Medium cutoff (MCO) dialyzers help remove larger middle molecules associated with symptoms related to the accumulation of uremic retention solutes. We investigated the effect of an MCO dialyzer on the improvement of quality of life (QOL) in maintenance hemodialysis (HD) patients. Forty-nine HD patients with high-flux dialysis were randomly assigned to either an MCO (Theranova 400, Baxter) or a high-flux (FX CorDiax 80 or 60, Fresenius Medical Care) dialyzer and completed the study. QOL was assessed at baseline and after 12 weeks of treatment using the Kidney Disease Quality of Life Short Form-36, and pruritus was assessed using a questionnaire and visual analog scale. The reduction ratios of middle molecules were also evaluated. Laboratory markers, including serum albumin, did not differ between the two groups after 12 weeks. Removals of kappa and lambda free light chains were greater for MCO dialyzer than high-flux dialyzer. The MCO group had higher scores than the high-flux group in the domains of physical functioning and physical role (75.2 ± 20.8 vs. 59.8 ± 30.1, P = 0.042; 61.5 ± 37.6 vs. 39.0 ± 39.6, P = 0.047, respectively), and the MCO group had lower mean scores for morning pruritus distribution and the frequency of scratching during sleep (1.29 ± 0.46 vs. 1.64 ± 0.64, P = 0.034; 0.25 ± 0.53 vs. 1.00 ± 1.47, P = 0.023, respectively). MCO dialyzers may improve patientreported outcomes, particularly the physical components of QOL and uremic pruritus, in patients with high-flux dialyzers. Patients on maintenance dialysis suffer variable symptoms such as fatigue, generalized weakness, and pruritus. These subjective conditions are assumed to be related to middle molecules that are not cleared by conventional hemodialysis (HD) 1. Middle molecules have molecular weights (MWs) ranging between 500 and 60,000 daltons, and their size is a barrier to removal with dialyzers 2,3. The accumulation of middle molecules is associated with specific complications such as amyloidosis, inflammatory reactions, oxidative stress, and endothelial dysfunction 3-5. Consequently, middle molecules contribute to morbidity and mortality and poor quality of life (QOL) in end-stage renal disease (ESRD) patients 6,7. High-flux dialysis, which has benefits for middle molecule clearance, has not displayed a clear mortality advantage compared with low-flux dialysis; the survival benefits of high-flux dialysis were only observed in patients with hypoalbuminemia and diabetes 8,9. Another dialytic modality, hemodiafiltration (HDF) with increased convection, has a higher efficiency for reducing middle-sized solutes than high-flux dialysis 10,11. Large randomized trials comparing HDF and high-flux dialysis have shown conflicting patient outcome results 12-15 ; however, recent results have consistently shown that HDF with a high convection volume improves patient survival 16-18. Medium cutoff (MCO) dialyzers are characterized by a more even distribution of larger pore sizes and a higher number of pores. MCO dialyzers have a higher permeability and...

The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-␤1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-␤1, ␣-smooth muscle actin (␣-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-␤1 and ␣-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-␤1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-␤1 and rhEPO for another 48 h. Increased expressions of ␣-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-␤1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-␤1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-␤1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-␤1-induced EMT.

The response to erythropoiesis stimulating agents (ESAs) is affected by inflammation linked to middle molecules in hemodialysis (HD) patients. We evaluated the effect of a medium cut-off (MCO) dialyzer on ESA resistance in maintenance HD patients. Forty-nine patients who underwent high-flux HD were randomly allocated to the MCO or high-flux group. The primary outcome was the changes of erythropoietin resistance index (ERI; U/kg/wk/g/dL) between baseline and 12 weeks. The MCO group showed significant decrease in the ESA dose, weight-adjusted ESA dose, and ERI compared to the high-flux group at 12 weeks (p < 0.05). The generalized estimating equation models revealed significant interactions between groups and time for the ESA dose, weight-adjusted ESA dose, and ERI (p < 0.05). Serum iron and transferrin saturation were higher in the MCO group at 12 weeks (p < 0.05). The MCO group showed a greater reduction in TNF-α and lower serum TNF-α level at 12 weeks compared to the high-flux group (p < 0.05), whereas no differences were found in the reduction ratio of hepcidin and serum levels of erythropoietin, erythroferrone, soluble transferrin receptor and hepcidin between groups. HD with MCO dialyzer improves ESA resistance over time compared to high-flux HD in maintenance HD patients. The MCO dialyzer provides superior removal of the inflammatory cytokine and thus improves iron metabolism in a hepcidin-independent manner.

Hypercholesterolemia is reported to increase reactive oxygen species (ROS) and to promote breast cancer progression. ROS play an important role in tumor biology, and xanthine oxidase (XO) is an enzyme that generates ROS. The effects of febuxostat (FBX), an XO inhibitor, on breast cancer cell migration under LDL stimulation in vitro and metastasis of breast cancer associated with hypercholesterolemia in vivo were studied. In vitro, FBX significantly inhibited LDL‐induced ROS production and cell migration. Treatment of small interfering RNA against XO was consistent with the findings of FBX treatment. In vivo, a significant increase of tumor growth and pulmonary metastasis was observed in a xenograft mouse model with 4T1 cells on a high cholesterol diet (HCD), both of which were markedly inhibited by FBX or allopurinol treatment. Moreover, ERK represented the main target‐signaling pathway that was affected by FBX treatment in a xenograft mouse model on an HCD evaluated by NanoString nCounter analysis. Consistently, MEK/ERK inhibitors directly decreased the LDL‐induced cell migration in vitro. In conclusion, FBX mitigates breast cancer cell migration and pulmonary metastasis in the hyperlipidemic condition, associated with decreased ROS generation and MAPK phosphorylation. The inhibition of ERK pathways is likely to underlie the XO inhibitor‐mediated suppression of breast cancer cell migration.—Oh, S.‐H., Choi, S.‐Y., Choi, H.‐J., Ryu, H.‐M., Kim, Y.‐J., Jung, H.‐Y., Cho, J.‐H., Kim, C.‐D., Park, S.‐H., Kwon, T.‐H., Kim, Y.‐L. The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia. FASEB J. 33, 7301–7314 (2019). http://www.fasebj.org

High glucose induces inflammatory and fibrosis markers in HPMCs partly through the TLR4/MyD88/NF-κB signaling pathway rather than TLR2. Therefore, TLR4 might be a therapeutic target for ameliorating peritoneal inflammation and fibrosis in PD.