[Pathogenesis of dialysis amyloidosis].
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Biomedical subjects
Publications and source records attributed to F Gejyo.
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By interfacing a polyacrylonitrile (PAN)-polyethyleneoxide (PEO) membrane with an ionically heparin-bound catheter, tubing, and module header, a totally antithrombogenic continuous ultrafiltration system (ACUS) was developed and its performance, persistent antithrombogenicity, and well-maintained ultrafiltration level were confirmed through animal experiments. Although the amount of heparin released and accumulated in vitro from those heparinized parts was very low and stable (on the order of 1 x 10(-2) U/cm2/min), partial thromboplastin time evaluated in vivo was not elongated during passage through the ACUS. Extracorporeal circulation time with the ACUS in unheparinized dog model was 458 +/- 302 min (n = 24), whereas those of partially modified (antithrombogenic) system did not exceed 100 min. As compared with that in a conventional continuous arteriovenous hemofiltration system, an extracorporeal circulation with the ACUS in an unheparinized dog model revealed significantly less fluctuation of platelet count, and no adherent platelets were observed on the surface of the PAN-PEO membrane. An ACUS consisting of a PAN-PEO membrane and heparinized parts was thus demonstrated to have good platelet compatibility. An ACUS with a surface area of 0.25 m2 was applied to two patients with acute renal failure. Hemofiltration without systemic heparinization lasted for 44 h per hemofilter, and a stable level of ultrafiltration was maintained. This system seems to be applicable for the clinical management of volume overload, especially in patients with bleeding tendencies or postoperative bleeding.
It is most important to differentiate destructive spondyloarthropathy (DSA) from vertebral osteomyelitis (VOM), both showing similar roentgenographic findings and evaluate the spinal involvement of DSA. Magnetic resonance imaging (MRI) is useful for morphological and biochemical analysis of spinal lesions, but few studies have been conducted on DSA. The authors detected 20 patients with DSA among 237 hemodialysis patients and conducted a study on 4 of them. The involved vertebral regions all showed low signal intensity on T1- and T2-weighted images. VOM can be visualized as areas of high signal intensity on T2-weighted images. In 2 of the patients, impingement was noted on the thecal sac both anteriorly and posteriorly. From the results of this study, MRI of DSA was shown to facilitate the exclusion of infectious processes and evaluation of spinal involvement.
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beta 2-Microglobulin (beta 2-MG)-related amyloidosis has been reported as a complication in long-term hemodialysis patients. We observed beta 2-MG amyloid deposits in synovial sheaths, bone cysts and gastric mucosa. They showed unique ultrastructural features, that is bundles or nodules consisting of curved or linear amyloid fibrils, associated with various cell reactions. The electron-microscopic histochemical study showed that they strongly stained with periodic acid-silver methenamine stain. A similar phenomenon was noticed in the spicules or bundles of amyloid fibrils in primary and secondary renal amyloidosis. With the cationic reagent toluidine blue 0, proteoglycan-like structures were observed around amyloid bundles and nodules, but not on each fibrils. Based on these results, we postulate that there is a close relationship between ultrastructural features and histochemical characteristics in beta 2-MG amyloid fibrils.
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Significant amounts of glycosaminoglycans (GAGs) were found in amyloid fibril preparations. Using two-dimensional electrophoresis to fractionate GAG mixtures, we quantified and identified for the first time the GAGs of the fibrils from carpal synovium of patients with amyloid associated with chronic hemodialysis. The total GAG content was small, but the GAG distribution (high relative content of chondroitin sulfate and hyaluronic acid and lack of the other GAGs) was unique, unlike that for the other amyloid fibril preparations. The amyloid-rich heart, liver, and spleen tissues, as well as the fibrils isolated from these tissues of patients with systemic forms (primary amyloid and secondary amyloid) of amyloid disease, were also analyzed for GAGs. Fibrils from heart tissue of a patient with primary amyloidosis, now examined for the first time, contained four major GAGs (chondroitin sulfate, dermatan sulfate, hyaluronic acid, and heparan sulfate).
A patient who developed mutilans-type arthropathy, splenomegaly, leukopenia, leg ulcer and massive hydroxyapatite accumulation during the course of progressive systemic sclerosis (PSS) was reported. A 56-years-old female had suffered Raynaud's phenomenon since the beginning of her third decade. She developed multiple symmetrical arthritis and morning stiffness at the age of 29, and was treated with NSAIDs and low dose corticosteroids under the diagnosis of rheumatoid arthritis (RA) Because of dysphagia and diarrhea, she was admitted in Niigata-Kenritsu Senami Hospital in September, 1987. Physical and roentgenographic examinations revealed diffuse scleroderma, mutilans-type arthropathy, lung fibrosis, splenomegaly and right leg ulcer. Laboratory examinations showed leukopenia, high titer of anti-DNA antibody, positive anti-Scl-70 antibody and mild hypocomplementemia. These findings suggested that she had PSS and Felty's syndrome. Furthermore, massive subcutaneous and intraarticular hydroxyapatite accumulation were noticed. The leg ulcer and laboratory data gradually improved with the combination therapy of corticosteroids, D-penicillamine and plasmapheresis. Although it has been well recognized that PSS patients reveal frequently the articular lesions similar to these of RA, severe mutilans-type arthropathy seen in this case is extremely rare. The joint contracture might be induced by hydroxyapatite accumulation, of which the early diagnosis seems to be very important in long-standing PSS patients.
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This study was undertaken to evaluate the relation between the urinary excretion of guanidinoacetic acid (GAA) and other substances in hypertensive patients (6 with borderline hypertension and 29 with hypertension) and 12 normal controls. In 10 of the hypertensive patients, GAA was measured before and after 4 weeks of treatment with calcium entry blocker. In hypertensive patients the rate of GAA urinary excretion was 43.5 +/- 17-4 micrograms/min, which was much lower than in the controls (77.2 +/- 35.9 micrograms/min) (p less than 0.01). There was no significant difference among these groups in creatinine clearance (CCr), serum creatinine (Cr), beta 2-microglobulin (BMG) or in the urinary excretion of BMG, N-acetyl-D-glucosaminidase (NAG) or radiosensitive microalbumin (mAlb). The urinary excretion rate of GAA was positively correlated with CCr (r = 0.62; p less than 0.01), and negatively correlated with mean blood pressure (r = -0.49; p less than 0.01). Finally, the GAA excretion was significantly correlated with urinary NAG (r = 0.24; p less than 0.05) and serum BMG (r = -0.31; p less than 0.05), but not with urinary mAlb (r = 0.12; p less than 0.05). Ten hypertensive patients followed for 4 weeks attained their ultimate mean blood pressure reduction after treatment (from 119.3 +/- 8.0 to 101.7 +/- 13.5 mm Hg; p less than 0.001), but the GAA/Cr ratio in the urinary excretion was significantly elevated (from 0.054 +/- 0.016 to 0.070 +/- 0.02; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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beta 2-Microglobulin (B2M) is the amyloid preprotein that accumulates in amyloid osteoarthropathy associated with hemodialysis. To elucidate the mechanism of such amyloidogenesis, we investigated the interaction between B2M and collagen in vitro by solid-phase enzyme immunoassay. Soluble collagens which had been solidified on plastic plates were allowed to react sequentially with B2M, peroxidase-conjugated antibody to B2M, and the substrate. The collagen-binding activity was dependent on the concentration of B2M and collagen, respectively. These results suggest that the collagen-binding affinity of B2M plays an important role in amyloidogenesis.
In the present study the complete amino acid sequence of human plasma Zn-alpha 2-glycoprotein was determined. This protein whose biological function is unknown consists of a single polypeptide chain of 276 amino acid residues including 8 tryptophan residues and has a pyroglutamyl residue at the amino terminus. The location of the two disulfide bonds in the polypeptide chain was also established. The three glycans, whose structure was elucidated with the aid of 500 MHz 1H NMR spectroscopy, were sialylated N-biantennas. The molecular weight calculated from the polypeptide and carbohydrate structure is 38,478, which is close to the reported value of approximately equal to 41,000 based on physicochemical measurements. The predicted secondary structure appeared to be comprised of 23% alpha-helix, 27% beta-sheet, and 22% beta-turns. The three N-glycans were found to be located in beta-turn regions. An unexpected finding was made by computer analysis of the sequence data; this revealed that Zn-alpha 2-glycoprotein is closely related to antigens of the major histocompatibility complex in amino acid sequence and in domain structure. There was an unusually high degree of sequence homology with the alpha chains of class I histocompatibility antigens. Moreover, this plasma protein was shown to be a member of the immunoglobulin gene superfamily. Zn-alpha 2-glycoprotein appears to be a truncated secretory major histocompatibility complex-related molecule, and it may have a role in the expression of the immune response.
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