Experience of using polymethyl methacrylate membranes for anti-HLA antibodies’ elimination by hemodialysis in renal transplant recipients

Introduction. In recipients with pre-existing sensitization with incompatible antigens of the main histocompatibility complex, the kidney graft survival after retransplantations directly depends on the level of anti-HLA antibodies. Despite many years of experience in using various methods: plasmapheresis, cascade filtration, immunosorption, intravenous administration of immunoglobulins, the use of polyclonal anti-lymphocytic agents, the search for more acceptable ways to reduce the level of anti-HLA antibodies still remains relevant nowadays.

The purpose of the study was to assess the effect of polymethyl methacrylate membrane-based dialyzers on the decrease in anti-HLA antibody level in renal transplant recipients.

Material and methods. The study included 20 kidney transplant recipients. The main study group consisted of 10 patients who underwent early postoperatoive hemodialysis using polymethyl methacrylate membrane-based dialyzers to decrease anti-HLA antibody level. A total of 53 hemodialysis procedures were performed, an average of 5.3 per patient. The comparison group included 10 recipients in whom plasmapheresis had been performed at similar timing after kidney transplantation aimed at reducing the anti-HLA antibody titers and whose data were studied retrospectively. A total of 38 plasmapheresis sessions were performed, an average of 3.8 per patient.

Results. In the main study group, a day after the hemodialysis procedure using polymethyl methacrylate membranebased dialyzers the level of anti-HLA antibodies decreased by an average of 28.3% in 6 of 10 patients (60%), and increased in 4 cases. Meanwhile, in the comparison group, the level of anti-HLA antibodies in venous blood after a plasmapheresis session decreased average by 44.6% in 8 patients of 10 (80%), and increased in 2 cases, on the contrary. Of note, there were no significant differences between the patients of the two compared groups either in the number of positive results (p> 0.05, Fisher's exact test), or in terms of the decrease in anti-HLA antibody level (p> 0.05, Mann – Whitney test). On days 2 and 5, in 50% of cases both after the hemodialysis procedure using polymethyl methacrylate membranebased dialyzers and after the plasmapheresis session, the patients showed an increase in the anti-HLA antibodies level compared to the baseline values. In the remaining cases, the level of anti-HLA antibodies in both groups was recorded at a lower range compared to the baseline values.

Conclusion. The use of polymethyl methacrylate membrane-based dialyzers in the renal allograft recipients having a high level of preexisting anti-HLA antibodies seems promising for the period of oligoanuria until the renal allograft function is restored, since both hemodialysis and the sorption of pre-existing (and also newly synthesized) antibodies take place simultaneously.

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2. Mizutani K, Shibata L, Ozawa M, Esquenazi V, Rosen A, Miller J, et al. Detection of HLA and MICA antibodies before kidney graft failure. Clin Transpl. 2006: 255–264. PMID: 18365383

3. Tanabe K, Ishida H, Omoto K, Shimizu T, Shirakawa H. Antibodymediated rejection: a single center experience at Tokyo Women's Medical University. Clin Transpl. 2006: 363–369. PMID: 18365390

4. Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8):1398–1406. PMID: 20634297 https://doi.org/10.1681/ASN.2009101065

5. Terasaki PI. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transpl. 2004;4:438–443. PMID: 14961999

6. Akalin E, Dinavahi R, Friedlander R, Ames S, de Boccardo G, Sehgal V, et al. Addition of plasmapheresis dicreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. Clin J Am Soc Nephrol. 2008;3(4):1160–1167. PMID: 18337549 https://doi.org/10.2215/CJN.05321107

7. Belitsky P, MacDonald AS, Lawen J, McAlister V, Bitter-Suermann H, Kiberd B. Use of rabbit anthymocyte globulin for inducation immunosuppression in high-risk kidney transplant recipients. Transplant Proc. 1997;29(7 Suppl 1):16S–17S. PMID: 9366920 https://doi.org/10.1016/S0041-1345(97)80003-6

8. Niwa T, Miyazaki T, Maeda K. Removal of furancarboxylic acid, a protein- bound uremic toxin, by hemodialysis using large – pore membrane dialyzer. Jpn J Artif Organs. 1995;24(3):694–696. https://doi.org/10.11392/jsao1972.24.694

9. Kunitomo T, Takeyama T, Kataoka H. Development of a PMMA membrane which can remove beta 2-microglobulin and its clinical significance. Contrib Nephrol. 1995;112:145–155. PMID: 7554986 https://doi.org/10.1159/000424103

10. Galli F, Benedetti S, Buoncristiani U, Piroddi M, Conte C, Canestrari F, et al. The effect of PMMA-based proteinleaking dialyzers on plasma homocysteine levels. Kidney Int. 2003;64(2):748–755. PMID: 12846775 https://doi.org/10.1046/j.1523-1755.2003.00134.x

11. Galli F, Benedetti S, Floridi A, Canestrari F, Piroddi M, Buoncristiani E, et al. Glycoxidation and inflammatory markers in patients on treatment with PMMA- based protein-leaking dialyzers. Kidney Int. 2005;67(2):750–759. PMID: 15673326 https://doi.org/10.1111/j.1523-1755.2005.67138.x

12. Aoike I. Long-term clinical experience with PMMA membrane. In: Ronco C. (ed.) Polymethylmethacrylate. A flexible membrane for a tailored dialysis. Contributions to Nephrology. Basel, Karger, 1999; 125. р. 205–212.

13. Ishikawa I, Chikazawa Y, Sato K, Nakagawa M, Imamura H, Hayama S, et al. Proteomic analysis of serum, outflow dialysate and adsorbed protein onto dialysis membranes (polysulfone and PMMA) during hemodialysis treatment using SELDI- TOF-MS. Am J Nephrol. 2006;26(4):372–380. PMID: 16873993 https://doi.org/10.1159/000094779

14. Birk HW, Kistner A, Wizemann V, Schiitterle G. Protein adsorption by artificial membrane materials under filtration condition. Artif Organs. 1995;19:411–415. PMID: 7625919

15. Lin HH, Liu YL, Liu JH, Chou CY, Yang YF, Kuo HL, et al. Uremic pruritus, cytokines, and polymethylmethacrylate artificial kidney. Artif Organs. 2008;32(6):468–472. PMID: 18422797 https://doi.org/10.1111/j.1525-1594.2008.00568.x

16. Cohen G, Rudnicki M, Schmaldienst S, Horl WH. Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant. 2002;17:879–883. PMID: 11981077

17. Contin C, Pitard V, Delmas Y, Pelletier N, Defrance T, Moreau JF, et al. Potential role of soluble CD40 in the humoral immune response impairment of ureamic patients. Immunology. 2003;110(1):131–140. PMID: 12941150

18. Hakim RM, Fearon DT, Lazarus JM. Biocompatibility of dialysis membranes: effects of chronic complement activation. Kidney Int. 1984;26(2):194–200. PMID: 6334194

19. Vaslaki L, Major L, Berta K, Karatson A, Misz M, Pethoe F, et al. On-Line Haemodiafiltration versus Haemodialy 1. Lachmann N, Terasaki PI, Schonemann C. Donor-specific HLA antibodies in chronic renal allograft rejection: a prospective trial with a four-year followup. Clin Transpl. 2006: 171–199. PMID: 18365377

20. Mizutani K, Shibata L, Ozawa M, Esquenazi V, Rosen A, Miller J, et al. Detection of HLA and MICA antibodies before kidney graft failure. Clin Transpl. 2006: 255–264. PMID: 18365383

21. Tanabe K, Ishida H, Omoto K, Shimizu T, Shirakawa H. Antibodymediated rejection: a single center experience at Tokyo Women's Medical University. Clin Transpl. 2006: 363–369. PMID: 18365390

22. Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8):1398–1406. PMID: 20634297 https://doi.org/10.1681/ASN.2009101065

23. Terasaki PI. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transpl. 2004;4:438–443. PMID: 14961999

24. Akalin E, Dinavahi R, Friedlander R, Ames S, de Boccardo G, Sehgal V, et al. Addition of plasmapheresis dicreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. Clin J Am Soc Nephrol. 2008;3(4):1160–1167. PMID: 18337549 https://doi.org/10.2215/CJN.05321107

25. Belitsky P, MacDonald AS, Lawen J, McAlister V, Bitter-Suermann H, Kiberd B. Use of rabbit anthymocyte globulin for inducation immunosuppression in high-risk kidney transplant recipients. Transplant Proc. 1997;29(7 Suppl 1):16S–17S. PMID: 9366920 https://doi.org/10.1016/S0041-1345(97)80003-6

26. Niwa T, Miyazaki T, Maeda K. Removal of furancarboxylic acid, a protein- bound uremic toxin, by hemodialysis using large – pore membrane dialyzer. Jpn J Artif Organs. 1995;24(3):694–696. https://doi.org/10.11392/jsao1972.24.694

27. Kunitomo T, Takeyama T, Kataoka H. Development of a PMMA membrane which can remove beta 2-microglobulin and its clinical significance. Contrib Nephrol. 1995;112:145–155. PMID: 7554986 https://doi.org/10.1159/000424103

28. Galli F, Benedetti S, Buoncristiani U, Piroddi M, Conte C, Canestrari F, et al. The effect of PMMA-based proteinleaking dialyzers on plasma homocysteine levels. Kidney Int. 2003;64(2):748–755. PMID: 12846775 https://doi.org/10.1046/j.1523-1755.2003.00134.x

29. Galli F, Benedetti S, Floridi A, Canestrari F, Piroddi M, Buoncristiani E, et al. Glycoxidation and inflammatory markers in patients on treatment with PMMA- based protein-leaking dialyzers. Kidney Int. 2005;67(2):750–759. PMID: 15673326 https://doi.org/10.1111/j.1523-1755.2005.67138.x

30. Aoike I. Long-term clinical experience with PMMA membrane. In: Ronco C. (ed.) Polymethylmethacrylate. A flexible membrane for a tailored dialysis. Contributions to Nephrology. Basel, Karger, 1999; 125. р. 205–212.

31. Ishikawa I, Chikazawa Y, Sato K, Nakagawa M, Imamura H, Hayama S, et al. Proteomic analysis of serum, outflow dialysate and adsorbed protein onto dialysis membranes (polysulfone and PMMA) during hemodialysis treatment using SELDI- TOF-MS. Am J Nephrol. 2006;26(4):372–380. PMID: 16873993 https://doi.org/10.1159/000094779

32. Birk HW, Kistner A, Wizemann V, Schiitterle G. Protein adsorption by artificial membrane materials under filtration condition. Artif Organs. 1995;19:411–415. PMID: 7625919

33. Lin HH, Liu YL, Liu JH, Chou CY, Yang YF, Kuo HL, et al. Uremic pruritus, cytokines, and polymethylmethacrylate artificial kidney. Artif Organs. 2008;32(6):468–472. PMID: 18422797 https://doi.org/10.1111/j.1525-1594.2008.00568.x

34. Cohen G, Rudnicki M, Schmaldienst S, Horl WH. Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant. 2002;17:879–883. PMID: 11981077

35. Contin C, Pitard V, Delmas Y, Pelletier N, Defrance T, Moreau JF, et al. Potential role of soluble CD40 in the humoral immune response impairment of ureamic patients. Immunology. 2003;110(1):131–140. PMID: 12941150

36. Hakim RM, Fearon DT, Lazarus JM. Biocompatibility of dialysis membranes: effects of chronic complement activation. Kidney Int. 1984;26(2):194–200. PMID: 6334194

37. Vaslaki L, Major L, Berta K, Karatson A, Misz M, Pethoe F, et al. On-Line Haemodiafiltration versus Haemodialy