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ABO incompatible kidney transplantation

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  1. ABO incompatible kidney transplantation Ulla B. Berg, Division of Pediatrics The presentation is based on slides from Gunnar Tydén and Helena Genberg, Division of Transplantation Surgery, Dept. of Clinical Science, Intervention and Technology, Karolinska University Hospital Huddinge, Stockholm, Sweden

  2. Reasons to increase the number of living donor renal transplants • The increasing discrepancy between the number of available deceased donor organs and the number of patients on the waiting list • The superior graft and patient survival rates obtained with living donor transplants

  3. Kidney transplantations in Stockholm 1990-2002

  4. Kidney transplantations in Stockholm 1990-2002 10 year survival Graft (%) Patient (%) Living donor 70 85 Deceased donor 40 55

  5. Evolution of living donor programmes • Parents, HLA- identical or haploidentical siblings • SpousesHLA-incompatible siblings • Emotionally related donors • Non-directed donationPaired exchange • Blood group incompatible • Cross match positive

  6. 40% Oag anti A Abanti B Ab 45% 10% Aag (A1~36%, A2~9%) anti B Ab Bag anti A ab The likelihood that two unrelated individuals are: - identical is 37.5% - compatible is 26.75% - incompatible is 35.75% AagBag no Ab 5%

  7. Immunohistochemistry for detection of A antigen in a blood group A1 kidney

  8. A1 A2 Breimer et al Transplantation 82: 479, 2006

  9. Previous experience in A1 and B AB0-incompatible kidney transplantation Year of first transplantation: 1955: Boston, Massachussets, USA, (Hume et al.) 8/10 grafts were lost in hyperacute rejection within the first week 1960: Murray 1964 Starzl Occassional patients survived Overall very poor results Therefore ABO incompatibility was considered an absolute contraindication to kidney transplantation

  10. Previous experience in A2 AB0-incompatible kidney transplantation • Year of publication: • 1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23) • 1987: London, UK (Welsh et al.) (n=16) • 1998: Kansas, USA (Nelson et al.) (n=50) • 1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15) • 2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15) Between 1974-1988 23 DD kidney transplantations across the A2 barrier were performed, using regular immunosuppression 1-year graft survival was approx. 55%.

  11. Previous experience in A1 and B AB0-incompatible kidney transplantation Year of first transplantation: 1955: Boston, Massachussets, USA, (Hume et al.) 1960: Murray 1964 Starzl 1981: Portsmouth, UK (Slapak et al.) 1982: Brussels, Belgium (Alexandre et al.) (n=26) 1989: Japan (Tanabe et al.)

  12. Present experiences in a series of 26 ABO-incompatible living donor renal allografts Alexandre GPJ, Squifflet JP et al Tranplantation Proceedings vol XIX no 6 1987 pp 4538-4542 • donor specific platelet transfusion • plasmapheresis • splenectomy • cyclosporin A, prednisolone, azathioprine • polyclonal Abs (ALG or ATG) • substance A or B 3 not splenectomized recipients hyperacutely rejected their grafts during the first postoperative week

  13. Replacement fluid(albumin, plasma) Plasma exchange plasma blood cells Plasma separation Disadvantages: Limited efficacy due to restrictions to the plasma volume processed. All plasma components are reduced including coagulation factors. Fluid replacement is necessary. Plasma discarded

  14. Lessons learned from ABO-incompatible living donor kidney transplantation: 20 years later.Squifflet JP, De Meyer M, Malaise J, Latinne D, Pirson Y, Alexandre GP. Exp Clin Transplant. 2004 2:208-13. • “Pretransplant therapies included platelets donor transfusion, 2 to 5 plasmapheresis sessions, cyclosporin A with or without azathioprine along with polyclonal Abs and splenectomy at the time of transplantation. After the last plasmapheresis session, when the level of 1/4 (ABO antibodies) was reached, all recipients received 5 mL of substance A or B.” 39 ABO incompatible living donor grafts Exp Clin Transplant. 2004 2:208-13.

  15. 39 ABOi tx <15 y 78% 59% >15 y Exp Clin Transplant. 2004 2:208-13

  16. 39 ABOi tx Rec. <15 y N=38 N=8

  17. Removal of Anti-A/B antibodies Double-filtration plasmapheresis (390) Protein A immunoadsorption (51) Cessation of the Anti-A/B antibody production Splenectomy(433) (Cyclophosphamide) (Deoxyspergualin) Anticoagulation therapy (ATG or ALG) Maintenance triple immunosuppression 441 patients 1989 - 2001 Protocol for AB0i transplantation in Japan Takahashi K, et al. Am J Transplant 2004;4:1089–96

  18. Double-filtration plasmapheresis Replacement fluid(albumin + Ringers) Plasma fractionator plasma Plasma separation filtration/centrifugation blood cells IgG/IgM fraction discarded

  19. Removal of Anti-A/B antibodies Double-filtration plasmapheresis (390) Protein A immunoadsorption (51) Cessation of the Anti-A/B antibody production Splenectomy(433) (Cyclophosphamide) (Deoxyspergualin) Anticoagulation therapy (ATG or ALG) Maintenance triple immunosuppression 441 patients 1989 - 2001 Protocol for AB0i transplantation in Japan Takahashi K, et al. Am J Transplant 2004;4:1089–96

  20. ABO-incompatible kidney transplantations in Japan N Year Incomp. Tx 441 1989-2001 Historical controls 1055 1986-1995 Takahashi K, et al. Am J Transplant 2004;4:1089–96

  21. Graft survival rate according to recipient age Takahashi K, et al. Am J Transplant 2004;4:1089–96

  22. Present protocol for ABO- incompatible kidney transplantations Removing existing ABO-antibodies Antigen-specific immunoadsorption (GlycosorbAB0®) Preventing rebound of ABO-antibodies Rituximab (Mabthera®) Tacrolimus/MMF/prednisolone IVIG (Gammagard®) Postop preemptive immunadsorption Am J Transplant. (2005) 5:145-8

  23. Antigen-specific immunoadsorption Glycosorb ABO column Y Y Y Y XXX Y Y Y Y Transplantation 2003 ;76:730-731

  24. Present protocol for ABO- incompatible kidney transplantations Removing existing ABO-antibodies Antigen-specific immunoadsorption (GlycosorbAB0®) Preventing rebound of ABO-antibodies Rituximab (Mabthera®) Tacrolimus/MMF/prednisolone IVIG (Gammagard®) Postop preemptive immunadsorption Am J Transplant. (2005) 5:145-8

  25. Tacrolimus/MMF/prednisolone Rituximab 375 mg/kg IVIG (0.5 g/kg) Glycosorb 1:128 1:64 1:32 1:16 1:8 1:4 1:2 1:1 <1:1 Anti-A1 IgG titre –30 –13 –6 –4 –2 Tx 2 4 6 8 10 12 Time (days) Am J Transplant. (2005) 5:145-8

  26. Am J Transplant. (2005) 5:145-8

  27. AB0 -incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up ABO-incomp. ABO-comp. Adults15 30 Mean rec.age 35.1 42.4 Mean don.age 52.8 49.0 Children 5 18 Mean rec.age 8.6 7.8 Mean don.age 42.5 42.8 Grafted during the same time period In adults: the same basic immunosuppression Genberg H et al Transplantation 85:1745-1754, 2008

  28. Rejection episodes in adult kidney recipients ABO-incomp. ABO-comp. N=15 N=30 Acute rejection (total) 1 (7%) 4 (13%) n.s. Antibody-mediated rej. 0 (0%) 1 (3%) n.s. Cellular rejections 1 (7%) 3 (10%) n.s. Chronic allograft nephrop. 0 (0%) 2 (7%) n.s. Genberg H et al Transplantation 85:1745-1754, 2008

  29. Rejection episodes in child kidney recipients ABO-incomp. ABO-comp. N=5 N=18 Acute rejection (total) 0 (0%) 3 (17%) n.s. Antibody-mediated rej. 0 (0%) 0 (0%) n.s. Cellular rejections 0 (0%) 3 (17%) n.s. Patient survival 100% 100% Graft survival 100% 95% Genberg H et al Transplantation 85:1745-1754, 2008

  30. 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 Cumulative event-free survival (months) in adult kidney recipients Event: rejection, graft loss or death ABOi: n=15 ABOc: n=30 Using chi-square test: p=ns Time after transplantation in months Genberg H et al Transplantation 85:1745-1754, 2008

  31. Post-transplant infections (adults) p=ns Genberg H et al Transplantation 85:1745-1754, 2008

  32. Mean-GFR and 95% CI in adults -comparing AB0i and AB0c kidney recipients p=ns Genberg H et al Transplantation 85:1745-1754, 2008

  33. GFR after tx in AB0c and AB0i children GFR (ml/min/1.73 m2 Time after transplantation (years)

  34. Growth after tx in AB0c and AB0i children

  35. What happens to the A/B antibodies following AB0i kidney transplantation using antigen-specific immunoadsorption and rituximab?

  36. 128 64 32 16 8 4 2 1 <1 B  O Prograf/Cellcept/Prednisolone Rituximab IVIG Glucosorb -30 -13 Tx

  37. 128 64 32 16 8 4 2 1 <1 A1  O Prograf/Cellcept/Prednisolone Rituximab IVIG Tx Glucosorb -30 -13 Tx

  38. Median Ig G, n=20 Pre tx 3 - 4 5 - 7 8 - 12 13 - 24 >24

  39. Rituximab Glycosorb 2003-09 Tx cancelled Follow up 2006-05 Rituximab Glycosorb 2003-10 Tx cancelled Follow up 2006-03 Rituximab Glycosorb 2005-05 Tx cancelled Follow up 2006-03

  40. Tx ect Arterial thrombosis Tx Tx ect Venous thrombosis Tx

  41. Tx HD Days 2007-01 2007-04 2006-01 LD

  42. The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations 60 consecutive transplantations • 27 A1 (A/O, A/B, AB/B) • 24 B (B/O, B/A, AB/A) • 9 A2(A/O,A/B) major incompatibilities • One patient died with functioning graft after 4 months • One graft was lost in non compliance after 22 months • All the remaining 58 grafts have normal function at a follow up of 1 - 60 months Tydén G et al Transplantation 2007 83:1153-1155

  43. The Stockholm/Freiburg/Uppsala experience with LD kidney transplantations performed 2002-2006 N Actual graft Actual Follow-up survival S-creatinine months (mean (min-max) ABO incomp. 60 97% 127 (42-203) 17.5 (2-61) ABO comp. 274 95% 133 (53-360) 21.1 (2-63) Tydén G et al Transplantation 2007 83:1153-1155

  44. The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations n Ab-titre Ab-titre Cancelled tx Mean no preop. range median >8 adsorp. adsorptions Stockholm 26 1:1-1:128 1:32 3 4.2 Freiburg 21 1:8-1:1024 1:128 5 7 Uppsala 13 1:1-1:32 1:8 0 3.9 Tydén G et al Transplantation 2007 83:1153-1155

  45. Sweden Stockholm Gothenburg Uppsala Malmö Germany Freiburg Hannover Berlin Heidelberg Mannheim Hamburg Stuttgart Erlangen Frankfurt Bochum The Netherlands Rotterdam United Kingdom London Birmingham Coventry Switzerland Basel Zurich Norway Oslo Denmark Copenhagen Greece Athens Spain Barcelona Australia Melbourne The European experience 25 centres > 200 kidney transplantations

  46. General conclusion • AB0i renal transplantation without splenectomy, canbe performed with excellent results, using antigen-specific immunoadsorption in combination with a single-dose of rituximab and a single-dose of IVIG in combination with standard immunosuppression • 5 year graft survival is equivalent to standard AB0 compatible living donors • Antigen-specific immunoadsorption in combination with rituximab effectively depletes anti-A/B antibodies

  47. General conclusion • There is no significant rebound of anti-A/B antibodies although splenectomy is not performed • A persistent low-grade anti-A/B antibody production following AB0i kidney transplantation is common but does not have any negative impact on graft function

  48. Acknowledgement Gunnar Tydén Transplantation surgery, Karolinska University Hospital Gunilla Kumlien Transfusion medicine, Karolinska University Hospital Helena Genberg Transplantation surgery, Karolinska University Hospital John Sandberg Amir Sedigh Torbjorn Lundgren Lars Wennberg Henrik Gjertsen Ingela Fehrman Nephrology, Karolinska University Hospital Gunnar Tufveson Transplantation, Uppsala Academic Hospital

  49. Extra costs for the procedure € • Glycosorb 10.000 – 40.000 • Apheresis (seven sessions at €1,000) 4.000 – 12.000 • Rituximab (one dose) 1.800 • IVIG 0.5g/kg (one dose) 1.000 Total 16.800 – 54.800