1

1

Il trapianto renale a Bergamo

Eliana Gotti

23 Dicembre 1954, ore: 8.00Ospedale Peter Bent Brigham di Boston

2

1.223,624 ORGAN TRANSPLANTS PERFORMED WORLDWIDE UP TO 2009

KidneyLiverHeartLungKidney/pancreasPancreas/IsletHeart/lungIntestine

873,538194,41987,82330,09524,0938,2434,476

937

Transplants n°

Cecka et al., Clinical Transplants, 2010

1

Kidney transplantation

In patients with end stage renal diseasesuccessful renal allotransplantation improves

the quality of life and increases survival ascompared with long-term dialysis treatment

Wolfe et al, N Engl J Med 1999

3

5

THE GAP BETWEEN KIDNEY TRANSPLANT DEMAND AND SUPPLY

US 84,766

Waiting list*

UNOS.org, 2010

Transplant* Death on waiting list °

(n) (n) (n)

16,829 5,251

Italy 6,808 1,651 102

* By December 31, 2009. °During 2009CNT, 2010

CAUSE DI INSUFFICIENZA RENALE CRONICA

• Diabete mellito 24 %

• Glomerulonefriti 11.8 %

• Pielonefriti /reflusso 7.8 %

• Malattia Policistica dell’adulto 7.5 %

• Malattia renovascolare 6.9 %

• Ipertensione 6 %

• Altre cause 15.6 %

• Diagnosi incerta 20.7 %

4

Controindicazioni relative a trapianto

• Età > 65

• Malattie cardiovascolari

• Obesità

• Infezione da HIV

• Pregressa neoplasia

• Epatite cronica B/C

Trapianto renale

- Da donatore: - cadavere- vivente

- Trapianto di rene singolo / doppio

- Trapianto pre-emptive

5

1

Trapianto renale

THE IMMUNOSUPPRESSIVE ARMAMENTARIUM TO CONTROL GRAFT

REJECTION1954

1960

1965

1970

1980

1990

1995-2005

None

Azathioprine

Steroids

Anti-T cell Abs

Cyclosporine

OKT3 mAb

MizoribineDeoxyspergualinTacrolimusMycophenolate mofetil/myforticBasiliximab/DaclizumabSirolimus/everolimusFTY720

6

Gjertson et al., 1992

% 1

-Yea

r Gra

ft S

urvi

val

100

80

60

40

20

075 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

Year of Transplant (1975-1990)

CsA

55-60

35-40 CsA + ST + AZA ‘83

ST + AZA ‘77

Acute rejection (%)

1

Analysis of UNOS data on patients with functioning kidney 1 year post transplant

Hariharan et al., N Eng J Med, 2000

GRAFT SURVIVAL AFTER RENAL TRANSPLANTATION IN THE PERIOD 1988-2004

OPTN website, 2009

years of transplant

Pro

ject

ed m

edia

n ha

lf-lif

e(y

ears

)

88 89 90 91 92 93 9594

Cadaver donor30

20

10

0

8

11

2004

13.8

1

7

THE MAINTENANCE IMMUNOSUPPRESSION

Maintenance immunosuppression is best achieved using combination of immunosuppressive agents

Combination therapy aims to minimize the side-effects of any single drug whilst targeting multiple steps in T-cell activation

Triple-drug regimen

Corticosteroids Calcineurininhibitor

Antiproliferativeagent

CALCINEURIN INHIBITOR NEPHROTOXICITY IS VIRTUALLY UNIVERSAL BY 10 YEARS AFTER TRANSPLANTATION

Nankivell et al., N Engl J Med, 2003

120 type 1 diabetic patients with kidney-pancreas transplant

961 kidney transplant biopsy: Tx to 10 years thereafterTriple-therapy immunosuppression: CsA or tacrolimus, Aza or MMF, prednisolone

100

60

0

80

40

1 yr

CN

-inhi

bito

r nep

hrot

oxic

ity(%

)

20

5 yrs 10 yrs

76.4

93.596.8

Post-Tx

8

Corticosteroids and calcineurin inhibitors are effective in reducing the incidence of acute rejection, but are a major cause of morbidity and mortality

As a result, a number of clinical trials have examined whether steroids or calcineurin inhibitors can be safely withdrawn after renal transplantation

One of the major questions remaining in clinical transplantation is whether it will be possible to induce states of true tolerance with little or no long-term drug therapy

…ideally one would like to alter the host’s initial contact with the graft to promote a state of donor-specific unresponsiveness

Carpenter, N Engl J Med, 1993

THE TARGET: TRANSPLANTATION TOLERANCE

9

17

All treatment protocols were approved by the Istituto Superiore di Sanità (ISS, Rome, Italy, Authorization n° 45253 (06)-PRE.21-882) and by the Institutional Review Board of the Ospedali Riuniti Bergamo (Delibera n°352 – March 18, 2008)

Written informed consents were obtained from all recipients and living kidney donors

Istituto Superiore di Sanità

17

ATTIVITÀ DI TRAPIANTO DI RENE:BERGAMO 1989-2010

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

1 14 29 30 31 39 37 36 44 42 36 35

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

43 40 37 37 36 43 44 33 41 28 43

31/12/2011 = 799

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Attività di Trapianto a Bergamo

- Da donatore vivente: 29

- Doppio trapianto: 68

- Trapianto combinato- cuore-rene: 5- fegato-rene: 30- rene-pancreas: 7

20

CURVA DI SOPRAVVIVENZA DEL TRAPIANTO DI RENE (END-POINT: DIALISI)

0

50

100

0 10 20Anni

Sop

ravv

iven

za d

elgr

aft(

cens

urat

a pe

r la

mor

te) %

UNOS registry37 %

11

6 12 18 24 30 360

102030405060708090

100

Sop

ravv

iven

za

dell’

orga

no

trapi

anta

to(%

)

p=0.83

0

Trapianto singolo o doppioBiopsia pre-trapianto: SIDonatore > 60 anni

Trapianto singolo Biopsia pre-trapianto: NODonatore < 60 anni

6 12 18 24 30 360

102030405060708090

100

p=0.02

Trapianto singolo o doppioBiopsia pre-trapianto: SIDonatore > 60 anniTrapianto singolo Biopsia pre-trapianto: NODonatore > 60 anni

Sop

ravv

iven

za

dell’

orga

no

trapi

anta

to (

%)

Mesi dal trapianto0

Remuzzi et al., N Engl J Med, 2006