1. Conversion from CNI to sirolimus Byung Chul Shin Division of Nephrology Chosun University Hospital, Gwangju

2. mTOR inhibitor mTOR: Mammalian Target Of Rapamycin 1999 USA EVEROLIMUS(CERTICAN) SIROLIMUS(RAPAMUNE)

3. mTOR Inhibitors Target site : mammalian target of rapamycin (mTOR), a key regulatory kinase in cell division. Sirolimus (Rapamune ® ) only available mTOR inhibitor in the US. Everolimus (Certican ® ) Administered once daily, 24-hour trough levels monitored. Metabolized by P450 3A system, with interactions similar to the CNIs.

4. Sirolimus: Mechanism of Action SRL: Sirolimus FKBP: FK Binding Protein mTOR: Mammalian target of rapamycin Cdk: cyclin-dependent kinase Stepkowski, Expert Rev Mol Med, 2000;2(4):1

5. Halloran, N Eng J Med, 2004;351:3715

6. Can mTOR inhibitor Replace CNI? Malignancy? Nephrotoxicity? CVA?

9. N Engl J Med. 2005 Mar 31;352(13):1317-23. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. Kaposi’s sarcoma in a transplant recipient After 1 month of Tx

10. Can mTOR Inhibitor Replace CNI? Malignancy? Nephrotoxicity? CVA?

11. Synergistic Nephrotoxicity The Combination of CNI and mTORI ng/g 0 30 60 90 120 150 CsA CsA+SRL * Drug interaction between mTORI and CsA in Kidney 0 1.5 3 4.5 6 7.5 SRLCsA+SRL ng/g * CsA conc. SRL conc.

12. SRL as a Primary Immnosuppressant Initial combination of SRL + CsA Acute Rejection↓ Followed by Elimination of CsA Preserve Graft Function

15. Lesson form Experimental and Clinical studies Kidney with already significant injury by CNI may be less likely to benefit from conversion to SRL Early conversion is essential to preserve graft function

16. Malignancy? Nephrotoxicity? CVA risk? Can mTOR Inhibitor Replace CNI?

17. Lipid Profile Posttransplant month mg/dL 168 80 98 58 237 179 165 52 302 217 195 88 256 252 174 58 0 50 100 150 200 250 300 350 400 450 0134 Chol TG LDL-c HDL-c

18. SRL itself does not cause serious pancreatic injury. Synergistic pancreatic injury with CNI. Conversion to SRL dose not improve DM in established CNI-induced DM. Influence of SRL on Diabetes

19. Switch from CNI to SRL(N=26) 30% increase of IGT New PTDM in 4 patients PTDM by CNI may NOT be considered as an indication for conversion to SRL

20. Can mTOR Inhibitor Replace CNI? Malignancy - Yes Yes ! Nephrotoxicity - Yes Yes ! CVA ? SUMMARY

21. “ Five" adverse effects ★ Hyperlipidemia Delayed wound healing Synergistic nephrotoxicity with CsA Proteinuria Lymphocele

22. 간헐적 발열과 기침, 객담배양검사에서 음성 SRL 에 의한 interstitial pnenumonitis 의심

24. Fritz Diekmann et al, Nephrol Dial Transplant (2006) 21: 562–568

27. Treatment Regimens SRL conversion : a single loading dose (12-20 mg) between 4 and 24 hours after the last dose of CNI. On day 2: 4 to 8 mg SRL - trough level 8 to 20 ng/mL MMF and azathioprine : reduced to 1.5 g/day and 75 mg/day CNI continuation : CsA (C0: 50 –250 ng/mL) or tacrolimus (C0: 4 –10 ng/mL) Schena et al, Transplantation 2009;87: 233–242

30. CHEN LI, et al. Transplantation Proceedings 40, 1411–1415 (2008) Switch from CNI to SRL(N=16) Creatinine level < 2.48 mg/dL No C4d deposition in PTC Serum creatinine level and the deposition of C4d in PTC -> important factors influencing therapeutic efficacy

31. CHEN LI, et al. Transplantation Proceedings 40, 1411–1415 (2008)

32. Slow Conversion Protocol SRL start : 2-4mg/daily without loading CNI reduced : 50% Short overlap phase : 7-10 days Target trough levels : 8-12ng/mL SRL given : 4hr after CsA, simultaneously tacrolimus Steroid Tx : no change MMF : maximum 1.5g/day

33. Slow CONVERSION weeks 0123 4 Sirolimus (8-12 ng/mL) Sirolimus (2-4 mg/day) CNI 50% Sirolimus CNI (CsA or TAC) MMF and/or steroid MMF (≤1.5 g/day) and/or steroids

34. Abrupt Conversion Protocol CNI withdrawn : day 1 SRL loading : 15-18mg SRL followed : 4-6mg/day SRL trough levels : 8-12ng/mL Other immunosuppressive drugs : unchanged Bactrim prophylaxis : 6 months Viorica Bumbea et al, Nephrol Dial Transplant 20: 2517-2523, 2005

35. Abrupt CONVERSION weeks 0123 4 Sirolimus (8-20 ng/mL) D1: Sirolimus (12-20 mg/day) Sirolimus CNI (CsA or TAC) MMF or AZA MMF (≤1.5 g/day) or AZA (75 mg/day) D2: Sirolimus (4-8 mg/day) -> 3-5 mg/day Bactrim

36. 결론  mTORI 는 CNI 를 대체할 수 있는 유용한 약제이다.  비가역적인 손상이 오기전에 조기전환이 중요.  mTOR inhibitor 의 부작용을 잘 알고 있어야 한다.