, and signaling pathway, PPARα, were selected as key in IgAN pathogenesis by combined weighted gene correlation network analysis of clinical traits and identification of differentially expressed genes from three datasets. FABP1 and PPARα levels were lower in IgAN than control kidney, and linearly positively correlated with one another, while FABP1 levels were negatively correlated with urinary albumin-to-creatinine ratio, and GPX4 levels were significantly decreased in IgAN. In human mesangial cells (HMCs), PPARα and FABP1 levels were significantly decreased after Gd-IgA1 stimulation and mitochondria appeared structurally damaged, while reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, and glutathione and GPX4 decreased, relative to controls. GPX4 levels were decreased, and those of ACSL4 increased on siPPARα and siFABP1 siRNA treatment. In PPARα lentivirus-transfected HMCs stimulated by Gd-IgA1, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPARα and GPX4, increased; and damaged mitochondria reduced. Hence, PPARα pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

A novel contrast-induced acute kidney injury mouse model based on low-osmolar contrast medium.

The contrast-induced acute kidney injury (CI-AKI) has been becoming the third common cause of hospital-acquired acute kidney injury. An ideal animal model is essential for understanding the pathophysiology of CI-AKI. Previous CI-AKI studies were mostly performed on rats with high-osmolar contrast medium (HOCM), which is unsuitable for transgenic researches. This study provides a novel, efficient and reproducible CI-AKI model which was developed in mouse by administrating a low-osmolar contrast medium (LOCM). First of all, we applied the frequently used pretreatments (uninephrectomy and water deprivation), which combined with HOCM on rats could induce CI-AKI, on mice with LOCM. Secondly, we attempted to find a novel pretreatment suitable for mouse and LOCM by combining two classic pretreatments(uninephrectomy, water deprivation and furosemide administration). Finally, we evaluate the kidney damage of the novel model. We found that this mouse model possessed a significant reduction in renal function, severe renal tissue damage, and increased renal tubular cells apoptosis, indicating that LOCM is a feasible inducer for CI-AKI mice model. Taken together, we found that uninephrectomy (UPHT) combined with 24 h water deprivation and furosemide administration 20 min before LOCM (iohexol, 10 ml/kg) application is a feasible pretreatment to establish a novel CI-AKI mouse model.

Automated peritoneal dialysis as a cost-effective urgent-start dialysis option for ESRD patients: A prospective cohort study.

BACKGROUND: Several studies have reported the feasibility of urgent-start peritoneal dialysis (PD) as an alternative to hemodialysis (HD) using a central venous catheter (CVC). However, the cost-effectiveness of automated peritoneal dialysis (APD) as an urgent-start dialysis modality has not been directly evaluated, especially in China. METHODS: We prospectively enrolled patients with end-stage renal disease (ESRD) who required urgent-start dialysis at a single center from March 2019 to November 2020. Patients were grouped according to their urgent-start dialysis modality (APD and HD). Urgent-start dialysis conducted until 14 days after PD catheter insertion. Then, PD was maintained. Each patient was followed until July 2021 or death or loss to follow-up. The primary outcome was the incidence of short-term dialysis-related complications. The secondary outcome was the cost and duration of the initial hospitalization. Technique survival, peritonitis-free or bacteriamia-free survival and patient survival were also compared. RESULTS: Sixty-eight patients were included in the study, of whom 36 (52.9%) patients were in APD group. Mean follow-up duration was 20.1 months. Compared with the HD group, the APD group had significantly fewer short-term dialysis-related complications. The cost of initial hospitalization was also significantly lower in APD patients. There was no significant difference between APD and HD patients with respect to duration of the initial hospitalization, technique survival rate, peritonitis-free or bacteriemia-free survival rate, and patient survival rate. CONCLUSION: Among ESRD patients with an urgent need for dialysis, APD as urgent-start dialysis modality, compared with HD using a CVC, resulted in fewer short-term dialysis-related complications and lower cost.

Incremental diagnostic value of CMR-derived LA strain and strain rate in dialysis patients with HFpEF.

OBJECTIVES: To test whether left atrial (LA) strain and strain rate add incremental value in the diagnosis of heart failure with preserved ejection fraction (HFpEF) in dialysis patients over clinical and conventional parameters only. BACKGROUND: HFpEF frequently occurs in dialysis patients, however, the diagnosis of HFpEF is difficult. Although HFpEF is always companied with LA dysfunction, the performance of novel LA parameters, LA strain, and strain rate, in the diagnosis of HFpEF among dialysis patients remains unknown. METHODS: In the study, 153 dialysis patients (57 without HFpEF and 96 with HFpEF) and 52 healthy controls underwent cardiovascular magnetic imaging (CMR). Three components of LA strain and strain rate, including reservoir, contractile, and booster pump, were assessed via the CMR feature tracking module. Extra diagnostic value was examined by Harrell's C-statistic. RESULTS: Compared with healthy controls and dialysis patients without HFpEF, dialysis patients with HFpEF had significantly impaired LA reservoir (εs) and contractile (εe) strain and strain rate (SRs, SRe), all p < 0.0001. Among these parameters, εs, εe, and SRe showed relatively high accuracy in diagnosing HFpEF among dialysis patients (areas under the curve: 0.84, 0.91, and 0.90, respectively). Reduction of εs, εe, and SRs provided incremental diagnostic value over conventional clinical and echocardiogram parameters. Combined with εs, εe or SRs, the diagnostic performance was further improved (Harrell's C-statistic: 0.83 vs. 0.96, 0.97, and 0.97, respectively, all p < 0.0001). CONCLUSIONS: CMR-derived εs, εe, and SRs might add incremental diagnostic value over conventional indexes in diagnosing HFpEF among dialysis patients.

Magnetic Resonance Imaging Quantification of Accumulation of Epicardial Adipose Tissue Adds Independent Risks for Diastolic Dysfunction among Dialysis Patients.

BACKGROUND: Diastolic dysfunction (DD) frequently occurs in dialysis patients; however, the risk factors of DD remain to be further explored in such a population. Epicardial adipose tissue (EAT) volume has proven to be an independent clinical risk factor for multiple cardiac disorders. PURPOSE: To assess whether EAT volume is an independent risk factor for DD in dialysis patients. STUDY TYPE: Case-control study. POPULATION: A total of 113 patients (mean age: 54.5 ± 14.4 years; 41 women) who had underwent dialysis for at least 3 months due to uremia. FIELD STRENGTH: A 3 T, steady-state free precession (SSFP) sequence for cine imaging, modified Look-Locker imaging (MOLLI) for T1 mapping and gradient-recalled-echo for T2*. ASSESSMENT: All participants were performed cardiac magnetic resonance imaging (MRI) and echocardiogram. For MRI images analysis, borders of the EAT were manually delineated, as well as, pericardial adipose tissue (PeAT) and paracardial adipose tissue (PaAT), T1 mapping, T2* mapping, global longitudinal strain (GLS), and left atrial strain. For echocardiogram assessments, the thickness of PaAT, e' velocity, E velocity, E/e ratio, A velocity, and deceleration time were measured. STATISTICAL TESTS: Univariate and multivariate logistic regressions were performed to explore the independent risk factors for DD. P value less than 0.05 was considered as significant. RESULTS: Compared with the DD(-) group, the DD(+) group had significantly more epicardial tissue fat (18.5 ± 1.3 vs. 30.9 ± 2.3) In addition, EAT volumes increased significantly with the grades of DD (grade 1 vs. grade 2 and 3: 27.9 ± 15.9 vs. 35.4 ± 13.1). Moreover, EAT had significant correlations with T1 mapping, T2* mapping, GLS, left atrial strain, e' velocity, and E/e ratio. EAT accumulation added an independent risk for DD (Odds Ratio = 1.03) over conventional clinical risk factors including age, diabetes mellitus, and hemodialysis. DATA CONCLUSION: EAT was associated with diastolic function, and its accumulation may be an independent risk factor for DD among dialysis patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Efficacy and safety of polysaccharide iron complex capsules compared with iron sucrose in hemodialysis patients: study protocol for a randomized, open-label, positive control, multicenter trial (IHOPE).

BACKGROUND: Anemia is one of the main complications of chronic kidney disease especially kidney failure, which includes treatment with erythropoiesis-stimulating agents and iron supplementation, including intravenous and oral iron. However, intravenous iron may pose limitations, such as potential infusion reactions. Oral iron is mainly composed of divalent iron, which can excessively stimulate the gastrointestinal tract. Iron polysaccharide complex capsules are a novel oral iron trivalent supplement with higher iron content and lower gastrointestinal irritation. However, since high-quality evidence-based medicinal support is lacking, it is necessary to conduct clinical studies to further evaluate the effectiveness and safety of oral iron polysaccharide complex in chronic kidney disease patients. METHODS: This randomized controlled trial uses an open-label, parallel group design, where the efficacy and safety of maintenance hemodialysis (MHD) participants is evaluated. The experimental group is assigned erythropoietins and iron polysaccharide complex (two capsules each time, bid), and the control group is assigned erythropoietin and sucrose iron (100mg, 2w) injection. Participants (aged 18-75 years) undergoing maintenance hemodialysis were considered for screening. Inclusion criteria included hemoglobin (Hb) ≥110g/L and < 130g/L, transferrin saturation (TSAT) > 20% and < 50%, and serum ferritin (SF) > 200µg/L and < 500µg/L. Exclusion criteria included acute or chronic bleeding, serum albumin < 35g/L, hypersensitive C-reactive protein (HsCRP) > 10 mg/L, and severe secondary hyperparathyroidism (iPTH ≥ 800 pg/mL). Full inclusion and exclusion criteria are described in the "Methods" section. The primary endpoint is TSAT of the participants at week 12. Secondary endpoints include Hb, SF, hematocrit (Hct), HsCRP, pharmacoeconomic evaluation, drug costs, quality of life, and indicators of oxidative stress. The treatment will last for 24 weeks with a follow-up visit at baseline (within 7 days prior to initial treatment) and weeks 4, 8, 12, 16, 20, and 24 after initial treatment. This clinical research includes 9 hemodialysis centers in mainland China and plans to enroll 186 participants. DISCUSSION: It is expected that it will provide strong evidence to reveal the clinical efficacy and safety of oral iron in the treatment of chronic CKD-related anemia in MHD patients through this clinical trial. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000031166 . Registered on March 23, 2020.

Intelligent "Internet Plus" services in the first case of home hemodialysis in mainland China.

BACKGROUND: Many studies have shown that compared with those who use other dialysis modalities, patients using home hemodialysis (HHD) have an increased rate of survival and better quality of life. It was noted in 2006 that there was opportunity for significant expansion of the use of HHD in many countries. China covers a vast area and has a large amount of end-stage renal failure patients. But in mainland China, all dialysis treatments are in-center, and the number of HHD patients is zero. In 2018, our hospital received the permission of the Shanghai government to carry out HHD. CASE PRESENTATION: We initiated four incident hemodialysis patients on an HHD regimen, one patient has been dialyzed in the home safely for 8 months. The biochemical parameters of the first patient remained stable on the regimen and he achieved standard Kt/V urea targets. Treatment-related adverse events were not reported during the follow-up. We combined HHD with intelligent "Internet Plus" real-time remote monitoring and introduced the Internet, especially visualization software, to replace traditional telephone and home visit methods. It is more intuitive and quicker to assist patients in performing home hemodialysis and improve the safety of treatment. CONCLUSIONS: HHD can be performed by selected trained patients in mainland China. Combined with the internet, visualization software, and traditional telephone and home visits, it is intuitive and quick to assist patients in carrying out HHD and improve the safety of treatment. HHD broadens the choices for uremia patients in China.

Inhibition of microRNA-130b Alleviated Podocyte Injury Induced by Puromycin Aminonucleoside in vitro.

OBJECTIVE: To investigate the effect of microRNA-130b (miR-130b) on podocyte injury induced by puromycin aminonucleoside (PAN) and its possible mechanisms. METHODS: The immortalized podocytes (HPC) were treated by 25, 50, or 100 µg/mL PAN, then real-time polymerase chain reaction (PCR) was used to detect the expression of miR-130b. The HPC were transfected with miR-130b inhibitor or normal control (NC) inhibitor, and then the cells were stimulated with 100 µg/mL PAN for 24h. Western blot was used to detect the protein expression of synaptopodin and nephrin. Phalloidin dying was used to detect the changes in the cytoskeleton. Flow cytometry was used to measure podocyte apoptosis. Luciferase reporter gene assays were performed to explore the interaction between miR-130b and PGC1α. RESULTS: PAN significantly upregulated the expression of miR-130b. The western blot showed that inhibition of miR-130b increased the protein expression of synaptopodin and nephrin compared to the negative control inhibitor group. The phalloidin dying showed that inhibition of miR-130b alleviated cytoskeletal remodeling of podocytes induced by PAN. Flow-cytometric analysis showed that apoptosis was decreased after miR-130b silencing. The miR-130b mimic could significantly down-regulate the protein expression of PGC1α, and the dual luciferase reporter assay showed that miR-130b induced a decrease in PGC1α 3'-UTR luciferase activity compared to the control mimic group, but there was no significant difference between the control mimic group and the mut·PGC1α 3'-UTR group. CONCLUSION: miR-130b ameliorates podocyte injury induced by PAN through inhibiting the expression of PGC1α.

A pilot study of thiamin and folic acid in hemodialysis patients with cognitive impairment.

OBJECTIVE: This study aimed to explore the effectiveness of thiamin and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis. METHOD: In the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n = 25, thiamin 90 mg/day combined with folic acid 30 mg/day) or control group (n = 25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety. RESULTS: Patients in treatment group had an increase of the MoCA score from 21.95 ± 3.81 at baseline to 25.68 ± 1.96 at week 96 (p < 0.001, primary outcome), as compared with the MoCA score from 20.69 ± 3.40 to 19.62 ± 3.58 in control group. Thiamin combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (p < 0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (p = 0.048). The proportion of adverse events in treatment group was significantly lower than that in control group. CONCLUSION: Hemodialysis patients with cognitive impairment treated with thiamin and folic acid had a significant improvement in MoCA score.

αKlotho protein has therapeutic activity in contrast-induced acute kidney injury by limiting NLRP3 inflammasome-mediated pyroptosis and promoting autophagy.

Contrast-induced acute kidney injury (CI-AKI) is a main cause of hospital-acquired renal failure. Nevertheless, limited measures have been shown to be effective for the treatment of CI-AKI. Here, we demonstrated that αKlotho, which is highly expressed in kidney, has therapeutic activity in CI-AKI. Our data showed that αKlotho expression levels were decreased both in the kidney and serum of CI-AKI mice. Administration of αKlotho protein protected the kidney and HK-2 cells against contrast-induced injury. Mechanistically, αKlotho reduced contrast-induced renal tubular cells pyroptosis by limiting NLRP3 inflammasome activation. Meanwhile, αKlotho up-regulated autophagy via inhibiting the AKT/mTOR pathway and decreased mitochondrial ROS level. Inhibition of autophagy blunted the suppression effect of αKlotho on NLRP3 inflammasome activation and cell pyroptosis in contrast-treated HK-2 cells. Taken together, our data suggest that αKlotho protein protects against CI-AKI through inhibiting NLRP3 inflammasome-mediated pyroptosis, which is likely by promoting autophagy. αKlotho may be a promising therapeutic strategy for CI-AKI.

Texture Analysis of Native T1 Images as a Novel Method for Noninvasive Assessment of Uremic Cardiomyopathy.

BACKGROUND: Noncontrast cardiac T1 times are increased in dialysis patients which might indicate fibrotic alterations in uremic cardiomyopathy. PURPOSE: To explore the application of the texture analysis (TA) of T1 images in the assessment of myocardial alterations in dialysis patients. STUDY TYPE: Case-control study. POPULATION: A total of 117 subjects, including 22 on hemodialysis, 44 on peritoneal dialysis, and 51 healthy controls. FIELD STRENGTH: A 3 T, steady-state free precession (SSFP) sequence, modified Look-Locker imaging (MOLLI). ASSESSMENT: Two independent, blinded researchers manually delineated endocardial and epicardial borders of the left ventricle (LV) on midventricular T1 maps for TA. STATISTICAL TESTS: Texture feature selection was performed, incorporating reproducibility verification, machine learning, and collinearity analysis. Multivariate linear regressions were performed to examine the independent associations between the selected texture features and left ventricular function in dialysis patients. Texture features' performance in discrimination was evaluated by sensitivity and specificity. Reproducibility was estimated by the intraclass correlation coefficient (ICC). RESULTS: Dialysis patients had greater T1 values than normal (P < 0.05). Five texture features were filtered out through feature selection, and four showed a statistically significant difference between dialysis patients and healthy controls. Among the four features, vertical run-length nonuniformity (VRLN) had the most remarkable difference among the control and dialysis groups (144 ± 40 vs. 257 ± 74, P < 0.05), which overlap was much smaller than Global T1 times (1268 ± 38 vs. 1308 ± 46 msec, P < 0.05). The VRLN values were notably elevated (cutoff = 170) in dialysis patients, with a specificity of 97% and a sensitivity of 88%, compared with T1 times (specificity = 76%, sensitivity = 60%). In dialysis patients, VRLN was significantly and independently associated with left ventricular ejection fraction (P < 0.05), global longitudinal strain (P < 0.05), radial strain (P < 0.05), and circumferential strain (P < 0.05); however, T1 was not. DATA CONCLUSION: The texture features obtained by TA of T1 images and VRLN may be a better parameter for assessing myocardial alterations than T1 times. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy.

The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.Abbreviations: BNIP3: BCL2/adenovirus E1B interacting protein 3; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EGLN2/PHD1: egl-9 family hypoxia-inducible factor 2; HIF1A: hypoxia inducible factor 1, alpha subunit; H-E: hematoxylin and eosin; IL18: interleukin 18; IL1B: interleukin 1 beta; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mRNA: messenger RNA; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family, pyrin domain containing 3; NS: normal saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RNA: ribonucleic acid; SEM: standard error of the mean; siRNA: small interfering RNA; TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin, alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VDAC: voltage-dependent anion channel; WT: wild-type.