Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

[Interaction between root exudates of medicinal plants and rhizosphere microorganisms and its application in ecological planting of Chinese medicinal materials].

The rhizosphere is an important place for material exchange between medicinal plants and soil. Root exudates are the medium of material and signal exchange between plants and soil and are the key factors in the regulation of rhizosphere microecology. Rhizosphere microorganisms are an important part of the rhizosphere microecology of medicinal plants, and the interaction between root exudates and rhizosphere microorganisms has an important influence on the growth and quality formation of medicinal plants. Rational utilization of the interaction between root exudates and rhizosphere microorganisms of medicinal plants is one of the important ways to ensure the healthy growth of medicinal plants and promote the development of ecological planting of Chinese medicinal materials. In the paper, the research status of root exudates and rhizosphere microorganisms of medicinal plants in recent years was summarized. The interaction mechanism between root exudates and rhizosphere microorganisms of medicinal plants, as well as the influence of rhizosphere microorganisms on the growth of medicinal plants, were analyzed. In addition, the advantages and promoting effects of intercropping ecological planting mode on rhizosphere microecology of medicinal plants and quality improvement of Chinese medicinal materials were explained, providing a good basis for the study of the interaction among medicinal plants, microorganisms, and soil. Furthermore, it could produce important theoretical and practical significance for the ecological planting and sustainable utilization of medicinal plants.

Effects of cadmium contamination on bacterial and fungal communities in Panax ginseng-growing soil.

BACKGROUND: Cadmium (Cd) contamination in soil poses a serious safety risk for the development of medicine and food with ginseng as the raw material. Microorganisms are key players in the functioning and service of soil ecosystems, but the effects of Cd-contaminated ginseng growth on these microorganisms is still poorly understood. To study this hypothesis, we evaluated the effects of microorganisms and Cd (0, 0.25, 0.5, 1.0, 2.0, 5.0, and 10.0 mg kg-1 of Cd) exposure on the soil microbial community using Illumina HiSeq high-throughput sequencing. RESULTS: Our results indicated that Cd-contaminated soil affected the soil microbial diversity and composition, and bacterial diversity was affected more than fungal diversity in Cd-contaminated soil, especially according to Shannon indices. The abundance of the soil microbial community decreased and the composition changed according to the relative abundances at the phylum level, including those of Saccharibacteria and Gemmatimonadetes in bacteria and Mortierellomycota in fungi. The LEfSe algorithm was used to identify active biomarkers, and 45 differentially abundant bacterial taxonomic clades and 16 differentially abundant fungal taxonomic clades were identified with LDA scores higher than 4.0. Finally, a heatmap of Spearman's rank correlation coefficients and canonical discriminant analysis (CDA) indicated that some key biomarkers, Arenimonas, Xanthomonadales, Nitrosomonadaceae, Methylophilales, Caulobacterales, Aeromicrobium, Chitinophagaceae, Acidimicrobiales, Nocardioidaceae, Propionibacteriales, Frankiales, and Gemmatimonadaceae, were positively correlated with the total and available Cd (p<0.05) but negatively correlated with AK, AP, and pH (p<0.05) in the bacterial community. Similarly, in the fungal community, Tubaria, Mortierellaceae, and Rhizophagus were positively correlated with the total and available Cd but negatively correlated with AK, AP, TK, and pH. CONCLUSION: Cd contamination significantly affected microbial diversity and composition in ginseng-growing soil. Our findings provide new insight into the effects of Cd contamination on the microbial communities in ginseng-growing soil.

Predicting the Spatial-Temporal Distribution of Human Brucellosis in Europe Based on Convolutional Long Short-Term Memory Network.

Brucellosis is a chronic infectious disease caused by brucellae or other bacteria directly invading human body. Brucellosis presents the aggregation characteristics and periodic law of infectious diseases in temporal and spatial distribution. Taking major European countries as an example, this study established the temporal and spatial distribution sequence of brucellosis, analyzed the temporal and spatial distribution characteristics of brucellosis, and quantitatively predicted its epidemic law by using different traditional or machine learning models. This paper indicates that the epidemic of brucellosis in major European countries has statistical periodic characteristics, and in the same cycle, brucellosis has the characteristics of piecewise trend. Through the comparison of the prediction results of the three models, it is found that the prediction effect of long short-term memory and convolutional long short-term memory models is better than autoregressive integrated moving average model. The first mock exam using Conv layer and data vectorizations predicted that the convolutional long short-term memory model outperformed the traditional long short-term memory model. Compared with the monthly scale, the prediction of the trend stage of brucellosis can achieve better results under the single model prediction. These findings will help understand the development trend and liquidity characteristics of brucellosis, provide corresponding scientific basis and decision support for potential risk assessment and brucellosis epidemic prevention and control, and reduce the loss of life and property.

[Effects of magnesium supply level on growth, nutrient element absorption and distribution, and quality of Panax quinquefolium].

This study aims to investigate the effects of different magnesium supply levels on the growth, nutrient absorption and distribution, and quality of Panax quinquefolium, and to determine the optimum content of exchangeable magnesium in soil. Three-year-old plants of P. quinquefolium were used in this study, and eight magnesium supply gradients(CK, Mg1-Mg7) were designed for indoor pot experiment(cultivation in soil). The plant growth indexes, nutrient element content in soil and plant, and root saponin content were determined at the end of the growth period. The correlation analysis of nutrient element content in aboveground and underground parts of P. quinquefolium showed significantly negative correlations of magnesium-calcium, magnesium-potassium, and magne-sium-manganese. With the increase in magnesium supply level, the biological absorption coefficient of magnesium increased, while that of total nitrogen, potassium, iron, and manganese decreased; the biological transfer coefficient of magnesium decreased, while that of nitrogen, phosphorus, calcium, iron, and manganese increased. The saponin content was analyzed by principal component analysis, which showed the comprehensive score in the order of Mg4(2.537), Mg2(1.001), Mg3(0.600), Mg1(0), Mg7(-0.765), CK(-0.825), Mg6(-0.922), and Mg5(-1.663). The partial least squares-path modeling(PLS-PM) showed that the correlation coefficients of exchangeable magnesium and pH with quality were-0.748 and-0.755, respectively, which were significant. Magnesium-calcium, magnesium-potassium, and magnesium-manganese showed antagonism in the nutritional physiology of P. quinquefolium. Excessive application of magnesium can lead to the imbalance of nutrient elements in P. quinquefolium. The content of exchangeable magnesium in soil suitable for the quality formation of P. quinquefolium was 193.34-293.34 mg·kg~(-1). In addition to exchangeable magnesium, pH was also important to the quality formation of P. quinquefolium. Therefore, exchangeable magnesium and pH could be regarded as monitoring factors for the quality formation of P. quinquefolium.

[Research progress on pesticide residues of Panax ginseng].

Panax ginseng, a perennial herb, is prone to diseases and insect pests in the growth process, which are primarily prevented and treated by pesticides. However, due to the lack of standardization in the types, frequencies, and doses of pesticides, pesticide residues have become the main exogenous pollutants of P. ginseng. To explore the risk of pesticide residues in P. ginseng, this paper summarized and analyzed the common pesticide residues in P. ginseng, detection techniques, and pesticide residue limit stan-dards based on the published literature in recent years. The results revealed that the main pesticide residues in P. ginseng were organochlorine pesticides, such as tetrachloronitrobenzene, pentachloronitrobenzene, and hexachlorobenzene, and the detection techniques were dominated by gas chromatography(GC), liquid chromatography(LC), or those combined with mass spectrometry(MS). Because of the long half-life and difficulty in degradation, organochlorine pesticides have become the main factor affecting the export of P. ginseng. It is worth mentioning that P. ginseng has been classified as food in Japan, South Korea, the European Union, and other countries, and the standards of pesticide residues and limits are stricter than those in China. The quality and safety of P. ginseng are prerequisites for the efficacy of Chinese medicine and the development of traditional Chinese medicine. The formulation of scientific and effective standards for pesticide application and limits would promote the high-quality development of the P. ginseng industry.

Construction of an integrated multi-layer textile for solar-driven steam generation.

Solar steam generation has widespread application in wastewater treatment, seawater desalination, liquid-liquid separation, and other fields, providing potential opportunities for producing fresh water. Up until now, most researchers in this field focused on enhancing the evaporation rate of the solar steam generation device. However, problems in terms of its portability and flexibility still exist when it comes to real application scenarios. Herein, we propose a novel, to the best of our knowledge, integrated multi-layer textile composed of reduced graphene oxide/cotton (RGO/cotton) fabric, cotton yarn, and polypropylene (PP) fabric for solar-driven steam generation. The evaporation rate obtained by the integrated multi-layer textile as prepared is ${0.83}\;{{\rm kg\cdot m}^{- 2}}\cdot{{\rm h}^{- 1}}$ under one sun solar radiation, which is 3.16 times higher than that of blank experiment and is superior to many previously reported works. Its remarkable evaporation performance is mainly attributed to the inherent multi-layer structures, where porous RGO/cotton fabric exhibits ultra-water vapor permeability, hydrophilic cotton yarn supplies water continuously, and low-density hydrophobic PP fabric hinders heat sustainably. Based on the results of application performance evaluation, the integrated multi-layer textile with scalable manufacturability, portability, durability, and flexibility is expected to boost the development of solar-driven steam generation.

Leflunomide plus low-dose prednisone in patients with progressive IgA nephropathy: a multicenter, prospective, randomized, open-labeled, and controlled trial.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide, and the optimal approach to its treatment remains a significant challenge. METHODS: We did a prospective, randomized, open-labeled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment, and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF + prednisone group) or conventionally accepted-dose prednisone [prednisone(alone) group] Our primary outcome was 24-h urine protein excretion (UPE) and secondary outcomes were serum albumin (sALB), serum creatinine (Scr), and eGFR. Safety was evaluated in all patients who received the trial medications. RESULTS: One hundred and eight patients [59 in LEF + prednisone group, 49 in prednisone (alone) group]were enrolled and finished their treatment and follow-up periods. There is no significant difference in the baseline level between the two groups. Compared with baseline, both groups showed a significant decrease in 24-h UPE (p < 0.01) and increase in sALB (p < 0.01), with stable Scr and eGFR throughout the 12-month treatment period. What's more, these effects were sustained through the 12-month follow-up period. However, there was no difference in 24-h UPE, sALB, Scr, and eGFR between the two groups (p > 0.05). At 12 months, a difference in overall response rate, relapsing rate, and incidence of adverse events between the two groups was not significant. CONCLUSIONS: The efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in the treatment of progressive IgAN are comparable.

Early serum cystatin C-enhanced risk prediction for acute kidney injury post cardiac surgery: a prospective, observational, cohort study.

Background: Acute kidney injury (AKI) is a common post-cardiac surgery complication. It leads to increased morbidity and mortality. The aim of our study is to identify the prevalence and risk factors of AKI and to demonstrate if early postoperative serum cystatin C (sCyC) could accurately predict the development of AKI.Methods: We prospectively studied 628 patients undergoing elective cardiac surgery. Pre-morbid and operative variables known to be or potentially associated with AKI or other adverse outcomes were examined. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria. Blood samples for biomarker measurement were collected at baseline, within 10 h of surgical completion and daily for three days. Logistic regression was used to assess predictive factors for AKI including 10 h sCyC. Model discrimination was assessed using receiver operator characteristic (ROC) curves.Results: AKI occurred in 178 (28.3%) patients, Stage 1 in 17.5%, Stage 2 in 8.6% and Stage 3 in 2.2%. Mortality rose progressively with increased AKI stage (non-AKI 0.2%, Stage 1 1.8%, Stage 2 11.1% and Stage 3 35.7%). Age > 75 years, baseline estimated glomerular filtration rate (eGFR), proteinuria, diabetes mellitus, hypertension, hyperuricaemia, NYHA classification >2, recent myocardial infarction were associated with AKI in univariate analysis. A multivariate logistic model with clinical factors (age, eGFR, hypertension, NYHA classification >2, combined surgery and operation time) demonstrated moderate discrimination for AKI (area under ROC curve [AUC] 0.75). The 10 h postoperative sCyC levels strongly associated with AKI. After multivariable adjustment, the highest quartile of sCyC was associated with 13.1 - higher odds of AKI, compared with the lowest quartile. Elevated 10 h sCyC levels associated with longer hospital stay, longer intensive care unit stay and duration of mechanical ventilation. The addition of 10 h sCyC improved model discrimination for AKI (AUC 0.81).Conclusions: AKI following cardiac surgery was identified using KDIGO criteria in around one fourth of the patients. These patients had significantly increased morbidity and mortality. When added to prediction model, 10 h sCyC may enhance the identification of patients at higher risk of AKI, providing a readily available prognostic marker.

Use of Both Serum Cystatin C and Creatinine as Diagnostic Criteria for Cardiac Surgery-Associated Acute Kidney Injury and Its Correlation with Long-Term Major Adverse Events.

BACKGROUND/AIMS: Cardiac surgery-associated acute kidney injury (CSA-AKI) was traditionally defined as an increase in serum creatinine (sCr) after cardiac surgery. Recently, serum cystatin C (sCyC) has been proposed to be a better biomarker in the prediction of AKI. The clinical utility and performance of combining sCyC and sCr in patients with AKI, particularly for the prediction of long-term outcomes, remain unknown. METHODS: We measured sCyC together with sCr in 628 patients undergoing cardiac surgery. sCyC and sCr were assessed at baseline and 24 and 48 h after surgery. CSA-AKI determined by sCr (CSA-AKIsCr) was defined as an sCr increase greater than 0.3 mg/dL or 50% from baseline. Major adverse events (MAEs; including death of any cause and dialysis) at 3 years were assessed. RESULTS: CSA-AKIsCr developed in 178 patients (28.3%). Three-year follow-up was available for 621 patients; MAEs occurred in 42 patients (6.8%). An increase in sCyC concentration ≥30% within 48 h after surgery was detected in 228 patients (36.3%). This was the best sCyC cutoff for CSA-AKIsCr detection (negative predictive value = 88.8%, positive predictive value = 58.3%). To evaluate the use of both sCyC and sCr as CSA-AKI diagnostic criteria, we stratified patients into 3 groups: non-CSA-AKI, CSA-AKI detected by a single marker, and CSA-AKI detected by both markers. By multivariable logistic regression analysis, the independent predictors of MAEs at 3 years were group 2 (non-CSA-AKI group as the reference, CSA-AKI detected by a single marker: odds ratio [OR] = 3.48, 95% confidence interval [CI]: 1.27-9.58, p = 0.016), group 3 (CSA-AKI detected by both markers: OR = 5.12, 95% CI: 2.01-13.09; p = 0.001), and baseline glomerular filtration rate (OR = 2.24; 95% CI: 1.27-3.95; p = 0.005). CONCLUSION: Combining sCyC and sCr to diagnose CSA-AKI would be beneficial for risk stratification and prognosis in patients after cardiac surgery.

Outcomes and practice patterns with hemodiafiltration in Shanghai: a longitudinal cohort study.

BACKGROUND: Globally, there is increased clinical interest and uptake of hemodiafiltration (HDF) for increased removal of uremic toxins. To date, there has been no epidemiological analysis of HDF in China. We present HDF practice patterns and associated mortality risk in Shanghai. METHODS: This is an observational, prospectively collected, retrospective analysis of 9351 Chinese patients initiating hemodialysis in Shanghai from 2007 to 2014. The primary exposure was hemodialysis sub-modality at inception, classified into hemodiafiltration (HDF) and hemodialysis (HD), with adjustment for concommitant hemoperfusion. The primary outcome was patient mortality. We used Cox proportional hazards regression and Fine and Gray's proportional subhazards regression, with multiple imputation of missing co-variates by the chained equation method, adjusting for demographic and clinical variables. RESULTS: Overall, patients in the cohort were younger, with a more males, and with a lower body mass index when compared to corresponding non-Asian cohorts. Mortality rate was low although it doubled over the period of observation. HDF utilization increased from 7% of patients in 2007 to 42% of patients in 2014. The majority of patients received HDF once a week. The adjusted hazard ratio of death (95% confidence intervals) for HDF versus HD was 0.85 (0.71-1.03), and corresponding sub-hazard ratio 0.86 (0.71-1.03). There was strong effect modification by age. In those aged 40-60 years, the hazard ratio (95% confidence intervals) was 0.65 (0.45-0.94), and sub-hazard ratio also 0.65 (0.45-0.95). CONCLUSIONS: Our study has certain limitations resulting from the limited number of co-variates available for modelling, missing data for some co-variates, and the lack of verification of data against source documentation. Notwithstanding, there is evidence of clinical benefit from HDF in China, and potential to improve patient outcomes through the greater removal of middle and larger uremic solutes.

Association of serum angiopoietin-2 with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients: a prospective cohort study.

BACKGROUND: To examine serum angiopoietin-2 (Angpt-2) in relation to malnutrition, inflammation, atherosclerosis and cardiac valvular calcification, so-called MIAC syndrome and its predictive role in outcomes of peritoneal dialysis (PD) patients. METHODS: A prospective observational study was conducted in 324 chronic PD patients. Biochemical analysis was performed at baseline for serum angiopoietins, albumin and high sensitive C-reactive protein (hs-CRP) and echocardiography was done to detect cardiac valvular calcification. Primary study end points were fatal or nonfatal cardiovascular events and mortality. RESULTS: The median of serum Angpt-2 levels was 5.44 ng/mL (interquartile range, 3.41-7.85). Across the three tertiles of serum Angpt-2, a significant trend effect was observed for body mass index, normalized protein catabolic rate, calcium × phosphorus product, hs-CRP, brain natriuretic peptide, lower-density lipoprotein cholesterol, left ventricular ejection fraction, total weekly urea clearance and residual renal function (all p < 0.05). Serum Angpt-2 showed a significant increase across the four groups of patients with increasing components of MIAC syndrome (p < 0.001). There were 77 deaths and 57 cardiovascular events. High serum Angpt-2 was an independent predictor of fatal and nonfatal cardiovascular events in PD patients (p = 0.02), however serum Angpt-2 was not an independent predictor of all-cause mortality (p = 0.3). CONCLUSIONS: Serum Angpt-2 showed close association with valvular calcification, atherosclerosis, inflammation and malnutrition, having significant independent prognostic value and is useful for cardiovascular event stratification in chronic PD patients. Angpt-2 might be a potential mediator of increased cardiovascular risk in patients undergoing PD treatment.

Variability of serum phosphorus and its association with mortality among hemodialysis patients
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OBJECTIVE: To determine the relationship between the variability of serum phosphorus and mortality among maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: A total of 502 MHD cases were studied from the Shanghai Renal Registry Network. Serum phosphorus variability was indicated by a coefficient of variation (CV). According to the CV median of serum phosphorus, patients were divided into two groups: a high-variability group (CV ≥ 0.226 mmol/L) and a low-variability group (CV < 0.226 mmol/L). Average phosphorus ≤ 1.78 mmol/L was defined as the standard phosphorus group and serum phosphorus > 1.78 mmol/L was defined as the non-standard phosphorus group. The relationship between serum phosphorus variability and all-cause and cardiovascular disease (CVD) mortality was assessed. RESULTS: In the 502 MHD cases, the average age of patients was 63.9 ± 14.60 years, and dialysis vintage was 82.0 (43.0 - 139.0) months. 118 patients (23.5%) died, succumbing to all-cause mortality, while 64 patients (14.3%) died from CVD. The high-variability group had increased all-cause mortality (27.7% vs. 19.3%, p = 0.028). Death from CVD was increased in the high-variability group, but had no statistical significance (15.4% vs. 10.0%, p = 0.082). Cox regression analysis showed that older age, low hemoglobin levels, a higher phosphorus CV, and low serum albumin were independent risk factors for all-cause and CVD mortality. The standard group with low-phosphorus variability had a decreased mortality compared with the non-standard group with high variability (15.3 vs. 29.2%, p = 0.047 and 6.0 vs. 15.0%, p = 0.033, respectively). The Kaplan-Meier method revealed that patients with low phosphorus variability had a decreased all-cause and CVD mortality (p = 0.023 and p = 0.047, respectively) compared with high phosphorus variability patients. CONCLUSION: Higher phosphorus CV was independently correlated with all-cause and CVD mortality. Low phosphorus variability with on-target levels resulted in decreased patient mortality. Thus, stable serum phosphorus levels may improve survival in MHD patients.
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Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model.

BACKGROUND: Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model. METHODS: 32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal® for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real-time PCR, immunohistochemical staining, and western blot. RESULTS: Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p < 0.05). CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001). CONCLUSION: PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model.

Different patterns of inflammatory and angiogenic factors are associated with peritoneal small solute transport and peritoneal protein clearance in peritoneal dialysis patients.

BACKGROUND: Both peritoneal small solute transport and peritoneal protein clearance are closely linked to outcomes in peritoneal dialysis (PD) patients. However, the associated factors of these two components are not fully understood so far. This study aimed to investigate the association between a panel of systemic and peritoneal inflammatory and angiogenic factors and peritoneal solute transport properties. METHODS: Stable PD patients in PD center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University were enrolled in present study. Serum and overnight effluent markers including angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), sTie-2, VEGF, IL-6 and IL-10 were determined. Mass transfer area coefficient of creatinine (MTACcr) and peritoneal protein clearance (Prcl) were calculated. Multivariable linear regression was used to examine the association between these markers and MTACcr as well as Prcl. RESULTS: A total of 320 patients were enrolled in present study, which consisted of 166 (51.9%) males with a mean age of 56.8 ± 14.2 years and a median PD duration of 32.5 (9.0-56.3) months. Multiple regression analyses showed that BSA, history glucose exposure, dialysate IL-6 AR and dialysate Ang-1 AR were independent associated factors of MTACcr, while BSA and serum Ang-1 were independent associated factors of Prcl. CONCLUSIONS: MTACcr representing peritoneal small-solute transport and Prcl representing peritoneal large molecular transport are associated with slightly different panels of inflammatory and angiogenic factors.

Three Versus 4 Daily Exchanges and Residual Kidney Function Decline in Incident CAPD Patients: A Randomized Controlled Trial.

BACKGROUND: Incident patients treated with continuous ambulatory peritoneal dialysis (CAPD) are often prescribed either 3 or 4 exchanges per day. However, the effects on residual kidney function and clinical outcomes of 3 versus 4 exchanges are not known. STUDY DESIGN: Prospective, randomized, controlled, open-label study. SETTING & PARTICIPANTS: Incident CAPD patients aged 18 to 80 years with glomerular filtration rates (GFRs; mean of renal urea and creatinine clearance from a 24-hour urine collection) ≥ 2mL/min and urine volume ≥ 500mL/d. Exclusion criteria included refusal for informed consent, history of maintenance hemodialysis therapy or transplantation, or limited life expectancy. INTERVENTION: 24-month intervention with 3- or 4-exchange CAPD using glucose-based peritoneal dialysis fluids. OUTCOMES: Primary outcomes were GFR, urine volume, and anuria-free survival. Secondary outcomes included peritonitis, patient survival, and technique survival. RESULTS: The study recruited 139 patients, 70 in the 3-exchange group and 69 in the 4-exchange group. Baseline body mass indexes were 21.4±3.0 and 21.9±3.2kg/m2 for the 3- and 4-exchange groups, respectively (P=0.4). After 24 months, for 3 versus 4 exchanges, GFR (1.6±2.0 vs 1.7±1.9mL/min; P=0.8), urine volume (505±522 vs 474±442mL/d; P=0.8), and anuria-free survival (log-rank test statistic = 0.055; P=0.8) did not differ between groups, but Kt/V (1.95±0.39 vs 2.19±0.48; P=0.03) and ultrafiltration (404±499 vs 742±512mL/d; P=0.004) were lower in the 3-exchange group. The 3-exchange group had nominally longer peritonitis-free survival time (log-rank test statistic = 3.811; P=0.05), and nominally fewer patients had peritonitis in this group, though this was not statistically significant (13% vs 26%; P=0.06). Patient survival (log-rank test statistic = 0.978; P=0.3) and technique survival (log-rank test statistic = 0.347; P=0.6) were similar between groups. LIMITATIONS: Single-center design; no formal sample-size calculations. CONCLUSIONS: In this small trial, CAPD regimens with 3 and 4 exchanges had similar effects on residual GFR, urine volume, and time to anuria. Incremental peritoneal dialysis starts appear safe when patients are monitored.

Prognostic Value of the Delivery Dialysis Dose on Twice-Weekly Hemodialysis Patients.

BACKGROUND: Few studies have evaluated the prognostic value of dialysis dose in twice-weekly hemodialysis (HD). A single-pool Kt/V (spKt/V) over 1.70 may benefit patients receiving twice-weekly maintenance HD. METHODS: This is a multicenter randomized controlled trial performed on 163 patients from 17 dialysis centers in Shanghai who were allocated to high- (n = 98) and standard-dose groups (n = 65) and followed through 96 weeks of study period. Therapeutic approaches were given to increase spKt/V to over 1.70 in the high-dose group. Data were collected every 12-24 weeks. The primary outcomes were all-cause mortality and major adverse cardio-cerebrovascular events (MACEs) occurrence, and secondary outcomes included residual kidney function (RKF) and health-related quality of life (HR-QOL). RESULTS: The spKt/V in high-dose and standard-dose groups were 1.80 ± 0.23 and 1.55 ± 0.19, respectively, after an 8-week intervention (p < 0.001). At the end of the study, SF-36 physical function and total score in high-dose group were 82 (69-90) and 74 (47-84), respectively, both of which were higher than those in the standard-dose group. Decline in urine volume was observed in both groups with no significant difference (p = 0.431). No difference was found in overall survival between the 2 groups (p = 0.580). The 1-year MACE-free survival for high-dose group was 84.49%, better than 76.72% for standard-dose group (p = 0.029). CONCLUSIONS: Higher spKt/V is also associated with MACE-free survival and better HR-QOL, especially in physical function aspect for twice-weekly dialysis patients. Increasing spKt/V over 1.70 in twice-weekly HD population does not cause loss of RKF.

Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.

BACKGROUND: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). METHODS: In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed. RESULTS: In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects. CONCLUSIONS: FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

Twice-Weekly Hemodialysis in China: Can It Be A Better Option for Initiation or Maintenance Dialysis Therapy?

Cumulative evidence indicates it may be worthwhile revisiting the twice-weekly hemodialysis (HD) regimen as a valid option for individualized or incremental treatments for selected patients with end-stage renal disease. In this article, we will review the current evidences on the potential pros and cons of twice-weekly HD compared to thrice-weekly HD including China's experience in the practice of twice-weekly HD. A prudent patient selection and close dialysis adequacy monitoring might be necessary for this medical treatment choice. More randomized prospective controlled studies for the critical evaluation of twice-weekly dialysis are encouraged.

Interleukin-6 trans-signalling induces vascular endothelial growth factor synthesis partly via Janus kinases-STAT3 pathway in human mesothelial cells.

AIMS: Interleukin-6 (IL-6) is a vital inflammatory factor in the peritoneal cavity of peritoneal dialysis (PD) patients. Because intraperitoneal inflammation is closely associated with angiogenesis, we sought to explore the effect of IL-6 on vascular endothelial growth factor (VEGF) synthesis and its transduction pathway in mesothelial cells. METHODS: Human mesothelial cells (Met-5A) were incubated with different concentrations of glucose and mannitol, and the effect of glucose and mannitol on the expression of IL-6 was determined. Then, the cells were stimulated by IL-6 with or without two soluble receptors of IL-6 (sIL-6R or sgp130), and VEGF synthesis was detected. Finally, the cells were incubated with IL-6/sIL-6R combined with or without the inhibitor of Janus kinases (JAK) AG490. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and its intracellular translocation were examined. RESULTS: 1. High glucose and mannitol could upregulate IL-6 mRNA expression and IL-6 secretion in mesothelial cells significantly, and there was no difference of its effect between high glucose and mannitol. 2. Met-5A was a cell line with a single IL-6 receptor. The IL-6/sIL-6R complex induced VEGF synthesis of mesothelial cells, which was alleviated by sgp130 or AG490. IL-6 trans-signalling could induce the phosphorylation of STAT3, which is recruited to the cellular nucleus of Met-5A cells. CONCLUSION: The present study might provide evidence that high glucose upregulates IL-6 synthesis in Met-5A cells, to some extent, depending on its osmolality and that IL-6 trans-signalling could induce VEGF synthesis partly dependent on the JAK/STAT3 pathway.