Il trapianto prima della dialisi

G.P. SegoloniCattedra di Nefrologia dell’Università di Torino

U.O.A.D.U. Nefrologia Dialisi e Trapianto (Dir. Prof G.Piccoli) Azienda Ospedaliera S.Giovanni diTorino

XV Corso di Aggiornamento in Nefrologia MedicaMilano 17 Novembre 2001

In fase di uremia terminale le scelte

possibili per garantire la sopravvivenza del

paziente dovrebberoessere 3

Emodialisi

Dialisi peritoneale

Trapiantorenale

Trapianto renale preventivo

Autore Tx pre referenza

D:Fryd 1968-84 1742 8% Transplant Proc XIX,1,1557-58; 1987

A.Foss 1984-96 Oslo (N) 141 39% Transplantation ,6,649-52 1998

Donnelly 1982-92 (CTS) 11.913 10% Transpl Proc 28,6,3566-70 1996

A.Asderakis 1980- 95 Manchester (UK)

1463 11% Nephrol Dial Transplant 13,1799-1803

Papalois VE 1984-98 Minnepolis (USA)

1849 21% Transplantation (4),625-31, 2000

NI0%

AHD1%

HF1%

HDF5%

CAPD12%

APD3%

IPD1%

TX1,1%

BHD76%

First RRT modality in ESRD incident patients - 1999

R SI ID NT

Questa discordanza solleva 2 domande fondamentali

• Quali sono le ragioni della trascurabile percentuale di questa scelta nel nostro Paese?

• Questo atteggiamento di rifiuto-diffidenza è giustificato oggi ?

Il trapianto renale preventivo

fattori contrari all’utilizzazione del trapianto prima della dialisi ( trapianto preventivo)

Risultati delle prime esperienze

Risultati attuali

Considerazioni finali

Andamento del trapianto da donatore vivente in Italia nel periodo 1993-2000

132119

107118 119

79 8288

0

20

40

60

80

100

120

140

1993 1994 1995 1996 1997 1998 1999 2000

Tx vivente

•Suppression of immunoresponsivness in uremia Wilson WEC, Kirkpatrick CH, Talmage DW Ann Intern Med 62,1-4, 1965

•Uremia as a state of immunodeficiency Birkelond SA Scand J Immunol ;5;107-122: 1976

• Is uremia immunosuppressive in renal transplantation? Hairy p, von Willebrand, Hochersted K et al tranaplantation ;34,268-72;

•Combined report on RDT in Europe 1981 Kramer P, Broyer M, Brunner EP. Proc Eur Dial Tranplant Ass 1982, 19, 4,

……..indeed several Authors have suggested that chronic pretransplant dialysis may be required to attain successful engraftment.

Il trapianto renale preventivo

fattori contrari all’utilizzazione del trapianto prima della dialisi ( trapianto preventivo)

Risultati delle prime esperienze

Risultati attuali

Considerazioni finali

Can renal transplantation be done safely without prior dialysis therapy ?

D Fryd , RJ Migliori Nl Ascher et al Transpl Proc vol XIX,1, 1557-58,1987

Analizza 1742 trapianti consecutivi eseguiti a Minneapolis nel periodo

1968 1884

Can renal transplantation be done safely without prior

dialysis therapy ? D Fryd , RJ Migliori Nl Ascher et al Transpl Proc vol

XIX,1, 1557-58,1987

Donor dialysis 1 year 3 years 1 year 3 years

All Yes (1404) 76 67 89 78

No (132) 80 64 88 70

CAD Yes (624) 71 58 80 71

No (36) 66 37 83 42

CAD post 1979

Yes (236) 77 67 86 84

No (22) 77 46 86 58

CAD Diab Yes (103) 84 63 87 75

No (19) 76 53 95 67

Survival (%) Graft Recipient

Il trapianto renale preventivo

fattori contrari all’utilizzazione del trapianto prima della dialisi ( trapianto preventivo)

Risultati delle prime esperienze

Risultati attuali

Considerazioni finali

Pre-emptive transplantation:- analysis of benefits and

hazards in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

• 85 trapianti preventivi (1981-88) paragonati con casi controllo “matched” per demografica, clinica e terapia

• Analizzati per sopravvivenza paziente e rene, incidenza del rigetto acuto, stato nutrizionale e riabilitazione

Pre-emptive transplantation:- analysis of benefits and

hazards in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

Pre.dialisi postdialisi

Diabete 32/85 15/84 <0.01

LD/HLA id 15 7 ns

LD/aplo 32 32 ns

CAD/MM 4,2 4 ns

Trasfusi (%) 33 65 < 0.001

Pre-emptive transplantation:- analysis of benefits and

hazards in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

anno 1 3 3 4 5

Ricevente 83 81 76 73 73 ns

90 81 80 77 76

Rene (LD) 77 77 75 71 67 ns

92 82 82 82 79

Rene (CAD) 82 76 68 66 66 ns

88 79 77 72 72

Sopravvivenza % Pre-dialisi Post-dialisi

Pre-emptive transplantation:- analysis of benefits and hazards

in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

Pre –dialisi Post-dialisi

Hyperacute 0 0 NS

Accelerated 2 2 NS

Acute 28 26 NS

irreversible 12 (43%) 7 (26%) NS

Chronic 11 10 NS

NonCompliance 7 0 <0.001

Pre-emptive transplantation:- analysis of benefits and

hazards in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

• Incidenza di perdita rene per

noncompliance 9% ( 7/85)

3/3 (100%) perdita ritrapianto per non compliance

Pre-emptive transplantation:- analysis of benefits and

hazards in 85 cases S. Katz et al Transplantation 2, 52,351-55 1991

Factors Pre-emptive(69) Control (68) pNormal social act. 49 38 nsFull time vocational 36 22 <0.05Part-time vocational 15 13 nsDisabled 9 21 <0.05Normal social act. 44 42 nsFull time vocational 38 20 <0.01Part-time vocational 6 9 nsDelayed rehabilit. 1 7 <0.05Disabled 10 18 <0.05

PRE

POST

…..and the job was lost in the “dialysis trap”

Thiel G. - LIVING KIDNEY DONOR TRANSPLANTATION- NEW DIMENSIONS-Transpl Int (1998) 11 (suppl 1): 50-56

Renal replacement therapy: the old way

Thiel G. - LIVING KIDNEY DONOR TRANSPLANTATION- NEW DIMENSIONS-Transpl Int (1998) 11 (suppl 1): 50-56

invalidityinvalidity pension pension (partial/total)(partial/total)

loss of job loss of job (partial/ total)(partial/ total)

Thiel G. - LIVING KIDNEY DONOR TRANSPLANTATION- NEW DIMENSIONS-Transpl Int (1998) 11 (suppl 1): 50-56

maintained job / life qualityRenal replacement

therapy: the new way of pre-emp- tive

transplantation, planned ahead for 2 years before end- stage renal failure

..no much longer than a summer holiday time

Pre-emptive transplantation for patients with renal

failure. An argument against waiting until dialysis

V.E.Papalois et al Transplantation 70,625-631, 2000

1984 –98

1849 Tx

385 pre-empt.

1984-89 9% CAD

27 % LD

1990-98 9,3% CAD

30 % LD

1464 Non pre-empt.

Minneapolis

Pre-emptive transplantation for patients with renal failure An argument against waiting until dialysis

V.E.Papalois et al Transplantation 70,625-631, 2000

Survival % 5 th year ND D p

CAD- recipient 93 77 0.001

LD- recipient 93 89,5 0.02

CAD graft 83 79 nsRA 35 39 ns

CR 19 22 ns

LD graft 92 85 0.006RA 30 32 ns

CR 30 32 ns

% noncompliance 0,97 2,1

Pre-emptive transplantation for patients with renal failure An argument against waiting until dialysis

V.E.Papalois et al Transplantation 70,625-631, 2000

Cause of death ND(%) D(%) p

Sepsis 0 5 0.05

Cardiac 0 8,3 0.03

Pulmonary 0 2 ns

Cerebrovasc. 1,4 2,7 s

Malignancy 3 3,4 ns

Sudden death 4 4,6 ns

…This finding can be attributed partly to better general health pretransplantation, the fact that the renal failure was not advanced and the beneficial effect of pre-emptive transplant

Living donor kidney transplantation in predialysis patients: experience of marginal donors in Europe and the

United StatesP.Donnelly, P. Oman, R Henderson and G. Opelz

Transpl Proc vol 28,6,3566-3570, 1996

Analizza 11.913 trapianti da donatore vivente

1214 eseguiti in fase predialisi

9.275 trattati con emodialisi

1424 trattati con CAPD

Donnelly P et al Transplant proc 28,6;3566-70 1996

P< 0.01

Pre-emptive

Donnelly P et al Transplant proc 28,6;3566-70 1996

Grat survival for off-spring donor kidneys transplanted to parents with or without prior dialysis

Materials and methods: 1463 consecutive first kidneytransplants performed in a single centre were analysed.The 161 patients (11%) transplanted without prior dialysiswere compared with the 1302 patients who had been dialysedprior to being transplanted. The pre-emptive group did notdiffer from the dialysis group in respect of donor age, donorand recipient gender, HLA mismatch, or cold ischaemic time,although there were more live donor transplants within the pre-emptive group.

Pre-emptive kidney transplantation: the attractive alternativeA Asderakis, and R JohnsonRenal Transplant Unit, - Manchester UK;

Nephrol Dial Transplant (1998) 13.1799-1803

Pre-emptive kidney transplantation: the attractive alternativeA Asderakis, and R Johnson

67% a 10 aa.

56% a 10 aa.

P = 0.05

Nephrol Dial Transplant (1998) 13.1799-1803

Pre-emptive kidney transplantation: the attractive alternativeA Asderakis, and R Johnson

63%

54,5%

Nephrol Dial Transplant (1998) 13.1799-1803

Pre-emptive kidney transplantation: the attractive alternativeA Asderakis, and R Johnson

Nephrol Dial Transplant (1998) 13.1799-1803

Rischio % assoluto di rigetto::

Pre-emptive kidney transplantation: the attractive alternativeA Asderakis, and R Johnson

Nephrol Dial Transplant (1998) 13.1799-1803

Effect of the use or non use of long term dialysis on the subsequent survival of renal transplantas from living donor

Mange, Kevin C: Joffe, Marshall M.; Feldman, Harold I NEJM 344(10) 8 march 2001 726-731

• Sorgente: U.S renal data System 8481 trapianti da donatore vivente

• 6662 dopo inizio dialisi• 1819 pre-emptive

• Analisi (unadjusted) ad 1 anno, da 1 a 2 anni, da 2 anni a fine dello studio

• Analisi multivariata ( adjusted) per i tre periodi senza tener conto del rigetto acuto e per il 1°anno tenendo conto (adjusted) del rigetto acuto

Effect of the use or non use of long term dialysis on the subsequent survival of renal transplants from living donor

Mange, Kevin C: Joffe, Marshall M.; Feldman, Harold I NEJM 344(10) 8 march 2001 726-731

Reduction in the rate of allograft failure for pre-emptive transplantation

1st year 2nd year >3rd year

unadjusted 34% (0.01) 44% ( 0.07) 62 % (0.002)

adjusted 52 % ( 0.002) 82% (0 .001) 86%( 0.001)

After adjustement for 1st AR in the 1st year

0.1

Effect of the use or non use of long term dialysis on the subsequent survival of renal transplants from living donor

Mange, Kevin C: Joffe, Marshall M.; Feldman, Harold I NEJM 344(10) 8 march 2001 726-731

Results of logistic regression analysis of predictors of biopsy confirmed acute rejection within six months after pre-emptive or

non pre-emptive transplantation

Duration of dialysis before Tx

vs pre-emptive transplantation

Adjusted odd ratio

p 0.001

1st quartile ( 1-174 days) 1,6 (1,2 – 2.2)

2nd quartile (175-329 days) 2,3 ( 1,7- 3.0)

3rd quartile ( 330 – 623 days) 3.0 ( (2,3-3,9)

4th quartile (> 623 days) 4.2(3.3- 5.3

Considerazioni generali

Pre-emptive kidney transplantationVanrenterghem Y. & Verberckmoes R.

Nephrol Dial Transplant (1998) 13: 2466- 2468

….at present concerns about pre-emptive transplantation are therefore much more

ethical than purely medical…..

1)At which point to consider pre-emptive transplantation?

The unpredictability of the organ supply and the difficulty in predicting for an individual patient the progress to renal

failure, may result in the transplantation of patients many months before renal replacement therapy is indeed really

needed.

Too early transplantation will of course increase the overall costs of renal replacement therapy as the same organ could be used in

the meantime to transplant a patient who is already on an expensive form of renal replacement therapy.

Pre-emptive kidney transplantation Vanrenterghem Y. & Verberckmoes R.

Nephrol Dial Transplant (1998) 13: 2466- 2468

Considering pre-emptive transplantation is therefore only acceptable if the evolution of the underlying renal disease is well documented and a prognosis of the progression of the renal disease can be made with a high degree of accuracy…..

….As most of the patients with a creatinine clearance < will become dialysis dependent within 1 year, it seems reasonable to put patients on the waiting list only when creatinine clearance has reached < 15 ml/min. This policy however is also only possible if the overall mean waiting time for finding a suitable kidney is no longer than 1 year. ..

< 15 ml/min

Pre-emptive kidney transplantation Vanrenterghem Y. & Verberckmoes R.

Nephrol Dial Transplant (1998) 13: 2466- 2468

Pre-emptive kidney transplantationVanrenterghem Y. & Verberckmoes R.

Nephrol Dial Transplant (1998) 13: 2466- 2468

Conclusions

• In conclusion, pre-emptive transplantation is for medical as well as for socio-economical reasons the preferred mode of renal

replacement therapy.

•In the context of the present organ shortage and the long waiting time for those patients already on dialysis, pre- emptive

transplantation from CAD cannot be realised.

•However in countries with a high donation rate, where the number of available cadaveric donor kidneys equals the yearly demand, pre-

emptive transplantation is justifiable when either medical or socioeconomical compelling reasons are present.

In case of living donor , pre-emptive transplantation may be

the treatment of choice

Conclusions

Pre-emptive kidney transplantationVanrenterghem Y. & Verberckmoes R.

Nephrol Dial Transplant (1998) 13: 2466- 2468

Per quanto riguarda la nostra realtà…..

Il trapianto renale da cadavere prima dell’inizio del trattamento dialitico rappresenta una soluzione limitata a candidati con situazioni cliniche particolari

• diabetici uremici di tipo I nel programma combinato di pancreas e rene

• pazienti con ossaluria primitiva in programma per trapianto combinato di fegato-rene

A.Humar et al Annals of Surgery vol 231,n°2, 269-275 , 2000

Fattori di rischio per trombosi e infezioni

Trombosi:Fattori di rischio Età don ( aa) < 20 1,8% 20/40 3,7% > 40 16 %

Anticoag. Si/No. 4% 11 % .06

Dialisi No/Si 11,4% 3% 0.1

Nel caso si programmi un trapianto renale da donatore

vivente • Non esistono limitazioni di nessun tipo al trapianto

“preventivo”• Nelle Linee Guida per il trapianto da donatore

vivente (Centro Nazionale Trapianti 10 gennaio 2001) è stato rimossa (per intervento del nefrologo) la primitiva indicazione di condizionare il trapianto da vivente ad una precedente iscrizione in lista di attesa da cadavere, proprio per permettere questo tipo di soluzione

Anno Accademico 2000-2001

XXVI corso di Aggiornamento in Nefrologia Dialisi e Trapianto – riunione del 01

• Su 22 nefrologi in rappresentanza dei 22 centri piemontesi – 19 erano perplessi-contrari al trapianto renale

preventivo– 3 favorevoli

• Centro Pediatrico

• Centro proponente

• Centro dialisi adulti

Attività di trapianto preventivo in centri con diversa esperienza nel trapianto da donatore vivente

periodo N° Tx Funzionanti

Policlinico –Croff ( Prof Ponticelli)

09/08/198709/10/01 17 15

Torino- Centro A.Vercellone

24/07/00 04/03/01 4 4

Centro Trapianti Renali “A.Vercellone”U.O.A.D.U. Nefrologia Dialisi Trapianto

Az. Osped S. Giovanni di Torino

Tipologia Numero %

Trapianti renali 1386

Da cadavere 1357 98 %

Da vivente 31 2

Da vivente (1999) 15 48 %

Sviluppo del programma trapianto da donatore

vivente presso il Centro “A. Vercellone”di Torino

0

5

10

15

20

25

1981-90 91-98 99-00 2001

Tx-LDin attesa

Dalla discussione del XXIV Simposio Nefrologico Veneziano

22 marzo 1997 Trapianto di rene da donatore vivente: stato dell’arte e

degli aspetti etici della donazione

• (Ponticelli) :…visto che ho la parola , ma solo per 30 secondi …. io credo che noi nefrologi siamo i maggiori responsabili dell’assoluta mancanza di sviluppo del trapianto da vivente in Italia . La grande maggioranza dei nostri pazienti o non viene informata o viene scoraggiata fin dall’inizio per avere un trapianto da vivente ……

In conclusione• Il trapianto renale preventivo merita oggi una

riconsiderazione da parte di tutti i nefrologi in quando i dati disponibili ne documentano esaurientemente la superiorità in termini di sopravvivenza ( paziente e rene) riabilitazione migliore.

• Ogni paziente orientato verso il trapianto da vivente deve essere messo al corrente della possibilità di essere trapiantato preventivamente