Association between serum 25-hydroxyvitamin D level and inflammatory markers in hemodialysis-treated patients.

OBJECTIVE: To investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) level with novel inflammatory markers in hemodialysis-treated patients. METHODS: A total of 167 maintenance hemodialysis-treated patients were enrolled in this cross-sectional study. The patients were divided into vitamin D deficiency (a serum 25(OH)D level <20 ng/mL) and nondeficiency (a serum 25(OH)D level ≥20 ng/mL) groups. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) were calculated by the complete blood cell count. The relationship between 25(OH)D level with other parameters was assessed by bivariate correlation analysis and linear regression analysis. RESULTS: There were significant differences between the two groups in terms of age, diabetes, levels of albumin, creatinine, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as NLR and MLR (p = .004, p = .031, p < .001, p = .043, p = .008, p = .006, p = .002, and p < .001, respectively). There exist negative correlations between serum 25(OH)D level with age, diabetes, alkaline phosphatase level, NLR, PLR, and MLR (p = .002, p = .002, p = .037, p = .001, p = .041, and p < .001, respectively) and positive correlations between serum 25(OH)D level with albumin level, creatinine level, phosphorus level, HDL-C, and LDL-C (p < .001, p < .001, p = .013, p = .02, p = .002, respectively). Multiple analysis results showed that sex, diabetes, albumin level and NLR were independently associated with serum 25(OH)D level (p = .021, p = .015, p = .033, and p = .041, respectively). High values of NLR and MLR were associated with patients with serum 25(OH)D deficiency. There were negative interplays between serum 25(OH) D level with NLR, PLR, and MLR and also an independent association between serum 25(OH) D level with NLR. CONCLUSION: Collectively, serum 25(OH)D level has a negative correlation with inflammatory markers.

Long-term efficacy, safety, and medication compliance of roxadustat on peritoneal dialysis patients with renal anemia affected by the COVID-19 pandemic: a retrospective study.

BACKGROUND: Current studies have limited data on long-term treatment safety and medication compliance of roxadustat for renal anemia in peritoneal dialysis (PD) patients. We aimed to analyze the long-term efficacy, safety, and medication compliance of roxadustat in the treatment of renal anemia in patients with PD who discontinued recombinant human erythropoietin (rhEPO) treatment due to the corona virus disease 2019 (COVID-19) outbreak. METHODS: We retrospectively collected patients who were switched from rhEPO to roxadustat in our hospital due to the pandemic. The criteria for subject inclusion: aged >18 years with a dialysis vintage >3 months, without malignant tumor, no severe cardiovascular and cerebrovascular diseases, and not combined hemodialysis. Patients were followed up until the end of December 2021. Hemoglobin (Hb), red blood cell (RBC) and hematocrit (Hct) were recorded at baseline, month 1-12 and month 20, and iron parameters at baseline, 3, 6, 9, 12, and 20 months were collected. The Morisky Medication Adherence Scale-8 (MMAS-8) was used to score medication compliance during rhEPO treatment and roxadustat treatment, and adverse reactions occurred during treatment were collected. The efficacy and medication compliance of roxadustat were analyzed using Wilcoxon rank sum test or t-test. RESULTS: The median follow-up time was 21.1 (20.6, 21.7) months. After 1 month of treatment, the Hb level was significantly increased by 9.4 g/L (95% CI: 6.0-12.8 g/L) compared with the baseline, follow up at 20 months showed the Hb level had remained stable, increased by 20.7 g/L (95% CI: 15.9-25.4 g/L) compared with before treatment. At the beginning of treatment, total iron binding capacity increased, transferrin saturation and serum ferritin decreased, serum iron remained stable during treatment. During roxadustat treatment, no patient discontinued treatment due to the pandemic, and the Morisky score was improved compared with that during rhEPO treatment [5.75 (4.25, 6.00) vs. 6.75 (5.75, 7.00), P=0.000]. There were no serious adverse events associated with roxadustat were observed. CONCLUSIONS: Roxadustat can effectively improve anemia and had good tolerance in patients undergoing PD who have difficult using rhEPO, and the medication compliance was better than rhEPO during the COVID-19.

Activation of TGR5 alleviates inflammation in rheumatoid arthritis peripheral blood mononuclear cells and in mice with collagen II­induced arthritis.

Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis resulting in progressive joint destruction. Persistent synovial inflammation is induced by activation of various inflammatory cells. G­protein­coupled bile acid receptor 1 (TGR5) is a G­protein­coupled receptor activated by various bile acids, which has been reported to act as a key adaptor in regulating various signaling pathways involved in inflammatory responses and a diverse array of physiological processes, including bile acid synthesis, lipid and carbohydrate metabolism, carcinogenesis, immunity and inflammation. In the present study, TGR5 expression was detected in RA peripheral blood mononuclear cells (PBMCs), and its association with clinical disease activity, histological synovitis severity and radiological joint destruction was analyzed. Subsequently, the role and potential underlying mechanisms of TGR5 in the PBMCs of patients with RA and mice with collagen II­induced arthritis (CIA) were investigated. PBMCs were obtained from 50 patients with RA and 40 healthy controls (HCs). The mRNA and protein expression levels of TGR5 were detected in PBMCs via reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and immunofluorescence staining, respectively. Additionally, the levels of proinflammatory cytokines were analyzed by RT­qPCR and enzyme­linked immunosorbent assay (ELISA). The activation of nuclear factor­κB (NF­κB) and IκB kinase a was determined via western blot analysis. The anti­arthritic and anti­inflammatory effects of LCA on mice with CIA were then investigated. The arthritis score was assessed, and the protein levels of proinflammatory cytokines in the plasma of mice were detected via ELISA. TGR5 mRNA expression was significantly downregulated in the PBMCs of patients with RA compared with in those of the HCs (0.53±0.58 for patients vs. 1.49±0.83 for HCs; P<0.001); similar findings were observed at the protein level. The mRNA expression levels of TGR5 in the PBMCs of patients with RA with a high 28­Joint Disease Activity Score (DAS28) were significantly decreased compared with in patients with a low DAS28 (0.81±0.65 for low score vs. 0.35±0.46 for high score; P=0.002). Furthermore, TGR5 expression was significantly correlated with the levels of C­reactive protein (r=­0.429; P=0.002) and the DAS28 (r=­0.383; P=0.006). RT­qPCR and ELISA analyses indicated that lithocholic acid (LCA, 10 mg/kg/day) attenuated lipopolysaccharide­induced proinflammatory cytokine production via inhibition of NF­κB activity in the PBMCs of patients with RA. In addition, the arthritis score was significantly decreased in LCA­treated CIA mice compared with in non­treated CIA mice. The increased production of tumor necrosis factor­α, interleukin (IL)­1ß, IL­6 and IL­8 was significantly reduced in the plasma of LCA­treated CIA mice compared with the control. In conclusion, TGR5 may contribute to the inflammation of PBMCs in patients with RA and mice with CIA.

CYLD suppression enhances the pro-inflammatory effects and hyperproliferation of rheumatoid arthritis fibroblast-like synoviocytes by enhancing NF-κB activation.

BACKGROUND: Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) actively drive joint inflammation and degradation by producing inflammatory cytokines and matrix-degrading molecules, making them key factors in the pathogenesis of RA. Cylindromatosis (CYLD) is a tumor suppressor that downregulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation by deubiquitinating NF-κB essential modulator and tumor necrosis factor receptor-associated factors 2 and 6. In this study, we aimed to determine CYLD expression in the synovium of patients with RA, analyze its correlation with NF-κB activation and clinical disease activity, further investigate CYLD expression in RA-FLSs, and explore CYLD's roles and mechanisms in the pro-inflammatory effects, proliferation, apoptosis, and cell cycles of RA-FLSs. METHODS: We obtained synovia from 50 patients with active RA and 20 with osteoarthritis (OA) and then cultured FLSs from the samples. We determined CYLD expression in the synovia of RA patients and in FLSs via reverse transcription polymerase chain reaction (RT-PCR). CYLD was depleted by lentiviral CYLD short hairpin ribonucleic acid. We used RT-PCR and enzyme-linked immunosorbent assay to analyze the expression of pro-inflammatory cytokines, matrix metalloproteinases (MMPs), and receptor activator of nuclear factor kappa-B ligand (RANKL). We detected cell proliferation using Cell Counting Kit-8 and examined cell apoptosis and cell cycle using flow cytometry. RESULTS: We obtained the following results: 1. In synovia from patients with RA, CYLD expression was significantly downregulated while NF-κB expression was distinctly upregulated, compared with synovia from patients with OA. Thus, there is a significant inverse correlation between CYLD and NF-κB in synovia affected by RA. 2. CYLD expression significantly decreased in RA-FLSs compared with OA-FLSs. 3. CYLD suppression enhanced the production of pro-inflammatory cytokines, MMPs, and RANKL by activating NF-κB in RA-FLSs. 4. CYLD suppression enhanced proliferation, reduced apoptosis, and increased cell division of RA-FLSs and aggravated the activity of NF-κB in RA-FLSs. CONCLUSIONS: Via its regulation of NF-κB activation, CYLD may be involved in the pathogenesis of synovial inflammation in RA as well as in the pro-inflammatory effects and hyperproliferation of RA-FLSs. CYLD may therefore provide a potential target for the treatment of RA.

Peritoneal dialysis treatment for severe lupus nephritis patients complicated with essential organ dysfunction.

The aim of the present study was to evaluate the clinical efficacy of peritoneal dialysis (PD) in patients with severe lupus nephritis (LN) complicated with organ dysfunction. In total, 13 severe LN patients complicated with multiple-organ dysfunction, who underwent PD treatment between November 2003 and September 2010, were enrolled in the study. Six patients received methylprednisolone pulse therapy due to lupus activity and progressive renal failure. These patients were complicated with severe edema, cardiac insufficiency and severe hypoalbuminemia. PD was applied to the patients, followed by the administration of immunosuppressants. Patients were followed-up to review the parameters of renal function, the immunological indexes and the systemic lupus erythematosus disease activity index. The results indicated that the general state of health was markedly improved following PD treatment, with edema abatement and improvement of heart function and physical strength. Serum creatinine levels significantly decreased from 6.3±1.6 to 2.6±1.0 mg/dl. A total of 10 cases ceased PD treatment during the follow-up, while three cases continued PD to the end of the follow-up period. The levels of albumin and hemoglobin exhibited a marked increase from 29.7±5.7 to 35.2±5.5 g/l and 8.7±1.8 to 9.8±1.8 g/l, respectively. There was one case of peritonitis, one case of peritoneal leakage and two cases of pneumonia. Therefore, PD may be a successful treatment method for severe LN patients complicated with essential organ dysfunction. PD not only improved the symptoms of edema and heart failure, but also played an important role in preserving residual renal function and improving the nutritional state of the patients. Thus, PD can be considered as a treatment option for patients with severe LN associated with acute kidney injury, however, selecting a suitable immunosuppressant during PD treatment is essential.

Clinical and pathological features of dense deposit disease in Chinese patients.

AIMS: Dense deposit disease (DDD) is a rare disease that has no universally effective treatment. Herein we explore the clinical and pathological features of DDD in Chinese patients and the therapeutic effect of Tripterygium wilfordii (TW). MATERIALS AND METHODS: Clinical and pathological data of 10 Chinese patients with biopsy-proved DDD were collected and analyzed retrospectively. RESULTS: The patients consisted of 6 males and 4 females. All of them had heavy proteinuria and microscopic hematuria. Gross hematuria, renal insufficiency, anemia, hypertension and low serum complement 3 (C3) occurred in 3, 3, 5, 6 and 8 cases, respectively. Under light microscopy (LM), 8 cases exhibited membranoproliferative glomerulonephritis (MPGN). Periodic acid-Schiff (PAS) stain disclosed intense PAS-positive bright ribbon-like thickening of glomerular basement membranes (GBM). Immunofluorescence mainly showed diffuse fine granular and short linear deposition of C3 along the glomerular capillary wall. Under electron microscopy, ribbon-like electrondense intramembranous deposits were identified in the lamina densa of the GBM, along the tubule basement membranes (TBM) and wall of Bowman's capsule. Before admission, 6 cases were treated with prednisone, cyclophosphamide and/or cyclosporin A with no response. Proteinuria in 8 cases who received TW during the course decreased at different degrees. CONCLUSIONS: The clinical and pathological features in DDD patients were various. The effect of TW in patients with DDD merits further investigation.

Clinical and pathological spectrums of aristolochic acid nephropathy.

AIM: To study the clinical and pathological characteristics of aristolochic acid nephropathy (AAN). METHODS: 86 patients with AAN during 2001 and 2009 in our department were recruited in this retrospective study. The clinical and pathological features were analyzed. RESULTS: There were 47 males and 39 females, aging from 12 to 69 years old. Abnormal urine analysis and gastro-intestinal diseases were two main underlying causes for patients taking aristolochic acid (AA) containing drugs. All patients suffered from renal function impairment. 19 patients (22.0%) presented with acute kidney injury (AKI), while 67 patients (78%) presented as chronic cases. Among them, 31 patients (36.0%) lacked symptoms, 30 patients (34.8%) were accompanied with hypertension, and 26 patients (30.2%) presented with gastrointestinal symptoms. Laboratory examination revealed elevated urine retinol-binding protein (RBP) (90.7%) and urine N-acetyl-ß-glucosaminidase (NAG) (80.2%). Anemia and glucosuria accounted for 64.0% and 58.1%, respectively. Renal biopsy showed prominent tubular brush border ablation (84.2%) in acute cases, while obvious tubular basement membrane (TBM) thickening (81.4%) and interstitial fibrosis were present in chronic cases. During the follow- up, 11 (57.9%) acute cases gained renal function recovery. They had lower urine RBP level and lower incidence of hypokalemia than the non-recovery acute cases. In the chronic group, 27 patients (40.2%) progressed to endstage renal disease (ESRD), with 11 dialysis and 5 renal transplantation cases. CONCLUSION: AAN patients usually suffered from renal impairment with an associated history of taking AA containing drugs. Proximal renal tubular dysfunction and structure destroying would be the main positive findings in laboratory tests and renal biopsy. Urine RBP and hypokalemia might determine the outcome of acute AAN patients.

Delayed renal function recovery from drug-induced acute interstitial nephritis.

INTRODUCTION: Acute interstitial nephritis, considered one of the major causes of reversible acute kidney injury, was frequently encountered as drug-treatment complication in the early stage of infection control. In some cases, drug-induced acute interstitial nephritis (DIAIN) resulted in delayed function recovery or chronic kidney disease. To study the underlying mechanism, the authors investigated the clinical and pathological features of DIAIN patients with delayed renal function recovery. The delayed recovery group consisted of patients with reduced renal function for more than 3 months after diagnosis. METHODS: In this retrospective study, 18 patients with DIAIN from January 2003 to December 2009 were identified as the delayed recovery group, whereas 54 patients with DIAIN who recovered completely within 3 months were treated as the control group. Clinical and pathological features were compared between the 2 groups. RESULTS: In the delayed recovery group, the average age at onset was 48.8 years, antibiotics and herbs were the 2 main causative drugs and the dominant extra-renal manifestation was gastrointestinal symptomatology. In comparison with patients in the control group, patients in the delayed recovery group had longer interval time from disease onset to hospitalization, and they presented with less oliguria. Moreover, these patients had higher levels of urine retinol binding protein, and more renal interstitial inflammatory cell infiltrations were observed in their renal histology. CONCLUSION: Aging, long interval time from disease onset to hospitalization and renal interstitial inflammatory cell infiltration may predict delayed renal function recovery.

[Effect of bushen jianpi decoction and its disassemble recipes on tumor growth in mice with transplanted primary hepatic carcinoma].

OBJECTIVE: To observe comparatively the effects of Bushen Jianpi Decoction (BJD) and its disassemble recipes on tumor growth in mice with transplanted primary hepatic carcinoma (PCH). METHODS: Fifty mice with transplanted PCH were randomly and equally divided into 5 groups. The blank control group consisted of untreated model mice, and 4 treated groups consisted of model mice treated with 5-FU (q. o. d, intraperitoneal injection, x 5), BJD and it disassemble recipes (Bushen portion and Jianpi portion, abbreviated as BSP and JPP hereafter) q. d. by gastrogavage for 10 successive days. The body mass, tumor size, serum vascular endothelial growth factor (VEGF) level, tumor cell apoptosis and percentage of cells, cell cycle as well as the apparent diffusion coefficient (ADC) detected by magnetic resonance imaging (MRI) were observed. RESULTS: Among the 4 treated groups, the heaviest body mass and the de-tumor body mass of mice, and the lowest tumor index were presented in the BJD treated group (P < 0.01 or P < 0.05); ADC in the BJD treated group and the 5-FU treated group was lower than that in the BSP treated group and JPP treated group (P < 0.05); the lowest VEGF level and tumor mass presented in the 5-FU group, and the highest presented in the JPP group (P < 0.01 or P < 0.05). Tumor inhibition rate and cell apoptosis rate in the 5-FU group was highest and in BJD group the secondary. As for cells of different cell cycles, comparisons between the 4 groups showed that S phase cell in 5-FU group < BJD group < BSP and JPP groups (P < 0.01 or P < 0.05); G0-G1 phase cell in BJD and BSP group < JPP group < 5-FU group (P < 0.01 or P < 0.05). No significant difference of G2-M phase cell was shown among them. CONCLUSIONS: The acting mechanism of BJD and its disassembled recipes on transplanted PCH may be inhibiting VEGF expression and accelerating tumor cell apoptosis. Change of MRI's ADC value was keeping in step with changing of VEGF and cell apoptosis. Thereby, it could objectively reflect the metabolism of tumor cells, being a new means for assessing the effect of Chinese materia medica.

Clinicopathological features and prognosis of Chinese patients with acute post-streptococcal glomerulonephritis.

AIM: To investigate clinicopathological and prognostic differences between adults and children with acute post-streptococcal glomerulonephritis (APSGN). METHODS: A retrospective case series of 112 patients with APSGN was undertaken. Patients were divided into two groups according to age: adults aged more than 17 years and children aged less than 15 years. RESULTS: The incidence of APSGN, especially in adults, has decreased in the past three decades. Children have had a higher incidence of macroscopic haematuria than adults (58.3% vs 32.7%, P < 0.05). Laboratory test showed that red blood cell count of urine sediment in children was more significant. On light microscopy, adults had more global glomerulosclerosis, tubular basement membrane thickening, tubular atrophy and interstitial fibrosis, while children had more glomerular infiltrating neutrophils and monocytes and cellular casts. Immunofluorescence microscopy showed that classical staining was seen more in children. The short-term prognoses were good in both children and adults. But the recovery rate of proteinuria in children was faster than that in adults. CONCLUSION: Adults with APSGN had similar clinical features as children except that children had more significant haematuria. On pathology, adults had more outstanding chronic changes by light microscopy and more untypical staining by immunofluorescence.

RGD-based strategies for improving antitumor activity of paclitaxel-loaded liposomes in nude mice xenografted with human ovarian cancer.

Tumor-targeting drug delivery systems are being the ideal carrier for systemic administration of antiproliferative drugs. RGD peptide (arginine-glycine-aspartic acid) modified liposomes containing paclitaxel (RGD-SSL-PTX). The arginine-glycine-aspartic acid tripeptide (RGD) modified sterically stabilized liposomes (SSL) containing paclitaxel (PTX) (RGD-SSL-PTX), which could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. The encapsulation efficiency was more than 90% and the mean particle size was of 120 nm with a narrow size distribution. It was indicated that significant cytotoxicity (3.5 times lower IC(50)) was found in the SKOV-3 human ovarian cancer cells treated with RGD-SSL-PTX preparation, as well as the intracellular uptake of liposomes (a 6.21-fold increase in fluorescence intensity), when compared to those of non-targeted liposomes (SSL). For in vivo antitumor activity, it was shown in the present study that RGD-SSL-PTX preparation had the strongest tumor growth inhibition among the test formulations (P < 0.05) in BALB/c nude mice xenografted with SKOV-3 solid tumor. Meanwhile, there was no significant change in the body weight of the animals treated with RGD-SSL-PTX for intravenous injection at a dose of 12.5 mg/kg. It was suggested that the RGD-SSL-PTX preparation might have a great advantage over present-day chemotherapy with Taxol in curing those tumors overexpressing integrin receptors.