Background: Patients on haemodialysis (HD) have high rates of cardiovascular (CV) disease and activation of the complement system. Despite evidence in non-renal patients that these may be linked, this association has received little attention in HD patients to date. In the setting of a randomised controlled trial we evaluated the relationships between baseline complement levels and subsequent CV events and mortality, in addition to the effects of HD with a vitamin E (VE)-coated dialysis membrane on circulating complement levels. Methods: A total of 260 HD patients were randomised to dialysis with a VE-coated dialysis membrane or non-VE coated equivalent for 12 months. Blood samples were taken at baseline, 6 and 12 months for measurement of C3, factor D, factor H and SC5b-9 levels. Data were collected prospectively on deaths and CV events. Results: Higher C3 levels at baseline were associated with subsequent CV events (hazard ratio 1.20 (1.01-1.42) per 0.1 mg/ml). Patients with intermediate SC5b-9 levels had significantly lower CV event rates and mortality than those with either high or low levels (p < 0.01). There were no effects of the VE-membranes on the complement components measured nor the clinical endpoints considered. Conclusions: The levels of C3 and SC5b-9 may have prognostic utility for predicting future CV events and/or mortality in HD patients - a relationship that requires further investigation. Dialysing prevalent HD patients with VE-bonded polysulfone membranes for a period of 12 months did not alter the circulating levels of the alternative complement pathway components considered here.

1.
van Greevenbroek MM, Jacobs M, van der Kallen CJ, Blaak EE, Jansen EH, Schalkwijk CG, Feskens EJ, Stehouwer CD: Human plasma complement C3 is independently associated with coronary heart disease, but only in heavy smokers (the CODAM study). Int J Cardiol 2012;154:158-162.
2.
Carter AM, Prasad UK, Grant PJ: Complement C3 and C-reactive protein in male survivors of myocardial infarction. Atherosclerosis 2009;203:538-543.
3.
Ajjan R, Grant PJ, Futers TS, Brown JM, Cymbalista CM, Boothby M, Carter AM: Complement C3 and C-reactive protein levels in patients with stable coronary artery disease. Thromb Haemost 2005;94:1048-1053.
4.
Muscari A, Massarelli G, Bastagli L, Poggiopollini G, Tomassetti V, Drago G, Martignani C, Pacilli P, Boni P, Puddu P: Relationship of serum C3 to fasting insulin, risk factors and previous ischaemic events in middle-aged men. Eur Heart J 2000;21:1081-1090.
5.
Onat A, Uzunlar B, Hergenc G, Yazici M, Sari I, Uyarel H, Can G, Sansoy V: Cross-sectional study of complement C3 as a coronary risk factor among men and women. Clin Sci (Lond) 2005;108:129-135.
6.
Engstrom G, Hedblad B, Berglund G, Janzon L, Lindgarde F: Plasma levels of complement C3 is associated with development of hypertension: a longitudinal cohort study. J Hum Hypertens 2007;21:276-282.
7.
Engstrom G, Hedblad B, Janzon L, Lindgarde F: Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: a population-based cohort study. Eur J Cardiovasc Prev Rehabil 2007;14:392-397.
8.
Szeplaki G, Prohaszka Z, Duba J, Rugonfalvi-Kiss S, Karadi I, Kokai M, Kramer J, Fust G, Kleiber M, Romics L, Varga L: Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women. Atherosclerosis 2004;177:383-389.
9.
Muscari A, Bozzoli C, Puddu GM, Sangiorgi Z, Dormi A, Rovinetti C, Descovich GC, Puddu P: Association of serum C3 levels with the risk of myocardial infarction. Am J Med 1995;98:357-364.
10.
Mellbin LG, Bjerre M, Thiel S, Hansen TK: Complement activation and prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care 2012;35:911-917.
11.
Chanard J, Lavaud S, Randoux C, Rieu P: New insights in dialysis membrane biocompatibility: relevance of adsorption properties and heparin binding. Nephrol Dial Transplant 2003;18:252-257.
12.
Deppisch R, Gohl H, Smeby L: Microdomain structure of polymeric surfaces - potential for improving blood treatment procedures. Nephrol Dial Transplant 1998;13:1354-1359.
13.
Hauser AC, Derfler K, Stockenhuber F, Janata O, Balcke P: Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components. Clin Sci (Lond) 1990;79:471-476.
14.
Cheung AK: Biocompatibility of hemodialysis membranes. J Am Soc Nephrol 1990;1:150-161.
15.
Volanakis JE, Barnum SR, Giddens M, Galla JH: Renal filtration and catabolism of complement protein D. N Engl J Med 1985;312:395-399.
16.
The Renal Association: UK Renal Registry: The Sixteenth Annual Report, 2013.
17.
Omata M, Higuchi C, Demura R, Sanaka T, Nihei H: Reduction of neutrophil activation by vitamin E modified dialyzer membranes. Nephron 2000;85:221-231.
18.
Pertosa G, Grandaliano G, Soccio M, Martino C, Gesualdo L, Schena FP: Vitamin E-modified filters modulate Jun N-terminal kinase activation in peripheral blood mononuclear cells. Kidney Int 2002;62:602-610.
19.
Lines SW, Carter AM, Dunn EJ, Lindley EJ, Tattersall JE, Wright MJ: A randomized controlled trial evaluating the erythropoiesis stimulating agent sparing potential of a vitamin E-bonded polysulfone dialysis membrane. Nephrol Dial Transplant 2014;29:649-656.
20.
Mollnes TE, Lea T, Harboe M, Tschopp J: Monoclonal antibodies recognizing a neoantigen of poly(C9) detect the human terminal complement complex in tissue and plasma. Scand J Immunol 1985;22:183-195.
21.
Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(5 suppl 3):S112-S119.
22.
Greenstein JD, Peake PW, Charlesworth JA: The kinetics and distribution of C9 and SC5b-9 in vivo: effects of complement activation. Clin Exp Immunol 1995;100:40-46.
23.
Podack ER, Muller-Eberhard HJ: SC5b-9 complex of complement: formation of the dimeric membrane attack complex by removal of S-protein. J Immunol 1980;124:1779-1783.
24.
Tschopp J, French LE: Clusterin: modulation of complement function. Clin Exp Immunol 1994;97(suppl 2):11-14.
25.
Ricklin D, Hajishengallis G, Yang K, Lambris JD: Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010;11:785-797.
26.
Mares J, Richtrova P, Hricinova A, Tuma Z, Moravec J, Lysak D, Matejovic M: Proteomic profiling of blood-dialyzer interactome reveals involvement of lectin complement pathway in hemodialysis-induced inflammatory response. Proteomics Clin Appl 2010;4:829-838.
27.
Baumgartner-Parzer SM, Seyfert UT, Mannhalter C: Possible clinical effects of the interaction of hemodialysis membranes with adhesion proteins. Kidney Int 1995;47:1115-1120.
28.
Mares J, Thongboonkerd V, Tuma Z, Moravec J, Matejovic M: Specific adsorption of some complement activation proteins to polysulfone dialysis membranes during hemodialysis. Kidney Int 2009;76:404-413.
29.
Ohi H, Sakamoto K, Hatano M: S protein (vitronectin) in hemodialysis patients. Nephron 1990;54:190-191.
30.
Laine P, Pentikainen MO, Wurzner R, Penttila A, Paavonen T, Meri S, Kovanen PT: Evidence for complement activation in ruptured coronary plaques in acute myocardial infarction. Am J Cardiol 2002;90:404-408.
31.
Meuwissen M, van der Wal AC, Niessen HW, Koch KT, de Winter RJ, van der Loos CM, Rittersma SZ, Chamuleau SA, Tijssen JG, Becker AE, Piek JJ: Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction. J Clin Pathol 2006;59:196-201.
32.
Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V: C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998;18:1386-1392.
33.
Vlaicu R, Niculescu F, Rus HG, Cristea A: Immunohistochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque. Atherosclerosis 1985;57:163-177.
34.
Distelmaier K, Adlbrecht C, Jakowitsch J, Winkler S, Dunkler D, Gerner C, Wagner O, Lang IM, Kubicek M: Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 2009;102:564-572.
35.
Doran JP, Howie AJ, Townend JN, Bonser RS: Detection of myocardial infarction by immunohistological staining for C9 on formalin fixed, paraffin wax embedded sections. J Clin Pathol 1996;49:34-37.
36.
Niculescu F, Rus HG, Vlaicu R: Activation of the human terminal complement pathway in atherosclerosis. Clin Immunol Immunopathol 1987;45:147-155.
37.
Buerke M, Murohara T, Lefer AM: Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion. Circulation 1995;91:393-402.
38.
Amsterdam EA, Stahl GL, Pan HL, Rendig SV, Fletcher MP, Longhurst JC: Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs. Am J Physiol 1995;268:H448-H457.
39.
Riley RD, Sato H, Zhao ZQ, Thourani VH, Jordan JE, Fernandez AX, Ma XL, Hite DR, Rigel DF, Pellas TC, Peppard J, Bill KA, Lappe RW, Vinten-Johansen J: Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization. J Thorac Cardiovasc Surg 2000;120:350-358.
40.
Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001;38:938-942.
41.
London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731-1740.
42.
Iyer A, Woodruff TM, Wu MC, Stylianou C, Reid RC, Fairlie DP, Taylor SM, Brown L: Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol 2011;58:479-486.
43.
Derzsy Z, Prohaszka Z, Rigo J Jr, Fust G, Molvarec A: Activation of the complement system in normal pregnancy and preeclampsia. Mol Immunol 2010;47:1500-1506.
44.
Naqvi SB, Collins AJ: Infectious complications in chronic kidney disease. Adv Chronic Kidney Dis 2006;13:199-204.
45.
The Renal Association: UK Renal Registry: The Seventeenth Annual Report, 2014.
46.
Pertosa G, Grandaliano G, Valente M, Montinaro V, Soccio M, Gesualdo L, Schena FP: In vivo evaluation of biocompatibility of a new dialyzer employing the vitamin E-modified cellulose membrane ‘Excebrane E': study of mechanisms involved in mononuclear cell activation. Contrib Nephrol 1999;127:200-207.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.