Shigeo Furuyoshi

A new treatment for dialysis-related amyloidosis with beta 2-microglobulin adsorbent column.

Dialysis-related amyloidosis (DRA) is characterized by the presence of β 2-microglobulin (β 2-m) in the plasma. In order to eliminate β 2-m from the circulating blood, the β 2-m selective adsorbent for direct hemoperfusion (DHP) was developed. A DHP column (BM-01), containing 350 ml of the adsorbent, was subjected to clinical trials. The column was connected with a PAN (AN69) membrane dialyzer in series and used 3 times a week for 1 week (11 patients), 4 weeks (5 patients), 6 months (1 patient) and 12 months (2 patients). The percent reduction (%) of β 2-m was for 16 patients (for 1 or 4 weeks), more than 65, and for 3 patients (for more than 6 months), 76.5 ± 4.9, 73.5 ± 5.7, 72.2 ± 6.2. At the end of each session, β 2-m plasma levels were found to be below 10 mg/L, with 3.4 mg/L being the lowest. The total amounts of β 2-m removed were 172.5 ± 22.3, 257.0 ± 75.6, 157.6 ± 32.2 and 429.8 mg/session at max. Two out of these three patients had a favorable effect on joint symptoms and ocular fundus. It can be concluded that this selective adsorption therapy may delay the progression of DRA, and is worth considering for wide application.

A novel adsorbent of circulating bacterial toxins and cytokines: the effect of direct hemoperfusion with CTR column for the treatment of experimental endotoxemia.

Objectives:The current study examined the ability of a new adsorbent, CTR, to remove enterotoxins, toxic shock syndrome toxin-1 (TSST-1), and cytokines from blood and/or serum in vitro and the effects of the extracorporeal treatment with CTR column on mortality rate and inflammatory responses to endotoxic shock in vivo. Design:Laboratory investigation. Setting:University and company experimental laboratory. Materials:CTR is composed of porous cellulose beads to which a hydrophobic organic compound with a hexadecyl alkyl chain has been covalently bound to the surface as a ligand. Human/bovine serum and human blood samples in vitro and Male Wistar rats were used. Interventions:CTR’s ability to adsorb bacterial toxins and cytokines related to sepsis in serum and/or blood was examined with an in vitro batch adsorption protocol. In vivo, male Wistar rats were anesthetized and assigned to one of three groups (n = 14 per group): Escherichia coli endotoxin (15 mg/kg intravenously) alone (endotoxemic), apheresis with control column without CTR for 120 mins (control column), or extracorporeal treatment with CTR column for 120 mins (CTR treatment). Measurements and Main Results:With use of the CTR adsorbent, the adsorption rates were 50% to 90% for enterotoxins, TSST-1, and cytokines such as TNF-&agr; and interleukin (IL)-6 in the batch tests. In vivo, the mortality rates at 8 hrs after endotoxin injection were 92%, 92%, and 14% for the endotoxemic, control column, and CTR treatment groups, respectively. Hypotension and elevated plasma cytokine concentrations and the infiltration of neutrophils of the lungs were less conspicuous in the CTR treatment group than in the other two groups. Conclusions:CTR, a novel adsorbent, effectively adsorbed small- to middle-sized proteins, such as cytokines, enterotoxins, and TSST-1 in vitro. Direct hemoperfusion apheresis with CTR column reduced mortality and had inhibitory effects on the inflammatory responses during endotoxemia in vivo. These findings suggest that extracorporeal blood purification with CTR column may be available to use for patients with sepsis and/or endotoxemia.

Effects of a New Extracorporeal System Using CTR on Mortality and Inflammatory Responses to Bacterial Toxin-Induced Multiple Organ Dysfunction Syndrome in Rabbits

Background/Aims: In the pathogenesis of multiple organ dysfunction syndrome (MODS) caused by bacterial infection, a complex series of systemically secreted bacterial toxins and cytokines are intensely associated. Our previous study demonstrated that a new adsorbent, CTR, was capable of removing cytokines and toxic shock syndrome toxin-1 (TSST-1) in vitro. Moreover, extracorporeal treatment with CTR reduced the high mortality rate and inhibited inflammatory responses in endotoxin-induced shock in rats. However, it is unclear whether CTR treatment will be an effective therapy for MODS. Here, we demonstrated the efficacy of a new extracorporeal system using CTR on MODS induced by bacterial toxins in rabbits. Methods: Direct hemoperfusion (DHP) apheresis with or without CTR for 120 min was performed in rabbits that had been intravenously infused with endotoxin and TSST-1. The mean arterial pressure was recorded and the plasma toxin and cytokine concentrations were measured during the treatment period. Mortality was assessed up to 7 days after exposure to the toxins. In addition, tissues specimens were examined using microscopy. Results: The mortality rates at 7 days after the injection of the toxins were 90 and 10% for the control and CTR groups, respectively. The plasma concentrations of TSST-1, tumor necrosis factor and interleukin-1 beta in the CTR group were significantly lower than those in the control group. Histopathological examination revealed that tissue damage, such as necrosis and depletion of lymphocytes in the spleen and mesenteric lymph node, was reduced in the CTR group, compared with that in the control group, at 24 h after toxin infusion. Conclusion: The new adsorbent CTR improved the mortality rate in a MODS rabbit model by adsorbing TSST-1 and cytokines. Further development of CTR may expand the scope of extracorporeal therapies for patients with MODS.

New Adsorbents for Extracorporeal Removal of β2-Microglobulin

It has been reported that the amyloid deposition is frequently found at various tissues and organs in chronic hemodialysis patients,and this amyloid protein is homologous to β2-microglobulin (BMG)1. To prevent the progression of amyloid deposition, the direct removal of BMG from circulating blood has been tried using improved hemodialyzer. However, as the removal rate of BMG by dialyzer is still below the BMG production rate, serum BMG level can not be controlled as low as required for the regression or prevention. Therefore, it is desired that the device for more intensive BMG removal will be developed.