Efficacy of lipid reduction with DALI and MONET.

BACKGROUND: Lipidapheresis techniques are increasingly used to treat drug-resistant hyperlipidemia but few efficacy studies under routine application are available. In this multicenter observational study we investigated direct adsorption of lipoproteins (DALI) and lipoprotein filtration (MONET) for the short and the long-term effects on lipid-lowering effects. METHODS: Data of 122 apheresis patients from 11 centers (DALI: n = 78, MONET: n = 44) were prospectively collected for a period of 2 years. Routine lipid measurements were evaluated (2154 DALI and 1297 MONET sessions). It was investigated whether the relative reduction of LDL-C during apheresis session achieves at least 60%. Also relative reduction of total cholesterol, HDL, triglyceride, and Lp(a) were analyzed. RESULTS: The relative reduction of LDL-C was at least 60%: DALI: 70.62%, 95% CI = [69.34; 71.90] and MONET: 64.12%, 95% CI = [60.79; 67.46]. Also triglycerides were reduced with both systems: DALI 38.63%, 95% CI = [33.95; 43.30] vs. MONET 57.68%, 95% CI = [51.91; 63.45]. Relative reductions of total cholesterol were in the range of 50% (DALI 95% CI = [46.49; 49.65] MONET 95% CI = [48.93; 55.26]) and of Lp(a) in the range of 65% (DALI 95% CI = [61.92; 65.83] MONET 95% CI = [63.71; 70.30]. HDL reduction was: DALI 15.01%, 95% CI = [13.22; 16.79] and MONET 22.59%, 95% CI = [19.33; 25.84]. For both devices treated patient plasma/blood volume and in case of DALI the use of the larger adsorber configurations (DALI 1000 and DALI 1250) were independent positive predictors of the relative reduction of LDL-C and of Lp(a). CONCLUSIONS: Both systems effectively improved lipid profile and reduced atherogenic lipids. The results point to the importance of the individualized application of these valuable therapies to achieve clinical targets.

Safety aspects of lipidapheresis using DALI and MONET - Multicenter observational study.

BACKGROUND: Lipidapheresis was introduced for intractable hyperlipidemia as a more selective therapy than plasma exchange aiming to enhance efficacy and limit side-effects. Although this therapy is regarded safe, multicenter data from routine application are limited. We investigated direct adsorption of lipoproteins (DALI) and lipofiltration (MONET) regarding the short and the long-term safety aspects. METHODS: This multicenter observational study prospectively evaluated 2154 DALI and 1297 MONET sessions of 122 patients during a period of 2 years. Safety parameters included clinical side-effects (adverse device effects, ADEs), technical complications, blood pressure and pulse rate. Also routinely performed laboratory parameters were documented. Analysis of laboratory parameters was not corrected for blood dilution. RESULTS: Overall 0.4% DALI and 0.5% MONET treatments were affected by ADE. Technical complications occurred in 2.1% and in 0.8% DALI and MONET sessions, respectively. The most frequent ADE was hypotension, and the majority of technical problems were related to vascular access. Both types of treatments led to a drop of thrombocytes in the range of 7-8%. Hematocrit and erythrocytes decreased only during the DALI treatments by about 6%. Leucocytes decreased during the DALI therapy (∼15%), whereas they increased during the MONET application (∼11%). MONET treatment was associated with a higher reduction of proteins (fibrinogen: 58% vs. 23%, albumin: 12% vs. 7%, CRP: 33% vs. 19% for MONET and DALI, respectively). Apart from severe thrombocytopenia in two DALI patients, changes of other parameters were typically transient. CONCLUSIONS: Under routine use the frequency of side-effects was low. Still, monitoring of blood count and proteins in chronic apheresis patients is recommended.

Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy.

BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes. METHODS: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014. RESULTS: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids. CONCLUSIONS: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Effects of citrate dialysate in chronic dialysis: a multicentre randomized crossover study.

BACKGROUND: Although citrate dialysate (CiDi) is regarded to be safe, dialysis modalities using higher dialysate volumes, like haemodiafiltration (HDF), may expose patients to higher citrate load and thus increase the risk of complications. We investigated the residual risk of CiDi compared with standard dialysate (StDi) in patients on different dialysis modalities and its effect on dialysis dose. METHODS: In a multicentre randomized crossover study, 92 dialysis patients (HDF post-dilution: n = 44, HDF pre-dilution: n = 26, haemodialysis: n = 25) were treated for 4 weeks with each dialysate (StDi and CiDi). Hypocalcaemia (ionized calcium ≤0.9 mmol/L), alkalosis (pH ≥7.55), post-treatment bicarbonate ≥32 mmol/L, pre-treatment bicarbonate ≥27 mmol/L, intra-dialytic events (IEs) and adverse events (AEs) between dialysis sessions were investigated as primary end points. The secondary objective was dialysis efficacy, i.e. dose and removal ratios of urea, creatinine, phosphate and ß-2-microglobulin. RESULTS: Post-dialysis overcorrection of bicarbonate (>32 mmol/L) was less frequent with CiDi (P = 0.008). Other predefined calcium and acid-base disturbances did not vary. There was no significant difference in IE. However, more patients developed AEs such as fatigue, muscle spasms or pain using CiDi (StDi: 41 versus CiDi: 55 patients, P = 0.02), particularly in the first 2 weeks of exposure. Dialysis efficacy was comparable with both dialysates. CONCLUSIONS: It can be confirmed that CiDi is not associated with the development of severe calcium and acid-base disorders, even when dialysis modalities with higher citrate loads are used. However, a refinement of the CiDi composition to minimize AEs is necessary.

Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study.

INTRODUCTION: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy is widely used in intensive care units (ICUs). However, concern exists about the safety of citrate in patients with liver failure (LF). The aim of this study was to evaluate safety and efficacy of RCA in ICU patients with varying degrees of impaired liver function. METHODS: In a multicenter, prospective, observational study, 133 patients who were treated with RCA and continuous venovenous hemodialysis (RCA-CVVHD) were included. Endpoints for safety were severe acidosis or alkalosis (pH ≤7.2 or ≥7.55, respectively) and severe hypo- or hypercalcemia (ionized calcium ≤0.9 or ≥1.5 mmol/L, respectively) of any cause. The endpoint for efficacy was filter lifetime. For analysis, patients were stratified into three predefined liver function or LF groups according to their baseline serum bilirubin level (normal liver function ≤2 mg/dl, mild LF >2 to ≤7 mg/dl, severe LF >7 mg/dl). RESULTS: We included 48 patients with normal liver function, 43 with mild LF, and 42 with severe LF. LF was predominantly due to ischemia (39 %) or multiple organ dysfunction syndrome (27 %). The frequency of safety endpoints in the three patient strata did not differ: severe alkalosis (normal liver function 2 %, mild LF 0 %, severe LF 5 %; p = 0.41), severe acidosis (normal liver function 13 %, mild LF 16 %, severe LF 14 %; p = 0.95), severe hypocalcemia (normal liver function 8 %, mild LF 14 %, severe LF 12 %; p = 0.70), and severe hypercalcemia (0 % in all strata). Only three patients showed signs of impaired citrate metabolism. Overall filter patency was 49 % at 72 h. After censoring for stop of the treatment due to non-clotting causes, estimated 72-h filter survival was 96 %. CONCLUSIONS: RCA-CVVHD can be safely used in patients with LF. The technique yields excellent filter patency and thus can be recommended as first-line anticoagulation for the majority of ICU patients. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN92716512 . Date assigned: 4 December 2008.

Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS: Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS: Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS: Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.

Citrate pharmacokinetics and calcium levels during high-flux dialysis with regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation is a very effective anticoagulation method for haemodialysis. However, it is not widely used, primarily due to the risk of hypocalcaemia. We studied citrate and calcium kinetics to better understand safety aspects of this anticoagulation method. METHODS: During 15 haemodialysis treatments with a calcium-free dialysis solution, citrate was infused pre-dialyser and calcium was substituted post-dialyser. Systemic and extracorporeal citrate and calcium concentrations were repeatedly measured to calculate citrate and calcium pharmacokinetics. RESULTS: Removal by dialysis constituted the major elimination pathway of citrate (83 +/- 5%). Systemic citrate load and concentrations were low (17 +/- 7 mmol/4 h, 0.3 +/- 0.15 mmol/l). Combined use of calcium-free dialysate and citrate infusion increased diffusible calcium to 80% of total calcium and induced substantial dialytic loss of calcium (43 +/- 4 mmol/4 h). Since calcium was substituted, systemic calcium balances were positive (approximately +5 mmol) and concentrations stable. Calcium supplementation correlated with calcium dialytic losses, which in turn were dependent on total calcium and haematocrit. CONCLUSIONS: When using calcium-free dialysate during citrate anticoagulation, hypocalcaemia is very likely unless calcium is re-infused, because large amounts of calcium are lost in the dialysate. However, an accumulation of citrate in the patient's systemic circulation is an unlikely cause of hypocalcaemia since most of the citrate is removed by dialysis. Calcium substitution and monitoring are the most important safety measures. We propose a rational approach based on haematocrit and total calcium for the choice of the starting calcium supplementation rate.