I'm sorry it is in mixed italian and english, but the message is quite clear.

1. CNI minimization
by Everolimus
Evolving strategies at a single centre
Decenzio BONUCCHI, MD
Nephrology, Dialysis and Renal Transplantation
Policlinico University Hospital, Modena - Italy

2. Nephrology, Dialysis and Renal Transplantation
Policlinico University Hospital, Modena - Italy
Case-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. Sirolimus e Everolimus
Pm 958 D
•Sopprimono la risposta alloimmune
•Inibiscono proliferazione e rimodellamento vascolare
Chapman JR 2007 Transplantation Proceedings
Inibiscono la risposta immune e NON immune nei confronti dell’allo-trapianto

4. Alterations in glucose metabolism by cyclosporine in rat brain slices
link to oxidative stress: interactions with mTOR inhibitors
Uwe 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. Everolimus, Sirolimus and Paclitaxel
on eluting stents by IVUS
Circulation 2007 Abstract 2770
R. Sakurai et al.
Everolimus riduce lo spessore intimale come sirolimus,
ma garantisce una migliore copertura dello stent

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. 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. 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. TLC ottimali di everolimus nel breve termine
Lorber et al. 2005
Clin Transplant

10. Everolimus “governa” il rischio di AR
CsA “governa” la tossicità.

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 associated
with freedom from acute rejection in de novo renal recipients.
ATC Toronto 2008; ICT Sidney 2008) Corbetta et al 2007 AST

12. EVEROLIMUS - 2° tappa:
minimizzazione della ciclosporina
Tedesco-Silva H et al. Studio 2306-2307:
12-month safety and efficacy of everolimus with reduced
exposure
cyclosporine in de novo renal transplant recipients
Transplant 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/ml
CsA C2 600-400 ng/ml

13. Fin dove spingere la riduzione del CNI
B201
A2306
Pascual J
2005 Transplantation

14. Strategie di conversione
I 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. Mechanisms of death-censored
kidney graft loss (1996-2006)
Unknown 1317 transplants
153 losses
Medical
Infections
Recurrent 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. 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 therapy
from P/CsA/MPS to therapy with P/CsA or P/EVL at 6 months after renal
transplantation is effective in preventing rejection. Double therapy with
P/MPS after withdrawal of P/CsA resulted in an increase in severe acute
rejection episodes. These results were the immediate reason to halt the
P/MPS arm. Serum creatinine values at the latest follow-up (8+/-5 months
after conversion and 14+/-5 months after transplantation) in the P/EVL
group 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. De Novo ? Conversione ?
•Raramente le strategie De Novo restano
tali.
•Le strategie di Conversione
generalizzata non rispondono sempre
alla realtà del singolo paziente
SEQUENZIALE !!

18. Razionale dell’IS SEQUENZIALE
Obiettivi:
Prevenire la DGF
Ridurre le complicanze chirurgiche
Prevenire il rigetto a breve e lungo termine
Fronteggiare la CAN
Ridurre il rischio infettivo
Ridurre il rischio cardio-vascolare
Ridurre il rischio metabolico
Uno schema rigido (De-novo o Conversione) non ha la
possibilità di contrastare le complicanze con il giusto
timing

19. HPK2 protocol (high protection K2)
“To protect against DGF, rejection, wound healing
delay, 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, tolerability
and individual risk factors
Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena

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=14
MDRD (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. HPK2 (Everolimus and low exposure Cyclosporine)- Group 2
vs
standard triple immunosuppression (CNI, MMF, st) – Group 1
In Extended-Criteria-Donor dual kidney transplantation
DKT: 35 pts
20 pts 1 death 14 pts
CNI-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. Recipients and donors characteristics
RECIPIENTS GROUP 1 (n = 14) GROUP 2 (n = 20)
Male/Female 10/4 14/6
Age (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%)
DONORS
Male/Female 7/7 10/10
Age (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 ± 0.84
MDRD GFR (ml/min) ± SD 88.99 ± 22.45 75,33 ± 20,95
Cause of death
• Cerebrovascular hemorrage 7 (50%) 13 (65%)
• Ictus 6 (42,86%) 4 (20%)
• Accidental trauma 0 3 (15%)
• Other 1 (7.14%) 0
Mean CKI (hours) ± SD 17.18 ± 2.86 16.21 ± 2.85
CMV positive donor/CMV negative
0 (0%) 1 (5%)
recipient
CMV 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. 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=14
MDRD (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. 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 0,029
GLICEMIA>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. 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

27. IRC e Trapianto Renale
STADIO 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

29. Causes of graft loss

30. HPK2 protocol (high protection K2)
“To protect against DGF, rejection, wound healing
delay, 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, tolerability
and individual risk factors
Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena

31. 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%)

32. Furian L et al – Calcineurin inhibitor-free immunosuppression in dual
kidney 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

33. 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

34. Studio IMPROVE
(Protocollo spontaneo Ev + TAC once a day)
Certican 2.25 mg monosomm.
n = 24
Media

35. ng/ml
Ev dose = 2.5 mg
6° ora

36. FIXED DOSE EVEROLIMUS 2.25 mg ONCE DAILY
n =27
*
11,0 ± 3,36 ng/ml
ng/ml
3,94 ± 2,16 ng/ml
Time - hours
* Isoniazide Prophylaxis Bonucchi D / Ghiandai G - 2010
36

37. Studio IMPROVE
(improving renal outcome
with prograf and everolimus in ECD kidney graft)
Braccio A: Tacrolimus mono + Evero mono
(monitoraggio Ev base e 6° ora)
Regola del 10 a 3 mesi
Braccio B: HPK2

38. Tacro TLC 4 ng/ml
Evero TLC 5.2 ng/ml

40. Studio EVIDENCE
Braccio A: CSA monosomministrazione per C2 350-700 ng/ml,
Everolimus once a day
Steroide
Braccio B: CSA + Ev b.i.d, sospensione steroide
Braccio C: CSA + Ev b.i.d. + steroide
Inserimento immediato degli IS
Emendamento del protocollo

41. Everolimus ed effetti collaterali
•Edema + (peso delle associazioni – Ca antagonisti, tiazolidinedioni)
•Polmonite interstiziale -

42. 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 assenti
adattato da Corbetta et al,
Exposure to everolimus and not to cyclosporine is associated
with freedom from acute rejection in de novo renal recipients.
ATC Toronto 2008; ICT Sidney 2008) Corbetta et al 2007 AST

43. INTERVENTI CHIRURGICI
INTERCORRENTI
• Sospensione/riduzione EVEROLIMUS (MMF,
steroide?)
• Copertura con basiliximab
(Holiday sec. M. Cantarovich)
• “Compensazione” con CSA

44. CMV e HPK2
Profilassi di Centro con Valganciclovir per 3 mesi

45. ?
BK virus

46. 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

48. 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 associated
with low rates of BPAR without adversely affecting renal function.
No evident PK interaction exists between Evl and Tac.

49. Nuovi scenari ed “Exit Strategy”
SIR EVE
? EC-MPA
?
TAC CSA

50. 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)

51. 51
HPK2 and HIV+ TX:
Short term AMF
Steroid withdrawal Raltegravir
Low-dose CSA + Integrase inhibitor
Everolimus long term
+
Enfuvirtide (T20):
fusion inhibitor
+ Lamivudine

52. Conclusions
(according to Modena Renal Transplant Centre)
•HPK2 offers an advantage in terms of GFR to ECD
dual kidney transplantations
•Once-a-day fixed-dose everolimus (EVIDENCE
EVOLUTION) could be a future option
•HPK2 in HIV+TX is in progress

53. 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.

54. Open issues
•Retro-conversion to CNI (surgery)
•Additive effects on edema by vasodilators
(TDZ, CCB)
•Aged living donor
•Conversion from nephrotoxicity in Pancreas
Transplantation Alone

55. Protocollo HPK2
Dosi Medie IS a 1 anno
Everolimus 1,3 mg/die
Ciclosporina 60 mg/die
Steroide 4,1 mg/die

56. Drop-out, diagnosi differenziale e loci communes
• Linfocele e guarigione delle ferite
• Edema
• Artralgie
• Proteinuria
• Trombocitopenia
• Microangiopatia trombotica (dose dipendente?)

57. Il follow-up attento e mirato salvaguarda il
paziente trapiantato insieme al proprio graft