Research on dialyzers with improved biocompatibility.

Until now cellulosic membranes, especially Cuprophan, are still widely applied in the treatment of uremic patients. The success of this type of membrane for routine hemodialysis is related to a number of very useful properties with respect to performance, handling and biocompatibility. However, during dialysis Cuprophan membranes induce transient leucopenia which is closely connected with incidentally occurring pulmonary disfunction. These phenomena are thought to be complement mediated and Cuprophan has been recognized as an activator of complement. Synthetic membranes, such as PAN and PMMA show less complement activation than their cellulosic counterparts. Nevertheless these synthetic membranes cannot meet the performance quality of Cuprophan for routine dialysis and therefore dialyzers with synthetic membranes need special precaution to prevent excessive ultrafiltration. Consequently, research has been focussed on the development of a new cellulose-based dialyzer in which excellent performance suitable for routine dialysis is combined with improved biocompatibility. Two different approaches have been followed for the realization of this objective: The application of thinner membranes and The application of modified cellulose.

The relationship between biocompatibility and interleukin-1.

Biocompatibility is redefined as the quality of being mutually tolerant with life. In so far as this represents a quality which is as likely to be achieved as is the alchemist's dream of turning lead into gold, a compromise approach is recommended. It is suggested that all extracorporeal or body invasive procedures stimulate the inflammatory defence mechanism of the body by stimulating the monocyte to produce a family of polypeptides currently known collectively as Interleukin-1 (IL-1). So far two dissimilar gene products have been cloned and there are probably more. The IL-1 group of polypeptides possess hormonal functions which orchestrate nearly every instrument of the body's defence system. Inducers of IL-1 are present in dialysate and induce bacterial pyrogen and acetate. In addition bacterial cell wall glycoprotein may be cleaved into muramyl peptides by the release of granulocyte lysozyme at the membrane interface. Muramyl dipeptides have been found in CAPD drain fluid and are more potent inducers of IL-1 than endotoxin. Membrane activation of the fifth component of the complement with the release of C5a will also induce monocytes to produce IL-1. The consequences of repeated stimulation of the acute phase response are undesirable and may include muscle wasting, osteopenia and bone cysts (Shrinking man syndrome), fibrosis of scapulo-humeral joints and the carpal-tunnel syndrome. These latter lesions are often associated with deposition of amyloid fibrils related to beta 2-microglobulin. Efforts to reduce these complications are urgently required.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement activation and hypersensitivity reactions to dialysis membranes.

Certain patients receiving hemodialysis experience recurrent chest pain, dyspnea, and hypotension during exposure to new cuprophane-membrane dialyzers (the "first-use syndrome"). Because activation of complement may be involved in these events, we examined in vivo complement activation with new cuprophane membranes and in vitro activation by zymosan in 6 such patients, and compared them with 10 patients who did not have symptoms during dialysis. All patients with the first-use syndrome had maximal complement activation 10 minutes after initiation of dialysis, with C3a des-arginine (desArg), the stable metabolite of C3 activation, equal to 8533 +/- 157 ng per milliliter (mean +/- S.E.M.). In asymptomatic patients the maximal C3a desArg value occurred at 15 minutes and was only 2907 +/- 372 ng per milliliter (P less than or equal to 0.0001). At a concentration of 3.8 x 10(-5) g of zymosan per milliliter, patients with the first-use syndrome had a C3a desArg level of 29.6 +/- 1.4 micrograms per milliliter, whereas it was only 16.6 +/- 2.3 micrograms per milliliter in asymptomatic patients (P less than or equal to 0.0001). Two other patients, who experienced cardiopulmonary collapse during the first two minutes of dialysis, had a C3a desArg level of 18,900 and 7800 ng per milliliter, respectively. We conclude that the occurrence of adverse symptoms associated with new cuprophane-membrane dialyzers correlates with complement activation.

The biocompatibility of artificial organs.

Thromboembolic events in very short-term ventricular assistance have been uncommon. However, patients who are bridged or have long-term artificial heart implantations have almost uniformly experienced serious thromboembolic sequelae. Anticoagulation regimens for this form of circulatory assistance have varied but results are inconclusive. Intravenous heparin is commonly used, while low molecular weight Dextran, aspirin, and other antithrombotic agents are occasionally used. Mechanical cardiac valve failures requiring reoperation are due primarily to thrombosis, tissue overgrowth, and structural failure. Reoperations of tissue valves indicate sterile degeneration, usually related to calcification and tears, as the principal cause of failure. Despite improvements in biomaterials and an appreciation of the influence of disordered flow on graft patency, antithrombotic therapy represents the most clinically relevant approach to prevention of occlusion of vascular prostheses. The location of neointimal hyperplasia in vascular prostheses is different from that in vein grafts, the effect concentrating at the anastomosis. No clear rationale exists for antithrombotic therapy for hyperplasia in this instance. However, a rationale does exist for early antithrombotic therapy to reduce surface thrombogenicity. The lessons learned from clinical trials of antithrombotic therapy in the case of vein grafts might be profitably studied with regard to synthetic grafts and other artificial organs. Early low-dose aspirin and, possibly, dextran-40 treatment are justified in this case. However, continuation of these therapies past the early healing phase does not appear warranted. Clinical and experimental studies with hemodialysis and other membranes suggest complement activation through the alternate pathway is commonly observed; the biologic responses are consistent with the known properties of C5a. Factors governing anaphylatoxin exposure can be ascribed to the nucleophilicity and number of surface reactive groups. Elimination of surface reactive groups, or binding of bystander plasma proteins such as albumin, may be expected to limit complement activation.

Enhancement of in-vitro human interleukin-1 production by sodium acetate.

Human blood monocytes were incubated in vitro in the presence of various concentrations of sodium acetate or sodium chloride or with medium alone. Intracellular and extracellular levels of interleukin-1 (IL-1) were measured. The production of intracellular IL-1 and the release of extracellular IL-1 were higher in the presence of acetate than in the presence of chloride or in medium alone. The concentrations of acetate used were comparable to those encountered by blood monocytes on the surface of haemodialysis membranes. Since complications of peritoneal dialysis, such as loss of ultrafiltration and progressive fibrosis of the peritoneum, have been associated with the use of sodium acetate as the exchange-fluid buffer, these results suggest that the widespread use of sodium acetate as a buffer during haemodialysis may be contraindicated.