title: Complement components as uremic toxins and their potential role as mediators of microinflammation.
abstract: Cardiovascular disease is the major cause of death in end-stage renal disease (ESRD) patients. There is growing evidence that atherogenesis is an inflammatory rather than a purely degenerative process leading to a state of microinflammation. This raises the issue of whether treatment modalities of ESRD contribute to the microinflammatory state. One potential candidate in this context is the complement system. Here we consider three potential pathways linking complement activation to progression of atherosclerosis: (1) complement activation on artificial surfaces depends on their physicochemical characteristics, the effect of which is amplified because of the accumulation of complement factor D; (2) the exposure of ESRD patients to endotoxin creates a microinflammatory state, and this may amplify complement-induced damage; exposure to endotoxin may result from frequent infections because of the impairment of host-defense mechanisms or from transfer of bacterial contaminants across dialysis membranes into the blood stream; and (3) direct transduction of proinflammatory signals from blood-material interactions to the vascular system. We conclude that the complement system is an important candidate system in the genesis of microinflammation and accelerated atherogenesis in ESRD. We advance the hypothesis that the generation of proinflammatory signals, in which the complement system appears to be involved--both through systemic and local activation--plays a role in the development of late complications of uremia, including coronary heart disease. This hypothesis provides a rationale to maximize the biocompatibility of the dialysis procedure, that is, selection of nonactivating materials, use of ultrapure dialysis fluid, and--still theoretical--high-flux dialysis to remove factor D.
authors.affiliation: Gambro Corporate Research, Hechingen, and Department of Internal Medicine, Ruperto Carola University Heidelberg, Heidelberg, Germany. reinhold.deppisch@gambro.com
authors.forename: R M
authors.initials: RM
authors.lastname: Deppisch
authors.forename: W
authors.initials: W
authors.lastname: Beck
authors.forename: H
authors.initials: H
authors.lastname: Goehl
authors.forename: E
authors.initials: E
authors.lastname: Ritz
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology; D001161:Arteriosclerosis / Q000209:etiology; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology; D003167:Complement Activation; D003165:Complement System Proteins / Q000378:metabolism*; D019446:Endotoxemia / Q000209:etiology; D006801:Humans; D007239:Infections / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D017582:Renal Replacement Therapy / Q000009:adverse effects; D014118:Toxins, Biological / Q000276:immunology* / Q000378:metabolism*; D014511:Uremia / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D014118:Toxins, Biological; D003165:Complement System Proteins; D002097:C-Reactive Protein