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Immunosuppressive strategies and infectious risk in solid organ transplantation

This study examines the immunosuppressive strategies used in solid organ transplantation and their impact on infectious risk. The goal is to reduce the incidence of viral infections and improve patient survival among transplant recipients.

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Immunosuppressive strategies and infectious risk in solid organ transplantation

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  1. Franco Citterio Director RenalTransplantation Unit Fondazione Policlinico Universitario A. Gemelli Università Cattolica S. Cuore Roma Immunosuppressivestrategies and infectiousrisk in solidorgantransplantation

  2. Immunosuppression and infectiousriskin solidorgantransplantation • Active problems to be solved • Immunosuppressivestrategies and infections • How to reduce incidence of viralinfections

  3. Patient survival among all transplantrecipients2008-2012 by organ

  4. Causes of death with a functioning graft after renal transplantation 67.874 first renal transplants, 1994–2000 Infections24.0% CVD 39.6% Tumours9.3% Others 27.2% USRDS = United States Renal Data System

  5. Immunosoppression in 2019 • CNIsCyclosporine / Tacrolimus • MMF / MPA / Aza • mTORiEverolimus / Sirolimus • Thymoglobuline • Basiliximab • Rituximab / Bortezomib • Eculizumab • Belatacept

  6. Current Immunosuppressive Agents Basiliximab Daclizumab Belatacept OKT3 Thymoglobulin Alentuzumab Sirolimus Everolimus Tacrolimus Cyclosporine MMF MPA Axathioprine Halloran PF. N Engl J Med 2004;351:2715–29

  7. Renal Transplantation in 2019 • Standard donor • Old for Old • Extended Criteria Donors • Hyperimmunized pts • Living donation • Standard / extended criteria donors • ABO incompatible • HLA incompatible positive crossmatch • Deceased Cardiac Death

  8. Data report SRTR-OPTN 2017 Immunosuppression regimen use in adult kidney transplantrecipientsInduction • AJT Volume 19, Issue S2, Pages: 1-516, February 2019 Special Issue:OPTN/SRTR Annual Data Report 2017

  9. Data report SRTR-OPTN 2017 Immunosuppression regimen use in adult kidney transplant recipients. Manteinance • AJT Volume 19, Issue S2, Pages: 1-516, February 2019 Special Issue:OPTN/SRTR Annual Data Report 2017

  10. The SYMPHONY study Ekberg, et al, New Eng J Med 2007;357:2562–2575.

  11. Standard Immunosuppression and Viral Infections J Am Soc Nephrol. 2018 Jul;29(7):1979-1991

  12. Cytomegalovirus

  13. CMV infection has multiple detrimental effects in organ transplant recipients CMVinfection Indirecteffects Directeffects CMV syndrome Organ - invasivedisease Acute / chronicrejection CAN / IFTA Opportunisticinfections Malignancy CVD and diabetes

  14. Similar proportions of kidney and liver transplant recipients developed viremia and CMV syndrome Viremia and CMV syndrome by donor:recipient serostatus in kidney and liver transplant recipients (n=689) Proportion of patients, %

  15. CMV infection in renal transplant recipients is associated with impaired survival Kaplan Meier analysis of overall recipient survival >100 days post-KTx High risk of mortality: 457 pts with diagnosis of nephrosclerosis, diabetic nephropathy and amyloidosis. 1.0 Low-risk* group/CMV  0.9 0.8 Low-risk* group/CMV + 0.7 0.6 High-risk† group/CMV  Long-term patient survival 0.5 High-risk† group/CMV + 0.4 0.3 Sagedal S, et al. Clin Transplant. 2007;21:309 0.2 0.1 0.0 2000 3000 1000 Days post-transplantation

  16. Benefits and limitations of prophylaxisversus preemptive therapy C. Kotton American Journal of Transplantation 2013; 13: 24–40

  17. University Hospital Grosshadern, Ludwig Maximilian’s University, Munich D • The current literature reviewed for RCTs in SOT comparing mTOR-I with a non-mTOR-I, CNI based treatment. • Cytomegalovirus incidence was assessed in studies comparing • mTOR-In based vs a CNI based therapy: 10 trials, n=3,100 pts • mTOR-I + CNI based vs a CNI-based therapy 15 trials, n=7,100 pts

  18. CMV occurrence mTORsi vs CNIs • 3,100 pts

  19. CMV occurrence mTORsi + CNIs vs CNIs 7,100 pts

  20. Cytomegalovirus CMV  causesincreasedmorbidity, mortality, and reducedallograftsurvival. Prophylaxismay control the virus butdoesnotcompletelyprevent virus reactivation Clinical data suggestthatmTORinhibitorsmayhave an anti-CMV effect

  21. BK polyoma virus

  22. BK-PyVANa,3 Infected tubular epithelial cellsb,3 Decoy cells in urinec,3 BKV replication is common in the renal transplant population BK polyoma virus-associated nephropathy BK-PyVAN1–10%1,2 BKV viraemia~10–20%2 BKV viruria 30–50%2 BKV seropositive 80–90%2,3

  23. Lower risk of BKV viremia with CsA vs tacrolimus in kidney transplant recipients BKV viremia in kidney transplant patients receiving MPA, corticosteroid plus tacrolimus or cyclosporine (n=682) • Risk factors for BKV viremia include • High corticosteroid dose until Month 3 • Use of tacrolimus instead of cyclosporine at Months 6 and 12 • Old age and male gender P=0.048 P=0.279 P=0.004 Tacrolimus P=0.494 BK viremia (%) P=0.095 Cyclosporine 1 2 3 6 12 Month Hirsch HH, et al. Am J Transplant. 2013;13:136–145

  24. BKV infections are less frequent with de novoeverolimus + low CNI at 24 months A2309: Month 24 results P=0.004 EVR 3–8 ng/mL N=274 MPA 1.44 g N=273 Reduced CSA + EVE CSA + MPA Cibrik D, et al. Transplantation. 2013;95(7):933-942.

  25. Everolimus + low CsA (n=274) MPA + standard CsA (n=273) Everolimus with CNI minimisation:reduced incidence of BKV infection A2309: 12-month analysis BKV Incidence at 12 months (%) Viruriab Viraemiac BKVN aInfection reported as adverse event; b,cBKV virus detected in the burine or cplasma:CNI, calcineurin inhibitor; CMV, cytomegalovirus; BKV, BK virus; BKVN, BKV nepropathy ; CsA, cyclosporin; MPA, mycophenolic acid Tedesco-Silva Jr H et al. Am J Transplant 2010;10:1401-1413

  26. BK POLYOMA VIRUS treatment • We suggest reducing immunosuppressive medications when BKV plasma NAT is persistently greater than 10000 copies/mL (107 copies/L). • KDIGO guidelines • Reduce CNIs + stop MMF + convertion to Everolimus ?

  27. EPSTEIN-BARR VIRUS

  28. EBV viremia increases risk of graft loss1-year post kidney transplantation Death censored graft loss in a prospective study inkidney transplant patients (n=383) GRAFT LOSS (HR, 1.84; 95% CI, 1.11–6.22; P=0.033) EBV - Death-censored graph survival (%) EBV + months

  29. Data report SRTR-OPTN 2017 Incidence of PTLD among adult kidney transplant recipientsby recipient EBV status at transplant, 2011-2015 • AJT Volume 19, Issue S2, Pages: 1-516, February 2019 Special Issue:OPTN/SRTR Annual Data Report 2017

  30. Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorder in SOT • The pathogenesisrelated to EBV’sability to transform and immortalize B lymphocytes • The Epstein–Barr virus genome in > 90% of B cell PTLD occurringearlywithin the first yearafter SOT • wide spectrum of clinicalconditions: • uncomplicatedinfectiousmononucleosis • self-limitedinfection • non-Hodgkin’slymphoma • truemalignancies

  31. Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorder in SOT • Diseasemay be nodal or extranodal • localizedoften in the allograft, or widelydisseminated. • may progress slowly or fulminantmultisystemsepsis-likesyndrome.

  32. Immunosuppression and infectiousriskin solidorgantransplantation • Active problems to solve today • Immunosuppressivestrategies and infections • How to reduce incidence of viralinfections

  33. The SYMPHONY study Ekberg, et al, New Eng J Med 2007;357:2562–2575.

  34. Symphony: significantly lower incidence of CMV infection with an mTORi than CNIs Incidence of CMV infectiona at 12 months (%) 20 p=0.003* 14.3 15 11 9.7 10 6.1 5 0 Standard CsA (n=410) Low CsA (n=413) Low tacrolimus (n=411) Sirolimus (n=411) *p value across all arms; significant between-group differenceaDetermined from reported adverse events CMV, cytomegalovirus; mTORi, mammalian target of rapamycin inhibitor; CsA, cyclosporin; CNI, calcineurin inhibitor Ekberg H et al. N Engl J Med 2007;357:2562–75 36

  35. Several recent studies have reported reduced post-transplant CMV incidence with mTORis Patients,n 112117 5358 410413411411 179183173 808080 8184 Study Tedesco-Silva et al 2007 Nashan et al 2004 Ekberg et al 2007ELITE-Symphony study Ekberg et al 2007CAESAR study Hernandez et al 2007 Larson et al 2006 Duration,months 12 36 12 12 24 12 Immunosuppression Everolimus + low CsA + steroidsEverolimus + low CsA + steroids + Bas Everolimus + SD CsA + steroids + BasEverolimus + low CsA + steroids + Bas SD CsA + MMF + steroidsLow CsA + MMF + steroids + DacLow tacrolimus + MMF + steroids + DacLow sirolimus + MMF + steroids + Dac MMF + steroids + DacLow CsA + MMF + steroids +DacSD CsA + MMF + steroids CsA + azathioprine + ATGCsA + MMF + BasTacrolimus + MMF + Bas Sirolimus + MMF + prednisoneTacrolimus + MMF + prednisone CMV incidence at 12 months, % 0.92.6 1.90 14.311.09.76.1 12.810.913.9 412025 312 CMV, cytomegalovirus; mTORi, mammalian target of rapamycin inhibitor; CsA, cyclosporin; Bas, basiliximab; SD, standard dose; MMF, mycophenolate mofetil; Dac, daclizumab; EC-MPS, enteric-coated mycophenolate sodium; ATG, anti-thymocyte globulin 37

  36. Potential mechanisms for antiviral action of mTORis Everolimus has a central role in several pathways related to proliferation Control of gene expression • Cell growth • Proliferation • Cell survival Everolimus P13-K Akt-PKB mTORC1 mTORC2 AKT/PKB, protein kinase B; eIF4, eukaryotic translation initiation factor; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; PI3K, phosphatidylinositol 3-kinase; S6K, S6 kinase. Populo H, et al. Int J Mol Sci 2012;13:1886–1918; Buchkovich NJ, et al. Nature Reviews Microbiology 2008; 6:266–75. S6K 4EBPs MuK1 eIF4E eIF4G eIF4A

  37. Transformstudy

  38. Standard Immunosuppression vs CNIs + mTORi and Viral Infections P =0.0004 P <0.001 P <0.001 J Am Soc Nephrol. 2018 Jul;29(7):1979-1991

  39. J Am Soc Nephrol. 2018 Jul;29(7):1979-1991

  40. J Am Soc Nephrol. 2018 Jul;29(7):1979-1991

  41. Conclusions • Viral infections are still a major complication of renal transplantation • CMV infection, syndrome and disease can be reduced with Everolimus vs standard CNIs therapy • BK infection and nephropathy can be reduced with Everolimus vs standard CNIs therapy

  42. Post-transplant complications in tolerance Mass General approach to induce tolerance D H Sacks tollerance Complications 43 0 0 0 0 % no tollerance 85 65 35 10 25 %

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