Post‐Dilution Hemodiafiltration With a Heparin‐Grafted Polyacrylonitrile Membrane

The aim of this multicenter, prospective study was to explore the possibility of carrying out routine sessions of post‐dilution hemodiafiltration with a polyacrylonitrile membrane grafted with heparin (HeprAN) and reduced anticoagulation. Forty‐four patients from eight centers were included in the study and treated by means of post‐dilution on‐line hemodiafiltration with automatic control of TMP, according to three different modalities tested consecutively: phase 1, polyethersulfone filter primed with heparinized saline and anticoagulated with continuous infusion of unfractionated heparin 1000/h; phase 2, HeprAN membrane filter primed with saline without heparin. Anticoagulation: a 1000‐unit bolus of unfractionated heparin at the start of session followed by a second one at the end of the second dialysis hour; phase 3, same filter and priming procedure as in phase 2; anticoagulation with nadroparin calcium at the beginning of treatment. Partial or massive clotting of the dialyzer occurred in less than 1% of sessions in phase 1; 10% and 7% in phase 2; and 1% and 2% in phase 3. Clotting limited to the drip chambers was observed in 13%, 34% and 12%, respectively. The study of coagulation parameters showed a better profile when low‐molecular weight heparin (LMWH) was used in association with HeprAN membrane, while the generation of TAT complexes did not differ from that observed with the standard anticoagulation modality used in phase 1. Our results suggest that the HeprAN membrane can be used safely in routine post‐dilution hemodiafiltration with reduced doses of LMWH.     

Soluble Vascular Endothelial‐Cadherin Levels in Patients With Sepsis Treated With Direct Hemoperfusion With a Polymyxin B‐immobilized Fiber Column

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. Several molecules are investigated as associated factors with capillary permeability and vascular endothelial (VE)‐cadherin internalization by vascular endothelial growth factor (VEGF)‐induced signaling through VEGF receptors leads to increased vascular endothelial cell detachment and trans‐endothelial permeability. We investigated serum soluble VE‐cadherin levels in septic patients. An enzyme‐linked immunoassay was used to measure serum soluble VE‐cadherin levels in 47 septic patients treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX). The serum soluble VE‐cadherin level of septic patients before PMX‐DHP was 3424.1 ± 2033.0 ng/mL, which was significantly lower than that of the controls (5862.0 ± 1521.2 ng/mL; P < 0.0001). The time course of serum soluble VE‐cadherin levels remained unchanged during PMX‐DHP therapy. There was no significant difference in serum soluble VE‐cadherin levels before PMX‐DHP therapy between survivors and non‐survivors, and there was no significant difference in those levels between the groups at any time after the initiation of PMX‐DHP therapy. There was no correlation between soluble VE‐cadherin levels and clinical data, except white blood cell count (r = ?0.277, P = 0.0009). There was no correlation between soluble VE‐cadherin levels and the levels of angiopoietin 1 and 2. In summary, the relationship between VE‐cadherin and capillary permeability in sepsis could not be demonstrated. Soluble VE‐cadherins are not reflected in the balance between intercellular junction plasticity and integrity, but VE‐cadherin stabilization by its phosphorylation or internalization may be associated with capillary permeability.     

Serum Hepcidin Levels Are Associated With Serum Triglycerides and Interleukin‐6 Concentrations in Patients With End‐Stage Renal Disease

Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end‐stage renal disease, who were on hemodialysis (HD) (N = 30) and peritoneal dialysis (N = 30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C‐reactive protein (CRP) and interleukin‐6 (IL‐6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P < 0.0001) levels of hepcidin, CRP and IL‐6 than NC. Hepcidin in dialysis patients is significantly related to age (r = 0.373, P = 0.012), serum triglycerides (r = 0.401, P = 0.005), HDL‐C (r = ?0.268, P = 0.048), CRP (r = 0.436, P = 0.0007) and IL‐6 (r = 0.569, P < 0.0001). In multiple regression analysis, hepcidin correlated independently with triglycerides (β = 0.402, P = 0.041) and IL‐6 (β = 0.559, P = 0.006). Moreover, patients with high triglycerides in combination with high IL‐6 levels have significantly increased concentrations of hepcidin than those with low triglycerides and low IL‐6 levels (P < 0.0001). Elevated levels of hepcidin in patients with CKD on dialysis may be related to the occurrence of high triglycerides and high IL‐6 serum concentrations. This probably suggests that hepcidin may play a role to the progression of atherosclerosis and inflammation, but this hypothesis should be further evaluated.     

Cost‐Effectiveness of LDL‐C Lowering With Evolocumab in Patients With High Cardiovascular Risk in the United States

Randomized trials have shown marked reductions in low‐density lipoprotein cholesterol (LDL‐C), a risk factor for cardiovascular disease (CVD), when evolocumab is administered. We hypothesized that evolocumab added to standard of care (SOC) vs SOC alone is cost‐effective in the treatment of patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD (ASCVD) with or without statin intolerance and LDL‐C >100 mg/dL. Using a Markov cohort state transition model, primary and recurrent CVD event rates were predicted considering population‐specific trial‐based mean risk factors and calibrated against observed rates in the real world. The LDL‐C–lowering effect from population‐specific phase 3 randomized studies for evolocumab was used together with estimated LDL‐C–lowering effect on CVD event rates per 38.67‐mg/dL LDL‐C lowering from a statin‐trial meta‐analysis. Costs and utilities were included from published sources. Evolocumab treatment was associated with both increased cost and improved quality‐adjusted life‐years (QALY): HeFH (incremental cost: US$153 289, incremental QALY: 2.02, incremental cost‐effectiveness ratio: US$75 863/QALY); ASCVD (US$158 307, 1.12, US$141 699/QALY); and ASCVD with statin intolerance (US$136 903, 1.36, US$100 309/QALY). Evolocumab met both the American College of Cardiology/American Heart Association (ACC/AHA) and World Health Organization (WHO) thresholds in each population evaluated. Sensitivity and scenario analyses confirmed that model results were robust to changes in model parameters. Among patients with HeFH and ASCVD with or without statin intolerance, evolocumab added to SOC may provide a cost‐effective treatment option for lowering LDL‐C using ACC/AHA intermediate/high value and WHO cost‐effectiveness thresholds. More definitive information on the clinical and economic value of evolocumab will be available from the forthcoming CVD outcomes study.