Natural intestinal metabolite xylitol reduces BRD4 levels to mitigate renal fibrosis.

Renal fibrosis is a typical pathological change from chronic kidney disease (CKD) to end-stage renal failure, which presents significant challenges in prevention and treatment. The progression of renal fibrosis is closely associated with the "gut-kidney axis," therefore, although clinical intervention to modulate the "gut-kidney axis" imbalance associated with renal fibrosis brings hope for its treatment. In this study, we first identified the close relationship between renal fibrosis development and the intestinal microenvironment through fecal microtransplantation and non-absorbable antibiotics experiments. Then, we analyzed the specific connection between the intestinal microenvironment and renal fibrosis using microbiomics and metabolomics, screening for the differential intestinal metabolite. Potential metabolite action targets were initially identified through network simulation of molecular docking and further verified by molecular biology experiment. We used flow cytometry, TUNEL apoptosis staining, immunohistochemistry, and Western blotting to assess renal injury and fibrosis extent, exploring the potential role of gut microbial metabolite in renal fibrosis development. We discovered that CKD-triggered alterations in the intestinal microenvironment exacerbate renal injury and fibrosis. When metabolomic analysis was combined with experiments in vivo, we found that the differential metabolite xylitol delays renal injury and fibrosis development. We further validated this hypothesis at the cellular level. Mechanically, bromodomain-containing protein 4 (BRD4) protein exhibits strong binding with xylitol, and xylitol alleviates renal fibrosis by inhibiting BRD4 and its downstream transforming growth factor-ß (TGF-ß) pathway. In summary, our findings suggest that the natural intestinal metabolite xylitol mitigates renal fibrosis by inhibiting the BRD4-regulated TGF-ß pathway.

Plasma exchange plus glucocorticoids in the treatment of immune checkpoint inhibitor-induced myocarditis: A case series and review.

Immune checkpoint inhibitors (ICIs), including antiprogrammed cell-death (PD)-1/anti-PD-ligand (PDL-1) monoclonal antibodies, are effective at improving the prognosis of patients with cancer. Among immune-related adverse events, myocarditis associated with anti-PD-1/anti-PD-L1 antibodies is rare but lacks effective treatment and mortality is very high. In this study, the authors extracted data from the previous 8 years from electronic medical records housed in the hospital information system to identify patients hospitalized with myocarditis putatively caused by anti-PD-1/anti-PD-L1 tumor therapy. Clinical data from these patients are reported. Four patients who developed myocarditis after undergoing treatment with anti-PD-1/anti-PD-L1 antibodies for malignant tumors, all of whom responded favorably to therapy consisting of plasma exchange and glucocorticoids for myocarditis, and all patients improved and were discharged from hospital. Plasma exchange plus systemic glucocorticoids may be effective for treating anti-PD-1/anti-PD-L1 antibody-induced myocarditis in patients with cancer.

Liberation of daidzein by gut microbial ß-galactosidase suppresses acetaminophen-induced hepatotoxicity in mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI). The impact of the gut microbiota and associated metabolites on APAP and liver function remains unclear. We show that APAP disturbance is associated with a distinct gut microbial community, with notable decreases in Lactobacillus vaginalis. Mice receiving L. vaginalis showed resistance to APAP hepatotoxicity due to the liberation of the isoflavone daidzein from the diet by bacterial ß-galactosidase. The hepatoprotective effects of L. vaginalis in APAP-exposed germ-free mice were abolished with a ß-galactosidase inhibitor. Similarly, ß-galactosidase-deficient L. vaginalis produced poorer outcomes in APAP-treated mice than the wild-type strain, but these differences were overcome with daidzein administration. Mechanistically, daidzein prevented ferroptotic death, which was linked to decreased expression of farnesyl diphosphate synthase (Fdps) that activated a key ferroptosis pathway involving AKT-GSK3ß-Nrf2. Thus, liberation of daidzein by L. vaginalis ß-galactosidase inhibits Fdps-mediated hepatocyte ferroptosis, providing promising therapeutic approaches for DILI.

COMMD5 is involved in the mechanisms of hypotension after parathyroidectomy in patients receiving hemodialysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common complication of end-stage renal disease. Parathyroidectomy (PTx) is often employed for treatment of severe SHPT. However, PTx may cause hypotension via unknown mechanisms. COMM domain-containing protein 5 (COMMD5) in the parathyroid glands has been linked to blood pressure regulation of spontaneously hypertensive rats. OBJECTIVE: To explore the relationship between COMMD5 levels and reduced BP after PTx in patients receiving hemodialysis (HD). METHODS AND RESULTS: (1) The study cohort included 31 patients receiving HD who underwent PTx. Serum COMMD5 levels were higher post-PTx vs. pre-PTx. (2) Sprague-Dawley rats (n = 22) were assigned to a 5/6 nephrectomy group or sham surgery group, vascular rings of the thoracic aorta from rats with CKD were incubated with COMMD5, and changes in vascular tension were compared. COMMD5 inhibited vasoconstriction of vascular rings with intact endothelium, but had no effect on vascular rings without the endothelium. (3) Human umbilical vein endothelial cells were stimulated with COMMD5 or small interfering RNA (siRNA). The expression levels of atrial natriuretic peptide (ANP) and endothelial nitric oxide synthase (eNOS) were up-regulated and down-regulated, respectively. CONCLUSIONS: Serum COMMD5 levels were increased after PTx in SHPT patients. COMMD5 promoted high expression of ANP and eNOS in endothelial cells, leading to vasodilation and resulting in hypotension.

CaMKII may regulate renal tubular epithelial cell apoptosis through YAP/NFAT2 in acute kidney injury mice.

AIM: Renal tubular epithelial cell (RTEC) apoptosis is important in acute kidney injury (AKI). Calcium/calmodulin-dependent protein kinase II (CaMKII) plays an important role in cell apoptosis, but its potential role in AKI remains unknown. METHODS: Using co-immunoprecipitation, immunofluorescence, immunohistochemistry, western blotting, flow cytometry, and cell transfection, this study aimed to verify whether CaMKII is involved in RTEC apoptosis and to explore the underlying mechanism. RESULTS: We found that CaMKII was involved in RTEC apoptosis. In adriamycin-induced AKI mice, serum creatinine levels, cell apoptosis, CaMKII activity, and nuclear factor of activated T cells 2 (NFAT2) levels increased, whereas nuclear Yes-associated protein (YAP) expression decreased; inhibition of CaMKII activity reversed these changes. Phosphorylated CaMKII could bind to phosphorylated YAP in the cytoplasm and block it from entering the nucleus, thereby failing to inhibit NFAT2-mediated cell apoptosis. Sequestrated phosphorylated YAP in the RTEC cytoplasm was finally degraded by ubiquitination. CONCLUSION: CaMKII may regulate RTEC apoptosis through YAP/NFAT2 in AKI mice. CaMKII may be a potent molecular target for AKI treatment.

Cardio-selective versus non-selective ß-blockers for cardiovascular events and mortality in long-term dialysis patients: A systematic review and meta-analysis.

BACKGROUND: Trials in patients receiving dialysis have demonstrated that ß-blockers reduce all-cause mortality and cardiovascular events. However, differences still exist within-class comparative effectiveness studies of the therapeutic benefits of ß-blockers in dialysis patients. OBJECTIVE: The purpose of this systematic review is to examine whether cardiovascular events and all-cause mortality differed between dialysis patients receiving cardio-selective and non-selective agents. METHODS: A comprehensive search of relevant articles from the PubMed, EMBASE, Cochrane Central Register and ClinicalTrials.gov was performed up to September 4, 2022, we included adults receiving ß-blockers to evaluate the effects of cardio-selective versus non-selective agents on mortality and cardiovascular events in the dialysis population. Hazard ratios (HRs) and 95% confidence intervals (CIs) were examined for the negative outcomes of cardiovascular events and death for any reason. The risk of bias in randomized controlled trials (RCTs) was assessed using Cochrane's risk of bias tool and the risk of bias in observational studies was assessed using a table designed according to the ROBINS-I tool, the evidence grade was assessed using the GRADE guideline. For all-cause mortality and cardiovascular events, the RevMan software (version 5.3) was used to calculate pooled HRs with 95% CI. The heterogeneity (I2) in statistics was used to examine the degree of heterogeneity among studies. RESULTS: Four observational studies, including 58, 652 long-term dialysis patients, were included in the meta-analysis. Compared to dialysis patients who took non-selective ß-blockers, who took cardio-selective ß-blockers was probably associated with fewer cardiovascular events (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.81, 0.89, heterogeneity [I2] = 0%, three trials, 52,077 participants, moderate-quality evidence) and may have lower all-cause mortality (HR = 0.83, 95% CI = 0.69, 0.99, I2 = 91%, four trials, 54,115 participants, low-quality evidence). CONCLUSIONS: This systematic review showed that cardio-selective ß-blockers are probably associated with fewer cardiovascular events and may have lower all-cause mortality in long-term dialysis patients than non-selective ß-blockers. The present study results need to be replicated using randomized controlled trials with longer observation durations.

Research output of artificial intelligence in arrhythmia from 2004 to 2021: a bibliometric analysis.

Background: With the advancement in machine learning (ML) and artificial neural networks as well as the development of portable electrocardiogram devices, artificial intelligence (AI) has been increasing in popularity over the years. In this study, we aimed to provide an overview of the research regarding the utilization of AI techniques to improve the diagnosis of arrhythmia. Methods: We extracted data published 2004 to 2021 from Web of Science database. The online analytic platform, Literature Metrology (http://bibliometric.com), was used to analyze publication trends, including information about journals, authors, institutions, collaborations between countries, citations, and keywords. Results: Keywords, such as deep learning, electrocardiogram (ECG), and convolutional neural network, have been increasing in frequency over the years. The analysis outcomes demonstrated that topics associated with AI, robotic prosthesis, and big data analysis for arrhythmia have become increasingly popular since 2016. Our study also found that atrial fibrillation (AF) and ventricular arrhythmia were the two ECG signal sharing the most interest. Conclusions: The utility of deep learning in diagnostics and the prognostication of arrhythmia has been gaining traction over the years, covering areas from electrocardiogram detection to atrial arrhythmogenesis model construction. Our study revealed the trend of topics from 2004 to 2021, which may help researchers to monitor future trends.

Long non-coding RNA TUG1 sponges microRNA-9 to protect podocytes from high glucose-induced apoptosis and mitochondrial dysfunction via SIRT1 upregulation.

Podocyte apoptosis and mitochondrial dysfunction serve a major role in diabetic nephropathy progression. The present study revealed a molecular mechanism regulating podocyte apoptosis and mitochondrial dysfunction. In vitro models were established using conditionally immortalized mouse podocyte clonal cells treated with high glucose (HG). Reverse quantitative-transcription PCR were used to detect gene expression, western blotting and immunofluorescence were used to detect protein expression, Cell Counting Kit-8 was used to detect cell viability and flow cytometry was used to detect cell apoptosis. HG treatment in the mouse podocyte clonal cells downregulated taurine-upregulated gene 1 (TUG1) expression and decreased viability in a dose-dependent manner. In addition, TUG1 knockdown (KD) increased HG-induced apoptosis, while TUG1 overexpression (OE) reduced HG-induced apoptosis in podocytes. HG-induced mitochondrial dysfunction was identified in podocytes, with increased reactive oxygen species levels, decreased complex I/III activity and decreased basal/maximal oxygen consumption rate. TUG1 KD worsened HG-induced mitochondrial dysfunction, and TUG1 OE reversed these effects. At the molecular level, TUG1 was revealed to promote sirtuin 1 (SIRT1) expression by sponging microRNA (miR)-9, and SIRT1 OE reversed the HG-induced apoptosis and mitochondrial dysfunction increased by TUG1 KD. The present data indicated that downregulation of TUG1 induced by HG was associated with HG-induced apoptosis and mitochondrial dysfunction in podocytes, and that TUG1 protected HG-induced podocytes by promoting SIRT1 expression via miR-9 inhibition.

Efficacy of medium cut-off dialyzers and comparison with high-flux dialyzers in patients on maintenance hemodialysis: A systematic review and meta-analysis.

Medium cut-off (MCO) dialyzers were designed to provide better clearance of uremic toxins. We conducted a meta-analysis comparing MCO with high-flux (HF) dialyzers for the effect on uremic toxins in maintenance hemodialysis (HD) patients. Five databases were systematically searched for relevant studies and nine studies were identified finally. Reduction ratio (RR) of urea, urea, creatinine, ß2-macroglobulin (ß2-MG), kappa free light chain (κFLC), and lambda FLC (λFLC) levels were not significantly different between MCO and HF dialyzers. But RR of ß2-MG, κFLC, and λFLC were greater for MCO than HF dialyzers. MCO dialyzers could better reduce tumor necrosis factor-α (TNF-α) levels. Subgroup analysis stratified by study design indicated that in randomized controlled trial (RCT) studies, albumin levels was lower in MCO than HF dialyzers group, but the two dialyzers treatments were equivalent in non-RCT subgroup. Compared with HF dialyzers, MCO dialyzers provided higher middle-molecules uremic toxins clearance and obviously reduced TNF-α levels.

Pharmacokinetics and Pharmacodynamics of Sacubitril/Valsartan in Maintenance Hemodialysis Patients with Heart Failure.

BACKGROUND: Heart failure (HF) is one of the main comorbidities in patients receiving maintenance hemodialysis (HD). Sacubitril/valsartan (SAC/VAL) is widely used in HF patients with reduced ejection fraction (HFrEF) or HF mid-range ejection fraction (HFmrEF). However, the pharmacokinetic (PK) and pharmacodynamic properties of SAC/VAL in HD patients with HF remain uncertain. OBJECTIVES: This study aimed to analyze the efficacy and PK properties of SAC/VAL in HD patients with HFrEF or HFmrEF. METHODS: HD patients with HFrEF or HFmrEF were treated with SAC/VAL 50 or 100 mg twice a day (BID) and the concentrations of valsartan and LBQ657 (active metabolite of SAC) were determined by high-performance liquid chromatography-tandem mass spectrometry during HD and on the days between HD sessions (interval days). N-terminal-pro B-type natriuretic peptide and high-sensitivity troponin T were measured, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography. RESULTS: The mean maximum plasma concentrations (Cmax) of LBQ657 and VAL on the interval days were 15.46 ± 6.01 and 2.57 ± 1.23 mg/L, respectively. Compared with previous values in patients with severe renal impairment and healthy volunteers, these levels both remained within the safe concentration ranges during treatment with SAC/VAL 100 mg BID. Moreover, SAC/VAL significantly improved LVEF in HD patients with HFrEF or HFmrEF (p < 0.05). CONCLUSIONS: HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.

Association between Cardiac Outcomes and Indoxyl Sulfate Levels in Hemodialysis Patients: A Cross-Sectional Study.

OBJECTIVE: Indoxyl sulfate (IS) is a protein-bound uremic toxin that is associated with cardiovascular events and mortality in hemodialysis (HD) patients. However, the factors affecting the levels of IS are currently unclear. This study aimed to investigate the factors influencing serum IS concentrations in HD patients. METHODS: We included 100 HD patients from Guangdong Provincial People's Hospital. Baseline characteristics, including sex, age, clinical features, duration of HD, echocardiography findings, electrocardiogram results, and biochemical indicators, were collected and analyzed in relation to serum total-form IS levels. RESULTS: Among all 100 patients, serum IS levels were significantly higher in patients aged ≥60 years, males, and patients with mitral regurgitation and inadequate dialysis. Among patients aged <60 years, IS levels were significantly higher among patients with mitral regurgitation compared with those without. Furthermore, multiple linear regression analysis identified sex, age, ventricular septal thickness, and mitral regurgitation as factors independently associated with serum IS (STDß = -0.475, 0.162, -0.153, 0.142, and 0.136, respectively; all p < 0.05) adjusted for body mass index, smoking, and fasting plasma glucose. CONCLUSIONS: Male sex, age ≥60 years, ventricular septal thickness, and mitral regurgitation are factors associated with high total serum IS concentrations in Chinese HD patients. Elevated IS levels may play a role in the process of mitral regurgitation in HD patients <60 years of age.

Comparison of 6 equations for estimating glomerular filtration rate in a Chinese benign hypertensive nephrosclerosis population.

ABSTRACT: Equations to estimate glomerular filtration rate (eGFR) are useful for monitoring tje renal status of benign hypertensive nephrosclerosis (BHN). This study aimed to compare the applicability of 6 equations (Cockcroft-Gault [CG] adjusted for body surface area, original modification of diet in renal disease [MDRD], American abbreviated MDRD, Chinese modified MDRD, Chinese abbreviated MDRD, and Chronic Kidney Disease Epidemiology [CKD-EPI]) to estimate GFR in a Chinese BHN population. A total of 179 patients diagnosed with BHN were enrolled. The GFR estimated by each equation was compared to the reference GFR (rGFR) measured using the dual plasma sampling technetium-labeled diethylenetriaminepentaacetic acid method. The Chinese modified and Chinese abbreviated MDRD equations overestimated the rGFR, while the CG, CG adjusted for body surface area, original MDRD, American abbreviated MDRD, and CKD-EPI equations underestimated the rGFR. The difference in performance between estimated GFR (eGFR) based on the American abbreviated MDRD equation and the rGFR was not statistically significant (P = .191), while differences in the others were statistically significant (P < .05). Furthermore, the advantages in deviation, absolute deviation, deviation degree, precision, and accuracy were also significantly different from those of the other equations. Our findings suggest that eGFR based on the American abbreviated MDRD equation is suitable for the Chinese BHN population.

GAP-43 ameliorates Podocyte injury by decreasing nuclear NFATc1 expression.

Podocyte injury is sufficient to cause glomerulosclerosis and proteinuria, eventually leading to kidney failure. Previous studies found that podocytes and neurons had similar biological characteristics. Growth-associated protein-43 (GAP-43) is a growth cone protein in neurons, and a marker of axonal and synaptic growth. However, it is not known whether GAP-43 is expressed in podocytes. Compared with normal glomerular podocytes, GAP-43 was significantly reduced in patients with glomerular diseases. GAP-43 also significantly reduced in lipopolysaccharide (LPS)-treated podocytes. We found that the decreased expression of nephrin, the cell marker of the podocyte, was significantly recovered with GAP-43 overexpression. In contrast, the migration ability in LPS-treated podocyte was reduction after GAP-43 overexpressing. Moreover, overexpression of GAP-43 attenuated podocyte apoptosis by up-regulating the ratio of Bcl-2/Bax with LPS treatment. Finally, Plaue and Rcan1 which are downstream target gene of NFATc1 decreased with overexpression of GAP-43 podocytes. We concluded that GAP-43 attenuated podocyte injury by inhibiting calcineurin/NFATc1 signaling. The findings may provide a promising treatment for podocyte injury-related diseases.

PPBP as a marker of diabetic nephropathy podocyte injury via Bioinformatics Analysis.

Diabetic nephropathy (DN) is a type of kidney injuries associated with diabetes mellitus and the prevalence of DN has increased dramatically. However, DN still pose problems in therapy, and prognosis. Identifying new DN biomarkers would be helpful in reducing morbidity and mortality from DN and developing novel preventive approaches. In the study, from GSE36336 dataset with DN glomeruli samples, we screened for 238 differentially expressed genes. Enrichment analysis were performed to find out biological function and diseases of DEGs. Next, depended on protein-protein interaction network, We identified top 10 hub genes (Serpine1, Cxcl10, Cfd, Ppbp, Retn, Socs2, Ccr5, Mmp8, Pf4, Cxcl9) may played potential roles in DN. Meanwhile, transcriptome sequencing on podocyte were performed to reconfirm the reliability of Ppbp. To verify the efficiency of the selected genes as biomarkers, several experiments like qRT-PCR, renal histologic analysis and immunofluorescence were conducted to validate. Our results showed that PPBP have the potential to become a novel biomarker for DN podocyte injury.

Thromboxane A2 is involved in the development of hypertension in chronic kidney disease rats.

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances，and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease-A Systematic Review and Meta-Analysis.

Background: To evaluate whether metformin use assuredly alters overall all-cause death in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods: Pubmed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to Feb. 29, 2020 with no language restriction. All related articles comparing all-cause death of T2DM and CKD patients after metformin use (monotherapy or combination) versus non-metformin treatment were identified. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using random-effects models regardless of the heterogeneity quantified by Cochrane χ2 and I2 statistics. Results: Totally 13 studies (9 cohort studies [CSs], 3 subanalyses or post-hoc analyses of randomized controlled trials [RCTs], and 1 nested case-control article) involving 303,540 patients were included. Metformin-based treatments relative to any other measure displayed significantly lower risks of all-cause mortality (Pooled RRs 0.71, 95%CI 0.61 to 0.84; I2 = 79.0%) and cardiovascular events (Pooled RRs 0.76, 95%CI 0.60 to 0.97; I2 = 87.0%) in CKD patients at stage G1-3, with substantial heterogeneity. Metformin use was not significantly related with these end points in advanced CKD patients. Conclusions: Metformin use is connected with significantly less risks of all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate CKD. However, RCTs with large sample sizes are warranted in the future to assess whether these key benefits extend to later stages of CKD by dose adjustment.

Effects of Carvedilol on Cardiovascular Events and Mortality in Hemodialysis Patients, A Systematic Review and Meta-Analysis.

Carvedilol, the third generation of vasodilators; serves as the blocker of non-selective beta-adrenergic receptor and alpha1 adrenergic receptor. It could protect the cardiovascular system of patients receiving dialysis treatment. However, current clinical trials discussing the therapeutic benefit of carvedilol on patients receiving dialysis treatment remain inconsistent. Consequently, we decided to perform a meta-analysis to evaluate the clinical efficacy of carvedilol on patients receiving dialysis treatment. A search was conducted using EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Wanfang database, Chinese National Knowledge Infrastructure (CNKI), and VIP information database up to February 2020. We research publications (include English and Chinese language) that discuss the effects of carvedilol on cardiovascular events, all-cause mortality, hospitalizations or left ventricular ejection fraction (LVEF) in dialysis population. Our analysis included 4 randomized control trials and 2 observational studies. We discussed the therapeutical effects of carvedilol on all-cause mortality, cardiovascular events, hospitalizations, and LVEF of patients receiving dialysis treatment. Totally, this analysis reported 2998 hemodialysis (HD) patients. We found a significant association between carvedilol and reduced incidence of all-cause mortality, cardiovascular events and hospitalizations in HD patients. In addition, carvedilol significantly improves LVEF (n = 241; WMD = 6.95; 95% CI, 0.54 to 13.36; I2 = 90%) in HD population. Our systematic review and meta-analysis demonstrates that carvedilol is associated with a reduced incidence of cardiovascular events, all-cause mortality and hospitalizations in patients on HD. Besides; carvedilol significantly improves LVEF in HD population. Nevertheless, high-quality and well-powered evidence is still needed, so as to further confirm the impacts of carvedilol on HD patients.

The Krüppel-like factor 15-NFATc1 axis ameliorates podocyte injury: a novel rationale for using glucocorticoids in proteinuria diseases.

Podocyte injury and loss contribute to proteinuria, glomerulosclerosis and eventually kidney failure. Recent studies have demonstrated that the loss of Kruppel-like factor 15 (KLF15) in podocytes increases the susceptibility to injury; however, the mechanism underlying the protective effects on podocyte injury remains incompletely understood. Herein, we showed that KLF15 ameliorates podocyte injury through suppressing NFAT signaling and the salutary effects of the synthetic glucocorticoid dexamethasone in podocyte were partially mediated by the KLF15-NFATc1 axis. We found that KLF15 was significantly reduced in glomerular cells of proteinuric patients and in ADR-, LPS- or HG-treated podocyets in vitro. Overexpression of KLF15 attenuated podocyte apoptosis induced by ADR, LPS or HG and resulted in decreased expression of pro-apoptotic Bax and increased expression of anti-apoptotic Bcl-2. Conversely, the flow cytometry analysis and TUNEl assay demonstrated that loss of KLF15 accelerated podocyte apoptosis and we further found that 11R-VIVIT, a specific NFAT inhibitor, and NFATc1-siRNA rescued KLF15-deficient induced podocyte apoptosis. Meanwhile, Western blot and RT-qPCR showed that the expression of NFATc1 was up-regulated in KLF15 silenced podocytes and reduced in KLF15 overexpressed podocytes. Mechanistically, ChIP analysis showed that KLF15 bound to the NFATc1 promoter region -1984 to -1861base pairs upstream of the transcription start site and the binding amount was decreased after treatment with LPS. The dual-luciferase reporter assay indicated that NFATc1 was a direct target of KLF15. In addition, we found that in vitro treatment with dexamethasone induced a decrease of NFATc1 expression in podocytes and was abrogated by knockdown of KLF15. Hence, our results identify the critical role of the KLF15-NFATc1 axis in podocyte injury and loss, which may be involved in mediating the salutary effects of dexamethasone in podocytes.

Treatment of Uremic Tumoral Calcinosis in Maintenance Hemodialysis Patients.

BACKGROUND/AIMS: Uremic tumoral calcinosis (UTC) is a rare disease with metastatic tissue calcification in maintenance hemodialysis (HD) patients. However, limited data are available on the treatment of UTC in HD patients. This article mainly discusses the diagnostic findings and efficacy of treatment on HD patients with UTC. METHODS: A retrospective analysis was conducted based on the data of 13 cases of UTC, including their clinical features, biochemical indicators, imaging findings, diagnosis, therapeutic methods, and follow-up results. Parathyroidectomy (PTX) or drug treatment was determined based on intact parathyroid hormone (iPTH) levels and clinical symptoms. RESULTS: All 13 patients were diagnosed as UTC definitely by imaging examination. The predominant areas involved were the buttocks (4 cases, 30.77%), shoulders (4 cases, 30.77%), and elbows (3 cases, 23.08%). Based on the levels of iPTH, cases were categorized into 2 different groups: PTX treatment group was associated with high levels of iPTH, while drug treatment group (lanthanum carbonate or sevelamer with sodium thiosulfate) was associated with lower iPTH levels. After PTX treatment, there was a significant decrease in serum iPTH, calcium (Ca), phosphate (P), and alkaline phosphatase levels (p < 0.05). In drug treatment group, the serum p levels were decreased significantly, along with a finding that hemoglobin levels were increased (p < 0.05). All the UTC had lessened or even disappeared after 4-6 months treatment. CONCLUSIONS: Although most UTC patients have an increased iPTH, a small number had lower iPTH levels. Based on iPTH levels and clinical symptoms, the patients were treated with PTX or drug therapy. With proper treatment, UTC disappeared without the need for surgery to remove calcinosis tissue.