Rituximab treatment for refractory nephrotic syndrome in adults: a multicenter retrospective study.

BACKGROUND: The treatment of refractory nephrotic syndrome (RNS) is full of challenges and the role of rituximab (RTX) is not well-established, thus this study aims to demonstrate the role of RTX in RNS. METHODS: This was a multicenter retrospective study of all adult patients receiving RTX for RNS. Patients enrolled were divided into two groups according to pathological pattern: 20 patients as a group of podocytopathy (including minimal change disease [MCD] and focal and segmental glomerulosclerosis [FSGS]), and 26 patients as membranous nephropathy (MN) group. The remission rate, relapse rate, adverse effects, and predictors of remission were analyzed. RESULTS: A total of 75 patients received RTX for RNS and 48 were available for analysis after exclusion criteria. No significant difference in the remission rate at 6 or 12 months was observed between the MCD/FSGS and MN cases (p > 0.05). The median duration of the first complete remission (CR) was 1 month in the podocytopathy group and 12.5 months in the MN group. Three relapses were associated with infection as the ultimate outcome, and 6 out of 48 remained refractory representing a response rate of 87.5% in RNS. Clinical predictors of cumulative CR were estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and mean arterial pressure (MAP) ≤103 mmHg at the beginning of therapy in patients with MN. No serious adverse effects were reported. CONCLUSIONS: RTX appears to be effective in RNS across various clinical and pathological subtypes, exhibiting a low relapse rate and minimal significant side effects in the majority of patients.

Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization.

Peritoneal fibrosis contributes to ultrafiltration failure in peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that histone deacetylase 6 (HDAC6) is critically implicated in high glucose peritoneal dialysis fluid (HG-PDF) induced peritoneal fibrosis, however, the precise mechanisms of HDAC6 in peritoneal fibrosis have not been elucidated. Here, we focused on the role and mechanisms of HDAC6 in chlorhexidine gluconate (CG) induced peritoneal fibrosis and discussed the mechanisms involved. We found Tubastatin A (TA), a selective inhibitor of HDAC6, significantly prevented the progression of peritoneal fibrosis, as characterized by reduction of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) protein deposition. Inhibition of HDAC6 remarkably suppressed the expression of matrix metalloproteinases-2 (MMP2) and MMP-9. Administration of TA also increased the expression of acetylation Histone H3 and acetylation α-tubulin. Moreover, our results revealed that blockade of HDAC6 inhibited alternatively M2 macrophages polarization by suppressing the activation of TGF-ß/Smad3, PI3K/AKT, and STAT3, STAT6 pathways. To give a better understanding of the mechanisms, we further established two cell injured models in Raw264.7 cells by using IL-4 and HG-PDF. Our in vitro experiments illustrated that both IL-4 and HG-PDF could induce M2 macrophage polarization, as demonstrated by upregulation of CD163 and Arginase-1. Inhibition of HDAC6 by TA significantly abrogated M2 macrophage polarization dose-dependently by suppressing TGF-ß/Smad, IL4/STAT6, and PI3K/AKT signaling pathways. Collectively, our study revealed that blockade of HDAC6 by TA could suppress the progression of CG-induced peritoneal fibrosis by blockade of M2 macrophage polarization. Thus, HDAC6 may be a promising target in peritoneal fibrosis treatment.

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF-1α-dependent signaling pathway.

The catalytic subunit of polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2), has been reported to be involved in angiogenesis in some tumors and autoimmune diseases. However, the mechanisms by which EZH2 regulates peritoneal angiogenesis remain unclear. We detected the expression of EZH2 in clinical samples and the peritoneal tissue of a mouse peritoneal fibrosis model induced by chlorhexidine gluconate (CG). In addition, we further investigated the mechanisms by which inhibition of EZH2 by 3-deazaneplanocin A (3-DZNeP) alleviated the CG-induced peritoneal fibrosis mouse model in vivo and 3-DZNeP or EZH2 siRNA treatment in cultured human peritoneal mesothelial cells (HPMCs) and human umbilical vein endothelial cells (HUVECs). The expression of EZH2 in the peritoneum of long-term peritoneal dialysis (PD) patients and the CG-induced peritoneal fibrosis mouse model was remarkably increased and this was positively associated with higher expression of vascular markers (CD31, CD34, VEGF, p-VEGFR2). Peritoneal injection of 3-DZNeP attenuated angiogenesis in the peritoneum of CG-injured mice; improved peritoneal membrane function; and decreased phosphorylation of STAT3, ERK1/2, and activation of Wnt1/ß-catenin. In in vitro experiments, we demonstrated that inhibition of EZH2 by 3-DZNeP or EZH2 siRNA decreased tube formation and the migratory ability of HUVECs via two pathways: the Wnt1/ß-catenin pathway and the IL-6/STAT3 pathway. Suppression of the Wnt1/ß-catenin pathway and the IL-6/STAT3 pathway subsequently reduced VEGF production in HPMCs. Using specific inhibitors of VEGFR2, ERK1/2, and HIF-1α, we found that a VEGFR2/ERK1/2/HIF-1α axis existed and contributed to angiogenesis in vitro. Moreover, phosphorylation of VEGFR2 and activation of the ERK1/2 pathway and HIF-1α in HUVECs could be suppressed by inhibition of EZH2. Taken together, the results of this study suggest that EZH2 may be a novel target for preventing peritoneal angiogenesis in PD patients. © 2022 The Pathological Society of Great Britain and Ireland.

A retrospective study of baseline peritoneal transport character and left ventricular hypertrophy in incident peritoneal dialysis patients: interrelationship and prognostic impacts.

BACKGROUND: Left ventricular hypertrophy is associated with adverse outcomes among peritoneal dialysis patients. The aim of this study was to evaluate the prognostic impact of baseline left ventricular hypertrophy and its relationship with baseline peritoneal transfer characteristics in peritoneal dialysis patients. METHODS: We enrolled 151 incident peritoneal dialysis patients to perform a multicentric retrospective cohort study since January 1, 2017 to January 31, 2021. Patients were grouped based on baseline dialysate-to-plasma creatinine ratio at 4 h as follows: low (<0.50), low average (0.5-0.64), high average (0.65-0.80) and high (≥0.81). Echocardiography and clinic data were recorded yearly. The Cox proportional hazards models and competing risk model were used to evaluate patients' survival. Generalized linear mixed models were performed to explore risk factors associated with left ventricular hypertrophy. RESULTS: During a median follow-up period of 33 months (range, 16-48 months), 21 (13.9%) patients died, including 16 (10.60%) cardiovascular deaths. Controlling the competing risks of switching to hemodialysis, kidney transplantation and loss to follow-up, baseline left ventricular hypertrophy was an independent risk factor for all-cause mortality (subdistribution hazard ratio, 2.645; 95% confidence interval, 1.156-6.056; p = 0.021). Baseline high and high average transport status were positively related to left ventricular mass index and left atrium diameter 2 years after PD initiation. CONCLUSION: Baseline fast peritoneal solute transport rate may be an effect factor for aggravating left ventricular hypertrophy which predicted poor outcomes for peritoneal dialysis patients. The findings offered important ideas for further prospective intervention study.