Development and validation of a novel nomogram model for predicting delayed graft function in deceased donor kidney transplantation based on pre-transplant biopsies.

BACKGROUND: Delayed graft function (DGF) is an important complication after kidney transplantation surgery. The present study aimed to develop and validate a nomogram for preoperative prediction of DGF on the basis of clinical and histological risk factors. METHODS: The prediction model was constructed in a development cohort comprising 492 kidney transplant recipients from May 2018 to December 2019. Data regarding donor and recipient characteristics, pre-transplantation biopsy results, and machine perfusion parameters were collected, and univariate analysis was performed. The least absolute shrinkage and selection operator regression model was used for variable selection. The prediction model was developed by multivariate logistic regression analysis and presented as a nomogram. An external validation cohort comprising 105 transplantation cases from January 2020 to April 2020 was included in the analysis. RESULTS: 266 donors were included in the development cohort, 458 kidneys (93.1%) were preserved by hypothermic machine perfusion (HMP), 96 (19.51%) of 492 recipients developed DGF. Twenty-eight variables measured before transplantation surgery were included in the LASSO regression model. The nomogram consisted of 12 variables from donor characteristics, pre-transplantation biopsy results and machine perfusion parameters. Internal and external validation showed good discrimination and calibration of the nomogram, with Area Under Curve (AUC) 0.83 (95%CI, 0.78-0.88) and 0.87 (95%CI, 0.80-0.94). Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: A DGF predicting nomogram was developed that incorporated donor characteristics, pre-transplantation biopsy results, and machine perfusion parameters. This nomogram can be conveniently used for preoperative individualized prediction of DGF in kidney transplant recipients.

Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.

Mitochondrial dysfunction is recognized as a pivotal contributor to the pathogenesis of renal ischemia-reperfusion (IR) injury. Mitophagy, the process responsible for removing damaged protein aggregates, stands as a critical mechanism safeguarding cells against IR injury. Currently, the role of deubiquitination in regulating mitophagy still needs to be completely elucidated. This study aimed to evaluate the impact of ubiquitin-specific peptidase 14 (Usp14), a deubiquitinase, in IR injury by influencing mitophagy. Utilizing a murine model of renal IR injury, Usp14 silencing was found to ameliorate kidney injury, leading to decreased levels of serum creatinine and blood urea nitrogen, alongside diminished oxidative stress and inflammation. In renal epithelial cells subjected to hypoxia/reoxygenation (H/R), Usp14 knockdown increased cell viability and reduced apoptosis. Further mechanistic studies revealed that Usp14 interacted with and deubiquitinated transcription factor AP-2 alpha (Tfap2a), thereby suppressing its downstream target gene, TANK binding kinase 1 (Tbk1), to influence mitophagy. Tfap2a overexpression or Tbk1 inhibition reversed the protective effects of Usp14 silencing on renal tubular cell injury and its facilitation of mitophagy. In summary, our study demonstrated the renoprotective role of Usp14 knockdown in mitigating renal IR injury by promoting Tfap2a-mediated Tbk1 upregulation and mitophagy. These findings advocate for exploring Usp14 inhibition as a promising therapeutic avenue for mitigating IR injury, primarily by enhancing the clearance of damaged mitochondria through augmented mitophagy.

The causal effect of triglyceride and high blood pressure on IgA nephropathy: a Mendelian randomization study.

Background: It has been reported that high blood pressure (HBP) and triglyceride (TG) are considered risk factors in immunoglobulin A nephropathy (IgAN). This study aimed to explore the causalities between HBP and TG, and IgAN on the basis of Mendelian randomization (MR) analysis. Methods: Firstly, the genome-wide association study (GWAS) summary data of IgAN (GCST90018866) and two exposure factors, TG (ukb-d-30870_raw) and HBP (ukb-a-437), were sourced from the GWAS Catalog and Integrative Epidemiology Unit (IEU) OpenGWAS databases, respectively. In this study, five methods were utilized to perform MR analysis after picking out single nucleotide polymorphisms (SNPs) as instrumental variables, including MR-Egger, weighted median, simple mode, weighted mode, and inverse variance weighted (IVW), followed by the sensitivity analysis containing the heterogeneity, horizontal pleiotropy test and leave-one-out (LOO) analysis. Finally, the enrichment analysis and interaction network construction of genes corresponding to SNPs of HBP and TG were performed. Results: The univariate MR results revealed that HBP and TG regarded as risk factors were causally related to IgAN [TG: p = 0.046, odds ratio (OR) = 1.065, 95% confidence interval (CI) = 1.001-1.133; HBP: p = 7.09 × 10-7, OR = 1.970, 95% CI = 1.507-2.575] based on random-effect IVM method, of which TG had a weaker impact. The reliability of these univariate MR results was certified by the sensitivity analysis, in which there was no horizontal pleiotropy and exaggerated influence of each SNP. Furthermore, HBP was markedly causally related to IgAN (p = 0.000512) with the help of multivariate MR analysis, rather than TG (p = 0.332). Therefore, when HBP and TG occur simultaneously, HBP is a direct influencing factor on IgAN. Ultimately, a total of 208 and 153 genes separately corresponding to SNPs of TG and HBP were included in enrichment analysis, and thereinto, genes relevant to TG were mainly enriched in lipid homeostasis and cholesterol metabolism, while genes concerned with HBP played their roles in regulation of cell growth, aldosterone synthesis and secretion and so forth. Conclusion: TG and HBP as risk factors were causally connected with IgAN, of which HBP was strongly related to the onset of IgAN, providing more reliable evidence for further exploring the relationship between TG and HBP and IgAN.

Defining the biogeographical map and potential bacterial translocation of microbiome in human 'surface organs'.

The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.

Single-cell sequencing reveals the evolution of immune molecules across multiple vertebrate species.

INTRODUCTION: Both innate and adaptive immune system undergo evolution from low to high vertebrates. Due to the limitation of conventional approaches in identifying broader spectrum of immune cells and molecules from various vertebrates, it remains unclear how immune molecules evolve among vertebrates. OBJECTIVES: Here, we utilized carry out comparative transcriptome analysis in various immune cells across seven vertebrate species. METHODS: Single-cell RNA sequencing (scRNA-seq). RESULTS: We uncovered both conserved and species-specific profiling of gene expression in innate and adaptive immunity. Macrophages exhibited highly-diversified genes and developed sophisticated molecular signaling networks along with evolution, indicating effective and versatile functions in higher species. In contrast, B cells conservatively evolved with less differentially-expressed genes in analyzed species. Interestingly, T cells represented a dominant immune cell populations in all species and unique T cell populations were identified in zebrafish and pig. We also revealed compensatory TCR cascade components utilized by different species. Inter-species comparison of core gene programs demonstrated mouse species has the highest similarity in immune transcriptomes to human. CONCLUSIONS: Therefore, our comparative study reveals gene transcription characteristics across multiple vertebrate species during the evolution of immune system, providing insights for species-specific immunity as well as the translation of animal studies to human physiology and disease.

HLA B eplet mismatches in the context of delayed graft function and low tacrolimus trough levels are risk factors influencing the generation of de novo donor-specific antibodies and acute rejection in the early stage after kidney transplantation.

BACKGROUND: De novo donor-specific antibody (dnDSA) generation and acute rejection (AR) are the main factors affecting long-term graft survival. This study aims to investigate human leukocyte antigen (HLA) eplet mismatching (MM), delayed graft function (DGF), and tacrolimus (TAC) trough levels on the occurrence of dnDSA and AR in the early stages after kidney transplantation (KT). METHODS: This retrospective study included 526 cases of deceased donation KT. The effects of DGF, HLA eplet MM, and TAC trough levels on dnDSA and AR occurrence were analyzed with logistic regression analysis. RESULTS: Multivariate logistic regression analysis showed the independent risk factor of dnDSA generation was HLA B eplet MM (OR: 1.201, 95% CI: 1.007-1.431, P = 0.041). The independent risk factors of AR occurrence include DGF (OR: 4.045, 95% CI: 1.047-15.626, P = 0.043), HLA B eplet MM (OR: 1.090, 95% CI: 1.000-1.187, P = 0.050), and TAC trough levels at 12 months (OR: 0.750, 95% CI: 565-0.997, P = 0.048). HLA B eplet MM combined with DGF and TAC trough levels at 12 months increased the predictive value of dnDSA (AUC 0.735) and AR (AUC 0.730) occurrence. HLA B eplet MM > 9 and TAC trough levels below 5.95 ng/mL at 12 months could increase the risk of early AR occurrence. CONCLUSIONS: HLA B eplet MM, DGF, and TAC trough levels at 12 months after KT could affect the occurrence of dnDSA and AR in the early stage of KT.

Neutrophil Membrane-Inspired Nanorobots Act as Antioxidants Ameliorate Ischemia Reperfusion-Induced Acute Kidney Injury.

Ischemia/reperfusion (I/R) injury causes excessive oxidative events and initiates destructive inflammatory responses, and it is an important promoter to the pathology of various pathema states. Ferroptosis is an iron-dependent type of nonapoptotic cell death accompanied by the accumulation of membrane lipid peroxide and consumption of polyunsaturated fatty acid, and it plays a key role in I/R injury diseases. Moreover, the excessive production of inflammatory cytokines contributes to the development of acute kidney injury. Here, we reported neutrophil membrane-coated copper-based nanoparticles (N-Cu5.4O@DFO NPs) for I/R kidney injury treatment. The highly biocompatible and stable N-Cu5.4O@DFO NPs showed excellent antioxidant and iron ion scavenging abilities in vitro. Our finding showed that the N-Cu5.4O@DFO NPs strategy could significantly accumulate in the inflammatory kidney, reduce oxidative damage events and inflammatory response, and finally achieve synergistic therapy against renal I/R injury. This work promotes the development of nanoantioxidant agents with multiple antioxidant properties for the therapy of other I/R injury diseases.

Cellular delivery of relaxin-2 mRNA as a potential treatment for kidney fibrosis.

Renal fibrosis is a pathological feature of chronic kidney disease and its progression correlates with kidney function impairment. Since there are currently no specific therapies for renal fibrosis, we explored whether inducing local production of the anti-fibrotic molecule relaxin-2 in kidney cells has potential as a strategy for suppressing the development of renal fibrosis. Our study examined whether delivery of relaxin-2 mRNA to kidney cells in vitro and in vivo could inhibit mechanisms leading to renal fibrosis. Transfecting relaxin-2 mRNA into cultured kidney cells inhibited fibrotic responses to TGF-ß1 in an autocrine or paracrine manner by reducing fibrotic gene expression in kidney tubules, and reducing proliferation in kidney fibroblasts and mesangial cells. Similarly, cubosomes assisted delivery of relaxin-2 mRNA to mouse kidneys alleviated the fibrosis and inflammation associated with renal injury following unilateral ureter obstruction (UUO). Therefore, relaxin-2 mRNA exhibits potential as a novel therapy for inhibiting fibrosis and inflammation in chronic kidney disease.

Effect of ureteral stricture in transplant kidney and choice of treatment on long-term graft survival.

BACKGROUND: To explore the risk factors of ureteral stricture in transplant kidney and the clinical effects of different treatment methods. METHODS: The 62 patients with transplant kidney ureteral stenosis as the experimental group, and another group of recipients from the same donor as the control group (n = 59 cases). The risk factors for ureteral stricture and the survival rate of transplant kidney were analyzed and compared. The 62 patients were divided into open operation, luminal operation, and magnetic compression anastomosis (MCA) operation group. The effect of the operation and the survival rate of transplant kidney among the three groups were compared. RESULTS: In our study, we found that the above differences were statistically significant in clinical data such as gender, multiple donor renal arteries, history of infection, and delayed graft function (DGF) between the two groups (P < 0.05). Urinary tract infection and DGF history were the independent risk factors for the development of ureteral stricture. The open operation had the best treatment effect and the survival rate of the transplant kidney, followed by the MCA, the stricture recurrence rate in the luminal operation was the highest. CONCLUSION: The ureteral stricture has a negative correlation with the long-term survival rate of the transplant kidney, the curative rate and long-term effect of open surgery are the best, stricture recurrence rate of luminal surgery is high, and it may require multiple operations in the future, the MCA is a new breakthrough and innovation in the treatment of ureteral stricture.

Postoperative fasting plasma glucose and family history diabetes mellitus can predict post-transplantation diabetes mellitus in kidney transplant recipients.

PURPOSE: To explore whether glycated albumin (GA) or fasting plasma glucose (FPG), both routinely monitored during patients' hospital stay, can be used to predict post-transplantation diabetes mellitus (PTDM). METHODS: All kidney transplantation recipients (KTRs) from January 2017 to December 2018 were followed-up for 1 year. PTDM was diagnosed from day 45 post-operation to 1 year. When the completeness was above 80%, FPG or GA data on the day was selected, analyzed, and presented as range parameters and standard deviation (SD) and compared between PTDM and non-PTDM groups in fluctuation and stable periods. The predictive cut-off values were determined via receiver operating characteristic (ROC) analysis. The PTDM combined predictive mode, formed by the independent risk factors derived from logistic regression analyses, was compared with each independent risk factor with the independent ROC curve test. RESULTS: Among 536 KTRs, 38 patients developed PTDM up to 1 year post-operatively. The family history diabetes mellitus (OR, 3.21; P = 0.035), the FPG SD in fluctuation period >2.09 mmol/L (OR, 3.06; P = 0.002), and the FPG maximum in stable period >5.08 mmol/L (OR, 6.85; P < 0.001) were the PTDM independent risk factors. The discrimination of the combined mode (area under the curve = 0.81, sensitivity = 73.68%, and specificity = 76.31%) was higher than each prediction (P < 0.05). CONCLUSIONS: The FPG standard deviation during the fluctuation period, FPG maximum during the stable period, and family history diabetes mellitus predicted PTDM with good discrimination and potential routine clinical use.

HLA class II antibody activation of endothelial cells induces M2 macrophage differentiation in peripheral blood.

BACKGROUND: Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. METHODS: We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. RESULTS: The stimulation of ECs by F(ab')2 fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68+ and CD163+ (M2-type) macrophages, respectively, but not CD86+ macrophages. CONCLUSION: These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation.

USP7 accelerates FMR1-mediated ferroptosis by facilitating TBK1 ubiquitination and DNMT1 deubiquitination after renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia/reperfusion (I/R) leads to acute kidney injury and is associated with cell ferroptosis, an oxidative programmed cell death. This study aims to explore whether USP7 regulates ferroptosis in rat kidneys suffered I/R and the underlying mechanisms. METHODS: Human renal tubular epithelial cells HK-2 were treated with hypoxia/reoxygenation (H/R) to establish a cell model. The expression of ubiquitin specific peptidase 7 (USP7) in H/R-treated cells was determined. USP7 siRNA was transfected into H/R-treated cells, followed by the detection of cell proliferation, iron ion concentration, oxidative stress levels and glutathione peroxidase 4 (GPX4) and solute carrier family 7-member 11 (SLC7A11) protein levels. Western blotting and immunoprecipitation analyses were performed to detect the effects of USP7 on the ubiquitination of TANK-binding kinase 1 (TBK1) and DNA methyltransferase 1 (DNMT1). Then, H/R-treated cells were transfected with USP7 siRNA alone or together with TBK1 siRNA. Co-immunoprecipitation was used to detect binding relationship between TBK1 and FMRP translational regulator 1 (FMR1). The level of DNMT1 and methylation ratio of the FMR1 promoter region were determined with chromatin immunoprecipitation and methylation specific PCR assays, respectively. Furthermore, USP7 siRNA and FMR1 siRNA were transfected alone or together into H/R-treated cells, followed by the detection of cell functions. An I/R rat model was constructed to analyze the effects of USP7 on renal function in rats. RESULTS: USP7 was significantly upregulated in H/R-treated cells. USP7 interference markedly increased HK-2 cell proliferation and the protein levels of GPX4 and SLC7A11, restrained the iron ion concentration, and ameliorated oxidative stress. USP7 promoted TRIM27-mediated TBK1 ubiquitination and degradation. USP7 inhibition resulted in increased ubiquitination and decreased stability of DNMT1. USP7 was able to recruit DNMT1 to the FMR1 promoter region, which increased promoter methylation rates and suppressed FMR1 expression. TBK1 or FMR1 overexpression could reverse the effects of USP7 on cell functions. Inhibition of USP7 alleviated renal ischemia-reperfusion injury in rats. CONCLUSIONS: USP7 inhibition attenuated I/R-induced renal injury by inhibiting ferroptosis through decreasing ubiquitination of TBK1 and promoting DNMT1-mediated methylation of FMR1.

Postoperative day 1 serum cystatin C level predicts postoperative delayed graft function after kidney transplantation.

Background: Delayed graft function (DGF) commonly occurs after kidney transplantation, but no clinical predictors for guiding post-transplant management are available. Materials and methods: Data including demographics, surgery, anesthesia, postoperative day 1 serum cystatin C (S-CysC) level, kidney functions, and postoperative complications in 603 kidney transplant recipients who met the enrollment criteria from January 2017 to December 2018 were collected and analyzed to form the Intention-To-Treat (ITT) set. All perioperative data were screened using the least absolute shrinkage and selection operator. The discrimination, calibration, and clinical effectiveness of the predictor were verified with area under curve (AUC), calibration plot, clinical decision curve, and impact curve. The predictor was trained in Per-Protocol set, validated in the ITT set, and its stability was further tested in the bootstrap resample data. Result: Patients with DGF had significantly higher postoperative day 1 S-CysC level (4.2 ± 1.2 vs. 2.8 ± 0.9 mg/L; P < 0.001), serum creatinine level (821.1 ± 301.7 vs. 554.3 ± 223.2 µmol/L; P < 0.001) and dialysis postoperative (74 [82.2%] vs. 25 [5.9%]; P < 0.001) compared with patients without DGF. Among 41 potential predictors, S-CysC was the most effective in the parsimonious model, and its diagnostic cut-off value was 3.80 mg/L with the risk score (OR, 13.45; 95% CI, 8.02-22.57; P < 0.001). Its specificity and sensitivity indicated by AUC was 0.832 (95% CI, 0.779-0.884; P < 0.001) with well fit calibration. S-CysC yielded up to 50% of clinical benefit rate with 1:4 of cost/benefit ratio. Conclusion: The postoperative day 1 S-CysC level predicts DGF and may be used as a predictor of DGF but warrants further study.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients.

BACKGROUND: The calcineurin inhibitor (CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation; however, the long-term prognosis of grafts has not been significantly improved. The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts. Sirolimus (SRL) has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts. Presently, the regimen and timing of SRL application after renal transplantation vary, and clinical data are scarce. Multicenter prospective randomized controlled studies are particularly rare. This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation. METHODS: Patients who receive four weeks of a standard regimen with CNI + mycophenolic acid (MPA) + glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study. At week 5, after the operation, patients in the experimental group will receive an additional administration of SRL, a reduction in the CNI drug doses, withdrawal of MPA medication, and maintenance of glucocorticoids. In addition, patients in the control group will receive the maintained standard of care. The patients' vital signs, routine blood tests, routine urine tests, blood biochemistry, serum creatinine, BK virus (BKV)/ cytomegalovirus (CMV), and trough concentrations of CNI drugs and SRL at the baseline and weeks 12, 24, 36, 48, 72, and 104 after conversion will be recorded. Patient survival, graft survival, and estimated glomerular filtration rate will be calculated, and concomitant medications and adverse events will also be recorded. CONCLUSION: The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017277.

Immune-Related Genes for Predicting Future Kidney Graft Loss: A Study Based on GEO Database.

Objective: We aimed to identify feature immune-related genes that correlated with graft rejection and to develop a prognostic model based on immune-related genes in kidney transplantation. Methods: Gene expression profiles were obtained from the GEO database. The GSE36059 dataset was used as a discovery cohort. Then, differential expression analysis and a machine learning method were performed to select feature immune-related genes. After that, univariate and multivariate Cox regression analyses were used to identify prognosis-related genes. A novel Riskscore model was built based on the results of multivariate regression. The levels of these feature genes were also confirmed in an independent single-cell dataset and other GEO datasets. Results: 15 immune-related genes were expressed differently between non-rejection and rejection kidney allografts. Those differentially expressed immune-related genes (DE-IRGs) were mainly associated with immune-related biological processes and pathways. Subsequently, a 5-immune-gene signature was constructed and showed favorable predictive results in the GSE21374 dataset. Recipients were divided into the high-risk and low-risk groups according to the median value of RiskScore. The GO and KEGG analysis indicated that the differentially expressed genes (DEGs) between high-risk and low-risk groups were mainly involved in inflammatory pathways, chemokine-related pathways, and rejection-related pathways. Immune infiltration analysis demonstrated that RiskScore was potentially related to immune infiltration. Kaplan-Meier survival analysis suggested that recipients in the high-risk group had poor graft survival. AUC values of 1- and 3-year graft survival were 0.804 and 0.793, respectively. Conclusion: Our data suggest that this immune-related prognostic model had good sensitivity and specificity in predicting the 1- and 3-year kidney graft survival and might act as a useful tool for predicting kidney graft loss.

WNT1-inducible signaling pathway protein 1 regulates kidney inflammation through the NF-κB pathway.

Inflammation is a pathological feature of kidney injury and its progression correlates with the development of kidney fibrosis which can lead to kidney function impairment. This project investigated the regulatory function of WNT1-inducible signaling pathway protein 1 (WISP1) in kidney inflammation. Administration of recombinant WISP1 protein to healthy mice induced kidney inflammation (macrophage accrual and production of tumor necrosis factor α (TNF-α), CCL2 and IL-6), which could be prevented by inhibition of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). Furthermore, inhibition of WISP1, by gene knockdown or neutralising antibody, could inhibit cultured macrophages producing inflammatory cytokines following stimulation with lipopolysaccharides (LPSs) and kidney fibroblasts proliferating in response to TNFα, which both involved NF-κB signaling. Kidney expression of WISP1 was found to be increased in mouse models of progressive kidney inflammation-unilateral ureter obstruction (UUO) and streptozotocin (STZ)-induced diabetic nephropathy (DN). Treatment of UUO mice with WISP1 antibody reduced the kidney inflammation in these mice. Therefore, pharmacological blockade of WISP1 exhibits potential as a novel therapy for inhibiting inflammation in kidney disease.

Self-polymerized polydopamine-based nanoparticles for acute kidney injury treatment through inhibiting oxidative damages and inflammatory.

The polydopamine nanoparticles (PDA NPs) as a self-polymerized form of dopamine have occurred with growing interest in biomedical applications in late years. Its natural-inspired feature as a conjugated polymer endows excellent inactivating capability for radical species to PDA-based nanoparticles that provide a theoretical foundation for applications in preventing inflammation-mediated acute kidney injury (AKI) from ROS. Here, we develop a polydopamine wrapped manganese ferrite nanoparticles (PDA@MF NPs) strategy for acute kidney injury therapy by synergistically scavenging ROS and producing O2, which further regulates macrophages amounts by decreasing M1-type and increasing M2-type. Water-soluble PDA@MF NPs were prepared in one step after the oxidative and self-polymerized process of the dopamine monomer. Here, the biodegradable PDA NPs were applied to scavenge ROS. MF NPs undertake continuous O2 production in an H2O2-based hypoxic environment. Based on this system, we aim to relieve the hypoxia, pathological symptoms, and inflammation via scavenging ROS during the O2 production process, and effective polarization to M2-type macrophages. PDA@MF NPs in this study were verified could significantly attenuate oxidative stress in vivo, reduce inflammatory events in renal, and improve renal function, which might be a potential treatment to inhibit oxidative damages and inflammatory events in renal AKI disease.

Predictive value of hypothermic machine perfusion parameters combined perfusate biomarkers in deceased donor kidney transplantation.

BACKGROUND: Delayed graft function (DGF) is the main cause of renal function failure after kidney transplantation. This study aims at investigating the value of hypothermic machine perfusion (HMP) parameters combined with perfusate biomarkers on predicting DGF and the time of renal function recovery after deceased donor (DD) kidney transplantation. METHODS: HMP parameters, perfusate biomarkers and baseline characteristics of 113 DD kidney transplantations from January 1, 2019 to August 31, 2019 in the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively analyzed using univariate and multivariate logistic regression analysis. RESULTS: In this study, the DGF incidence was 17.7% (20/113); The multivariate logistic regression results showed that terminal resistance (OR: 1.879, 95% CI 1.145-3.56) and glutathione S-transferase (GST)(OR = 1.62, 95% CI 1.23-2.46) were risk factors for DGF; The Cox model analysis indicated that terminal resistance was an independent hazard factor for renal function recovery time (HR = 0.823, 95% CI 0.735-0.981). The model combining terminal resistance and GST (AUC = 0.888, 95% CI: 0.842-0.933) significantly improved the DGF predictability compared with the use of terminal resistance (AUC = 0.756, 95% CI 0.693-0.818) or GST alone (AUC = 0.729, 95% CI 0.591-0.806). CONCLUSION: According to the factors analyzed in this study, the combination of HMP parameters and perfusate biomarkers displays a potent DGF predictive value.