Quantification of Lipoteichoic Acid in Hemodialysis Patients With Central Venous Catheters.

Hemodialysis patients with central venous catheters (CVCs) have chronic systemic inflammation, the source of which may be related to intraluminal bacterial biofilm. There is currently no non-invasive method to adequately evaluate intraluminal biofilm. Lipoteichoic acid (LTA) is a Gram-positive bacterial cell wall component that is spontaneously shed. The purpose of this study was to determine whether LTA could be quantified in biological samples and to evaluate potential relationships to markers of inflammation. Heparin-locked catheter aspirate was drawn from both the arterial and venous ports of each CVC prior to dialysis initiation. Venous blood from the dialysis circuit was collected 30 min after dialysis initiation. LTA was quantified in aspirate and plasma. Key markers of inflammation (interleukin-6, and hepcidin) and endothelial dysfunction (soluble vascular endothelial cadherin) were also determined in plasma samples. Catheter aspirate and systemic blood samples were obtained from 40 hemodialysis patients. The median (range) duration of catheter use was 130 (20-1635) days. Unexpectedly, median (range) plasma LTA concentrations (ng/mL) were significantly higher than catheter aspirate LTA concentrations [3.93 (0.25-15) vs. 2.38 (0.1-8.1), respectively, p = 0.01] in the majority (70%) of patients. Area under the receiver operator characteristic (ROC) curve showed good potential prognostic value of catheter aspirate LTA predicting systemic LTA concentrations with an area under the curve of 0.815 (95% CI, 0.68-0.95). A significant correlation was found between LTA and serum ferritin (r = 0.32, p = 0.04), however, there were no significant correlations between LTA and the other inflammation biomarkers assessed. LTA is quantifiable in aspirate and plasma of hemodialysis patients with CVCs and warrants further investigation to determine potential clinical application to intraluminal biofilm evaluation.

How to select a nanosimilar.

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability.

Tumor necrosis factor-α induces increased lung vascular permeability: a role for GSK3α/ß.

We tested the hypothesis that glycogen synthase kinase 3α/ß (GSK3α/ß) modulates tumor necrosis factor-a (TNF) induced increased lung vascular permeability. Rats were treated with TNF (i.v., ~100ng/ml) or vehicle 0.5h, 4.0h and 24.0h prior to lung isolation. Rats were co-treated with the GSK3α/ß inhibitors SB216763 (0.6mg/kg) or TDZD-8 (1.0mg/kg). After TNF, the isolated lung was assessed for hemodynamics, wet-dry/dry weight (W-D/D) and extravascular albumin. Extravascular albumin significantly increased at TNF-24h compared to Control. In the GSK3α/ß-inhibited+TNF groups, extravascular albumin was similar to the Control and respective SB216763 and TDZD-8 groups. In separate studies, to assess GSK3α/ß-activity, lung lysate was assessed for phospho-GSK3α/ß-Ser(21/9), total GSK3α/ß, un-phospho-ß-catenin-Ser(33/37) and total ß-catenin. In the TNF-4.0h group, there was no change in GSK3α/phospho-GSK3α-Ser(21) but there was an increase in GSK3ß/GSK3ß-Ser(9) compared to Control, indicating GSK3ß activation at TNF-4.0h. GSK3ß activation was verified because there was a decrease in un-phospho-ß-catenin-Ser(33/37)/ß-catenin in the TNF-4.0 group, a specific outcome for GSK3ß activation. In the SB216763+TNF group, un-phospho-ß-catenin-Ser(33/37) was similar to Control, indicating prevention of TNF-induced GSK3ß activation. In the TNF-24h group, there were increases in the biomarkers of inflammation phospho-eNOS-Ser (1117) and oxidized protein, which did not occur in the SB216763+TNF-24h and TDZD-8+TNF-24h groups. In the SB216763+TNF-24h and TDZD-8+TNF-24h groups, un-phospho-ß-catenin-Ser(33/37) was greater than in the Control, indicating continued inhibition of GSK3ß. The data indicates that pharmacologic inhibition of GSK3ß inhibits TNF induced increased endothelial permeability associated with lung inflammation.

Therapeutic use of the phosphate binder lanthanum carbonate.

Hyperphosphatemia is recognized as a principal mineral disorder in chronic kidney disease (CKD) that leads to the development of secondary hyperparathyroidism. Recent data indicate that hyperphosphatemia is associated with accelerated cardiac calcification and increased mortality in patients with CKD. Control of serum phosphorus is accomplished with phosphate binder therapies that include calcium and aluminum salts. Recently, calcium-based binders have undergone reevaluation because of their association with cardiac calcification. The non-calcium, non-aluminum binder sevelamer hydrochloride has been associated with slower progression of cardiac calcification in clinical trials. Lanthanum carbonate is a newer phosphate binder with phosphate binding activity similar to aluminum salts making this agent a compelling alternative; however, more data are needed to evaluate long-term safety and effects on cardiovascular end points.

Non-transferrin-bound iron is associated with enhanced Staphylococcus aureus growth in hemodialysis patients receiving intravenous iron sucrose.

BACKGROUND: Hemodialysis vascular access infections are most frequently caused by Staphylococcus spp. The purpose of this study was to determine if S. aureus growth is enhanced after administration of IV iron sucrose and to establish a relationship between the appearance of non-transferrin-bound iron (NTBI) and S. aureus growth. METHODS: Serum samples were obtained from 12 hemodialysis patients receiving maintenance doses of 100 mg of iron sucrose at baseline and 5, 30, 90, 220 min and 48 h after iron administration. Assays for NTBI and transferrin saturation were performed. S. aureus isolates were used to inoculate patient serum samples. Bacterial growth was determined by optical density. RESULTS: Six of 12 patients had NTBI present within 30 min of the iron dose. NTBI was present more frequently in patients with baseline transferrin saturation values >30% (p < 0.05). Bacterial growth was significantly greater in patients who had NTBI present at 5, 90 and 220 min after iron administration compared to those who did not have NTBI present. CONCLUSIONS: Doses of 100 mg of iron sucrose are associated with the presence of NTBI and enhanced S. aureus growth.