Prevalence and risk factors of relapse in patients with ANCA-associated vasculitis receiving cyclophosphamide induction: a systematic review and meta-analysis of large observational studies.

BACKGROUND: Clinical relapses are common in patients with ANCA-associated vasculitis (AAV). The aim of this systematic review was to estimate time-point prevalence and risk factors of relapse. METHODS: We searched PubMed, Embase, and Cochrane Library databases from their inception to March 30, 2020. Cohorts and post-hoc studies were included for the estimation of summary cumulative relapse rates (CRRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Sensitivity and meta-regression analyses were also performed. RESULTS: Of the 42 eligible studies, 24 studies with 6236 participants were used for the pooled analyses of CRRs. The summary 1-year, 3-year, and 5-year CRRs were 0.12 (95% CI, 0.10-0.14), 0.33 (0.29-0.38), and 0.47 (0.42-0.52), respectively. In meta-regressions, the baseline age was positively associated with 1-year CRR. The proportion of granulomatosis with polyangiitis was positively associated with 5-year CRR. Twenty-eight studies with 5390 participants were used for the meta-analysis of risk factors for relapse, including a lower level of baseline serum creatine, proteinase 3 (PR3)-ANCA positivity at diagnosis, an ANCA rise, extrarenal organ involvement (including lung, cardiovascular, upper respiratory, and gastrointestinal involvement), intravenous (vs oral) cyclophosphamide induction, a shorter course of immunosuppressant maintenance, and maintenance with mycophenolate mofetil (vs azathioprine). CONCLUSIONS: Our systematic review demonstrated that the 1-year, 3-year, and 5-year cumulative probabilities of relapse were ∼12%, 33%, and 47% in AAV patients receiving cyclophosphamide induction, respectively. Early identification of risk factors for relapse is helpful to the risk stratification of patients so as to achieve personalized treatment.

Red blood cell distribution width and peritoneal dialysis-associated peritonitis prognosis.

Objective: Red blood cell distribution width (RDW) is a parameter of the heterogeneity of circulating erythrocyte size. Recent researches have pointed out a link among RDW, chronic kidney disease, and inflammation. We sought to investigate the prognostic value of baseline RDW in patients with peritoneal dialysis-associated peritonitis (PDAP).Methods: Our study included 337 peritonitis episodes experienced by 202 patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD) at a single center from 2013 to 2018. Episodes were categorized according to the tertiles of baseline RDW levels (T1, <13.2%; T2, 13.2-14.3%; T3, >14.3%). Routine logistic regression and generalized estimating equation (GEE) were used to estimate the association between RDW and treatment failure, which was defined as relapse/recurrent episodes, catheter removal, or death during therapy.Results: After adjusting for other potential predictors, RDW exhibited an incremental relationship with the risk of treatment failure. The baseline RDW of T3 indicated a 43% and 52% increased venture of treatment failure in logistic and GEE analyses, respectively, compared with T1. As a continuous variable, the fitting curve based on restricted cubic spiline showed that the relationship was nonlinearly but positively correlated. The multivariate model A (combined RDW with baseline age, albumin, serum ferritin, and duration on CAPD) showed an area under the curve of 0.671 (95% confidence interval, 0.5920.749) for the prediction of treatment failure.Conclusions: A Higher baseline level of RDW was significantly associated with a greater rate of treatment failure among PDAP episodes independent of other potential predictors.

Role of Endothelial Cells in Renal Fibrosis.

Renal fibrosis has been regarded as the common pathway of end-stage renal failure. Understanding the fundamental mechanism that leads to renal fibrosis is essential for developing better therapeutic options for chronic kidney diseases. So far, the main abstractions are on the injury of tubular epithelial cells, activation of interstitial cells, expression of chemotactic factor and adhesion molecule, infiltration of inflammatory cells and homeostasis of ECM. However, emerging studies revealed that endothelial cells (ECs) might happen to endothelial-to-mesenchymal transition (EndMT) dependent and/or independent endothelial dysfunction, which were supposed to accelerate renal fibrosis and are identified as new mechanisms for the proliferation of myofibroblasts as well. In this chapter, we are about to interpret the role of ECs in renal fibrosis and analyze the related molecules and pathways of both EndMT and EndMT independent endothelial dysfunction.

Neutrophil-to-Lymphocyte Ratio and Treatment Failure in Peritoneal Dialysis-Associated Peritonitis.

Objective: We sought to explore if there is an association between neutrophil-to-lymphocyte ratio (NLR) and treatment failure in patients with peritoneal dialysis-associated peritonitis (PDAP). Methods: Our cohort involved 337 episodes of PDAP experienced by 202 patients who were undergoing continuous ambulatory peritoneal dialysis at a single center from 1 July 2013 to 30 June 2018. The exposures were log-transformed NLR and a categorical variable grouped by the tertiles of NLR levels (T1, <3.75; T2, 3.75-6.53; and T3, >6.53) at baseline. Generalized estimating equation (GEE) and restricted cubic spline (RCS) analyses were done to determine the association between NLR and treatment failure, defined as catheter removal or all-cause mortality during therapy. Results: After adjusting for other potential predictors, the log-transformed NLR exhibited an incremental relationship with the risk of treatment failure (odds ratio, 1.82; 95% confidence interval, 1.05-3.15). RCS analyses showed that the relationship was positively and linearly correlated (P for nonlinearity = 0.104). As a three-level categorical variable, in reference to T1, the T3 of NLR showed a 3.41-fold increased venture of treatment failure in fully adjusted model. Subgroup analyses suggested that the prognostic relevance of NLR in PDAP was particularly significant in gram-negative peritonitis. Conclusions: A greater level of NLR at baseline was remarkably associated with a higher incidence of treatment failure among PDAP episodes regardless of other potential risk factors.

Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m2, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg. MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER: NCT02063100 on ClinicalTrials.gov.

Micro-vesicles from mesenchymal stem cells over-expressing miR-34a inhibit transforming growth factor-ß1-induced epithelial-mesenchymal transition in renal tubular epithelial cells in vitro.

BACKGROUND: The use of microRNAs in the therapy of kidney disease is hampered by the difficulties in their effective delivery. Micro-vesicles (MVs) are known as natural carriers of small RNAs. Our prior research has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) are capable of attenuating kidney injuries induced by unilateral ureteral obstruction and 5/6 sub-total nephrectomy in mice. The present study aimed to evaluate the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-ß1-induced fibrosis and apoptosis in vitro. METHODS: Bone marrow MSCs were modified by lentiviruses over-expressing miR-34a, from which MVs were collected for the treatment of human Kidney-2 (HK-2) renal tubular cells exposed to TGF-ß1 (6 ng/mL). The survival of HK-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and Annexin V-Light 650/propidium iodide (PI) assays. The expression levels of epithelial markers (tight junction protein 1 [TJP1] and E-cadherin) and mesenchymal markers (smooth muscle actin alpha (α-SMA) and fibronectin) in HK-2 cells were measured using Western blot analysis and an immunofluorescence assay. In addition, changes in Notch-1/Jagged-1 signaling were analyzed using Western blotting. Data were analyzed using a Student's t test or one-way analysis of variance. RESULTS: MiR-34a expression increased three-fold in MVs generated by miR-34a-modified MSCs compared with that expressed in control MVs (P < 0.01, t = 16.55). In HK-2 cells, TJP1 and E-cadherin levels decreased to 31% and 37% after treatment with TGF-ß1, respectively, and were restored to 62% and 70% by miR-34a-enriched MSC-MVs, respectively. The expression of α-SMA and fibronectin increased by 3.9- and 5.0-fold following TGF-ß1 treatment, and decreased to 2.0- and 1.7-fold after treatment of HK-2 cells with miR-34a-enriched MSC-MVs. The effects of miR-34a-enriched MSC-MVs on epithelial-mesenchymal transition (EMT) markers were stronger than control MSC-MVs. The effects of miR-34a-enriched MSC-MVs on these EMT markers were stronger than control MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. It was further observed that elevation of Notch-1 and Jagged-1 induced by TGF-ß1 was inhibited by miR-34a-enriched MSC-MVs. In addition, TGF-ß1 exposure also induced apoptosis in HK-2 cells. Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-ß1-triggered apoptosis in HK-2 cells, the effects were less significant than control MSC-MVs (control:TGF-ß1: miR-nc-MV:miR-34a-MV = 1.3:0.6:1.1:0.9 for MTT assay, 1.8%:23.3%:9.4%:17.4% for apoptosis assay). This phenomenon may be the result of the pro-apoptotic effects of miR-34a. CONCLUSIONS: The present study demonstrated that miR-34a-over-expressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-ß1 in renal tubular epithelial cells, possibly through inhibition of the Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with an anti-fibrotic molecule may represent a novel strategy for the treatment of renal injuries.

Safety, Effectiveness, and Manipulability of Peritoneal Dialysis Machines Made in China: A Randomized, Crossover, Multicenter Clinical Study.

BACKGROUND: Automated peritoneal dialysis (APD) can cater to individual needs, provide treatment while asleep, take into account the adequacy of dialysis, and improve the quality of life. Currently, independent research and development of APD machines made in China are more conducive to patients. A randomized, multicenter, crossover study was conducted by comparing an APD machine made in China with an imported machine. The safety, effectiveness, and manipulability of the two machines were compared. METHODS: Two hundred and sixty patients who underwent peritoneal dialysis (PD) on a regular basis in 18 centers between August 2015 and February 2016 were included. The inclusion criteria include age ≥18 years and PD ≥30 days. The exclusion criteria were as follows: hemodialysis; exit site or tunnel infection; and peritonitis ≤30 days. The patients were randomly divided into Group A, who were first treated with a FM machine made in China, then changed to an imported machine; and Group B, who were treated using the reverse sequence. APD treatment was performed with 10 L/10 h and 5 cycles of exchange. After 72 h, the daily peritoneal Kt/V, the accuracy of the injection rate, accuracy of the injection temperature, safety, and manipulability of the machine were assessed. Noninferiority test was conducted between the two groups. RESULTS: The daily peritoneal Kt/V in the APD machine made in China and the imported APD machine were 0.17 (0.14, 0.25) and 0.16 (0.13, 0.23), respectively. There was no significant difference between the groups (Z = 0.15, P = 0.703). The lower limit of the daily Kt/V difference between the two groups was 0.0069, which was greater than the noninferiority value of -0.07 in this study. The accuracy of the injection rate and injection temperature was 89.7% and 91.5%, respectively, in the domestic APD machine, which were both slightly better than the accuracy rates of 84.0% and 86.8% in the imported APD machine (89.7% vs. 84.0%, P = 0.2466; 91.5% vs. 86.8%, P = 0.0954). Therefore, the APD machine made in China was not inferior to the imported APD machine. The fuselage of the imported APD machine was space-saving, while the APD machine made in China was superior with respect to body mobility, man-machine dialog operation, alarm control, and patient information recognition. CONCLUSIONS: The FM machine made in China was not inferior to the imported APD machine. In addition, the FM machine made in China had better operability. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02525497; https://clinicaltrials.gov/ct2/results?cond=&term=NCT02525497&cntry=& state=&city=&dist=.

[The effect of calcyclin binding protein on gastric cancer cell proliferation].

OBJECTIVE: To study the effect of calcyclin binding protein (CacyBP) on the proliferation of gastric cancer cells. METHODS: CacyBP siRNA expression vector was constructed and transfected into the gastric cancer cells of the line SGC7901 (SGC/CacyBP-siRNA cells). Blank vector mU6 was transfected too as control group (SGC/mU6 cells). Western blotting and semi-quantitative RT-PCR were used to detect the protein expression and mRNA expression of CacyBP in the transfected cells. Immunofluorescence staining was used to detect the intensity of green fluorescence. The cell growth was determined by MTT method. Western blotting and semi-quantitative RT-PCR were used to detect the protein expression and mRNA expression of beta-catenin, cyclooxygenase-2 (COX-2), cyclin D1, rac1, and heat shock protein (HSP) 70. The protein level of beta-catenin in the nuclei of the transfected cells was detected. Twenty-fife nude mice were randomly divided into 5 groups to be inoculated with the SGC7901 cells stably transfected with CacyBP siRNA expression vector and the size of tumor was observed 1, 2, 3, 4, and 5 weeks after the inoculation respectively. The blank vector mU6 was inoculated as control group. RESULTS: The mRNA expression and protein expression of endogenous CacyBP in the SGC/CacyBP-siRNA cells were both markedly lower than those of the SGC/mU6 cells. Immunofluorescence staining showed weaker green fluorescence in the SGC/CacyBP-siRNA cells than the SGC/mU6 cells. MTT method showed that the growth of the SGC/CacyBP-siRNA cells was significantly faster than that of the SGC/mU6 cells (P < 0.01). Western blotting showed remarkable up-regulation of the protein expression of beta-catenin, COX-2, cyclin D1, rac1, and HSP 70 in the SGC/CacyBP-siRNA cells; and semi-quantitative RT-PCR showed remarkable up-regulation of the mRNA expression of COX-2 and cyclin D1 in the SGC/CacyBP-siRNA cells, however, the mRNA expression of HPS70, rac1, and beta-catenin showed no significant differences between these 2 groups. The size of tumor of the mice inoculated with SGC/CacyBP-siRNA cells was significantly larger than that of the mice inoculate with SGC/mU6 cells (P < 0.01). The survival times of the nude mice inoculated with SGC/CacyBP-siRNA1 and SGC/CacyBP-siRNA1 cells respectively were 60 d +/- 8 d and 50 d +/- 4 d, both significantly shorter than that of the control group (75 d +/- 9 d, both P < 0.01). CONCLUSION: The down-regulation of CacyBP can promote the proliferation of gastric cancer cells and aggravate their malignant behavior.

0.9% saline is neither normal nor physiological.

The purpose of this review is to objectively evaluate the biochemical and pathophysiological properties of 0.9% saline (henceforth: saline) and to discuss the impact of saline infusion, specifically on systemic acid-base balance and renal hemodynamics. Studies have shown that electrolyte balance, including effects of saline infusion on serum electrolytes, is often poorly understood among practicing physicians and inappropriate saline prescribing can cause increased morbidity and mortality. Large-volume (>2 L) saline infusion in healthy adults induces hyperchloremia which is associated with metabolic acidosis, hyperkalemia, and negative protein balance. Saline overload (80 ml/kg) in rodents can cause intestinal edema and contractile dysfunction associated with activation of sodium-proton exchanger (NHE) and decrease in myosin light chain phosphorylation. Saline infusion can also adversely affect renal hemodynamics. Microperfusion experiments and real-time imaging studies have demonstrated a reduction in renal perfusion and an expansion in kidney volume, compromising O2 delivery to the renal parenchyma following saline infusion. Clinically, saline infusion for patients post abdominal and cardiovascular surgery is associated with a greater number of adverse effects including more frequent blood product transfusion and bicarbonate therapy, reduced gastric blood flow, delayed recovery of gut function, impaired cardiac contractility in response to inotropes, prolonged hospital stay, and possibly increased mortality. In critically ill patients, saline infusion, compared to balanced fluid infusions, increases the occurrence of acute kidney injury. In summary, saline is a highly acidic fluid. With the exception of saline infusion for patients with hypochloremic metabolic alkalosis and volume depletion due to vomiting or upper gastrointestinal suction, indiscriminate use, especially for acutely ill patients, may cause unnecessary complications and should be avoided. More education regarding saline-related effects and adequate electrolyte management is needed.

ABCG2 protects kidney side population cells from hypoxia/reoxygenation injury through activation of the MEK/ERK pathway.

Breast cancer resistance protein 1 (BCRP1/ABCG2) is used to identify the side population (SP) within a population of cells, which is enriched for stem and progenitor cells in different tissues. Here, we investigated the role of extracellular signal-regulated kinase (ERK) 1/2 in the signaling mechanisms underlying ischemic/hypoxic conditions in kidney SP cells. Kidney SP cells were isolated using Hoechst 33342 dye-mediated fluorescein-activated cell sorting and then incubated under hypoxia/reoxygenation (H/R) with or without verapamil, a selective BCRP1/ABCG2 inhibitor. ABCG2 expression, ERK activity, cell viability, metabolic activity, and membrane damage were tested after H/R treatment. To evaluate the role of ERK 1/2 on the expression and function of ABCG2, the expression of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), which preferentially activates ERK, was upregulated by transfection with the recombinant sense expression vector pcDNA3.1-MEK and downregulated by pretreatment with U0126, a specific MEK inhibitor. We found that hypoxia activated ERK activity in the kidney SP cells but not in non-SP cells both in vitro and in vivo. Overexpression of MEK mimicked hypoxia-induced ABCG2 expression. Contrarily, U0126 inhibited hypoxia- and MEK-upregulated ABCG2 expression. Furthermore, H/R induced significant increases in nuclear, metabolic, and membrane damage in both SP cells and non-SP cells; however, this H/R-induced cytotoxicity was much more severe in non-SP cells than in SP cells. Notably, the viability of kidney SP cells was enhanced by MEK overexpression and inhibited by U0126. Verapamil treatment reversed MEK-induced viability of kidney SP cells. When administered systemically into animals with renal ischemia/reperfusion injury, the SP cells significantly improved renal function, accelerated mitogenic response, and reduced cell apoptosis. However, this improved therapeutic potential of SP cells was significantly reduced by pretreatment with verapamil. Collectively, these findings provide evidence for a crucial role for the MEK/ERK-ABCG2 pathway in protecting kidney SP cells from ischemic/hypoxic injury.

Current pattern of Chinese dialysis units: a cohort study in a representative sample of units.

BACKGROUND: Understanding the characteristics of Chinese dialysis patients and the current practice trends is the first step to evaluate the association between practice pattern and outcome in these populations. In the present study, we evaluated the status of medical treatment and characteristic features of chronic dialysis patients in China. METHODS: Through a clustering sampling, we selected 9 centers from the largest dialysis facilities in 6 cities around China. All adult undergoing dialysis in the selected units were screened. A total of 2388 (1775 on hemodialysis (HD) and 613 on peritoneal dialysis (PD)) patients were finally enrolled. All data were collected at enrollment on the bases of review of medical records. RESULTS: In this cohort, 1313 (55.0%) were male. The mean age was 54 years old. The median time for dialysis was 26 months (12 - 51 months). Seventy-five percent of patients were on HD and 25.0% on PD. Among PD patients, about 21% patients did not receive dialysis adequacy. For HD patients, about 14.0% of them did not achieve dialysis adequacy when the target of kt/V was set as 1.2. Only 44.7% of patients achieved blood pressure target of 140/90 mmHg. About 60% of patients did not reach the hemoglobin target of 110 g/L even though 85.0% of them were treated with erythropoietin. In addition, 48.5% of the patients had uncontrolled mineral metabolism revealed by the high calcium-phosphate product. Compared with HD patients, higher level of serum glucose, triglyceride, and total and low density lipoprotein cholesterol were more common in PD patients. CONCLUSIONS: This observational study suggests that many Chinese dialysis patients did not achieve the therapeutic target, particularly in blood pressure control, anemia correction, and mineral balance. PD patients were more likely to suffer metabolic disturbance.