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Background and Aims IgA nephropathy (IgAN) is the most type of primary glomerulonephritis and one of the major causes of end-stage renal disease (ESRD). The KDIGO clinical practice guidelines for glomerulonephritis suggest not the use of immunosuppressive drugs in IgAN patients with estimated glomerular filtration rate (eGFR) ≤50 mL/min/1.73m2. However, VALIGA study showed that immunosuppressive drugs were more frequently used in IgAN patients with eGFR < 30 mL/min/1.73m2 than in those with eGFR ≥ 30 ml/ min/1.73m2 (60% vs. 44 %; p = 0.004). The immunosuppressive drugs could be effective for IgAN with renal insufficiency in few studies, such as corticosteroids combined oral cyclophosphamide (CS + oral CTX). Therefore, in our present study, we evaluated the efficacy and treatment-related complications of the patients with eGFR from 15 ml/min/1.73m2 to 59 ml/min/1.73m2 who receive supportive care, or CS, or CS + oral CTX. Method 1602 renal biopsy–proven patients were reviewed between January 2008 and December 2016 in the Xijing Hospital. Patients were excluded from the study if they had secondary IgAN. The inclusion criteria were the primary IgAN with eGFR from 15 ml/min/1.73m2 to 59 ml/min/1.73m2 (n = 389). We extracted the patients with receive supportive care, or corticosteroids, or corticosteroids combined oral cyclophosphamide (n = 212). We further excluded patients: < 8 glomeruli (n = 10), diabetes mellitus (n = 4), a follow-up less than 6 months (n = 22), and incomplete data (n = 7). The remaining 169 patients were included in the study (Figure 1). The data included baseline demographic at renal biopsy, renal biopsy, treatment, follow-up parameters and outcomes. The primary endpoint was the combined event of a ≥ 50% reduction in eGFR and/or ESRD. Univariate and multivariate Cox regression analyses were conducted to determine which variables were associated with renal survival. Variables were entered into a multivariate Cox regression model using an Enter method, which were derived from adjusted models: model 1 was adjusted for age, sex, MAP, proteinuria, and eGFR; model 2 was adjusted for the variables in model 1 plus RAS; model 3 was adjusted for the variables in model 1 plus M1, E1, S1, T1-2, and C1-2; model 4 was adjusted for the variables in model 3 plus RAS. Results In all patients, the mean age was 36.0 years, the median proteinuria at the time of the biopsy was 1.6 g/day, the mean MAP was 108.7 mmHg, and eGFR was 40.4 ml/min/per 1.73 m2, the mean follow-up period was 43.3 months, 75 (44.9%) patients had reached combined event. The cumulative 5-year and 10-year renal survival rate were 39.3% and 9.3%, respectively, in the no-IS group ; 56.5% and 25.1%, respectively, in the CS group and 63.4% and 27.1%, respectively, in the CS + CTX group (Figure 2). Both univariate and multivariate Cox analyses shown that CS did not reduce the risk of combined event, whereas CS + CTX significantly reduced the risk of combined event. CS + CTX (HR = 0.367, 95%CI 0.198-0.682, P = 0.002) was notably associated with the risk of combined event after adjusted for age, sex, MAP, proteinuria, eGFR, M1, E1, S1, T1-2, C1-2, and ARB. The two groups did not differ significantly in treatment-related complications. Conclusion CS + oral CTX is possibly more effective than supportive care, or CS for IgAN patients with eGFR from 15 ml/min/1.73m2 to 59 ml/min/1.73m2. Furthermore, randomized controlled trials further verified the findings of the present study.

Background and Aims The application of microRNAs (miRNAs) in the therapy of kidney diseases is hampered by difficulties in delivering miRNAs effectively. Nano-sized microvesicles (MVs) are known as natural carriers of small RNAs. Our prior work has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) attenuated kidney injuries induced by unilateral ureteral obstruction and 5/6 subtotal nephrectomy in mice. The present work aimed at evaluating the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-β1 induced fibrosis and apoptosis in vitro. Method Bone marrow MSCs were further modified by lentiviruses overexpressing miR-34a, and MVs were collected from these MSCs to treat HK-2 renal tubular cells exposed to TGF-β1. Alterations in epithelial-mesenchymal transition (EMT) and cell survival were further determined. Results We first demonstrated that MVs generated by miR-34a-modified MSCs contained more miR-34a. By analyzing the expression levels of epithelial markers (E-cadherin and Tight Junction Protein 1 (TJP1)) and mesenchymal markers (α-SMA and fibronectin), we found that the pro-fibrotic TGF-β1 induced EMT was remarkably suppressed by miR-34a-enriched MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. We further found that the elevation in Notch-1 and Jagged-1 induced by TGF-β1 was inhibited by miR-34a-enriched MSC-MVs. The inhibitory effects of miR-34a-enriched MSC-MVs on EMT and Notch signaling pathway were stronger than the control MSC-MVs. In addition, TGF-β1 exposure also induced apoptosis in HK-2 cells. Although miR-34amofidied MSC-MVs could inhibit TGF-β1-triggered apoptosis in HK-2 cells, the effects were less significant than the control MSC-MVs. This phenomenon may be resulted from the pro-apoptotic effects of miR-34a. Conclusion Our study demonstrates that miR-34a-overexpressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-β1 in renal tubular epithelial cells, possibly through inhibiting Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with anti-fibrotic molecule may present a novel strategy for treatment of renal injuries.

Background and Aims The combined of cyclophosphamide, thalidomide and dexamethasone (CTD) haven’t reported in treatment of LCDD, and how the renal pathologic injury changes after treatment is still unknown. Method Here we descript a LCDD patients who undergone repeated renal biopsy after treatment. Results We report a 56-year-old woman presented with nephrotic syndrome, impaired renal function, and serum M-protein of IgG lambda. First renal biopsy showed severe nodular glomerulosclerosis with single lambda light chain linear deposit along GBM. The patient treated with 14 cycles CTD regimen, and reached the complete hematologic response and renal response. At the 29 months of follow up, the repeated biopsy showed the glomerular nodular sclerosis attenuated significantly, only trace granular electron-dense deposits along inner side of GBM.(Details in figure 1: The pathological findings of the first (A-D) and second (E-H) renal biopsy.) Conclusion This case highlights the hematologic response not only can improve the renal function, but also alleviate the renal nodular sclerosis. And the low-cost regimen, CTD, maybe a good choice.

Background and Aims Severe hypercalcemia, poor conservative treatment effect, or combined with renal dysfunction, heart failure, intermittent hemodialysis treatment is recommended. But calcium-free hemodialysis could cause rebound of serum calcium, hypovolemia and hypotension. Continuous renal replacement therapy (CRRT) is the most commonly used treatment in critically ill patients with severe AKI. Some case reports showed that CRRT successed control calcium with stable hemodynamics, no rebound hypercalcemia, but there was only one case used continuous venovenous hemofiltration (CVVH). During CVVH treatment, clotting in the extracorporeal circuit shortens the filter and catheter lifespan, causes blood loss, and decreases solute clearance, consequently, reduces the effectiveness of CVVH and increases the treatment cost and medical stuff’s workload. So how to safely decrease calcium level and how to choose appropriate anticoagulants during CVVH in esvere hypercalcemia patients is a challenging work. We conducted a retrospective study to evaluate the efficacy and safety of regional citrate anticoagulation (RCA) versus low molecular weight heparin (LMWH) anticoagulation for CVVH in severe hypercalcemia patients. Method Between January 2014 and May 2019, severe hypercalcemia patients requiring CVVH were screened and divided into the RCA and LMWH-anticoagulation group according to the CVVH anticoagulation strategy they accepted. Serum calcium reduction rate (RRSeCa), filter lifespan, bleeding, totCa/ionCa ratio, citrate accumulation, and catheter occlusion were evaluated as outcomes. Results Of the 33 included patients, RCA and LMWH-anticoagulation were employed for CVVH in 14 and 43 filters, respectively. The serum calcium reduction rate (RRSeCa) was not significantly different between the LMWH-anticoagulation and RCA group (P = 0.320). Compared to LMWH-anticoagulation, RCA significantly prolonged the filter lifespan (> 72 hours vs. 24.0 hours [IQR, 15.0-26.0], P = 0.012). The incidence of filter failure was 55.8% (24/43) in the LMWH -anticoagulation group and 21.4% (3/14) in the RCA group (P = 0.033), respectively. The adjusted results demonstrated that RCA could significantly reduce the risk of filter failure (P = 0.028, 95% CI 0.076-0.859, HR = 0.255). No citrate accumulation was observed in RCA-CVVH patients. Conclusion In patients with severe hypercalcemia who underwent CVVH, both RCA CVVH and LMWH-anticoagulation CVVH could effectively decrease calcium levels. RCA CVVH had better filter lifespan and no obvious adverse events, compared with the LMWH-anticoagulation CVVH. Further prospective, randomized, control studies are warranted to obtain robust evidences.

Background and Aims Continuous renal replacement therapy (CRRT) has been widely used in the critical care setting and anticoagulation is usually necessitated. However, critically ill patients are commonly at incremental risk of bleeding, which contributed to the hesitation of anticoagulant use for CRRT in clinical practice. The current guideline recommended CRRT proceed without anticoagulation in patients with contraindication to citrate and increased bleeding risk. Nevertheless, the efficacy of anticoagulation-free CRRT remains inconsistent. Therefore, the purpose of our present systematic review is to evaluate the efficacy and safety of anticoagulant-free CRRT based on the current literatures. Method We conducted a comprehensive search of PubMed (US National Library of Medicine, Bethesda, MD, USA), Cochrane Library databases and EMBASE from database inception to January 12, 2019 for potential candidate studies. Studies included adult critically ill (age > 18 years) patients with increased bleeding risk, and underwent CRRT without anticoagulation were considered for the inclusion. Results Finally, 17 observational studies and 3 randomized controlled trials with 1615 patients were included in our present meta-analysis. There was no significant difference in filter lifespan between the anticoagulation-free and systemic heparin group. The filter lifespan was significantly prolonged in the citrate (WMD -23.01, 95%CI [-28.62, -17.39], P < 0.001; I2 = 0%, P = 0.53) and nafamostat (WMD -8.4, 95%CI [-9.9, -6.9], P < 0.001; I2 = 33.7%, P = 0.21) groups, compared with anticoagulation-free group. The averaged filter lifespan of the anticoagulation-free CRRT ranged from 10.2 to 52.5 hours. Conclusion The filter lifespan in anticoagulation-free patients with increased bleeding risk was comparable to that in patients without increased bleeding risk underwent systemic heparin anticoagulation CRRT. Nafamostat was not recommended for CRRT anticoagulation due to its drawbacks. Currently, the optimal choice of anticoagulation strategy for critically ill patients without citrate contraindications at high risk of bleeding should be regional citrate anticoagulation. Further studies should focus on the special cut-off value of activated partial thromboplastin time (APTT), international normalized ratio (INR) and platelet (PLT) count, at which the anticoagulation-free CRRT would be beneficial.

BACKGROUND Long-term peritoneal dialysis (PD) results in functional and structural alterations of the peritoneal membrane. Previous studies have suggested that high glucose (HG) could induce transdifferentiation of peritoneal mesothelial cells into myofibroblasts, but the molecular mechanisms of HG-induced epithelial-to-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs) are unclear. This study was undertaken to elucidate the effects and mechanisms of Twist on HG-induced EMT of HPMCs. METHODS HPMCs were exposed to 5.6 mM glucose [normal glucose (NG)], 50 mM glucose (HG) or 50 mM glucose with Si-Twist or pcDNA3.1-Twist. Western blot and immuocytochemistry were performed to determine Twist, E-cadherin and α-smooth muscle actin (α-SMA) protein expression. MMP2 and MMP9 were detected by zymography. Rats were daily instilled with PD fluid and lipopolysaccharide (LPS) or sodium chloride during 6 weeks. Histological analyses were carried out in parietal peritoneum. Twist was detected by western blotting. RESULTS Twist and α-SMA protein and immuocytochemistry were significantly increased in HG-conditioned media compared to NG media. E-cadherin protein was lower in pcDNA3.1-Twist-transfected HPMCs compared to pcDNA3.1 cells. Twist protein was upregulated 12 h after HG stimulation. MMP9 was increased in pcDNA3.1-Twist-transfected HPMCs compared to pcDNA3.1 cells. Exposure of rat peritoneum to PD fluid and LPS resulted in an increase of extracellular matrix deposition. Twist and α-SMA were stained in the PD fluid group and compared to the control group. Twist protein was significantly increased in the PD group. CONCLUSIONS In conclusion, HG-induced Twist expression might contribute to EMT of HPMCs. Twist may control EMT of HPMCs by regulating MMP9.