Practical use of everolimus in kidney transplantation

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Practical use of everolimus in kidney transplantation

  1. 1. CNI minimization by Everolimus Evolving strategies at a single centre Decenzio BONUCCHI, MDNephrology, Dialysis and Renal Transplantation Policlinico University Hospital, Modena - Italy
  2. 2. Nephrology, Dialysis and Renal Transplantation Policlinico University Hospital, Modena - ItalyCase-load: 35-40 TX/year (22-54)Cadaveric (single and dual)Living donor (hyper-immune)HIV+Combi (liver-kidney)Pancreas and kidney-pancreas (recruitment and FU)Case-mix: complexity medium-high
  3. 3. Sirolimus e Everolimus Pm 958 D•Sopprimono la risposta alloimmune•Inibiscono proliferazione e rimodellamento vascolareChapman JR 2007 Transplantation ProceedingsInibiscono la risposta immune e NON immune nei confronti dell’allo-trapianto
  4. 4. Alterations in glucose metabolism by cyclosporine in rat brain sliceslink to oxidative stress: interactions with mTOR inhibitorsUwe Christians, Sven Gottschalk, Jelena Miljus, Carsten Hainz, Leslie Z Benet, Dieter Leibfritz and Natalie Serkova Everolimus antagonizza la DISFUNZIONE MITOCONDRIALE indotta da CsA British Journal of Pharmacology (2004) 143, 388–396.
  5. 5. Everolimus, Sirolimus and Paclitaxelon eluting stents by IVUSCirculation 2007 Abstract 2770R. Sakurai et al. Everolimus riduce lo spessore intimale come sirolimus, ma garantisce una migliore copertura dello stent
  6. 6. Le esperienze del trapianto di cuore• Miglior profilo lipidico con Everolimus rispetto a Sirolimus (G. Tenderich et al 2007 Clin Transplant)• Efficacia degli stent medicati con Everolimus (Grube E et al Circulation 2004;109:2168–71.• Bassa incidenza di infezione da CMV (JA Hill et al 2007 Transplantation)
  7. 7. Il paradigma di Nankivell• …reliance on CsA is inappropriate for long-term immunosuppression of kidney transplant recipients. (Nankivell et al 2004 Transplantation) e l’equilibrato scetticismo di Kahan
  8. 8. EVEROLIMUS - 1° tappa:ciclosporina a dose piena Vitko S et al. Studio B201: Three-year efficacy and safety results from a study of everolimus versus micophenolate mofetil in de novo renal transplant patients Am J Transplant 2005 • Ev 1,5 mg/die è equivalente a MMF 2 g/die • CsA C0 100-300 ng/ml • Soglia di protezione contro Rigetto Acuto: Ev TLC> 3 ng/ml • cGFR NS • Ev riduce infezioni virali • Ev induce dislipidemia
  9. 9. TLC ottimali di everolimus nel breve termine Lorber et al. 2005 Clin Transplant
  10. 10. Everolimus “governa” il rischio di ARCsA “governa” la tossicità.
  11. 11. Valutazione combinata di 2 immunosoppressori La “regola del 12” Rischio di rigetto nei primi 3 mesi post-TX Everolimus “governa” il rischio di AR CsA “governa” la tossicità.adattato da Corbetta et al,Exposure to everolimus and not to cyclosporine is associatedwith freedom from acute rejection in de novo renal recipients.ATC Toronto 2008; ICT Sidney 2008) Corbetta et al 2007 AST
  12. 12. EVEROLIMUS - 2° tappa:minimizzazione della ciclosporinaTedesco-Silva H et al. Studio 2306-2307:12-month safety and efficacy of everolimus with reduced exposurecyclosporine in de novo renal transplant recipientsTransplant International 2006• No induzione:Rigetti 16.4% con Ev 3 mg vs 25.9% con Ev 1.5 mg/die• Basiliximab:14.3 vs 13.6%Ev TLC 6-8 ng/mlCsA C2 600-400 ng/ml
  13. 13. Fin dove spingere la riduzione del CNI B201 A2306 Pascual J 2005 Transplantation
  14. 14. Strategie di conversioneI pazienti con CAN e proteinuria minima beneficiano della conversione.(Cr < 2 mg%; VFG > 40 ml/min; proteinuria < 750 mg)In relazione al crescente ruolo svolto dalle recidive di malattia di base,la biopsia ha un ruolo irrinunciabile nella guida della scelta di conversione.
  15. 15. Mechanisms of death-censored kidney graft loss (1996-2006) Unknown 1317 transplants 153 losses Medical InfectionsRecurrent dis.Immunologic Cell-mediated Antibody-mediated 0 5 10 15 20 25 30 35 40 Percent of losses (Ziad El-Zoghby, Cosio et al AJT 9:527-535, 2009)
  16. 16. Quando effettuare la conversione ?Transplantation. 2009 Aug 15;88(3):421-8.Minimization of maintenance immunosuppression early after renal transplantation:an interim analysis.Bemelman FJ et al.CONCLUSIONS: We conclude that switching immunosuppressive therapyfrom P/CsA/MPS to therapy with P/CsA or P/EVL at 6 months after renaltransplantation is effective in preventing rejection. Double therapy withP/MPS after withdrawal of P/CsA resulted in an increase in severe acuterejection episodes. These results were the immediate reason to halt theP/MPS arm. Serum creatinine values at the latest follow-up (8+/-5 monthsafter conversion and 14+/-5 months after transplantation) in the P/EVLgroup were lower than in the P/CsA group. A 3-6 mesi la triplice consente di caratterizzare il paziente e di scegliere la duplice terapia di mantenimento
  17. 17. De Novo ? Conversione ?•Raramente le strategie De Novo restanotali.•Le strategie di Conversionegeneralizzata non rispondono semprealla realtà del singolo pazienteSEQUENZIALE !!
  18. 18. Razionale dell’IS SEQUENZIALEObiettivi:Prevenire la DGFRidurre le complicanze chirurgichePrevenire il rigetto a breve e lungo termineFronteggiare la CANRidurre il rischio infettivoRidurre il rischio cardio-vascolareRidurre il rischio metabolicoUno schema rigido (De-novo o Conversione) non ha lapossibilità di contrastare le complicanze con il giustotiming
  19. 19. HPK2 protocol (high protection K2)“To protect against DGF, rejection, wound healingdelay, chronic CNI toxicity, viral infections and CV risk”Basal IS:•Basiliximab induction•Delayed CSA (serum creatinine 3-2.5 mg%(C2 1000)•MPA (720 mg bid) K2•Steroid (500 mg intra-operative)Switch at POD 21:•Certican 0.75 mg bid (TLC 8-10)•CSA (C2 300-400)•Steroid tapering to 4 mg in 3 steps every 14 days•MPA stop (max overlap 7 days)Maintenance: Lacedelli, Compagnoni•Certican TLC 6-8 and Bonatti – Italy•CSA C2 200-250 1954•Steroid according to clinical response, tolerabilityand individual risk factors Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena
  20. 20. HPK2 (Everolimus and low exposure Cyclosporine)- Group 2 vs Standard triple immunosuppression (CNI, MMF, st) – Group 1 In Extended-Criteria-Donor dual kidney transplantation GLOMERULAR FILTRATION RATE 90 * 80 * n=20 70 n=18 * n=14MDRD (ml/min) 60 n=14 n=10 n=12 50 n=20 n=14 n=13 n=13 n=12 40 n=13 30 20 group 2 group 1 10 0 pre-switch 1 month 3 months 6 months 12 months 18 months n = number of patients at timepoint * = p<0,05
  21. 21. HPK2 (Everolimus and low exposure Cyclosporine)- Group 2 vsstandard triple immunosuppression (CNI, MMF, st) – Group 1 In Extended-Criteria-Donor dual kidney transplantation DKT: 35 pts 20 pts 1 death 14 ptsCNI-EVER-STER (infective and surgical CNI-MMF-STER (group 2) complications) (group 1) 1 lymphocele* 1 follow up not reached 1 follow up not reached 3 months 3 months 18 pts 13 pts 1 acute rejection 1 thrombocytopenia 1 delayed wound healing 1 follow up not reached 6 months 6 months 14 pts 13 pts 3 follow up not reached 12 months 12 months 12 pts 13 pts 1 peripheral edema 1 switch to Sirolimus* 1 switch to Sirolimus 18 months 18 months 10 pts 12 pts
  22. 22. Recipients and donors characteristicsRECIPIENTS GROUP 1 (n = 14) GROUP 2 (n = 20)Male/Female 10/4 14/6Age (median years) 61 (56-70) 61 (52-71)Body weight (median Kg) 62.2 (52-96.2) 70.4 (46-86.8)BMI (median) 25.3 (17.4-33.7) 24.5 (17.7-28.8)Pre-transplant diabetes 0 2 (10%)DGF 3 (21.4%) 6 (30%)DONORSMale/Female 7/7 10/10Age (median years) 73 (58-79) 72 (58-85)Body weight (median Kg) 68.5 (55-92) 78.5 (57-92)BMI (median) 24.6 (21.8-30) 26 (22-31.8)Karpinski Score mean ± SD 4.30 ± 0.79 4.83 ± 0.84MDRD GFR (ml/min) ± SD 88.99 ± 22.45 75,33 ± 20,95Cause of death• Cerebrovascular hemorrage 7 (50%) 13 (65%)• Ictus 6 (42,86%) 4 (20%)• Accidental trauma 0 3 (15%)• Other 1 (7.14%) 0Mean CKI (hours) ± SD 17.18 ± 2.86 16.21 ± 2.85CMV positive donor/CMV negative 0 (0%) 1 (5%)recipientCMV positive recipient 14 (100%) 19 (95%)BMI = body mass index; DGF = delayed graft function; GFR = glomerular filtration rate; SD = standard deviation; CKI =cold kidney ischemia; CMV = pre-transplant cytomegalovirus sierology
  23. 23. HPK2 (Everolimus and low exposure Cyclosporine)- Group 2 vs Standard triple immunosuppression (CNI, MMF, st) – Group 1 In Extended-Criteria-Donor dual kidney transplantation GLOMERULAR FILTRATION RATE 90 * 80 * n=20 70 n=18 * n=14MDRD (ml/min) 60 n=14 n=10 n=12 50 n=20 n=14 n=13 n=13 n=12 40 n=13 30 20 group 2 group 1 10 0 pre-switch 1 month 3 months 6 months 12 months 18 months n = number of patients at timepoint * = p<0,05
  24. 24. Impatto funzionale e metabolico di HPK2 TRAPIANTI DOPPI TRIPLICE CON HPK2 HPK2 CICLOSPORINA nº pazienti; sesso(F/M) 27; 5F/22M 11; 1F/10M 12; 3F/9M Età media al tx 59,4 ± 9,4 61,8 ± 5,5 61,8 ± 5,6 Dimissione/ 6 mesi Var % p Pre-Tx 6 mesi Pre-Tx 6 mesi p Pre-Tx Creatinina (mg/dL) 1,78 ± 0,6 1,56 ± 0,48 - 23,4% 0,019 1,35 ± 0,5 1,66 ± 0,5 ns MDRD 48 ± 26,3 54,6 ± 15 + 21 % 0,05 65,5 ± 25 45,5 ± 13,5 0,024 CH totale (mg/dL) 185,7 ± 43,5 229,8 ± 55 + 23,7 % 0,0003 230,6 ± 60,2 201,9 ± 46,1 ns HDL (mg/dL) 54,8 ± 22,8 60 ± 16,8 + 9,38 % ns 58,8 ± 12,8 50,7 ± 18,8 ns LDL (mg/dL) 109,5 ± 45,7 132,6 ± 36,8 + 21 % 0,03 138,4 ± 34,9 120,4 ± 35,9 ns TG (mg/dL) 148,9 ± 79,2 220 ± 104,8 + 47,7 % 0,006 200,5 ± 82,4 160,1 ± 68,4 ns GLICEMIA (mg/dL) 94,9 ± 14,9 98 ± 15,1 + 3,2 % ns 102 ± 9,2 91 ± 11,8 0,029GLICEMIA>100 mg/dlL (n° pz) 10 11 7 2 Diabete (n° pz) 1 6 0 2 0 1 F insulina 2 0 0 A ADO 5 2 1 R M statine 23 7 3 A C Ω-3 15 6 2 I Cortisone (mg//die) 4 5,59
  25. 25. Rischio cardio-vascolare nel “old-to-old”• Spettanza di vita• Ruolo del GFR come fattore indipendente di RCV• Ruolo della dislipidemia nel RCV (possibilità di correzione farmacologica)• Il trapianto da rene marginale si pone obiettivi specifici differenti rispetto al trapianto standard
  26. 26. IRC e Trapianto RenaleSTADIO DESCRIZIONE FG PREVALENZA a 1 anno (ml/min/1.73 m2) Popolazione % 0 A rischio aumentato ≥ 90 con fattori di rischio per IRC 1 Danno renale con FG ≥ 90 normale o aumentato 2 Lieve riduzione del FG 89-60 25 3 Moderata riduzione del FG 59-30 60 4 Severa riduzione del FG 29-15 15 5 IR terminale o dialisi <15
  27. 27. Causes of graft loss
  28. 28. HPK2 protocol (high protection K2)“To protect against DGF, rejection, wound healingdelay, chronic CNI toxicity, viral infections and CV risk”Basal IS:•Basiliximab induction•Delayed CSA (serum creatinine 3-2.5 mg%(C2 1000)•MPA (720 mg bid) K2•Steroid (500 mg intra-operative)Switch at POD 21:•Certican 0.75 mg bid (TLC 8-10)•CSA (C2 300-400)•Steroid tapering to 4 mg in 3 steps every 14 days•MPA stop (max overlap 7 days)Maintenance: Lacedelli, Compagnoni•Certican TLC 6-8 and Bonatti – Italy•CSA C2 200-250 1954•Steroid according to clinical response, tolerabilityand individual risk factors Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena
  29. 29. Studio ZEUS; EC-MPA + CSA o +Ev 150 + 150 pz randomizzati dopo 4.5 mesi• Vantaggio di 10.1 ml/min a un anno per Ev• Lieve prevalenza di drop-out nel gruppo Ev- EC-MPA (12.2% vs 5.7%)
  30. 30. Furian L et al – Calcineurin inhibitor-free immunosuppression in dualkidney transplantation from elderly donors.Clinical Transplant 2006• Induzione ATG• Sirolimus through 10-15 ng/ml• MMF 1 gr. POD 5• Steroide 4 mg• Drop-out: 6 AR e 5 side effects – 11/31• CMV 3% vs. 48%• Funzione renale: Sir>CsA a 6 mesi (p<0.01)• NS a un anno
  31. 31. Everolimus + tacrolimus Transplantation. 2008 Mar 27;85(6):821-6. Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness. Chan L, Greenstein S, Hardy MA, Hartmann E, Bunnapradist S,Cibrik D, Shaw LM, Munir L, Ulbricht B, Cooper M; CRADUS09 Study Group. Drugs. 2007;67(13):1931-43. Tacrolimus once-daily formulation: in the prophylaxis of transplant rejection in renal or liver allograft recipients. Cross SA, Perry CM
  32. 32. Studio IMPROVE(Protocollo spontaneo Ev + TAC once a day)Certican 2.25 mg monosomm. n = 24 Media
  33. 33. ng/ml Ev dose = 2.5 mg 6° ora
  34. 34. FIXED DOSE EVEROLIMUS 2.25 mg ONCE DAILY n =27 * 11,0 ± 3,36 ng/mlng/ml 3,94 ± 2,16 ng/ml Time - hours * Isoniazide Prophylaxis Bonucchi D / Ghiandai G - 2010 36
  35. 35. Studio IMPROVE(improving renal outcomewith prograf and everolimus in ECD kidney graft)Braccio A: Tacrolimus mono + Evero mono (monitoraggio Ev base e 6° ora) Regola del 10 a 3 mesiBraccio B: HPK2
  36. 36. Tacro TLC 4 ng/mlEvero TLC 5.2 ng/ml
  37. 37. Studio EVIDENCEBraccio A: CSA monosomministrazione per C2 350-700 ng/ml, Everolimus once a day SteroideBraccio B: CSA + Ev b.i.d, sospensione steroideBraccio C: CSA + Ev b.i.d. + steroideInserimento immediato degli ISEmendamento del protocollo
  38. 38. Everolimus ed effetti collaterali •Edema + (peso delle associazioni – Ca antagonisti, tiazolidinedioni) •Polmonite interstiziale -
  39. 39. Valutazione combinata di 2 immunosoppressori La “regola del 12” – Caso Clinico TX in HIV Mar 09 Protocollo HPK2-HIV (no MMF) Lug 09 TLC Ev 8.69 e C2 383 Cr 0.8 mg% Edemi imponenti Ipotesi di sospensione Ev e innesto di MMF = No x rischio Infettivo (CMV +/-) Nov 09 TLC Ev 4.05 e C2 782 ng/ml Cr 1.19 mg% Edemi assentiadattato da Corbetta et al,Exposure to everolimus and not to cyclosporine is associatedwith freedom from acute rejection in de novo renal recipients.ATC Toronto 2008; ICT Sidney 2008) Corbetta et al 2007 AST
  40. 40. INTERVENTI CHIRURGICI INTERCORRENTI• Sospensione/riduzione EVEROLIMUS (MMF, steroide?)• Copertura con basiliximab (Holiday sec. M. Cantarovich)• “Compensazione” con CSA
  41. 41. CMV e HPK2Profilassi di Centro con Valganciclovir per 3 mesi
  42. 42. ?BK virus
  43. 43. BK virus• Treatment – Only effective therapy is immune reconstitution (i.e. reduction of immunosuppressant therapy) – Cidofivir and leflunomide are effective in reducing viral load, but do very little to change the course of disease, and are both nephrotoxic• One must effectively walk the tightrope between progressive renal destruction secondary to infection, and acute rejection causing graft loss
  44. 44. Transplantation. 2010 Jul 15;90(1):31-7. Optimal everolimus concentration is associated with risk reduction for acute rejection in de novo renal transplant recipients. Chan L, Hartmann E, Cibrik D, Cooper M, Shaw LM.CONCLUSIONS:Evl trough levels > or =3 ng/mL plus Tac are associatedwith low rates of BPAR without adversely affecting renal function.No evident PK interaction exists between Evl and Tac.
  45. 45. Nuovi scenari ed “Exit Strategy” SIR EVE ? EC-MPA ? TAC CSA
  46. 46. Kidney transplantation in HIV+Aims: •Control of HIV replication •Bridge ARV without interactions •Light interaction between IS and ARV therapy •Low rate of infections •Low CV risk in insulin-resistant patients •Results: •6/7 functionig grafts after a mean FU of 18 months •1 graft loss due to AM/BPAR; protocol amended •(NO Thymo confirmed; AMF added (the same as HPK2)
  47. 47. 51HPK2 and HIV+ TX:Short term AMFSteroid withdrawal RaltegravirLow-dose CSA + Integrase inhibitorEverolimus long term + Enfuvirtide (T20): fusion inhibitor + Lamivudine
  48. 48. Conclusions (according to Modena Renal Transplant Centre)•HPK2 offers an advantage in terms of GFR to ECDdual kidney transplantations•Once-a-day fixed-dose everolimus (EVIDENCEEVOLUTION) could be a future option•HPK2 in HIV+TX is in progress
  49. 49. EVEROLIMUS – Prospettive a medio termine• Everolimus come elemento portante della IS a lungo termine• Associazione a AMF (Studio ZEUS)• Utilizzo di CsA a dosi di 20- 40 mg/die per sostenere la concentrazione di Ev (fluconazolo come booster)• La sospensione dello steroide è possibile nel 60% dei pazienti (Montagnino G et al. 2005 Transpl Proc)• E’ ipotizzabile uno schema semplificato, con Everolimus in monosomministrazione.
  50. 50. Open issues•Retro-conversion to CNI (surgery)•Additive effects on edema by vasodilators(TDZ, CCB)•Aged living donor•Conversion from nephrotoxicity in PancreasTransplantation Alone
  51. 51. Protocollo HPK2Dosi Medie IS a 1 annoEverolimus 1,3 mg/dieCiclosporina 60 mg/dieSteroide 4,1 mg/die
  52. 52. Drop-out, diagnosi differenziale e loci communes• Linfocele e guarigione delle ferite• Edema• Artralgie• Proteinuria• Trombocitopenia• Microangiopatia trombotica (dose dipendente?)
  53. 53. Il follow-up attento e mirato salvaguarda ilpaziente trapiantato insieme al proprio graft

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