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ABO incompatible kidney transplantation Ulla B. Berg, Division of Pediatrics The presentation is based on slides from Gunnar Tydén and Helena Genberg,

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Presentation on theme: "ABO incompatible kidney transplantation Ulla B. Berg, Division of Pediatrics The presentation is based on slides from Gunnar Tydén and Helena Genberg,"— Presentation transcript:

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, 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 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 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 The superior graft and patient survival rates obtained with living donor transplants

3 Kidney transplantations in Stockholm

4 4 10 year survival Graft (%)Patient (%) Living donor7085 Deceased donor4055

5 5 Evolution of living donor programmes Parents, HLA- identical or haploidentical siblings Parents, HLA- identical or haploidentical siblings Spouses HLA-incompatible siblings Spouses HLA-incompatible siblings Emotionally related donors Emotionally related donors Non-directed donation Paired exchange Non-directed donation Paired exchange Blood group incompatible Blood group incompatible Cross match positive Cross match positive

6 6 O ag anti A Ab anti B Ab A ag B ag no Ab A ag (A 1 ~36%, A 2 ~9%) anti B Ab B ag anti A ab 40% 5% 45%10% The likelihood that two unrelated individuals are: - identical is 37.5% - compatible is 26.75% - incompatible is 35.75% The likelihood that two unrelated individuals are: - identical is 37.5% - compatible is 26.75% - incompatible is 35.75%

7 Immunohistochemistry for detection of A antigen in a blood group A 1 kidney

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

9 9 Previous experience in A 1 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 Occassional patients survived Overall very poor results Therefore ABO incompatibility was considered an absolute contraindication to kidney transplantation

10 10 Previous experience in A 2 AB0-incompatible kidney transplantation Year of publication: Year of publication: 1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23) 1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23) 1987: London, UK (Welsh et al.) (n=16) 1987: London, UK (Welsh et al.) (n=16) 1998: Kansas, USA (Nelson et al.) (n=50) 1998: Kansas, USA (Nelson et al.) (n=50) 1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15) 1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15) 2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15) 2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15) Between DD kidney transplantations across the A 2 barrier were performed, using regular immunosuppression 1-year graft survival was approx. 55%. Between DD kidney transplantations across the A 2 barrier were performed, using regular immunosuppression 1-year graft survival was approx. 55%.

11 11 Previous experience in A 1 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 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 pp donor specific platelet transfusion donor specific platelet transfusion plasmapheresis plasmapheresis splenectomy splenectomy cyclosporin A, prednisolone, azathioprine cyclosporin A, prednisolone, azathioprine polyclonal Abs (ALG or ATG) polyclonal Abs (ALG or ATG) substance A or B substance A or B 3 not splenectomized recipients hyperacutely rejected their grafts during the first postoperative week

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

14 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 : –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 :

15 15 Exp Clin Transplant : <15 y >15 y 78% 59% 39 ABOi tx

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

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

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

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

20 20 ABO-incompatible kidney transplantations in Japan NYear NYear Incomp. Tx Historical controls Takahashi K, et al. Am J Transplant 2004;4:1089–96

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

22 22 Present protocol for ABO- incompatible kidney transplantations 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 23 Antigen-specific immunoadsorption XXX Glycosorb ABO column YY Y Y Y Y Y Y Transplantation 2003 ;76:

24 24 Present protocol for ABO- incompatible kidney transplantations 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 25 –30–13–6–4–2Tx :128 1:64 1:32 1:16 1:8 1:4 1:2 1:1 <1:1 Anti-A1 IgG titre Glycosorb IVIG (0.5 g/kg)Rituximab 375 mg/kg Tacrolimus/MMF/prednisolone Time (days) Am J Transplant. (2005) 5:145-8

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

27 27 AB0 -incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up Genberg H et al Transplantation 85: , 2008 ABO-incomp.ABO-comp. Adults1530 Mean rec.age Mean don.age Children 518 Mean rec.age Mean don.age Grafted during the same time period In adults: the same basic immunosuppression

28 28 Rejection episodes in adult kidney recipients ABO-incomp.ABO-comp. N=15N=30 Acute rejection (total)1(7%)4(13%)n.s. Antibody-mediated rej.0(0%)1(3%)n.s. Cellular rejections1(7%)3(10%)n.s. Chronic allograft nephrop.0(0%)2(7%)n.s. Genberg H et al Transplantation 85: , 2008

29 29 Rejection episodes in child kidney recipients ABO-incomp.ABO-comp. N=5N=18 Acute rejection (total)0(0%)3(17%)n.s. Antibody-mediated rej.0(0%)0(0%)n.s. Cellular rejections0(0%)3(17%)n.s. Patient survival100%100% Graft survival100% 95% Genberg H et al Transplantation 85: , 2008

30 ABOi: n=15 ABOc: n=30 Time after transplantation in months Using chi- square test: p=ns Cumulative event-free survival (months) in adult kidney recipients Event: rejection, graft loss or death Genberg H et al Transplantation 85: , 2008

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

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

33 33 GFR (ml/min/1.73 m 2 Time after transplantation (years) GFR after tx in AB0c and AB0i children

34 34 Growth after tx in AB0c and AB0i children

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

36 B O <1 Glucosorb IVIG Prograf/Cellcept/Prednisolone Rituximab Tx

37 A1 O <1 Glucosorb Tx IVIG Prograf/Cellcept/Prednisolone Rituximab Tx

38 Pre tx Median Ig G, n= >24

39 Tx cancelled Rituximab Glycosorb Rituximab Glycosorb Rituximab Glycosorb Follow up Follow up Follow up

40 Tx Tx ect Arterial thrombosis Tx Tx ect Venous thrombosis

41 LD Tx HD Days

42 42 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 months Tydén G et al Transplantation : The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations

43 43 Tydén G et al Transplantation : NActualgraftActualFollow-up survivalS-creatininemonths (mean (min-max) (mean (min-max) ABO incomp.6097%127 (42-203) 17.5 (2-61) ABO comp.27495%133 (53-360) 21.1 (2-63) The Stockholm/Freiburg/Uppsala experience with LD kidney transplantations performed

44 44 nAb-titreAb-titreCancelled txMean no preop. rangemedian>8 adsorp.adsorptions Stockholm261:1-1:1281: Freiburg211:8-1:10241:12857 Uppsala131:1-1:321:803.9 Tydén G et al Transplantation : The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations

45 The European experience –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 25 centres > 200 kidney transplantations

46 46 General conclusion AB0i renal transplantation without splenectomy, can be 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 AB0i renal transplantation without splenectomy, can be 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 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 Antigen-specific immunoadsorption in combination with rituximab effectively depletes anti-A/B antibodies

47 47 General conclusion There is no significant rebound of anti-A/B antibodies although splenectomy is not performed 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 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 49 Extra costs for the procedure Glycosorb – Glycosorb – Apheresis (seven sessions at 1,000)4.000 – Apheresis (seven sessions at 1,000)4.000 – Rituximab (one dose)1.800 Rituximab (one dose)1.800 IVIG 0.5g/kg (one dose)1.000 IVIG 0.5g/kg (one dose)1.000 Total –


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