Polymethylmethacrylate Membrane Research Articles

Synthesis and biocompatibility of a novel silicone hydrogel containing phosphorylcholine

A novel poly (methyl methacrylate-co-2-methacryloyloxyethyl phosphorylcholine-co-tris(trimethylsiloxy)-3-methacryloxypropylsilane) terpolymer (PMMT) was synthesized and the anti-biofouling properties were studied in order to evaluate the potential of this silicone hydrogel to be used as contact lens material. The chemical structure was characterized by IR, 1H-NMR and elemental analysis. Poly methyl methacrylate (PMMA) and poly (methyl methacrylate-co-tris (trimethylsiloxy)-3-methacryloxypropylsilane) (PMT) were also synthesized to compare with PMMT. Protein adsorption measurement showed that for PMMT-2 membrane (MPC: 16.6 mol%), the amount of adsorbed proteins was decreased by 75.3% and 76.8% compared with PMMA and PMT membranes, respectively. SEM pictures showed clearly that PMMT films suppressed the adhesion of platelets. Water structure in polymers was determined by differential scanning calorimetry, and PMMT-2 possessed more freezing water content than PMMT-1 (MPC: 14.5 mol%). The equilibrium water content of PMMT-2 membrane reached 55%, which might offer comfortable wear feeling, and the introduction of MPC increased the wettability of the polymer surface dramatically. Both the terpolymers PMMT-1 and PMMT-2 exhibited high transparency (relatively constant at approximately 96%) in the visible light wave range. Moreover, oxygen transmissibility ( Dk/ t) of the terpolymers met the requirement for a lens to be worn safely overnight. It could be concluded that the novel silicone hydrogel containing MPC unit was an effective candidate material for making biomaterials, particularly for contact lenses.

Passive and Facilitated Transport of Cyanocobalamin (Vitamin B12) across Polymeric Membranes in Artificial Kidneys

Clearance of molecules by closed-circuit low-volume dialysis systems is limited by the accumulation of compounds in the dialysate and loss of the diffusion gradient. We sought to maintain dialysance of selected solutes by inducing “sink conditions” through the use of antibody-specific binding in the receiver compartment. Vitamin B12 was used as the test molecule since it is of clinically relevant size (molecular weight 1355 Da) and its clearance has been well-characterized for many dialyzer membranes. Using an in vitro haemodialysis model we perfused high-flux polymethylmethacrylate and low-flux polysulfone dialyzer membranes with known amounts of vitamin B12 through the intracapillary space. Clearances over time were calculated until equilibrium was reached within the fixed dialysate volume after 60 minutes. Anti-B12 monoclonal antibodies were then added to the receiver compartment reservoir. Under these sink conditions B12 clearance was restored, amounting to 77% and 118% of the integrated pre-equilibrium clearance for the high- and low-flux haemofilters, respectively. The magnitude of enhancement was such that the antibodies increased vitamin B12 clearance in low-flux dialyzers to levels observed in the high-flux devices. These studies demonstrate the feasibility of antibody-based sink conditions so as to promote substantial and highly selective solute clearance into small volume recirculating extracorporeal circuits.

Effectiveness of continuous venovenous hemodiafiltration using a polymethylmethacrylate membrane hemofilter judging from a multiplex suspension array system in septic shock patients

Septic shock is a condition associated with diffuse coagulopathy and multiple organ failure, and frequently ends in death. The effectiveness of continuous venovenous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (CVVHDF using PMMA) for critically ill patients has also been reported. This treatment was showed as cytokine adsorption therapy, but there are not so many reports in the world.

Zero Mortality of Continuous Veno-venous Hemodiafiltration with PMMA Hemofilter after Pediatric Cardiac Surgery

Continuous veno-venous hemodiafiltration (CVVH) is used as one of the modalities of continuous renal replacement therapy (CRRT) in pediatric intensive units. The aim of our study was to investigate the use of CVVH in small children with acute renal failure (ARF) after cardiac surgery. Between June 2005 and June 2008, 7 patients who required dialysis after pediatric cardiac surgery without ECMO underwent CVVH with polymethylmethacrylate membrane (PMMA) treatment. The definition of ARF was based on a 100% rise in serum creatinine (Cr) concentration, oliguria. On the other hand, PMMA-CVVH was weaned in patients with satisfactory urine output, stable biochemical markers of renal function and adequate fluid balance. All patients treated with PMMA-CVVH alone (4 boys, 3 girls) had a median age of 36 months and a median body weight of 11 kg. The averaged established time from cardiac operation to CVVH was 2.6 days. There was a significant decrease in the post-filter compared with pre-filter levels of BUN, Cr, potassium concentration. There were no significant changes in systolic blood pressure, lactate level and CRP; however, it was unnecessary for all patients to use epinephrine. Continuous veno-venous hemodiafiltration with PMMA-CVVH without ECMO achieved a surprisingly Zero mortality.

Trial use of a polymethylmethacrylate membrane for the removal of free immunoglobulin light chains in dialysis patients.

Background. Free immunoglobulin light chains (FLCs) accumulate at high levels in the blood of dialysis patients and are likely to cause immunodeficiency during periods of dialysis. Our group examined the blood FLC concentration, κ/λ ratio and rates of FLC removal in different dialysis modes using different dialysis membranes.Methods. Polymethylmethacrylate (PMMA) membrane (BG-PQ, Toray) under the haemodialysis (HD) condition was used for seven chronic maintenance dialysis patients who had been treated by hemodiafiltration (HDF) (five polyester-polymer alloy (PEPA) and two polysulphone) in a crossover fashion. FLCs in serum were measured with a FREELITE™ Human Kappa Free Kit and Lambda Free Kit prepared by Binding Site, UK (supplied by Medical & Biological Laboratories Co., Ltd, Japan). Each κ-type and λ-type FLC was quantitatively measured with a Dade Behring BNII™. Western blotting was conducted using a goat anti-human κFLC polyclonal antibody.Results. The κ and λ serum FLCs in HD patients (n = 7) were 157.4 ± 88.9 and 121.9 ± 56.3 mg/L, respectively, and were accumulated in concentrations 4- to 16-fold higher than the concentrations in healthy controls. The κ/λ ratio was included in the reference range (0.26–1.65). In the HD cases dialysed with PMMA membrane, the FLCs were removed mainly by adsorption, leaving only very small quantities in the whole dialysis waste fluid. The ratio between the total removed quantity and albumin leakage ((κ+λ)/Alb) was higher in the PMMA HD group than in the HDF group, and the rate of κFLC removal was higher than the rate of λFLC removal. The serum κFLC in dialysis patients had a multimer structure. In western blotting, the adsorbed κFLC (including multimer structure) detected in the PMMA membrane exceeded that detected in the dialysate with the polysulphone membrane.Conclusions. Although the FLCs were removed at high rates under the HDF condition, they were also effectively removed by adsorption with the PMMA membrane under the HD condition. It may be possible to effectively remove the FLC multimer with a PMMA membrane via adsorption. In future studies on FLC removal in patients with chronic renal failure, it will be necessary to assess not only the quantity of simple removal from the blood but also the qualitative properties, such as the degree to which accumulation and removal rates depend on the κ/λ ratio and multimer structures.

Effect of different synthetic membranes on laboratory parameters and survival in chronic haemodialysis patients.

Background. A number of studies suggested that the type of dialysis membrane is associated with differences in long-term outcome of patients undergoing haemodialysis, both in terms of morbidity and mortality. In the majority of dialysis units, synthetic membranes are being used. However, no studies are available so far for comparison between different biocompatible membranes. Therefore, we studied the influence of high- and low-flux polysulphone membranes (PS) in comparison with polymethylmethacrylate (PMMA) membranes on mortality and morbidity on the basis of various laboratory parameters.Methods. In a cohort study, data of 260 consecutive haemodialysis patients entering our dialysis unit in the years 2003–07 were collected, comparing 435 PS patient-years and 85 PMMA patient-years. PMMA membranes (n = 33) were used for those patients who did not tolerate (e.g. for pruritus) PS membranes (n = 227). Low-flux dialysers (n = 233) were compared with high-flux (n = 37). Laboratory values were evaluated by unpaired t-test, and mortality was evaluated by log-rank test and Cox regression analysis adjusted for age, diabetes and laboratory parameters.Results. Patients in our dialysis unit had a high cardiovascular risk as demonstrated by a proportion of 63% of peripheral arterial disease. Despite this, cumulative survival was almost 60% after 5 years on dialysis. It was slightly but not significantly higher in patients on PMMA (68%) compared with PS dialysers (54%) and on high-flux (61%) versus low-flux membranes (54%). After accounting for the confounding effect of age and diabetes in the multivariate Cox regression analysis, there was no impact of the membranes used (high- or low-flux, PMMA or PS) on survival. Only age at the onset of dialysis showed a significant influence on survival (P ≤ 0.001). Independent predictors of mortality in all patients in the multivariate Cox regression analysis were age, haemoglobin, leucocytes, C-reactive protein (CRP) and creatinine. Laboratory parameters between the high- and low- flux groups were not different. PS-treated patients showed significantly (P ≤ 0.05) higher values for leucocytes, thrombocytes, ferritin, and CRP and lower values for haemoglobin, transferrin, creatinine, uric acid, creatine kinase (CK), and sodium than PMMA-treated patients. Irrespective of the membrane used, in deceased patients, the following laboratory values were higher than for patients alive: leucocytes, thrombocytes, ferritin and CRP; the following were lower: haemoglobin, iron, total protein, urea, creatinine, uric acid and CK.Conclusions. The data of 260 severely ill haemodialysis patients showed a slightly, but not significantly, reduced mortality in patients treated with PMMA membranes in comparison with PS and with high-flux membranes compared with low-flux. High- or low-flux membranes exhibited no difference in laboratory values. However, in PMMA patients, laboratory data with respect to inflammation, anaemia and nutrition were significantly improved compared with the PS group. A similarly positive laboratory pattern was seen in patients alive compared with patients deceased with both membrane types. The favourable effect of PMMA membranes may be explained by the reduced activation of catabolic components and inflammation, which, in turn, would result in an improved nutrition and better response to recombinant human erythropoietin.

Potential role of the soluble form of CD40 in deficient immunological function of dialysis patients: new findings of its amelioration using polymethylmethacrylate (PMMA) membrane.

Even though numerous studies have helped to better delineate abnormalities of either innate or adaptive immune system in end-stage renal disease (ESRD) patients, understanding immune dysfunctions in ESRD patients remains a very complex puzzle with missing pieces. In this context, we showed that the soluble form of CD40 (sCD40) is elevated in ESRD patients and is associated with a lack of response to hepatitis B vaccination. Interestingly, although most dialysis membranes are unable to clear sCD40, we demonstrated that polymethylmethacrylate (PMMA) BK-F membranes (Toray Medical Company, Japan) allow a dramatic diminution of the molecule. We took advantage of this observation to address the question of the potential usefulness of PMMA membrane (BK-F series) in the improvement of humoral immune response of ESRD patients. We, thus, present our recent data highlighting the potential role of BK-F membrane in the improvement of hepatitis B vaccination of ESRD patients who failed to mount a protective immune response despite one or more well-conducted anterior vaccination.Taken as a whole, our findings reinforced the concept of seeing dialysis membranes not just as a simple diffusive device but as a tool to tailor dialysis procedure to improve the global quality of life of ESRD patients. This opens a wide area of investigation, notably for the management of immunological dysfunction of ESRD patients.

Filtration and Adsorption of Albumin in Commercial Hemofilters

The aim of this study is to perform ultrafiltration experiments in vitro with several commercial hemofilters for continuous renal replacement therapy (CRRT) in aqueous albumin solution and in various modifications of bovine blood in order to discuss separation characteristics of albumin.In aqueous solution system, 2000 mL of a single component albumin solution (2.552 g/L) was used. Flow rates of the albumin solution and ultrafiltration were 100 and 10 mL/min, respectively, and the experiment was performed for 720 min at 310 K. Adsorption of albumin was evaluated from the time courses of the concentration profile and sieving coefficient (s.c.). We investigate two polymethylmethacrylate (PMMA), two polysulfone (PS) and one polyacrylonitrile (PAN) hemofilters with four kinds of bovine blood test solutions as well as the aqueous solution.PMMA that has strong adsorption characteristics showed relatively low s.c. for albumin (0.01–0.03) in aqueous albumin solution. PMMA membrane with enlarged pore size showed two times higher s.c. for albumin than that with normal pore size. Albumin concentration in the reservoir in aqueous experiments decreased approximately by 20% and 50% in 630 min using the PMMA membranes with normal and enlarged pores, respectively. On the other hand, albumin concentration decreased by only 5.0% and 4.4 to 5.5% using PAN and PS hemofilters, respectively. The discrepancy may be explained by the physical structures of the membrane, i.e. albumin molecules may have been occlusively trapped by the entirely dense structure of PMMA.In the PS membrane, s.c. for albumin in the aqueous system was not significantly different from those found in various bovine serum systems which implied that a very small amount of albumin was adsorbed by the PS membrane due to reduced hydrophobicity caused by the use of a large amount of hydrophilic agent.

劇症型Ａ群溶血性連鎖球菌感染症に対し，ポリメチルメタクリレート膜血液濾過器を用いた持続的血液濾過透析を２系列同時施行した特発性細菌性腹膜炎の１救命例

原発性硬化性胆管炎による肝硬変患者が，Streptococcus pyogenesを起因菌とした特発性細菌性腹膜炎を発症し，劇症型A群溶血性連鎖球菌感染症（toxic shock-like syndrome, TSLS）に陥った。著明な高サイトカイン血症を呈する敗血症性ショックに対し，通常の敗血症治療に加え，2系列同時施行するポリメチルメタクリレート膜血液濾過器を用いた持続的血液濾過透析（continuous hemodiafiltration involving two consoles using a polymethylmethacrylate membrane hemofilter, double PMMA-CHDF）を行い，難治性ショックから離脱し救命し得た。TSLSの病態として，スーパー抗原活性をもつstreptococcal pyrogenic exotoxinがT細胞受容体と反応する結果惹起される著明な高サイトカイン血症が考えられている。そのため，従来の治療法では制御困難な高サイトカイン血症に対して，今回施行したdouble PMMA-CHDFが有用である可能性が示唆された。

Selection of acute blood purification therapy according to severity score and blood lactic acid value in patients with septic shock

Aim:As an alternative method for acute blood purification therapy, continuous venovenous hemodiafiltration (CVVHDF) has been reported as an effective clinical treatment for critically ill patients, but the optimal column for performing CVVHDF remains controversial.Patients and Methods:We used direct hemoperfusion using a polymyxin B-immobilized fiber column (DHP-PMX) to treat 88 patients with septic shock. To determine the optimal acute blood purification therapy, we subsequently divided the patients into three groups: the first group underwent CVVHDF using a polymethylmethacrylate membrane hemofilter (PMMA) after undergoing DHP-PMX (28 cases), the second group underwent CVVHDF using a polyacrylonitrile membrane hemofilter (PAN) after undergoing DHP-PMX (26 cases), and the third group did not undergo CVVHDF after undergoing DHP-PMX (34 cases).Results:The overall survival rate was 54.5%, and patient outcome was significantly related to the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the sepsis-related organ failure assessment (SOFA) score, and the blood lactic acid value before treatment (all P<0.0001). Only the PMMA-CVVHDF group showed a better outcome (survival rate of 78.6%) compared with the other groups (P = 0.0190). In addition, only the PMMA-CVVHDF group showed a significant improvement in the blood lactic acid level on day 3 (P = 0.0011).Conclusion:Our study suggests that the PMX column might be effective during the early phase of septic shock, before a high level of lactic acid is present. Furthermore, a PMMA column might be the most useful column for performing CVVHDF after DHP-PMX treatment, as suggested by the blood lactic acid value.

Evaluation of Oxidant-Antioxidant Balance in Patients on Maintenance Haemodialysis: A Comparative Study of Dialyzers Membranes

Background: Haemodialysis (HD) exacerbates oxidative stress (OS). The polymethyl-methacrylate (PMMA)-BK-F membrane ameliorates OS and inflammation markers compared to polyacrylonitrile (PAN/AN69) and cellulose membranes. This may be due to the size of pore radius, high flux or other specific properties of PMMA membranes. Aim: To compare OS and inflammatory status in HD-treated end stage renal disease patients with membranes of different pore size radius and flux. Methods: 47 patients of both sexes were studied. The HD membranes with which the patients were normally treated were changed to BK-P or B-3 membranes for 6 months. Intracellular and extracellular components of the oxidant-antioxidant balance (OAB), C-reactive protein (CRP), β2-micro-globulin (β2µ-globulin), albumin and transferrin were measured. Results: A significant decrease in red cell membrane thiobarbituric acid reacting substances and an increase in cytosolic superoxide dismutase (SOD) and plasma total antioxidant substances were observed in all patients after 6 months of treatment with BK-P and B-3 membranes except SOD and CRP in patients previously dialysed with triacetate cellulose membranes. Albumin and transferrin remained unmodified. β2µ-globulin significantly decreased after treatment with PMMA membranes. Conclusion: BK-P and B-3 HD membranes improved the OAB, β2µ-globulin and CRP compared to PAN/AN69 and cellulose diacetate membranes.

Amount of adsorbed albumin loss by dialysis membranes with protein adsorption

Polymethylmethacrylate (PMMA) membrane is the first synthetic polymeric hollow fiber used in dialyzers that is known to adsorb beta(2)-microglobulin. Polyester polymer alloy (PEPA), a blend of two polymers, i.e., polyarylate and polyethersulfone, is another dialysis membrane material with adsorption characteristics. In this study, the adsorption and permeation characteristics of BG-1.6PQ (PMMA) and FLX-15GW (PEPA) dialyzers were investigated by performing ultrafiltration experiments using chymotrypsinogen (molecular weight 25,000) and albumin (molecular weight 66,000) as test solutes. Although PMMA and PEPA had the same sieving coefficient for chymotrypsinogen at steady state, PMMA showed approximately 20% higher fractional adsorption than PEPA under the same initial concentrations. The fractional adsorption for albumin was approximately 20% in PEPA regardless of the ultrafiltration flow rate. The fractional adsorption for albumin in PMMA, however, increased as the ultrafiltration flow rate increased and reached 50%-60% after 10 h. Since PEPA has two skins, one inside and one outside the hollow fiber, proteins may have been adsorbed mainly by these two layers. However, since PMMA is a uniform membrane and since the higher the ultrafiltration flow rate, the higher the fractional adsorption found in PMMA, adsorption may be the result of the occlusion of the dense structure of the membrane. The amount of albumin loss is often clinically evaluated by measuring the amount of permeated albumin in the dialysate. However, when dialyzers with adsorption characteristics are examined, the loss by adsorption should also be taken into account.

A Circulating β2-Microglobulin Intermediate in Hemodialysis Patients

Background/Aims: A misfolded β₂-microglobulin (β₂m) is a principle component in dialysis-related amyloidosis. However, no such conformational variant of β₂m has yet been reported in a clinical setting. Capillary electrophoresis is a tool that can identify the conformational variant of β₂m. Methods: Capillary electrophoresis was used to measure a transitional intermediate from native β₂m (N-β₂m) to the amyloid β₂m. This technique was utilized to assay for intermediate β₂m (I-β₂m) in serum from 31 hemodialysis (HD) patients before and after HD, 5 patients with non-dialysis chronic renal failure (CRF), and 5 healthy persons. Results:The predialysis values of serum I-β₂m and N-β₂m were 2.7 ± 1.4 and 29.4 ± 6.8 mg/l, respectively, in the HD patients. The presence of serum I-β₂m correlated weakly with the total serum β₂m concentration in all HD patients. The serum N-β₂m concentration decreased significantly during two types of dialysis treatment: by 32.8% on HD using a polymethylmethacrylate (PMMA) membrane and by 71.2% on online hemodiafiltration (HDF) with a polysulfone (PS) membrane. On the other hand, a dialysis-associated change in serum I-β₂m varied from –36.4 to +203.5% in HD patients using PMMA and from –70.8 to +62.5% in online HDF patients using PS. Moreover, a rebound β₂m profile suggested that I-β₂m might be immobilized in the extracellular space. Conclusion: This study demonstrated that two or three conformational isomers of β₂m were probably ubiquitously recognized in human serum. Though no progressive increase in serum I-β₂m concentration could be found along with HD, this study shows a significantly poor removal of I-β₂m in comparison to N-β₂m in patients receiving ongoing dialysis treatment, even with online HDF.

Plasmatic cytokines and intermittent hemodialysis with polymethylmethacrylate membrane in septic shock patients

Sepsis is mediated by many biologically active inflammatory mediators, including interleukins. IL-6, IL-8, and IL-10 *P < 0.05. are correlated with increased mortality in septic shock acute renal failure (ARF) [1]. ARF treatment requires renal replacement therapy (RRT). The cytokine plasmatic level during and after hemodialysis (HD) in septic ARF is partially described [2]. Polymethylmethacrylate (PMMA) hemodialyser membranes own high adsorptive capacity [3]. In this prospective observational trial, we study the plasmatic level of IL-6, IL-8 and IL-10 during and after the first HD seance with PMMA membrane in septic shock patients with ARF.

Pharmacokinetics and pharmacodynamics of once-daily arbekacin during continuous venovenous hemodiafiltration in critically ill patients

This study examined the pharmacokinetics of arbekacin during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamics to consider arbekacin dosage adaptation in CVVHDF. Arbekacin was administered by 0.5-h infusion once daily, using a polymethyl methacrylate membrane hemofilter, to three critically ill patients undergoing CVVHDF; the flow rates were 0.8 l/h for the filtrate and 0.6 l/h for the dialysate. The drug concentrations in plasma and in the filtrate-dialysate were determined using a fluorescence polarization immunoassay and analyzed pharmacokinetically. The average sieving coefficient of arbekacin was 0.739 and the average drug clearance by CVVHDF was 1.03 l/h. A pharmacokinetic model with three compartments (1, central; 2, peripheral; 3, filtrate-dialysate side hemofilter) accurately reflected the concentration-time data for both plasma and filtrate-dialysate. The pharmacokinetic model assessed the pharmacodynamic profile of arbekacin once-daily regimens (0.5-h infusions) at filtrate-dialysate flow rates of 1.4 and 2.8 l/h, and demonstrated that only the 150-mg and 200-mg regimens achieved an effective target range for C(max) (9-20 microg/ml), suggesting that empirical dosages lower than the usual 150-200 mg should be avoided in patients undergoing CVVHDF. The minimum regimens needed to achieve an effective pharmacodynamic target for the free C(max)/MIC ratio (>8) were 75 mg for an MIC of 0.5 microg/ml, 200 mg for an MIC of 2 microg/ml, and 400 mg for an MIC of 4 microg/ml. These results will help us to better understand the pharmacokinetics of arbekacin during CVVHDF, while also helping in the selection of the appropriate arbekacin regimens, based on a pharmacodynamic assessment, for patients receiving this renal replacement therapy.

The role of hypercytokinemia in the pathophysiology of tumor lysis syndrome (TLS) and the treatment with continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF)

Objective To examine the role of hypercytokinemia in the pathophysiology of tumor lysis syndrome (TLS) and the efficacy of continuous hemodiafiltration in the treatment of TLS. Design and setting Retrospective observational study in a general intensive care unit of a university hospital. Patients Four patients with hematological disorder developing TLS after the treatment of anti-tumor chemotherapy. Interventions Continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) was performed at the onset of TLS. Blood samples were collected daily after ICU admission, and clinical parameters and blood levels of cytokines were evaluated. Measurements and results All four patients underwent induction anti-tumor chemotherapy, during which they developed hyperuricemia, hyperkalemia, and acute renal failure. Two of them also developed multiple organ failure. Serum levels of tumor necrosis factor (TNF) -alpha, interleukin-6 (IL-6), and IL-10 prior to the initiation of PMMA-CHDF were 102 ± 85 pg/mL, 1097 ± 546 pg/mL, and 98 ± 83 pg/mL, respectively (mean ± SD). After three days of PMMA-CHDF treatment, corresponding blood levels were 37 ± 55 pg/mL, 326 ± 511 pg/mL, and 9 ± 8 pg/mL, respectively. Thus, all cytokine levels were significantly decreased by three days of PMMA-CHDF treatment ( p < 0.05, paired t-test). Following three days of PMMA-CHDF treatment, blood urea nitrogen (BUN) and serum creatinine (Cre.) were significantly decreased (pre/post BUN 42.3 ± 15.4/16.5 ± 8.4 mg/dL, p < 0.05, pre/post Cre. 2.7 ± 1.2/1.2 ± 0.6 mg/dL, mean ± SD, p < 0.05). Furthermore, the clinical condition of each patient was improved after the treatment of PMMA-CHDF, and all of four patients were survived. Conclusion Hypercytokinemia plays a pivotal role in the pathophysiology of TLS and PMMA-CHDF may be an effective therapeutic modality for TLS patients not only as renal replacement therapy but also as a cytokine modulator.

Continuous hemodiafiltration in the treatment of reactive hemophagocytic syndrome refractory to medical therapy

Reactive (or secondary) hemophagocytic syndrome (RHS) is a potentially lethal condition and characterized by hypercytokinemia. Immune modulating drugs sometimes fail to achieve satisfactory control. Therefore we investigate the efficacy of continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter (PMMA-CHDF) for cytokine removal in patients with RHS. Eight consecutive patients who admitted to our ICU with RHS complicating organ failures and refractory to medical therapy were initiated intensive care including PMMA-CHDF. Although remission was achieved in six patients, remaining two patients died of exacerbation of underlying diseases. Changes in blood levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) as indices of cytokine network activation, and serum ferritin level as an index of severity of RHS were investigated during PMMA-CHDF. PMMA-CHDF performed for 3 days significantly reduced blood TNF-α level (183 ± 159 pg/ml to 84 ± 98 pg/ml, p < 0.05) and also blood IL-6 level (1113 ± 903 pg/ml to 402 ± 411 pg/ml, p < 0.01). Furthermore, serum ferritin level was significantly decreased 3 days after initiation of PMMA-CHDF (52390 ± 65168 ng/ml to 4136 ± 2932 ng/ml, p < 0.05) although it tended to increase before initiation of PMMA-CHDF. No PMMA-CHDF-related adverse events were observed in any of the patients. PMMA-CHDF was effective to remove cytokine and improved disease severity. Thus, PMMA-CHDF may be an adjunctive treatment in RHS refractory to medical therapy.

Clinical evaluation of plasma insulin and C-peptide levels with 3 different high-flux dialyzers in diabetic patients on hemodialysis

Changes in plasma immunoreactive insulin (IRI) and connecting-peptide immunoreactivity (CPR) concentrations during hemodialysis (HD) were evaluated in diabetic HD patients with 3 different high-flux membranes. The removal properties of the membranes were compared. In this prospective controlled study, 15 stable diabetic patients on HD were randomly selected for 6 HD sessions with 3 different membranes: polysulfone (PS), cellulose triacetate (CTA), and polymethylmethacrylate (PMMA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session. At 60 minutes after dialysis initiation, blood samples were obtained from both the A and venous (V) sites of the dialyzer to investigate the clearance and removal properties of the membranes. The plasma IRI and CPR levels decreased significantly at each time point with all 3 membranes. IRI clearance with the PS membrane was significantly higher than that with the CTA and PMMA membranes. No difference was observed in the IRI reduction rate between the 3 membranes. CPR clearance and reduction rate with the PMMA membrane were lower than with the PS and CTA membranes. No significant difference was observed in serum creatinine clearance and reduction rates between the 3 membranes; however, serum urea nitrogen clearance was significantly lower with the PMMA membrane compared with the PS and CTA membranes. A significantly high beta2-microglobulin clearance and reduction rate was achieved in the order PS > CTA > PMMA. Plasma IRI and CPR are cleared by HD; their clearance rates differ with the dialyzer membranes. Plasma IRI clearance with the PS membrane is higher than that with the CTA and PMMA membranes.

Adsorption of nafamostat mesilate by hemodialysis membranes.

The adsorption of the anticoagulant nafamostat mesilate (FUT-175) by five different hemodialysis membranes was studied in vivo and in vitro. In vivo, FUT-175 was adsorbed strongly by a polyacrylonitrile (AN69) membrane and slightly by another polyacrylonitrile (J-PAN) membrane but not by Cuprophan (CU), hemophan (HE), or polymethylmethacrylate (PMMA) membranes during hemodialysis performed in 4 patients in whom FUT-175 was used as an anticoagulant. Only during hemodialysis using the AN69 membrane did FUT-175 not induce a significant prolongation of celite-activated coagulation time. In vitro studies showed that FUT-175 was adsorbed by the AN69, J-PAN, and PMMA membranes but not by the CU and HE membranes. Methylene blue, a dye that possesses a cationic portion in its chemical structure, stained AN69, J-PAN, and PMMA membranes. Since FUT-175 also possesses a cationic portion, we conclude that FUT-175 is adsorbed by negatively charged membranes via an ionic bond and is unsuited for use as an anticoagulant in hemodialysis using an AN69 membrane because of that membrane's marked capacity to adsorb FUT-175.

Continuous Hemodiafiltration with PMMA Hemofilter in the Treatment of Patients with Septic Shock

Septic shock is the most severe form of sepsis. It is widely accepted that cytokines play pivotal roles in the pathophysiology of septic shock. We reported previously that continuous hemodiafiltration (CHDF) using a polymethylmethacrylate (PMMA) membrane hemofilter removed various cytokines from blood continuously and efficiently, mainly by adsorption to membrane matrix of the hemofilter. Furthermore, in April 2000, we introduced to clinical practice a rapid assay system that determines blood levels of IL (interleukin)-6 in approximately 30 min. This enabled us to routinely measure blood IL-6 as an index of cytokine cascade activation in critically ill patients for real-time clinical monitoring of hypercytokinemia. The aim of the present cohort study was to evaluate the clinical efficacy of PMMA-CHDF in septic shock, a typical condition associated with hypercytokinemia. Forty-three patients with septic shock were assessed by monitoring of blood IL-6 level with a rapid assay system and immediate initiation of critical care including PMMA-CHDF for cytokine removal. Following initiation of PMMA-CHDF, early improvement of hemodynamics was noted, as well as an increase in urine output. PMMA-CHDF treatment improved both hypercytokinemia (assessed by measurement of blood IL-6 level) and dysoxia (assessed by measurement of blood lactate level). The present findings suggest that cytokine-oriented critical care using PMMA-CHDF might be an effective strategy for the treatment of septic shock.