Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

2005 Japanese Society for Dialysis Therapy guidelines for vascular access construction and repair for chronic hemodialysis.

The guideline committee of Japanese Society for Dialysis Therapy (JSDT), chaired by Dr Ohira, has published an original Japanese guideline, 'Guidelines for Vascular Access Construction and Repair for Chronic Hemodialysis'. The guideline was created mainly because of the existence of numerous factors characteristic of Japanese hemodialysis therapy, which are described in this report, and because we recognized the necessity for standardization in vascular access-related surgeries. This guideline consists of 10 chapters, each of which includes guidelines, explanations or comments and references. The first chapter discusses informed consent of vascular access (VA)-related surgeries, which often resulted in trouble between dialysis staff and patients. The second chapter describes the fundamentals of VA construction and timing of the introduction of hemodialysis with emphasis on the avoidance of catheter indwelling if at all possible. In the third chapter, arteriovenous fistula (AVF) construction and management are discussed from the viewpoint of the most preferable type of VA. The fourth chapter deals with arteriovenous grafts (AVG) which has recently increased in clinical applications. The factors which improve the AVG patency rate are discussed and postoperative management methods are emphasized to avoid possible complications. The fifth chapter deals with short and long-term vascular catheters. It is emphasized that these methods are definitely effective but, at the same time, are apt to be associated with several serious complications and might result in vascular damage. In the sixth chapter, superficialization of an artery is explained. This was originally for emergency use or backup but has been used permanently in 2-3% of Japanese hemodialysis patients. In the seventh chapter, methods for the use of VA are described and the buttonhole method is referred to as one of the options for patients who complain of intense pain at every cannulation. In the eighth chapter, the importance of continuous monitoring is stressed for maintaining appropriate function of VA. As a rule, the internal shunt type VA (AVF, AVG) places a burden on cardiac function. Thus, in the ninth chapter, it is stressed that VA construction, maintenance and repair should always be carried out with consideration of cardiac function which is not constant but variable. The 10th chapter forms one of the cores of this guideline and deals with repair and timing of VA. It is shown how to select a surgical or interventional repair method. In the final 11th chapter, VA types and resultant morbidity and mortality of hemodialysis patients are reviewed.

In preparation for a treatment guideline for suitable vascular access repair in Japan.

In cases of vascular access (VA) for hemodialysis including arteriovenous fistula and arteriovenous graft, venipuncture and hemostasis are usually repeated three times a week. Accordingly, it is assumed that VA vascular disorders are worsened following long-term hemodialysis. In particular, angiostenosis frequently occurs and results in insufficient blood flow or increased venous pressure. Additionally, stenosis is a major cause of VA occlusion. While VA intervention treatment is mainstream for VA stenosis, its major advantage lies in its less invasiveness because it is a percutaneous treatment. A further advantage of this treatment procedure is that the existing VA can be preserved intact. For practical use of VA intervention treatment, however, compliance with the therapeutic indication guideline is required. In K/DOQI of the United States, such a guideline has already been formulated based on evidence and specialist opinion, while the guideline of the European Vascular Access Society is presented in the form of a flowchart. The Japanese Society for Dialysis Therapy is currently preparing a guideline for the construction and maintenance of VA, which introduces the timing and principles of repair of VA in the following six categories: (i) stenosis; (ii) occlusion; (iii) venous hypertension; (iv) steal syndrome; (v) excess blood flow; and (vi) infection. Except for infection, most of the treatments for these events involve VA intervention, thus the need for the guideline for VA intervention treatment is becoming widely recognized.

Effects of low molecular weight heparin on the frequencies of intradialytic arrhythmias in hemodialysis patients.

Arrhythmia is known to cause sudden death in hemodialysis patients. Heparin administration releases lipoprotein lipase from the capillary endothelial cell surface, resulting in an increase in the plasma levels of free fatty acids; higher levels of free fatty acids may affect the occurrence of arrhythmias. This study assessed whether the occurrence of arrhythmias during hemodialysis could be suppressed by replacing unfractionated heparin with low molecular weight heparin. Ten dialysis patients who had supraventricular premature contraction and/or ventricular premature contraction were monitored by the Holter electrocardiograph system during hemodialysis. To investigate the effect of each form of heparin on plasma lipid metabolism, the lipoprotein lipase and lipid levels before and during hemodialysis were measured. The occurrence of arrhythmias was significantly suppressed in hemodialysis using low molecular weight heparin, as compared with hemodialysis using unfractionated heparin. Lower lipoprotein lipase and free fatty acids levels were also observed in hemodialysis using low molecular weight heparin. The authors concluded that hemodialysis using low molecular weight heparin instead of unfractionated heparin could be effective in protecting hemodialysis patients with arrhythmias against arrhythmia-related cardiac events.

Studies on unfolded beta-microglobulin at C-terminal in dialysis-related amyloidosis.

BACKGROUND: In 1997, Stoppini et al reported that monoclonal antibody specific to the C-terminal 92-99 of beta(2)-microglobulin (beta(2)m) had been capable of inhibiting fibrillogenesis of beta(2)m in vitro. Meanwhile, recent studies have indicated that an acidifying procedure can unfold conformation of the precursor protein, leading to fibril formation of beta(2)m as well as a transthyretin. METHODS: We thus prepared monoclonal antibody specific to the C-terminal 92-99 (mAb 92-99), and investigated its reactivity in plasma ultrafiltrate and amyloid tissues from 18 hemodialysis patients with dialysis-related amyloidosis (DRA). RESULTS: beta(2)m extracted from ultrafiltrate showed no reaction for mAb 92-99, whereas acidified beta(2)m from ultrafiltrate showed a reaction for mAb 92-99. Similarly, a homogenate of carpal amyloid tissues showed a strong reaction for mAb 92-99 on immunoblotting. Immunohistochemical study showed also a distinct staining for mAb 92-99 in 7 Congophilic specimens from DRA patients. More interestingly, staining for mAb 92-99 could be found in most, though not all, non-Congophilic tissues. CONCLUSION: This study demonstrates that the monoclonal antibody specific to the C-terminal 92-99 of beta(2)m can detect the conformational intermediate in amyloidogenesis of beta(2)m ex vivo, and demonstrates that an unfolded beta(2)m at C-terminal could be found not only in Congophilic area but even in non-Congophilic area as well.

[New molecular marker in dialysis setting--misfolded beta 2-microglobulin].

More than 25 clinical settings in amyloidosis have been acknowledged in which a peculiar criminal protein, a precursor protein, has been identified. As of now, however, the mechanism of amyloidogenesis, by which a precursor protein is transformed irreversibly into an amyloid protein, remains to be clarified. We speculated that a study of the molecular conformation of beta 2-microglobulin (beta 2 m), a precursor protein in dialysis-related amyloidosis (DRA), might provide a typic model of amyloidogenesis in other precursor proteins. Therefore, we investigated the misfolding of beta 2 m in DRA using a specific monoclonal antibody against C-terminal peptide 92-99 of beta 2 m. Our study indicated the possibility that the monoclonal antibody specific for C-terminal 92-99 of beta 2 m can detect a pre-amyloid state in amyloidogenesis in vivo, which might take place in the extravascular space.

Short-term biological effects of a new and less acidic fluid for peritoneal dialysis.

BACKGROUND: Conventional peritoneal dialysates are potentially bioincompatible and seem to be a causative factor for peritoneal sclerosis. Recent studies demonstrated that a new type of dialysate has a positive long-term clinical effect on dialysis patients. METHODS: In this study, to elucidate the short-term biological effects of a newly developed dialysate of higher pH on the peritoneal membrane, we assessed macrophage proportions and several markers (inflammatory cytokines, cancer antigen 125 (CA125) and albumin) in spent dialysates before and 2 weeks after the change to the new fluid from a conventional fluid. RESULTS: We found that the use of the new dialysate decreased intraperitoneal levels of inflammatory cytokines, CA125 and albumin associated with the decrease of macrophage populations in dialysis effluents. CONCLUSION: These observations suggest that a new and less acidic fluid reduces pro-inflammatory potential in the peritoneum, and thus affords better preservation of peritoneal membrane integrity in uremic patients on peritoneal dialysis.

Changes in oxidative stress and microcirculation by low-density lipoprotein apheresis.

Low-density lipoprotein apheresis (LDLA) leads to an improvement of microcirculation during the very early stages of treatment, and continued treatment may produce antiatherogenic effects in patients with peripheral arterial disease (PAD). Suppression of oxidative stress, improvement of endothelial functions and alteration in the action of vasoactive compounds may occur with the improvement of the rheological property of blood as a result of aggressive removal of atherogenic factors including LDL, possibly resulting in the suppression of development of atherosclerosis. As these effects of LDLA may ameliorate not only PAD but also ischemia in other organs, it is suggested that repeated LDLA prevents the progression of atherosclerotic diseases and probably improves the long-term prognosis of patients with PAD.