Clinical phenotypes and prognosis of IgG4-related diseases accompanied by deteriorated kidney function: a retrospective study.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a multiorgan autoimmune disorder that causes irreversible injury. Deteriorated kidney functions are common but easily ignored complications associated with IgG4-RD. Yet the clinical manifestations and prognosis of this specific entity have not been fully illustrated. METHOD: Three hundred fifty patients with IgG4-RD were retrospectively enrolled and divided into 119 IgG4-RD with chronic kidney disease (IgG4-RD CKD+) and 231 IgG4-RD without CKD (IgG4-RD CKD-). Demographic clinical and laboratory characteristics and survival of two cohorts were compared using restricted cubic splines, logistic and Cox regression, and Kaplan-Meier analysis. A nomogram was generated for calculating the probability of CKD in IgG4-RD. RESULTS: The spectrum of organ involvement was different between IgG4-RD CKD+ and CKD- cohorts (p<0.001). Lung (26.89%) and retroperitoneum (18.49%) involvement were more common in the IgG4-RD CKD+ cohort. Increased serum potassium and phosphorus, reduced calcium levels, and hypocomplementemia (all p<0.05) were observed in IgG4-RD CKD+. Restricted cubic splines revealed a U-shaped plot regarding associations between serum potassium and CKD. Kaplan-Meier analysis demonstrated significantly lower long-term survival rates in IgG4-RD patients with kidney function at CKD stages 4-5. Cox regression revealed declined kidney functions (G4 HR 6.537 (95% CI: 1.134-37.675)) associated with increased all-cause mortality in IgG4-RD patients. A nomogram was constructed to predict CKD in IgG4-RD promptly with a discrimination (C-index) of 0.846. CONCLUSIONS: CKD in IgG4-RD was associated with poor outcomes and electrolyte disturbances. Patients with IgG4-RD should be aware of possible deterioration in kidney function. The nomogram proposed would help to identify the subtle possibility of CKD in IgG4-RD. Key points • IgG4-related diseases with deteriorated kidney function have specific clinical and laboratory characteristics. • It is crucial to recognize and address the negative impact of deteriorating kidney function in IgG4-related diseases to prevent further harm. • The nomogram proposed would help to identify subtle kidney involvement by evaluating the possibility of CKD in IgG4-related diseases.

A case of TM infection with challenging differential diagnosis from lymphoma post-renal transplant.

BACKGROUND: Lymphomas involving the gastrointestinal tract may be manifested as anti-inflammatory tract bleeding, abdominal lymph node enlargement, or even perforation of the gastrointestinal tract. After organ transplantation, the likelihood of post-transplant lymphoproliferative disorders increases, and some rare infections may also appear. CASE PRESENTATION: Herein, we report a living transplant patient with talaromycosis marneffei (TSM) or Talaromyces marneffei (TM) infection with gastrointestinal hemorrhage and systemic lymph node enlargement, which presented clinically as lymphoma. CONCLUSION: This case is TSM in a kidney transplant patient, confirmed by lymph node biopsy and blood culture. The patient discharged from hospital successfully under the treatment of antifungal therapy and immunosuppressive therapy. Physicians should be aware that TSM can mimic lymphoma, and early diagnosis and treatment can benefit the outcomes.

Unraveling Intestinal Microbial Shifts in ESRD and Kidney Transplantation: Implications for Disease-Related Dysbiosis.

The composition of the gut microbiome is profoundly influenced by the accumulation of toxins in end-stage renal disease (ESRD) and specific medical treatments during kidney transplantation (KT). However, variations in results may arise due to factors such as genetics, dietary habits, and the strategy of anti-rejection therapy. Therefore, we conducted a 16S rRNA sequencing study to characterize intestinal microbiomes by using 75 fecal specimens obtained from 25 paired Chinese living donors (LDs) of kidneys and recipients before and after KT. Surprisingly, similar enterotypes were observed between healthy LDs and ESRD recipients. Nonetheless, following KT, the fecal communities of recipients exhibited distinct clustering, which was primarily characterized by Escherichia-Shigella and Streptococcus at the genus level, along with a reduction in the diversity of microbiota. To further explore the characteristics of gut microorganisms in early rejection episodes, two recipients with biopsy-proven borderline changes during follow-up were enrolled in a preliminary sub-cohort study. Our findings reveal a comparable construction of gut microbiota between ESRD patients and their healthy relatives while also highlighting the significant impact of KT on gut microbial composition.

Artificial Urinary Biomarkers for Early Diagnosis of Acute Renal Allograft Rejection.

Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.

Multivalent SnO2 quantum dot-decorated Ti3C2 MXene for highly sensitive electrochemical detection of Sudan I in food.

Quantum dots functionalization has been proven to be a simple modification strategy for improving the electroanalytical performance of two-dimensional electrode materials by increasing the specific surface area and active reaction sites. Herein, a new electrochemical sensing platform was fabricated by SnO2 quantum dot-functionalized Ti3C2 MXene (Ti3C2-SnO2QDs) for the highly sensitive detection of Sudan I in food. Ti3C2-SnO2QDs were prepared via in situ synthesis, which can control the nucleation and growth of SnO2QDs, resulting in the well-dispersed SnO2QDs with 2-3 nm size on the intersheet surface of MXene. Moreover, the formation of Ti3C2-SnO2QDs can effectively restrict the aggregation of Ti3C2 and improve the stability of SnO2QDs in aquatic environment. The prepared nanocomposite can be used as an improved modified material to further increase the electrocatalytic performance and electrochemical signal of Sudan I on the surface of a glassy carbon electrode. Under optimized conditions, the proposed analytical method displayed a linear dependence for Sudan I concentration ranging from 0.008 to 10 µM with a detection limit of 0.27 nM (S/N = 3) by electrochemical cyclic voltammetry. This sensor with excellent selectivity, reproducibility and accuracy was quantitatively validated in commercial ketchup and chili powder. This Ti3C2-SnO2QDs-based Sudan I sensor is expected to expand the application of MXene nanocomposites in electrochemical analysis and is envisioned as a promising candidate for monitoring illegal food additives in real food samples.

Helper T Cell (CD4+) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity.

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4+) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.

Plasma Donor-Derived Cell-Free DNA Levels Are Associated With the Inflammatory Burden and Macrophage Extracellular Trap Activity in Renal Allografts.

Recent studies have confirmed the role of plasma donor-derived cell-free DNA (ddcfDNA) as a reliable non-invasive biomarker for allograft injury after kidney transplantation. Whereas the variability of plasma ddcfDNA levels among recipients has limited their clinical use. This study aimed to explore the intrinsic factors associated with plasma ddcfDNA elevation by investigating the impact of Banff lesions and inflammatory infiltrates on ddcfDNA levels in kidney transplant recipients. From March 2017 to September 2019, a total of 106 kidney transplant recipients with matched allograft biopsies were included, consisting of 13 recipients with normal/nonspecific changes, 13 recipients with borderline changes, 60 with T cell-mediated rejection, and 20 with antibody-mediated rejection. Histologic classification was performed according to the Banff 2017 criteria by two experienced pathologists. Plasma ddcfDNA fractions ranged from 0.12% to 10.22%, with a median level of 0.91%. Banff histology subelements including glomerulitis, intimal arteritis, and severe interstitial inflammation were correlated with increased plasma ddcfDNA levels. The inflammatory cell infiltrate in the allografts was phenotyped by immunochemistry and automatically counted by digital image recognition. Pearson correlation analysis revealed a significant positive correlation between macrophage infiltrations in allografts and plasma ddcfDNA levels. Additionally, macrophage extracellular trap (MET) activity was significantly associated with the rise in plasma ddcfDNA levels. Our findings demonstrated that plasma ddcfDNA could reflect the inflammatory state in renal allografts and suggested the potential role of METs in the pathogenesis of allograft injury.

In Vivo Kidney Allograft Endothelial Specific Scavengers for On-Site Inflammation Reduction under Antibody-Mediated Rejection.

Kidney transplantation is the most effective therapy for patients with end-stage renal disease. However, antibody-mediated rejection (ABMR) threatens long-term survival of renal grafts. Although ABMR can be controlled by donor-specific antibody clearance and B- or (and) plasma-cells inhibition, the treatment often causes severe side effects in patients. Therefore, there is need to explore site-specific scavengers. In this study, a nanovehicle carrying an anti-inflammatory drug is developed with complement component 4d targeting, a specific biomarker expressed on allograft endothelium under ABMR. Moreover, the nanovehicle is endowed with photothermal properties to control drug release. Analysis through systematic in vitro and in vivo toxicity, non-invasive targeted imaging, and in situ remote controlled drug release show the nanovehicle specifically targets allograft kidney endothelium, releases an anti-inflammatory drug, methylprednisolone, locally upon laser irradiation, and promotes recovery of injured endothelium, without affecting systemic inflammation or innate immune responses. This strategy has the potential for future clinical application in ABMR treatment.

The Pharmacological Mechanism of the Effect of Plant Extract Compound Drugs on Cancer Pain Based on Network Pharmacology.

Objective: We systematically analyzed the mechanism of plant-derived drugs alleviating cancer pain in our hospital through network pharmacology, so as to provide the possibility of further application of traditional Chinese medicine in the treatment of cancer pain. Methods: We used TCMSP, ETCM, and TCMID databases to mine the active ingredients of plant-derived drugs. We combined OMIM, GeneCards, and DrugBank databases to mine and match the common targets of plant-derived drugs for cancer pain. We used the STRING platform and Cytoscape software to analyze and screen out the core targets. We used GO and KEGG methods to analyze the biological processes, molecular functions, cellular composition, and signaling pathways involved in the reduction of cancer pain by plant-derived drugs. Results: We found 153 active ingredients from botanical drugs by TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, TCMSP), ETCM (The Encyclopedia of Traditional Chinese Medicine), and TCMID (Traditional Chinese Medicine Integrated Database) databases, covering 341 protein targets in human body. Combined with OMIM (Online Mendelian Inheritance in Man), GeneCards, and DrugBank databases, we excavated and matched 141 targets of plant-derived drugs and cancerous pain diseases. Through the analysis of the STRING platform and Cytoscape software, 19 core targets including TNF, MAPK1, JUN, and IL-6 were screened out. Go and KEGG enrichment showed that plant-derived drugs alleviated cancer pain processes involving 193 biological processes, 47 molecular functions, 22 cell components, and 118 signaling pathways. By screening genes involved in KEGG signaling pathway, it was found that plant-derived drugs were mainly associated with PI3K-Akt signaling pathway, tumor necrosis factor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway, and HIF-1 signaling pathway in alleviating cancer pain. Conclusion: These results indicate that botanical drugs can positively affect the expression of inflammatory factors and apoptotic factors in the process of treatment and relief of cancer pain, which is expected to have a potential therapeutic effect on the relief of cancer pain.

Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy.

BK polyomavirus-associated nephropathy (BKPyVAN) is a common cause of allograft failure. However, differentiation between BKPyVAN and type I T cell-mediated rejection (TCMR) is challenging when simian virus 40 (SV40) staining is negative, because of the similarities in histopathology. This study investigated whether donor-derived cell-free DNA (ddcfDNA) can be used to differentiate BKPyVAN. Target region capture sequencing was applied to detect the ddcfDNAs of 12 recipients with stable graft function, 22 with type I TCMR, 21 with proven BKPyVAN, and 5 with possible PyVAN. We found that urinary ddcfDNA levels were upregulated in recipients with graft injury, whereas plasma ddcfDNA levels were comparable for all groups. The median urinary concentrations and fractions of ddcfDNA in proven BKPyVAN recipients were significantly higher than those in type I TCMR recipients (10.4 vs. 6.1 ng/mL, P<0.001 and 68.4% vs. 55.3%, P=0.013, respectively). Urinary ddcfDNA fractions (not concentrations) were higher in the BKPyVAN-pure subgroup than in the BKPyVAN-rejection-like subgroup (81.30% vs. 56.64%, P=0.025). With a cut-off value of 7.81 ng/mL, urinary ddcfDNA concentrations distinguished proven BKPyVAN from type I TCMR (area under the curve (AUC)=0.848, 95% confidence interval (95% CI): 0.734 to 0.963). These findings suggest that urinary ddcfDNA is a non-invasive biomarker which can reliably differentiate BKPyVAN from type I TCMR.

Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation.

Allograft rejection after renal transplantation remains a challenge to overcome. Interleukin (IL)-21, a cytokine with pleiotropic effects, maintains immune homeostasis post-transplantation. Here, we report higher levels of IL-21 in kidney transplant recipients with non-rejection (NR) than in recipients with T cell-mediated rejection (TCMR, P < 0.001) and antibody-mediated rejection (ABMR, P = 0.005). We observed a negative correlation between IL-21 and creatinine (Cr) levels (P = 0.016). The receiving operating characteristic (ROC) curve showed a promising diagnostic value of IL-21 to identify acute rejection with an area under the curve (AUC) of 0.822 (P < 0.001). In contrast, exogenous administration of IL-21 accelerated acute rejection in a comparative translational kidney transplant (KT) mouse model. Reduced IL-21 levels in the peripheral blood were observed in KT mice after IL-21 injection. Further analysis revealed that increased IL-21 levels in the spleen induced proliferation of CD4+ T cells and CD19+ B cells after IL-21 treatment. Our findings suggest a critical function of IL-21 in kidney transplantation and the potential involvement of the IL-21/IL-21R pathway in acute rejection management.

Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: A prospective cohort study.

Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker for monitoring allograft status. However, whether dd-cfDNA can reflect real-time anti-rejection treatment effects remains unclear. We prospectively recruited 28 patients with acute renal rejection, including 5 with ABMR, 12 with type IA or type IB rejection, and 11 with type IIA or IIB rejection. dd-cfDNA levels in peripheral blood were measured using human single nucleotide polymorphism (SNP) locus capture hybridization. The percentage of dd-cfDNA (dd-cfDNA%) declined significantly from 2.566 ± 0.549% to 0.773 ± 0.116% (P < .001) after anti-rejection therapy. The dd-cfDNA% decreased steadily over the course of 3 days with daily methylprednisolone injections, but no significant difference in the dd-cfDNA% was observed between the end of anti-rejection therapy and 2 weeks later. Changes in the dd-cfDNA% (∆dd-cfDNA%) demonstrated a positive correlation with estimated glomerular filtration rates at 1 month (ρ = 2.570, P = .022), 3 months (ρ = 3.210, P = .027), and 6 months (ρ = 2.860, P = .019) after therapy. Thus, the dd-cfDNA assay shows prognostic capabilities in therapy outcome and allograft recovery; however, its ability is inhibited by methylprednisolone regardless of the types of rejection. Additionally, a reassessment of frequency intervals for testing is required.

Preparation of Robust Hydrogen Evolution Reaction Electrocatalyst WC/C by Molten Salt.

Tungsten carbide (WC) is an alternative to the costly and resource-constrained Pt-based catalysts for hydrogen evolution reaction (HER). In this work, a one-step facile and easily scalable approach is reported, to synthesize ultrafine WC by molten salt. Benefiting from the ideal synergistic catalytic effect between the highly active WC nanoparticles and the conductive graphitic carbon, and strong charge transfer ability, the unique WC/C hybrids demonstrated excellent HER performance in both acid and alkaline medias with overpotentials of 112 and 122 mV, at a current density of 10 mA cm-2 and Tafel slopes of 54.4 and 68.8 mV dec-1, in acid and alkaline media, and remarkable stability. With the simplicity and low-cost of the synthetic approach, the strategy presented here can be extendable to the preparation of other transition metal-based/carbon hybrids for versatile applications.

Sliding Mode Fault Tolerant Control for Unmanned Aerial Vehicle with Sensor and Actuator Faults.

The unmanned aerial vehicle (UAV) has been developing rapidly recently, and the safety and the reliability of the UAV are significant to the mission execution and the life of UAV. Sensor and actuator failures of a UAV are one of the most common malfunctions, threating the safety and life of the UAV. Fault-tolerant control technology is an effective method to improve the reliability and safety of UAV, which also contributes to vehicle health management (VHM). This paper deals with the sliding mode fault-tolerant control of the UAV, considering the failures of sensor and actuator. Firstly, a terminal sliding surface is designed to ensure the state of the system on the sliding mode surface throughout the control process based on the simplified coupling dynamic model. Then, the sliding mode control (SMC) method combined with the RBF neural network algorithm is used to design the parameters of the sliding mode controller, and with this, the efficiency of the design process is improved and system chattering is minimized. Finally, the Simulink simulations are carried out using a fault tolerance controller under the conditions where accelerometer sensor, gyroscope sensor or actuator failures is assumed. The results show that the proposed control strategy is quite an effective method for the control of UAVs with accelerometer sensor, gyroscope sensor or actuator failures.

BrainEXP: a database featuring with spatiotemporal expression variations and co-expression organizations in human brains.

Summary: Gene expression changes over the lifespan and varies among different tissues or cell types. Gene co-expression also changes by sex, age, different tissues or cell types. However, gene expression under the normal state and gene co-expression in the human brain has not been fully defined and quantified. Here we present a database named Brain EXPression Database (BrainEXP) which provides spatiotemporal expression of individual genes and co-expression in normal human brains. BrainEXP consists of 4567 samples from 2863 healthy individuals gathered from existing public databases and our own data, in either microarray or RNA-Seq library types. We mainly provide two analysis results based on the large dataset: (i) basic gene expression across specific brain regions, age ranges and sexes; (ii) co-expression analysis from different platforms. Availability and implementation: http://www.brainexp.org/. Supplementary information: Supplementary data are available at Bioinformatics online.

Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3ß/ß-catenin axis activation.

Peritoneal fibrosis is a severe complication arising from long-term peritoneal dialysis (PD). Tamoxifen (Tamo) has been clinically proven effective in a series of fibrotic diseases, such as PD-associated encapsulating peritoneal sclerosis (EPS), but the mechanisms underlying Tamoxifen's protective effects are yet to be defined. In the present study, C57BL/6 mice received intraperitoneal injections of either saline, 4.25% high glucose (HG) PD fluid (PDF) or PDF plus Tamoxifen each day for 30 days. Tamoxifen attenuated thickening of the peritoneum, and reversed PDF-induced peritoneal expression of E-cadherin, Vimentin, matrix metalloproteinase 9 (MMP9), Snail, and ß-catenin. Mouse peritoneal mesothelial cells (mPMCs) were cultured in 4.25% glucose or 4.25% glucose plus Tamoxifen for 48 h. Tamoxifen inhibited epithelial-to-mesenchymal transition (EMT) as well as phosphorylation of glycogen synthase kinase-3ß (GSK-3ß), nuclear ß-catenin, and Snail induced by exposure to HG. TWS119 reversed the effects of Tamoxifen on ß-catenin and Snail expression. In conclusion, Tamoxifen significantly attenuated EMT during peritoneal epithelial fibrosis, in part by inhibiting GSK-3ß/ß-catenin activation.

fMRI classification method with multiple feature fusion based on minimum spanning tree analysis.

Resting state functional brain networks have been widely studied in brain disease research. Conventional network analysis methods are hampered by differences in network size, density and normalization. Minimum spanning tree (MST) analysis has been recently suggested to ameliorate these limitations. Moreover, common MST analysis methods involve calculating quantifiable attributes and selecting these attributes as features in the classification. However, a disadvantage of these methods is that information about the topology of the network is not fully considered, limiting further improvement of classification performance. To address this issue, we propose a novel method combining brain region and subgraph features for classification, utilizing two feature types to quantify two properties of the network. We experimentally validated our proposed method using a major depressive disorder (MDD) patient dataset. The results indicated that MSTs of MDD patients were more similar to random networks and exhibited significant differences in certain regions involved in the limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit, which is considered to be a major pathological circuit of depression. Moreover, we demonstrated that this novel classification method could effectively improve classification accuracy and provide better interpretability. Overall, the current study demonstrated that different forms of feature representation provide complementary information.

Beta-catenin participates in dialysate-induced peritoneal fibrosis via enhanced peritoneal cell epithelial-to-mesenchymal transition.

Long-term exposure to peritoneal dialysate with high glucose (HG) leads to peritoneal fibrosis and thus decreases dialysis efficiency. In this study, we explored the role of ß-catenin in this process. C57BL/6 mice received daily intraperitoneal injection with 10% of the body weight of saline (control), 4.25% glucose peritoneal dialysis fluid (PDF), or PDF combined with 5 mg·kg-1 of the ß-catenin inhibitor ICG-001 (PDF+ICG) for 30 days. Also, mice peritoneal epithelial cells (mPECs) were cultured in 4.25% glucose (HG) or combined with 10 µm ICG-001 (HG+ICG) for 48 h. We found greater thickness of the parietal peritoneum in the PDF-treated mice. Additionally, lower expression of E-cadherin, higher expression of Vimentin, ß-catenin, and Snail, and activation of ß-catenin was observed in the mice and in HG-treated mPECs, all of which were reversed by ICG-001. The changes in E-cadherin and Vimentin indicated occurrence of the epithelial-to-mesenchymal transition (EMT). Thus, ß-catenin signaling participates in the process of HG-induced peritoneal fibrosis, and the EMT of peritoneal epithelial cells is one of the underlying mechanisms of this pathological change.