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 ㎡,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 measu res: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-β1-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.Microvesicles(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)-β1-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-β1(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-β1,respectively,and were restored to 62%and 70%by miR-34a-enriched MSC-MVs,respectively.The expression ofα-SMA and fibronectin increased by 3.9-and 5.0-fold following TGF-β1 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-β1 was inhibited by miR-34a-enriched MSC-MVs.In addition,TGF-β1 exposure also induced apoptosis in HK-2 cells.Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-β1-triggered apoptosis in HK-2 cells,the effects were less significant than control MSC-MVs(control:TGF-β1: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-β1 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.

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 bal- ance 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 hyperohloremia 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 hemody- namics. Microperfusion experiments and real-time imaging studies have demonstrated a reduction in renal perfusion and an expansion in kidney volume, compromising 02 delivery to the renal perenchyma 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, in- creases 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 gastroin- testinal 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.

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.