CD73 as a T cell dysfunction marker predicting cardiovascular and infection events in patients undergoing hemodialysis.

BACKGROUND: T cell dysfunction observed in patients undergoing hemodialysis (HD) has been linked to an extremely high morbidity of cardiovascular events (CVEs) and infections. The cell-surface 5'-nucleotidase CD73 sets the balance between pro-inflammatory nucleotides and anti-inflammatory adenosine. METHODS: A total of 395 patients who had been receiving HD for at least six months were evaluated for proportions of CD73+ cells in both the CD4+ T cell and CD8+ T cell compartment and followed for one year to document CVEs and infections. Differences in the proportions of CD73-expressingT cells between healthy controls and patients undergoing HD were compared. The relationship between CD73+ T cells and clinical outcomes was analyzed using the Kaplan-Meier curve and Cox regression. RESULTS: HD was significantly related to a lower fraction of CD4+CD73+ T cells. In patients on HD, lower proportions of CD4+ CD73+T cells and CD8+ CD73+T cells were both associated with systemic inflammation and T cell terminal differentiation. More importantly, a lower CD4+CD73+T cell ratio independently predicted CVEs and infection in these patients. CONCLUSION: We identified CD73 as a T cell dysfunction marker predicting cardiovascular and infection events in patients undergoing HD, which provides a potential target in future studies of uremia-related immune dysfunction.

Effects of p-cresol, a uremic toxin, on cancer cells.

Background: Though p-cresol exists at a low concentration in the blood, it accumulates in various organs of uremic patients. Previous research has shown that the p-cresol promoted bladder cancer cell invasion and migration. This study aims to see if p-cresol had similar effects on kidney cancer cells and liver cancer cells. Methods: For 48 hours, 786-O human renal cancer cells and HepG2 human liver cancer cells were treated with p-cresol at concentrations of 0, 10, 20, 40, and 70 µM. The effects of p-cresol on cell viability, apoptosis, migration, and invasion were then analyzed using the CCK-8, TUNEL, and Transwell migration/invasion assays, respectively. Results: P-cresol at 0 to 70 µM for 48 hours had no significant toxic effects on 786-O cells or HepG2 cells. We chose 40 µM p-cresol for 48 hours for the following experiment. The viability and proliferation of 786-O cells and HepG2 cells were unaffected after 48 hours of treatment, with 40 µM p-cresol. However, 40 µM p-cresol for 48 hours promoted HepG2 cell migration and invasion but did not have the same effect on the 786-O cell line. Conclusions: P-cresol may be responsible for HepG2 cells' malignant biological behavior. Because the liver is the primary site of p-cresol metabolism, it is important to study the responses of cancer cells in the liver to p-cresol.

Decreased Peripheral Naïve T Cell Number and Its Role in Predicting Cardiovascular and Infection Events in Hemodialysis Patients.

Patients with end-stage renal disease (ESRD) are at high risk of morbidity and mortality from cardiovascular and infectious diseases, which have been found to be associated with a disturbed immune response. Accelerated T-cell senescence is prevalent in these patients and considered a significant factor contributing to increased risk of various morbidities. Nevertheless, few studies have explicated the relevance of T-cell senescence to these fatal morbidities in ESRD patients. In this study, we designed a longitudinal prospective study to evaluate the influence of T-cell senescence on cardiovascular events (CVEs) and infections in hemodialysis (HD) patients. Clinical outcomes of 404 patients who had been on HD treatment for at least 6 months were evaluated with respect to T-cell senescence determined using flow cytometry. We found that T-cell senescence was associated with systemic inflammation. High-sensitivity C-reactive protein was positively associated with decreased naïve T cell levels. Elevated tumor necrosis factor-α and interleukin 6 levels were significantly associated with lower central memory T cell and higher T effector memory CD45RA cell levels. Decreased CD4+ naïve T cell count was independently associated with CVEs, whereas decreased CD8+ naïve T cell count was independently associated with infection episodes in HD patients. In conclusion, HD patients exhibited accelerated T-cell senescence, which was positively related to inflammation. A reduction of naïve T cell could be a strong predictor of CVEs and infection episodes in HD patients.

The significance of serum levels of soluble interleukin-2 receptor in patients undergoing maintenance hemodialysis.

Background: Elevated serum levels of sIL-2R are commonly observed in patients undergoing maintenance hemodialysis (MHD). However, the clinical implications in these subjects are unclear. This study is aimed to assess the significance of elevated sIL-2R levels in MHD patients.Methods: A total of 382 MHD patients were followed-up from September 2016 to December 2019. Patients were divided into two groups: high sIL-2R, with sIL-2R levels ≥2-fold of the upper limit of normal (710 U/ml); and low sIL-2R, with sIL-2R levels < 2-fold the upper limit of normal. The relationships between sIL-2R levels and other clinical parameters, as well as patient prognosis were both assessed.Results: The median concentration of sIL-2R was 1268 U/mL. A total of 372 (97.38%) patients exhibited sIL-2R levels higher than the upper limit of the normal range. Multiple linear regression analysis revealed that monocyte count (ß = 0.1571, p = 0.01), and ß2-MG (ß = 0.2635, p < 0.0001), hemoglobin (ß = -0.1610, p = 0.001), SCr (ß = -0.3471, p < 0.0001), and HDL-C (ß = -0.1091, p = 0.029) levels were independent factors influencing serum concentrations of sIL-2R. High sIL-2R was significantly correlated with non-cardiovascular-related mortality (OR 2.97 [95% CI 1.59-5.56; p = 0.001), of which 39 (82.98%) were attributed to infection and/or cancer.Conclusions: Elevated sIL-2R is prevalent in MHD patients and related with several unfavorable parameters. sIL-2R appears to have no ability to predict cardiovascular mortality, which accounts for approximately one-half of all deaths. However, sIL-2R may be beneficial in predicting noncardiovascular mortality.

Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease.

Introduction: Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential "missing link." Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS. Methods: In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells in vitro. Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis. Results: Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells. Conclusion: The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.

The Predictive Value of NT-Pro-Brain Natriuretic Peptide for Risk of Pneumonia in Patients on Maintenance Hemodialysis.

BACKGROUND/AIMS: Pneumonia is a common type of infection in maintenance hemodialysis (MHD) patients, while the treatment and prevention progress still keep limited. N-terminal-pro-brain natriuretic peptide (NT-proBNP) is an important marker in reflecting cardiac failure which also is a risk factor for pneumonia. This study aimed to determine the possible predictive value of NT-proBNP for pneumonia in MHD patients. METHODS: In this prospective study, the basic information of 276 MHD patients was collected in Fudan university Zhongshan hospital, followed up for 1 year. The primary endpoint was the first pneumonia event during follow-up. The value of NT-proBNP in patients with pneumonia and without pneumonia was analyzed, to elucidate the predictive value of the NT-proBNP in hemodialysis patients with pneumonia. RESULTS: Two hundred and seventy-six patients were finally enrolled in this prospective study, including 170 men. The mean age was 59.7 ± 14.0 years old. The average duration of hemodialysis is 56 (30-82.8) months. Enrolled patients were followed up for 1 year. During follow-up, 38 patients got pneumonia. After adjustment for other confounding factors, age (hazard ratio [HR] 1.031, 95% CI 1.003-1.060, p = 0.028), log NT-proBNP (HR 2.512, 95% CI 1.124-5.612, p = 0.025), history of smoking (HR 6.326, 95% CI 2.505-15.974, p < 0.001), ß2-microglobin (HR 1.042, 95% CI 1.007-1.079, p = 0.019), and history of cerebrovascular disease (HR 2.303, 95% CI 1.107-4.719, p = 0.026) were independent predictors of pneumonia. Receiver operating characteristic curves of log NT-proBNP to predict 1 year pneumonia cases, log NT-proBNP had an area under the curve of 0.647 (95% CI [0.564-0.729], p < 0.01). CONCLUSIONS: NT-proBNP is a predictive factor of pneumonia in hemodialysis patients.

Acute effect of one session of hemodiafiltration with endogenous reinfusion on uremic toxins and inflammatory mediators.

AIMS: To investigate the acute effects of hemodiafiltration with endogenous infusion on the elimination of uremic toxins and inflammatory mediators in patients with end-stage renal disease. MATERIALS AND METHODS: A total of 37 end-stage renal disease patients undergoing chronic hemodialysis received a single hemodiafiltration with endogenous infusion dialysis treatment. The acute effects of one hemodiafiltration with endogenous infusion session on uremic toxins and inflammatory mediators were assessed by comparing the pre- and post-hemodiafiltration with endogenous infusion concentrations. RESULTS: Hemoglobin and albumin were stable during hemodiafiltration with endogenous infusion therapy. The mean reduction ratios of ß2-microglobulin, p-cresyl sulfate, and indoxyl sulfate were 43.60%, 40.91%, and 43.64%, respectively. Tumor necrosis factor-α also decreased significantly at a mean rate of 28.10%, while the concentrations of interleukin-6 and high-sensitivity C-reactive protein remained unchanged after one session of hemodiafiltration with endogenous infusion. CONCLUSION: The hemodiafiltration with endogenous infusion system is a new dialysis technique that combines diffusion, convection, and adsorption processes. It allows for extensive solute removal, including protein-bound uremic toxins and some pro-inflammatory cytokines, but does not cause nutrient loss and inflammatory response during the treatment. Although the effect after a single hemodiafiltration with endogenous infusion session is limited, it may be improved by repeated and long-term treatment.

Incidence, Risk, and Prognosis of Cancer in Patients on Chronic Hemodialysis.

BACKGROUND: Information concerning the cancer issue in Chinese patients on hemodialysis (HD) was lacking. Thus, we examined data from our dialysis registry to investigate the incidence of cancer, identify the possible factors, and explore outcomes after cancer diagnosis in patients on chronic HD. METHODS: A retrospective cohort study of 639 new-onset end-stage renal disease patients who started HD therapy during the period from July 1999 to December 2017 was retrieved from the database in our dialysis center. All eligible patients were followed up until renal transplantation, death, or end of study (March 31, 2019). The definition of a newly diagnosed cancer was that diagnosed 6 months after HD therapy initiation. RESULTS: Within a median follow-up period of 5.61 years, 58 patients (9.08%) have been diagnosed with cancer with the incidence of 1,494 per 105 person-years. The mean duration from HD initiation to cancer diagnosis was 5.22 ± 3.55 years. Digestive cancer (32.76%) was the most common followed by urologic cancer (18.97%) and lung cancer (15.52%). Advanced age at starting HD therapy (hazard ratio [HR] 1.04) and erythropoietin dosage ≥20,000 U/week (HR 1.95) were independent predictors for cancer occurrence. Of the 256 deaths during the follow-up period, 29 cases (11.33%) were attributed to cancer, with the mortality rate of 717 per 105 person-years. The 1-, 5-, and 10-year cumulative survival rates after cancer diagnosis were 58.73, 34.64, and 20.41%, respectively. A total of 32 patients (55.17%) did not receive any anti-cancer therapy, and the mortality in those patients was significantly increased as compared to patients who received anti-cancer therapy. CONCLUSION: Cancer is common in HD patients due to the improved survival, and it has a negative effect on patient prognosis. Many patients have failed to receive optimal anti-cancer therapy, which calls for effective communication and cooperation among patients, dialysis unit, and oncology teams.

HMGB1 gene silencing inhibits neuroinflammation via down-regulation of NF-κB signaling in primary hippocampal neurons induced by Aß25-35.

High mobility group box 1 protein (HMGB1) is potentially triggered by Aß oligomers and other sterile injuries, and is a non-histone DNA binding nuclear protein with roles in neural development and neurodegeneration, which contribute to memory impairment and chronic neuroinflammation in the brain. However, the exact molecular mechanisms of HMGB1 activation in Alzheimer's disease (AD) were previously unknown. The present study aimed to elucidate the effects of HMGB1 in Aß25-35-induced neuroinflammation in hippocampal neuron cultures. RNA interference (RNAi) HMGB1 treatment significantly reduced Aß25-35-induced HMGB1 expression by almost 70% in primary hippocampal neurons. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) demonstrated that short hairpin RNA (shRNA) for HMGB1 ameliorated Aß25-35-treated neuroinflammation, including activation of advanced glycosylation end product-specific receptor (RAGE), toll-like receptor 4 (TLR4), and nuclear factor-kappa B (NF-κB)-p65, as well as induced the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), IL-6, and HMGB1 in primary hippocampal neurons and the culture supernatant. In addition, pretreatment with HMGB1-shRNA dramatically reduced both the degree of nuclear-cytoplasmic HMGB1 translocation of HMGB1 and NF-κB DNA binding. Together, the data indicate that HMGB1 mediates the pathogenesis of AD by activating RAGE/TLR4 signaling and that shRNA targeting HMGB1 may be a promising therapeutic strategy for treating AD.

Two new guaiane-type sesquiterpenes from Curcuma kwangsiensis and their inhibitory activity of nitric oxide production in lipopolysaccharide-stimulated macrophages.

Two new guaiane-type sesquiterpenes, kwangsiensis A and B (1-2) were isolated from the roots of Curcuma kwangsiensis. Their structures were elucidated by extensive spectroscopic methods, including NMR, circular dichroism (CD) and high-resolution mass-spectrometry. The anti-inflammatory activity of the two compounds was evaluated on the basis of their inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse RAW 264.7 macrophages. Compounds 1 and 2 showed moderate inhibitory activities with IC50 values of 27.4 and 35.1 µM, respectively.