Renal Failure最新文献

Purpose: This study aimed to investigate the inhibitory effect of chrysophanol on renal fibrosis and its molecular mechanism.

Methods: Initially, potential targets of chrysophanol were predicted through network pharmacology analysis, and a protein-protein interaction network of these targets was constructed using Venn diagrams and the STRING database. GO enrichment analysis predicted the biological process of chrysophanol in treating renal fibrosis. Subsequently, both in vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) induced CKD mouse model and HK-2 cell model, respectively. In the mouse model, different doses of chrysophanol were administered to assess its renal protective effects through biochemical indicators, histological examination, and immunofluorescence staining. In the cell model, the regulatory effect of chrysophanol on the Trx-1/JNK/Cx43 pathway was evaluated using western blotting and flow cytometry.

Results: Chrysophanol treatment significantly ameliorated renal dysfunction and histopathological damage in the UUO mouse model, accompanied by a reduction in serum oxidative stress markers. Furthermore, chrysophanol markedly upregulated the expression of Trx-1 in renal tissues and inhibited the activation of the JNK/Cx43 signaling pathway. At the cellular level, chrysophanol enhanced the activity of Trx-1 and downregulated the JNK/Cx43 signaling pathway, thereby inhibiting TGF-β induced oxidative stress and cell apoptosis.

Conclusion: This study demonstrated a significant inhibitory effect of chrysophanol on renal fibrosis, mediated by the activation of Trx-1 to inhibit the JNK/Cx43 pathway. These findings provide experimental support for the potential use of chrysophanol as a therapeutic agent for renal fibrosis.

Background: Tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) as a noninvasively measured index of right ventricular-pulmonary artery uncoupling is associated with poor outcomes in heart failure patients. However, the relationship by which the TAPSE/PASP is linked to atrial fibrillation (AF) in peritoneal dialysis (PD) patients is not clear. We aimed to investigate the relationship between the TAPSE/PASP and AF in PD patients.

Methods: This study was divided into two parts. First, we included 329 PD patients. All the subjects provided detailed a medical history, laboratory analysis and transthoracic echocardiography on admission. We evaluated the differences in the TASPE/PASP ratios between the AF and non-AF groups. Second, a total of 121 patients were followed up to compare mortality between the AF and non-AF groups.

Results: Age, BNP, RDW, LA, and septal E/e' were significantly higher, and TAPSE/PASP was significantly lower in patients with AF than in those without AF (p < 0.05). Moreover, the TAPSE/PASP was more pronounced in persistent AF patients. PD patients with AF had a greater risk of mortality (7.2%) than did those without AF (3.8%) after an average follow-up of 12 months. Kaplan-Meier analysis revealed that patients with TAPSE/PASP ratios ≤ 0.715 had a greater risk of mortality than did those with TAPSE/PASP ratios > 0.715.

Conclusions: The results suggested that the TAPSE/PASP was lower in AF patients than in non-AF patients. The TAPSE/PASP may be a useful factor for predicting mortality in AF patients with PD, but large-scale prospective studies are needed for verification.

Fabry disease, a lysosomal storage disease, is an uncommon X-linked recessive genetic disorder stemming from abnormalities in the alpha-galactosidase gene (GLA) that codes human alpha-Galactosidase A (α-Gal A). To date, over 800 GLA mutations have been found to cause Fabry disease (FD). Continued enhancement of the GLA mutation spectrum will contribute to a deeper recognition and underlying mechanisms of FD. In this study, a 27-year-old male proband exhibited a typical phenotype of Fabry disease. Subsequently, family screening for Fabry disease was conducted, and high-throughput sequencing was employed to identify the mutated gene. The three-level structure of the mutated protein was analyzed, and its subcellular localization and enzymatic activity were determined. Apoptosis was assessed in GLA mutant cell lines to confirm the functional effects. As a result, a new mutation, c.777_778del (p. Gly261Leufs*3), in the GLA gene was identified. The mutation caused a frameshift during translation and the premature appearance of a termination codon, which led to a partial deletion of the domain in C-terminal region and altered the protein's tertiary structure. In vitro experiments revealed a significant reduction of the enzymatic activity in mutant cells. The expression was noticeably decreased at the mRNA and protein levels in mutant cell lines. Additionally, the subcellular localization of α-Gal A changed from a homogeneous distribution to punctate aggregation in the cytoplasm. GLA mutant cells exhibited significantly higher levels of apoptosis compared to wild-type cells.

Background: Secondary hyperparathyroidism (SHPT) is a prevalent chronic complication in patients undergoing hemodialysis. Parathyroidectomy (PTX) is crucial for reducing mortality and improving the prognosis in the treatment of refractory hyperparathyroidism. However, it is often associated with a number of postoperative complications such as postoperative hypotension, hyperkalemia, and hungry bone syndrome. A previous study demonstrated that low blood pressure influences the patency of autogenous arteriovenous fistulas (AVF). Few studies have examined AVF dysfunction following PTX. This study aimed to identify and describe the risk variables associated with AVF dysfunction after PTX.

Methods: Cases of AVF dysfunction after PTX between 2015 and 2021 were studied. Four controls were identified for each patient and were matched for sex and age. Biochemical parameters and blood pressure of the patients before and after PTX were recorded. Risk factors for AVF dysfunction after PTX were identified using conditional logistic regression analysis.

Results: Sixteen patients and 64 controls were included in this study. Baseline demographic and laboratory data were compared. Patients in the AVF dysfunction group had lower levels of postoperative calcium than the controls. After surgery, calcium levels decreased more in patients with AVF dysfunction than in the control group. The decrease in systolic blood pressure (ΔSBP) after PTX was greater in the AVF dysfunction group than that in the control group. For each 1 mmHg increment in ΔSBP, the risk of AVF dysfunction after surgery increased by 11.6% (OR = 1.116, 95% CI, 1.005-1.239, p = .040). The likelihood of developing AVF dysfunction after surgery was twelvefold higher in diabetic patients than in non-diabetic patients (OR = 12.506, 95% CI, 1.113-140.492, p = .041). Among patients with ΔSBP > 5.8 mmHg after PTX, the AVF failure rate was significantly greater in patients with diabetes than in those without diabetes. Patients with a history of AVF failure had a nine-fold higher risk of developing AVF dysfunction (OR = 9.143, 95% CI, 1.151-72.627, p = .036). Serum albumin, hemoglobin, ΔiPTH, and age were not independent predictors of AVF dysfunction. The cutoff value for SBP was 5.8 mmHg, as determined by the Youden index of the receiver operating characteristic curve.

Conclusion: Decreased systolic blood pressure (ΔSBP) after PTX, diabetes, and AVF failure history were risk factors for AVF dysfunction following PTX in patients with SHPT. Diabetes patients with ΔSBP > 5.8 mmHg were more prone to AVF dysfunction after PTX.

Anti-human thymocyte globulin-Fresenius (ATG-F) is frequently utilized to achieve successful induction for kidney transplantation recipients. This study aimed to examine the association between the ATG-F dose-to-recipient-weight ratio (ADR) and the risk of developing urinary tract infections (UTIs) following kidney transplantation. Data of kidney transplant recipients who underwent ATG-F-induction peri-operatively in a medical center were retrospectively collected, and the incidence of UTIs during the first postoperative year was also recorded. The risk of UTI associated with ADR was analyzed, and receiver operating characteristic curves were drawn to determine the optimal ADR, followed by Cox regression models. In total, 131 recipients were included, with an UTI incidence of 19.08% and a mean interval of 3.08 months. The optimal ADR was 6.34, involving 41 and 90 patients in the low ADR and high ADR groups, respectively. The UTI-free rate in the low ADR group was significantly higher than that in the high ADR group (p = 0.007). Cox regression analysis indicated that a high ADR independently increased the risk of UTI following kidney transplantation (hazard ratio: 5.306, 95% confidence interval: 1.243-22.660, p = 0.024). There was no significant difference in rejection rate between the high ADR and low ADR groups. In conclusion, a high ADR increased the incidence of early postoperative UTI among kidney transplant recipients.

Background: Body mass index (BMI) is associated with diabetic nephropathy (DN). However, the mediator factors in the BMI-DN effects remain unclear.

Methods: Univariate and multivariate Mendelian randomization (MR) analysis were performed to estimate the association between six lifestyles (moderate to vigorous physical activity levels, years of schooling, BMI, nap during day, number of treatments/medications taken and coffee intake) and DN. MR Egger, Weighted median, Simple mode, and Weighted mode was supplemental methods to Inverse variance weighted. Sensitivity analysis included heterogeneity test, horizontal pleiotropy test, and Leave-One-Out. Additionally, mediation MR was conducted to evaluate the mediating role of lifestyles between BMI and DN. Finally, functional enrichment analysis based on the mediation MR results was performed.

Results: univariate and multivariate Mendelian randomization (MR) analysis were performed to estimate the association between six lifestyles (moderate to vigorous physical activity levels, years of schooling, BMI, nap during day, number of treatments/medications taken and coffee intake) and DN. MR Egger, Weighted median, Simple mode, and Weighted mode was supplemental methods to Inverse variance weighted. Sensitivity analysis included heterogeneity test, horizontal pleiotropy test, and Leave-One-Out. Additionally, mediation MR was conducted to evaluate the mediating role of lifestyles between BMI and DN. Finally, functional enrichment analysis based on the mediation MR results was performed.

Conclusion: our results supported mediation role of vigorous physical activity level and number of treatments/medications in BMI-DN effects.

Chronic disease progression models are available for several highly prevalent conditions. For chronic kidney disease (CKD), the scope of existing progression models is limited to the risk of kidney failure and major cardiovascular (CV) events. The aim of this project was to develop a comprehensive CKD progression model (CKD-PM) that simulates the risk of CKD progression and a broad range of complications in patients with CKD. A series of literature reviews informed the selection of risk factors and identified existing risk equations/algorithms for kidney replacement therapy (KRT), CV events, other CKD-related complications, and mortality. Risk equations and transition probabilities were primarily sourced from publications produced by large US and international CKD registries. A patient-level, state-transition model was developed with health states defined by the Kidney Disease Improving Global Outcomes categories. Model validation was performed by comparing predicted outcomes with observed outcomes in the source cohorts used in model development (internal validation) and other cohorts (external validation). The CKD-PM demonstrated satisfactory modeling properties. Accurate prediction of all-cause and CV mortality was achieved without calibration, while prediction of CV events through CKD-specific equations required implementation of a calibration factor to balance time-dependent versus baseline risk. Predicted annual changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio were acceptable in comparison to external values. A flexible eGFR threshold for KRT equations enabled accurate prediction of these events. This CKD-PM demonstrated reliable modeling properties. Both internal and external validation revealed robust outcomes.

Aim: This study explored the effect and mechanism of MAFF and HDAC6 on renal fibrosis and inflammation in lupus nephritis (LN).

Methods: IL-33 treated renal epithelial cells and MRL/lpr mice were respectively used for in vitro and in vivo experiments. The expressions of HDAC6, MAFF, and KLF5 were measured in cells and renal tissues. Before and after cell transfection, the morphological changes in renal tissues were observed using Hematoxylin and eosin (H&E) and Masson staining. The proteinuria, serum creatinine (SCr), blood urea nitrogen (BUN), and double-stranded DNA (dsDNA) levels were detected by biochemical analysis. The expressions of fibrosis and inflammation related proteins (including α-SMA, Vimentin, IL-1β, IL-6, and TNF-α), p65, and iNOS were also detected. The relationship among MAFF, HDAC6, and KLF5 was determined by chromatin immunoprecipitation and dual luciferase reporter gene assay.

Results: Renal tissues and cell models had elevated expressions of HDAC6 and KLF5, and decreased MAFF expression. HDAC6 suppression or MAFF overexpression led to suppression of proteinuria, SCr, BUN, and dsDNA levels, as well as attenuation of inflammatory infiltration and collagen deposition. HDAC6 can suppress MAFF expression via deacetylation to abolish its suppression of KLF5 expression, thus increasing KLF5 expression. In vivo and in vitro experiments showed the suppressive effect of HDAC6 suppression on renal fibrosis and inflammation can be abolished by KLF5 overexpression.

Conclusion: HDAC6 suppresses MAFF expression via deacetylation to elevate KLF5 expression, which consequently enhances fibrosis and inflammatory response in LN.

Objective: This study aimed to investigate the therapeutic effects of sulforaphane and the role of the Nrf2-Keap1/HO-1/ROS pathway in AngII-induced oxidative stress in podocyte injury.

Methods: Mouse mpc5 podocytes were divided into four groups: control (Con), AngII, AngII + sulforaphane (AngII + SFN), and control + sulforaphane (Con + SFN). Western blotting was used to detect protein expression of Nrf2-Keap1, antioxidant enzyme HO-1, and apoptosis-related proteins. ROS levels were measured using a ROS assay kit, and cell survival and viability were assayed using the CCK-8 kit. Molecular interactions between Nrf2 and sulforaphane were analyzed computationally.

Results: Compared with the Con group, podocytes treated with AngII alone exhibited inhibited proliferation, reduced cell viability, lower Bcl-2 expression, and higher cleaved caspase 3 expression. In the presence of sulforaphane, AngII group showed a mild inhibition on podocyte proliferation but did not induce the aforementioned changes in Bcl-2 and cleaved caspase 3 expression. Similarly, compared to the Con group, AngII treatment alone had lower Nrf2 expression and higher Keap1 expression in podocytes, accompanied by a significant decrease in ROS content. However, in the presence of sulforaphane, AngII failed to induce increases in Nrf2 and a decrease in Keap1 expression, as well as ROS levels. Furthermore, cells treated with sulforaphane exhibited higher HO-1 levels than control cells, and co-incubation with AngII did not alter HO-1 levels. Computational modeling revealed hydrophobic interactions between sulforaphane and the amino acid LYS-462 of Nrf2, as well as hydrogen bonding with amino acid HIS-465. The binding score between sulforaphane and Nrf2 was -4.7.

Conclusion: Sulforaphane alleviated AngII-induced podocyte oxidative stress injury via the Nrf2-Keap1/HO-1/ROS pathway, providing new insights into therapeutic compounds for mitigating chronic kidney disease.

The UK Deceased Donor Kidney Transplant Outcome Prediction (UK-DTOP) Tool, developed using advanced artificial intelligence (AI), significantly enhances the prediction of outcomes for deceased-donor kidney transplants in the UK. This study analyzed data from the UK Transplant Registry (UKTR), including 29,713 transplant cases between 2008 and 2022, to assess the predictive performance of three machine learning models: XGBoost, Random Survival Forest, and Optimal Decision Tree. Among these, XGBoost demonstrated exceptional performance with the highest concordance index of 0.74 and an area under the curve (AUC) consistently above 0.73, indicating robust discriminative ability and calibration. In comparison to the traditional Kidney Donor Risk Index (KDRI), which achieved a lower concordance index of 0.57, the UK-DTOP model marked a significant improvement, underscoring its superior predictive accuracy. The advanced capabilities of the XGBoost model were further highlighted through calibration assessments using the Integrated Brier Score (IBS), showing a score of 0.14, indicative of precise survival probability predictions. Additionally, unsupervised learning via k-means clustering was employed to identify five distinct clusters based on donor and transplant characteristics, uncovering nuanced insights into graft survival outcomes. These clusters were further analyzed using Bayesian Cox regression, which confirmed significant survival outcome variations across the clusters, thereby validating the model's effectiveness in enhancing risk stratification. The UK-DTOP tool offers a comprehensive decision-support system that significantly refines pre-transplant decision-making. The study's findings advocate for the adoption of AI-enhanced tools in healthcare systems to optimize organ matching and transplant success, potentially guiding future developments in global transplant practices.