Clinical Investigation

Kidney International (1994) 46, 1680–1687; doi:10.1038/ki.1994.468

Soluble complement receptor type 1 inhibits complement activation induced by hemodialysis membranes in vitro

Alfred K Cheung, Charles J Parker and Mary Hohnholt

Medical and Research Services, Veterans Affairs Medical Center, Salt Lake City, and Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

Correspondence: Alfred K Cheung MD, Renal Section (11H), VA Medical Center, 500 Foothill Blvd., Salt Lake City, Utah 84148, USA.

Received 7 April 1994; Revised 5 July 1994; Accepted 5 July 1994.

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Abstract

Soluble complement receptor type 1 inhibits complement activation induced by hemodialysis membranes in vitro. A variety of bioincompatible events that occur during hemodialysis have been attributed to complement activation. However, cause-effect relationships have been based primarily on indirect evidence and the results of in vitro studies, because an acceptable method for inhibiting complement activation during clinical hemodialysis has been unavailable. Methods for inactivating complement in vitro are available, but the most commonly used of these techniques (heat inactivation and chelation of divalent cations) lack specificity. A recombinant, soluble form of human complement receptor type 1 (sCR1) has been developed recently and shown to inhibit complement activation in vivo. Here, we report studies aimed at determining the effects of sCR1 on dialysis-induced complement activation and neutrophil degranulation. In a concentration dependent fashion, sCR1 inhibited plasma complement activation by cuprophan membrane in vitro. Using a maximally inhibitory concentration (30 microg/ml), sCR1 blocked generation of C3a(desArg) by cuprophan, cellulose acetate, and polymethylmethacrylate membranes by 90%, 84%, and 84%, respectively. In contrast, elastase release (a measure of neutrophil degranulation) was inhibited by 70%, 70%, and 44%, respectively, suggesting that dialysis-induced neutrophil activation is mediated in part by noncomplement dependent mechanisms. Both heat- and EDTA-treatment of plasma abolished dialysis membrane-induced complement activation, but these treatments also affected noncomplement dependent components of the degranulation process. These observations show that, compared with other commonly used methods for inhibiting dialysis induced complement activation, sCR1 is more specific. An additional advantage of sCR1 is its potential for use in the clinical setting.

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References

  1. Müller-Eberhard HJ: Complement: Chemistry and pathways, in Inflammation, edited by Gallin JI, Goldstein IM, Snyderman R, New York, Raven Press, 1988, pp 21–54
  2. Frank MM, Fries LF: Complement, in Fundamental Immunology, edited by Paul WE, New York, Raven Press, 1989, pp 679–702
  3. Fearon DT: Cellular receptors for fragments of the third component of complement. Immunol Today 5:105–110, 1984
  4. Hugli TE: Biochemistry and biology of anaphylatoxins. Complement 3:111–127, 1986 | PubMed | ChemPort |
  5. Craddock PR, Fehr J, Dalmasso AP, Brigham KL, Jacob HS: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 59:879–888, 1977 | PubMed | ISI | ChemPort |
  6. Chenoweth DE, Cheung AK, Henderson LW: Anaphylatoxin formation during hemodialysis: Effects of different dialyzer membranes. Kidney Int 24:764–769, 1983 | PubMed | ChemPort |
  7. Schindler R, Llnnenweber S, Schulze M, Oppermann M, Dinarello CA, Shaldon S, Koch K-M: Gene expression of interleukin-1beta during hemodialysis. Kidney Int 43:712–721, 1993 | PubMed | ISI | ChemPort |
  8. Zaoui PM, Stone WJ, Hakim RM: Effects of dialysis membranes on beta2-microglobulin. Kidney Int 38:962–968, 1990 | Article | PubMed | ISI | ChemPort |
  9. Craddock PR, Fehr J, Brigham KL, Kronenberg R, Jacob HS: Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 296:769–774, 1977 | PubMed | ISI | ChemPort |
  10. Frank MM, Rapp HJ, Borsos T: Studies on the terminal steps of immune hemolysis. I. Inhibition by trisodium ethylenediaminetetraacetate (EOTA). J Immunol 93:409–413, 1964
  11. Cheung AK, Parker CJ, Hohnholt M: beta2 integrins are required for neutrophil degranulation induced by hemodialysis membranes. Kidney Int 43:649–660, 1993
  12. Kabat EA, Mayer MM: Experimental Immunochemistry (2nd ed). Springfield, CC Thomas, 1961, pp 159–160
  13. Götze O, Müller-Eberhard HJ: The C3-activator system: An alternative pathway of complement activation. J Exp Med 134:90S–108S, 1971 | PubMed | ChemPort |
  14. Arnaout MA: Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood 75:1037–1050, 1990 | PubMed | ISI | ChemPort |
  15. Van Strijp JAG, Russell DG, Tuomanen E, Brown EJ, Wright SD: Ligand specificity of purified complement receptor type three (CD11b/CD18, ambeta2, Mac-1): Indirect effects of an ARG-GLY-ASP (RGD) sequence. J Immunol 151:3324–3336, 1993 | PubMed | ChemPort |
  16. Dykman TR, Cole JL, Iida K, Atkinson JP: Polymorphism of human erythrocyte C3b/C4b receptor. Proc Natl Acad Sci USA 80:1698–1702, 1983 | Article | PubMed | ChemPort |
  17. Ross GD: Complement receptor type 1 (CR1), in Current Topics in Microbiology and Immunology: Membrane Defenses Against Attack by Complement and Perforin, edited by Parker CJ, New York, Springer-Verlag, 1992, pp 31–41
  18. Weisman HF, Bartow T, Leppo MK, Marsh HC Jr, Carson GR, Concino MF, Boyle MP, Roux KH, Weisfeldt ML, Fearon DT: Soluble human complement receptor type 1: In vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249:146–151, 1990 | Article | PubMed | ISI | ChemPort |
  19. Cheung AK, Parker CJ, Wilcox L, Janatova J: Activation of the alternative pathway of complement by hemodialysis membranes. Kidney Int 36:257–265, 1989 | PubMed | ISI | ChemPort |
  20. Hill J, Lindsay TF, Ortiz F, Yeh CG, Hechtman HB, Moore FD Jr: Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat. J Immunol 149:1723–1728, 1992 | PubMed | ISI | ChemPort |
  21. Cheung AK, Hohnholt M, Gilson J: Adherence of neutrophils to hemodialysis membranes: Role of complement receptors. Kidney Int 40:1123–1133, 1991
  22. Nakane PK, Kawaoi A: Peroxidase-labeled antibody: A new method of conjugation. J Histochem Cytochem 22:1084–1091, 1974 | PubMed | ISI | ChemPort |
  23. Glantz SA: Primer of Biostatistics (3rd ed). New York, McGraw-Hill, 1992
  24. Pangburn MK: Activation of complement via the alternative pathway. Fed Proc 42:139–143, 1983 | PubMed |
  25. Pangburn MK: Alternative pathway of complement. Meth Enzymol 162:639–653, 1988
  26. Pangburn MK, Müller-Eberhard HJ: Complement C3 convertase: Cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells. Proc Natl Acad Sci USA 75:2416–2420, 1978 | PubMed | ChemPort |
  27. Kazatchkine MD, Fearon DT, Austen KF: Human alternative complement pathway: Membrane-associated sialic acid regulates the competition between B and beta1H for cell-bound C3b. J Immunol 122:75–81, 1979 | PubMed | ISI | ChemPort |
  28. Fearon DT: Regulation of membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative pathway. Proc Natl Acad Sci USA 75:1971–1975, 1978 | PubMed | ChemPort |
  29. Meri S, Pangburn MK: Discrimination between activators and nonactivators of the alternative pathway of complement: Regulation via a sialic acid/polyanion binding site on factor H. Proc Natl Acad Sci USA 87:3982–3986, 1990 | PubMed | ChemPort |
  30. Cheung AK, Parker CJ, Janatova J: Analysis of the complement C3 fragments associated with hemodialysis membranes. Kidney Int 35:576–588, 1989
  31. Cheung AK, Parker CJ, Janatova J, Brynda E: Modulation of complement activation on hemodialysis membranes by immobilized heparin. J Am Soc Nephrol 8:1328–1337, 1992
  32. Bhakdi S, Fassbender W, Hugo F, Carreno M-P, Berstecher C, Malasit P, Kazatchkine MD: Relative inefficiency of terminal complement activation. J Immunol 141:3117–3122, 1988
  33. Wilson E, Rice WG, Kinkade JM Jr, Merrill AH Jr, Arnold RR, Lambeth JD: Protein kinase C inhibition by sphingoid long-chain bases: Effects on secretion in human neutrophils. Arch Biochem Biophys 259:204–214, 1987
  34. HöRl WH, Riegel W, Schollmeyer P, Rautenberg W, Neumann S: Different complement and granulocyte activation in patients dialyzed with PMMA dialyzers. Clin Nephrol 25:304–307, 1986 | PubMed |
  35. Hörl WH, Steinhauer HB, Riegel W, Schollmeyer P, Schafer RM, Heidland A: Effect of different dialyzer membranes on plasma levels of granulocyte elastase. Kidney Int 33(Suppl 24):S90–S91, 1988
  36. Schaefer RM, Heidland A, Hörl WH: Effect of dialyzer geometry on granulocyte and complement activation. Am J Nephrol 7:121–126, 1987
  37. Cheung AK, Hohnholt M, Leypoldt JK, DeSpain M: Hemodialysis membrane bioincompatibility: The case of erythropoietin. Blood Purif 9:153–163, 1992
  38. Himmelfarb J, Ault KA, Holbrook D, Leeber DA, Hakim RM: Intradialytic granulocyte reactive oxygen species production: A prospective, crossover trial. J Am Soc Nephrol 4:178–186, 1993 | PubMed | ISI | ChemPort |
  39. Weiss SJ, Regiani S: Neutrophils degrade subendothelial matrices in the presence of alpha-1-proteinase inhibitor: cooperative use of lysosomal proteinases and oxygen metabolites. J Clin Invest 73:1297–1303, 1984 | PubMed | ISI | ChemPort |
  40. Maher ER, Wickens DG, Griffin JFA, Kyle P, Curtis JR, Dormandy TL: Increased free-radical activity during haemodialysis? Nephrol Dial Transplant 2:169–171, 1987 | PubMed | ChemPort |
  41. Webster RO, Hong SR, Johnston RB Jr, Henson PM: Biological effects of the human complement fragments C5a and C5adesArg on neutrophil function. Immunopharmacol 2:201–219, 1980
  42. Cain JA, Newman SL, Ross GD: Role of complement receptor type three and serum opsonins in the neutrophil response to yeast. Complement 4:75–86, 1987

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