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ABO-incompatible Living Kidney Transplantation

Hyatt Regency Century Plaza Hotel Los Angeles, California, USA January 26 th , 2014. Terasaki Festschrift 2014. ABO-incompatible Living Kidney Transplantation. Kazunari Tanabe, MD, PhD Department of Urology, Kidney Center Graduate School of Medicine, Tokyo Women’s Medical University.

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ABO-incompatible Living Kidney Transplantation

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  1. Hyatt Regency Century Plaza Hotel Los Angeles, California, USA January 26th, 2014 Terasaki Festschrift 2014 ABO-incompatible Living Kidney Transplantation Kazunari Tanabe, MD, PhD Department of Urology, Kidney Center Graduate School of Medicine, Tokyo Women’s Medical University

  2. Desensitization for ABO-incompatible Living Kidney Transplantation • Pre-transplant antibody removal: avoid anti-blood type antibody induced ABMR. • Intensifiedpost-transplant immunosuppression: inhibit re-elevation of blood group antibody titers.

  3. Various Techniques of Anti-blood Group Antibody Removal PEX Regular PEX All antibody isotypes DFPP Only anti-A or B antibodies IA Glycosorb Protein A Mainly IgG Most antibody isotypes Therasorb Current Opin Organ Transplant 2012

  4. What is an Acceptable Anti-blood Group IgG Antibody Titer at Transplantation? 4x-8x: in most reports 32x-64x: at our institution

  5. Clinical Outcome of ABO-ILKT

  6. European Experience IVIG (0.5g/kg) Rituximab (375mg/m2) Glycosorb ABO apheresis Prophylactic IA Tac 0.2mg/kg/day MMF 2g/day 1g/day 100mg/day Pred 30mg/day 10mg/day -30 -10 Transplantation 30 90 Time (days) IVIG = intravenous immunoglobulin; Tac = tacrolimus; MMF = mycophenolate mofetil; Pred = prednisolone

  7. Genberg, et al. Transplantation 2008

  8. Long-term Outcome of ABO-incompatible Living Donor Kidney Transplantation Based on Antigen-specific Desensitization at Freiburg, Germany Nephrol Dial Transplant 2010; 25: 3778–3786

  9. Outcome of ABO-Incompatible Kidney Transplantation in the Johns Hopkins Death Censored Graft Survival ABO-i ABO-c (matched control)

  10. Graft Survival of ABO-Incompatible Living Kidney Transplantation in Japan (%) 100 n=1,878 2001-2010 90 80 70 60 1989-2010 (all) 50 1989-2000 40 30 20 10 0 Time (Year) 0 5 10 15 20 25 * Source by the questionnaire from 212 Transplant Centers Takahashi K et al. Transplantation NowV0l.24 No.6 November 2011 Japanese ABO-incompatible Organ Transplantation Committee

  11. Number of Kidney Transplants and ABO-ILKT in Tokyo Women’s Medical University (ABO-ILKT, n=455) ABO-ILKT: 20-30% of Living Kidney Transplants

  12. 20-year Patient Survival 10 years 20 years 96.5% 92.9% 100% 88.4% 85.9% 97.1% 92.8% 80% 86.6% 84.4% 60% Cumulative Probability ABO-C ABO-I 40% 20% Log-rank test： 0.740 0% Months 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patient at risk (Kaplan-Meier Estimates )

  13. 20-year Graft Survival 100% 10 years 88.7% 80% 76.3% 20 years 86.0% 65.3% 60% 72.2% 55.6% Cumulative Probability 59.1% 40% 53.0% 20% ABO-C Log-rank test： 0.144 ABO-I 0% Months 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patient at risk (Kaplan-Meier Estimates )

  14. Does Anti-blood Type Antibody Cause Problem?

  15. 1996-2002 No correlation between baseline IgG titers and graft survival rate Shimmura, Tanabe et al., Transplantation 2005

  16. Case Report • 24-year-old female • A to O incompatible Tx • CXMs: CDC, AHG-CDC, FCXM: all negative • Baseline anti-A IgG titer: x32,768 • PEX 10 times prior to TX • Immunosuppression: FK, MMF, MP, RIT, SIM • Anti-A titer at transplant: x64 • Post-transplant anti-A titer rapidly returned to high levels • Antibody titers: POD1 x64, POD3 x128, POD5 x256

  17. Clinical Course 32,768x 256x Anti-B titer (log scale) 128x Serum creatinine (mg/dl) 64x (day )

  18. Biopsy (POD13) Anti-A antibody: 128x Slight cellular infiltration(i0)

  19. Biopsy (POD73) No rejection Serum Cr. : 1.5mg/dl Antibody titer: 16x

  20. ABO-ILKT Recipients with High Titer of Anti-A/B IgG

  21. Results

  22. Summary and Question • ABO-ILKT with high titer of baseline IgG antibody could be performed successfully. • What is the upper limit of antibody titer at Tx ? We could accept up to 64x routinely, even sometime 128x, but no idea for higher titers.

  23. Patient group ABO-ISplenctomy (2001-2004) ABO-I Rituximab (2005-2009) ABO-C w/o Spx nor Rit (2001-2009)

  24. ABO-ISpx (2001-2004) ABO-I Rit (2005-2009) ABO-C (2001-2009) Graft Survival Log-rank test： 0.632 100% 80% 60% Cumulative Probability 40% 20% 0% 0 1 2 3 4 5 6 7 8 9 10 ABO-I Spx: splenectomy ABO-I Rit: Rituximab injection ABO-C: ABO-Compatible (year) Kohei N, Tanabe K Am J Transplantation 2012; 12: 469-476

  25. Significant Reduction of DSA and Chronic ABMR in ABO-ILKT ABO-ILKT/Spx ABO-ILKT/Rit ABO-CLKT Post-Tx DSA 2 (4.4%) 2 (3.5%) 29 (34.9%) p<0.0001 ABO-ILKT/Spx ABO-ILKT/Rit ABO-CLKT De novo DSA 1 (2.2%) 1 (1.7%) 15 (18.1%) p=0.029 ABO-ILKT/Spx ABO-ILKT/Rit ABO-CLKT Chronic ABMR w/DSA 2 (4.4%) 2 (3.5%) 19 (22.9%) p=0.002 Kohei N, Tanabe K AJT 2012; 12: 469-76

  26. Adverse Events Incidence of post-transplant infectious complication was not different between ABO-ILKT and ABO-CLKT Kohei N, Tanabe K AJT 2012; 12: 469-76

  27. The Latest 10-year Outcome of ABO-incompatible Living Kidney Transplantation at TWMU

  28. The Latest 10-year Outcome of ABO-ILKT at TWMU 2001-2013 ABO-ILKT n=206 ABO-CLKT n= 522 Immunosuppression: DFPP Splenectomy or rituximab injection FK/MMF/St and basiliximab induction No IVIG No post-transplant prophylactic PEX

  29. Patient Survival(2001-2013) 99.0% 99.0% 99.0% 100% 97.0% 94.7% 91.3% 80% 60% ABO-I (n=206) Cumulative Probability ABO-C(n=522) 40% 20% Log-rank test： 0.030 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Months (Kaplan-Meier Estimates )

  30. Graft Survival(2001-2013) 93.0% 91.7% 91.7% 100% 92.8% 84.7% 80% 78.4% 60% Cumulative Probability ABO-I (n=206) ABO-C(n=522) 40% 20% Log-rank test： 0.290 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Months (Kaplan-Meier Estimates )

  31. Take Home Messages • Long-term outcome of ABO-ILKT over 20 years was not different from that of ABO-CLKT . • B-cell depleting treatment could significantly reduce the post-transplant DSA (both preformed and de novo), and eventually prevent acute and chronic ABMR according to our ABO-ILKT data. • High titer of anti-blood group antibodies is not a risk factor for ABO-ILKT.

  32. Acknowledgement Tokyo Women’s Medical University Department of Urology Masashi Inui, MD., PhD Tomokazu Shimizu, MD, PhD Taiji Nozaki, MD, PhD Hideki Ishida, MD, PhD Kazuya Omoto, MD, PhD Graduate School of Medicine, Urology Toshio Hirai, MD Naoki Kohei, MD Keiko Sai, MD Keiko Ikemiyagi, MD Shougo Sawada, MD Rumi Shibahara , MD Takafumi Yagisawa, MD Section of Renal and Urological Pathology Shigeru Horita Yutaka Yamaguchi, MD, PhD Kazuho Honda, MD, PhD Section of Transplant Immunology Miyuki Furusawa, PhD Yachiyo Medical Center , Tokyo Women’s Medical University Masashi Inui, MD, PhD Toda General Hospital Department of Urology Tomokazu Shimizu, MD, PhD Okubo Hospital Hiroki Shirakawa, MD, PhD STATZ corp. Department of Statistics Kazunori Shimada, PhD

  33. Thank you for your attention

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