Le migliori strategie immunosoppressive per il paziente con re-trapianto Prof. Maurizio Salvadori FIRENZE

Best Therapy for Kidney Re- Transplantation? PREVENTION!!!!

Registries CTS OPTN UNOS USRDS SRTR Canadian Registry Guidelines UK Guidelines Kdigo Canadian Guidelines Reviews Original papers DATA SOURCES

Main biases in affording the issue of best therapy in kidney retransplantation Few if any RCT Cohort studies are affected by several bias: Most are retrospective First transplant may be lost for different causes Re-transplants occur in different era with respect to first transplant Re-transplant patients may be affected by more comorbidities with respect to first transplant

Rao PS, 2006

HR=1.66 HR=0.64 HR=0.42 Rao PS, 2006

First transplant Re-transplant Sellers MT, 2004

Maintenance immunosuppression Most retransplant patients are given CNI ( TAC) + MPA TAC + MPA is given in the vast majority of sensitised patients Graft survival rate looks similar

Induction therapy Non depletional antibodies are preferred to depletional treatment Survival rate looks similar with respect to no induction Only in sensitised patients (> 30%) induction therapy offers better outcomes

Univariate analysis of risk factors for graft survival in retransplant patients Variables p Variables p Recipient age 0.285 Donor age 0.151 Recipient sex 0.924 Donor sex 0.476 Donor reletionship <0.001 Blood group 0.272 Primary renal disease 0.841 HLA-A,B mismatches 0.325 HLA-DR mismatches 0.201 Time to first graft loss <0.001 Primary graft nephrectomy 0.054 Ischaemia time 0.188 Time to diuresis 0.511 Primary immunosuppression <0.001 Total steroid dose (at 3 months) 0.034 Number acute rejections 0.439 Post-transplant hypertension 0.570 Chronic allograft nephropathy 0.090 Mean serum creatinine at 1 year 0.024 Time to retransplantation 0.062 El-Agroudy A, 2004

Multivariate analysis of risk factors for graft survival in retransplant patients Variable p Consanguinity 0.006 Primary immunosuppression 0.001 Time to first graft loss 0.004 Mean serum creatinine at 1 year <0.001 El-Agroudy A, 2004

Characteristics of re-transplants and first transplant patients Re-Transplant First Transplant El-Agroudy A, 2004

Abouljoud MS, 1995

Almond PS, 1991

Arnol M, 2008

Risk factors for re-transplant survival 1 transplant survival < 1 year Time to re-transplant > 1 year Marginal donors PRA Primary Immunosuppression Induction therapy Nephrectomy

Messages from guidelines

Screening for potential living donor kidney transplant recipients for clinically relevant antibodies is important for ensuring optimal donor selection and graft survival UK Guidelines for kidney living donation, 2005

The technique used for the cross-match test should be sensitive and clinically relevant. Cross-match tests should be capable of distinguishing T lymphocyte and B lymphocyte populations and should discriminate between IgG and IgM antibodies. The use of a flow cytometric technique is recommended, particularly for sensitised patients and re-transplantation, as the conventional cytotoxic cross-match is not sufficiently sensitive UK Guidelines for kidney living donation, 2005

Patients with a previous transplant Assess patients with a previous graft loss carefully for: Malignancy Cardiovascular disease Increased immunological risk European Association of Urology, 2010

Reccomendation Pre-transplant work-up for patients with retransplantation or previous non-renal transplantation should focus on the immunological risk, including a thorough analysis for the presence of anti-hla antibodies European Association of Urology, 2010

64: 1 graft; 163: >1 graft 64: 1 graft; 163: >1 graft Noel C. 2009

Noel C. 2009

Re-transplants: 85% Gurk-Turner C, 2008

Gurk-Turner C, 2008

Ott U, 2008

Barocci S, 2009

Soran A, 2000

Opelz G, 1976

Human leukocyte antigen matching has been de-emphasized in the allocation of renal allografts and further discounting is planned in the United Network of Organ Sharing kidney allocation model. An unforeseen consequence of poorer matching could be increased sensitization for candidates pursuing retransplantation Transplantation, 2009

Meier-Kriesche HU, 2009

Dawson KL, 2011

Scornik JC, 2011

House AA, 2007

Donor-directed antibodies detected by solid phase assays (even those that are weak ) present an unacceptable risk factor to the patient

TOSCANA I pazienti al 2 Trapianto o successivi potranno utilizzare donatori con mismatch comuni a condizione che i loro sieri, anche storici, non abbiano mai presentato positività della PRA. In questi casi il Centro Trapianti interessato, opportunamente informato dal Laboratorio di Istocompatibilità, potrà decidere se procedere o meno al trapianto. CNT documento finale allocazione reni 19 agosto 2011

DDA after early transplantectomy appeared frequently but later than expected. In view of the growing number of marginal donors and the possible necessity of retransplantation, it is considered important to prolong the time of serum sampling and screening to at least 4 months. Immunization might escape attention when serum screening is restarted only from the time the patient is again referred to the waiting list.

Lenaers J, 2006

Lorenz M, 2004

Lefaucheur JASN 2010

Willicombe AJT, 2011

New Therapies Eculizumab Proteosome Inhibitors

Jordan SC, 2006

Mai, Transplantation, 2009

Mai ML, 227

54% Retransplants

54% Retransplants Vo AA, 2010

Vo AA, 2010

27/34 retransplants Morath C, 2010

Morath C, 2010

First Tx Retransplant Induction* 10 (37%) 20 (74.1%) IL-2R 3 (11.1%) 13 (48.1%) Thymo 0 (0%) 5 (18.5%) OKT3 2 (7.4%) 0 (0%) ATG 5 (18.5%) 0 (0%) Multi 0 (0%) 2 (7.4%) Maintenance CsA 22 (81.5%) 9 (33%) TAC 2 (7.4%) 17 (63%) Other 3 (11.1%) 1 (3.7%) No patient initially induced with a T-cell-depleting antibody underwent induction with a T-cell-depleting antibody at retransplant Johnson SR 2006

Ramos E, Transplantation 2004

After a mean follow-up of 34.6 months all patients Were found to have good graft function with a mean creatinine of 1.5 mg/dl. It can be concluded that patients with graft loss caused by BKAN can safely undergo retransplantation Ramos E, Transplantation 2004

Canadian guidelines, 2005

Predictors of after re-transplant BK virus replication Factors Viremia clearance n (%) Transplant nephrectomy n (%) BKV replication (n=11) No BKV replication (n=20) 6 (55) 20 (100) <0.003 3 (27) 10 (50) 0.3 Pre-emptive n (%) 5 (45) 5 (25) 0.4 Induction use n (%) 9 (81) 17 (85) 0.9 Maintenance immunosuppression (triple) 5 (45) 12 (60) 0.5 p

126 Re-Tx (2004-2008)

Back up slides

Meier-Kriesche HU, 2009

Scemla A, 2010

Canadian guidelines, 2005

El-Agroudy A, 2004

Meier-Kriesche HU, 2009

Dawson KL, 2011

House AA, 2007

70 Colonna1 60 50 40 30 20 10 0 CsA Only CsA + AZA CsA + AZA + STE CsA + STE AZA + STE CsA Only CsA + AZA CsA + AZA + STE CsA + STE AZA + STE

Lefaucheur JASN 2010

Anglicheau D, Am J Transpl, 2007

27/34 retransplants Morath C, 2010

Morath C, 2010