CNI minimization by Everolimus

Evolving strategies at a single centre

Decenzio BONUCCHI, MD

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

Nephrology, Dialysis and Renal Transplantation

Policlinico University Hospital, Modena - Italy

Sirolimus e Everolimus

•Sopprimono la risposta alloimmune•Inibiscono proliferazione e rimodellamento vascolareChapman JR 2007 Transplantation Proceedings

Inibiscono la risposta immune e NON immune nei confronti dell’allo-trapianto

Pm 958 D

Alterations in glucose metabolism by cyclosporine in rat brain sliceslink to oxidative stress: interactions with mTOR inhibitors

Uwe Christians, Sven Gottschalk, Jelena Miljus, Carsten Hainz, Leslie Z Benet, Dieter Leibfritz and Natalie Serkova

British Journal of Pharmacology (2004) 143, 388–396.

Everolimus antagonizza la DISFUNZIONE MITOCONDRIALE indotta da CsA

                                                                                                                                                                                     

                      

Circulation 2007 Abstract 2770R. Sakurai et al.

Everolimus, Sirolimus and Paclitaxelon eluting stents by IVUS

Everolimus riduce lo spessore intimale come sirolimus, ma garantisce una migliore copertura dello stent

• 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)

Le esperienze del trapianto di cuore

• …reliance on CsA is inappropriate for long-term immunosuppression of kidney transplant recipients. (Nankivell et al 2004 Transplantation)

Il paradigma di Nankivell

e l’equilibrato scetticismo di Kahan

Vitko S et al. Studio B201:

Three-year efficacy and safety results from a study of

everolimus versus micophenolate mofetilversus 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

EVEROLIMUS - 1° tappa: ciclosporina a dose piena

Lorber et al. 2005Clin Transplant

TLC ottimali di everolimus nel breve termine

Everolimus “governa” il rischio di AR

CsA “governa” la tossicità.

Valutazione combinata di 2 immunosoppressori La “regola del 12”

Rischio di rigetto nei primi 3 mesi post-TX

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

Everolimus “governa” il rischio di AR

CsA “governa” la tossicità.

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

EVEROLIMUS - 2° tappa: minimizzazione della ciclosporina

Pascual J2005 Transplantation

Fin dove spingere la riduzione del CNI

B201A2306

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.

Strategie di conversione

Mechanisms of death-censored kidney graft loss (1996-2006)

0 5 10 15 20 25 30 35 40

Immunologic

Recurrent dis.

Infections

Medical

Unknown

Percent of losses

Cell-mediated Antibody-mediated

1317 transplants

153 losses

1317 transplants

153 losses

(Ziad El-Zoghby, Cosio et al AJT 9:527-535, 2009)

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.

Quando effettuare la conversione ?

A 3-6 mesi la triplice consente di caratterizzare il paziente e di

scegliere la duplice terapia di mantenimento

De Novo ? Conversione ?

•Raramente le strategie De Novo restano tali.•Le strategie di Conversione generalizzata non rispondono sempre alla realtà del singolo paziente

SEQUENZIALE !!

Obiettivi:Prevenire la DGFRidurre le complicanze chirurgichePrevenire il rigetto a breve e lungo termineFronteggiare la CANRidurre il rischio infettivoRidurre il rischio cardio-vascolareRidurre il rischio metabolico

Uno schema rigido (De-novo o Conversione) non ha la possibilità di contrastare le complicanze con il giusto timing

Razionale dell’IS SEQUENZIALE

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)•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:•Certican TLC 6-8•CSA C2 200-250•Steroid according to clinical response, tolerability and individual risk factors

Lacedelli, Compagnoniand Bonatti – Italy1954

K2

Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena

0

10

20

30

40

50

60

70

80

90

pre-switch 1 month 3 months 6 months 12 months 18 months

MD

RD

(m

l/min

)

group 2

group 1

**

*

n=20

n=20

n=12

n=10

n=13

n=12

n=13

n=14

n=13

n=18

n=14

n=14

n = number of patients at timepoint* = p<0,05

GLOMERULAR FILTRATION RATE

HPK2 (Everolimus and low exposure Cyclosporine)- Group 2vs

Standard triple immunosuppression (CNI, MMF, st) – Group 1In Extended-Criteria-Donor dual kidney transplantation

DKT: 35 pts

14 ptsCNI-MMF-STER

(group 1)

20 ptsCNI-EVER-STER

(group 2)

1 follow up not reached

1 acute rejection 1 thrombocytopenia 1 delayed wound healing 1 follow up not reached

1 lymphocele* 1 follow up not reached

1 peripheral edema 1 switch to Sirolimus*

3 follow up not reached

3 months18 pts

6 months14 pts

12 months12 pts

18 months10 pts

18 months12 pts

12 months13 pts

6 months13 pts

3 months13 pts

1 switch to Sirolimus

1 death(infective and surgical

complications)

HPK2 (Everolimus and low exposure Cyclosporine)- Group 2vs

standard triple immunosuppression (CNI, MMF, st) – Group 1In Extended-Criteria-Donor dual kidney transplantation

RECIPIENTSRECIPIENTS 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%)

DONORSDONORS

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 recipient 0 (0%) 1 (5%)

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

Recipients and donors characteristics

0

10

20

30

40

50

60

70

80

90

pre-switch 1 month 3 months 6 months 12 months 18 months

MD

RD

(m

l/min

)

group 2

group 1

**

*

n=20

n=20

n=12

n=10

n=13

n=12

n=13

n=14

n=13

n=18

n=14

n=14

n = number of patients at timepoint* = p<0,05

GLOMERULAR FILTRATION RATE

HPK2 (Everolimus and low exposure Cyclosporine)- Group 2vs

Standard triple immunosuppression (CNI, MMF, st) – Group 1In Extended-Criteria-Donor dual kidney transplantation

TRAPIANTI DOPPI

HPK2 HPK2 TRIPLICE CON 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/ Pre-Tx

6 mesi Var % p Pre-Tx 6 mesi Pre-Tx 6 mesi p

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

A

R

M

A

C

I

insulina 2 0 0

ADO 5 2 1

statine 23 7 3

Ω-3 15 6 2

Cortisone (mg//die) 4 5,59

Impatto funzionale e metabolico di HPK2

• 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

Rischio cardio-vascolare nel “old-to-old”

IRC e Trapianto Renale

STADIO DESCRIZIONE FG

(ml/min/1.73 m2)

PREVALENZA a 1 anno

Popolazione

%

0 A rischio aumentato 90 con fattori di rischio per IRC

1 Danno renale con FG normale o aumentato

90

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

Causes of graft loss

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)•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:•Certican TLC 6-8•CSA C2 200-250•Steroid according to clinical response, tolerability and individual risk factors

Lacedelli, Compagnoniand Bonatti – Italy1954

K2

Nefrologia, Dialisi e Trapianto Renale – AOU Policlinico di Modena

Studio ZEUS; EC-MPA + CSA o +Ev150 + 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%)

• 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

Furian L et al – Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors.

Clinical Transplant 2006

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

Everolimus + tacrolimus

Media

Certican 2.25 mg monosomm.

n = 24

Studio IMPROVE (Protocollo spontaneo Ev + TAC once a day)

Ev dose = 2.5 mg

6° ora

ng/ml

n =27

3,94 ± 2,16 ng/ml

11,0 ± 3,36 ng/ml

ng/m

l

Time - hours

*

FIXED DOSE EVEROLIMUS 2.25 mg ONCE DAILY FIXED DOSE EVEROLIMUS 2.25 mg ONCE DAILY

* Isoniazide Prophylaxis Bonucchi D / Ghiandai G - 2010

36

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

Tacro TLC 4 ng/mlEvero TLC 5.2 ng/ml

Studio EVIDENCE

Braccio 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. + steroide

Inserimento immediato degli ISEmendamento del protocollo

Everolimus ed effetti collaterali

•Edema + (peso delle associazioni – Ca antagonisti, tiazolidinedioni)

•Polmonite interstiziale -

Valutazione combinata di 2 immunosoppressori La “regola del 12” – Caso Clinico

TX in HIV Mar 09Protocollo HPK2-HIV (no MMF)

Lug 09TLC Ev 8.69 e C2 383Cr 0.8 mg%Edemi imponenti

Ipotesi di sospensione Ev e innesto di MMF = No x rischioInfettivo (CMV +/-)

Nov 09TLC Ev 4.05 e C2 782 ng/mlCr 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

INTERVENTI CHIRURGICIINTERCORRENTI

• Sospensione/riduzione EVEROLIMUS (MMF, steroide?)

• Copertura con basiliximab (Holiday sec. M. Cantarovich)

• “Compensazione” con CSA

CMV e HPK2

Profilassi di Centro con Valganciclovir per 3 mesi

BK virus

?

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

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.

SIR EVE

CSATAC

?

?EC-MPA

Nuovi scenari ed “Exit Strategy”

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)

Enfuvirtide (T20): fusion inhibitor

RaltegravirIntegrase inhibitor

HPK2 and HIV+ TX:Short term AMFSteroid withdrawalLow-dose CSAEverolimus long term

+

+

51

+ Lamivudine

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

• 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.

EVEROLIMUS – Prospettive a medio termine

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

Dosi Medie IS a 1 anno

Everolimus 1,3 mg/dieCiclosporina 60 mg/dieSteroide 4,1 mg/die

Protocollo HPK2

• Linfocele e guarigione delle ferite• Edema• Artralgie• Proteinuria• Trombocitopenia• Microangiopatia trombotica (dose dipendente?)

Drop-out, diagnosi differenziale e loci communes

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