Experiência Brasileira em Dessensibilizacão Pré-Transplante Renal. Maria Cristina Ribeiro de Castro Serviço de Transplante Renal e Laboratório de Imunologia do Incor – FMUSP Hospital Samaritano - SP

Dialysis patients in Brazil Dialysis cost in Brazil: R$ 2 million (without drugs and hospitalizations)

Jan/2009: in dialysis (39,2%) on the WL - 42,8% with Hb 5 - Mortality rate: 17% per year. Brazilian Dialysis Report, SBN ( Sesso - J Bras Nefrol 2010;32(4): )

Months N. Pt N. Deaths Death probability Pt survival Actuarial survival  0 – ,1989 (19,89%) 0,8011 (80,11%) 0,8011 (80,11%)  12 – ,1138 (11,38%) 0,8862 (88,62%) 0,7099 (70,99%)  24 – ,1318 (13,18%) 0,8682 (86,82%) 0,6163 (61,63%)  36 – ,1269 (12,69%) 0,8731 (87,31%) 0,5380 (53,80%)  48 – ,1086 (10,86%) 0,8914 (89,14%) 0,4795 (47,95%)  60 – ,1851 (18,51%) 0,8149 (81,49%) 0,3907 (39,07%)  72 – ,0666 (6,66%) 0,9334 (93,34%) 0,3646 (36,46%)  84 – ,3333 (33,33%) 0,6667 (66,67%) 0,2430 (24,30%) SURVIVAL ON DIALYSIS (RS, non–diabetics)* (MEINEN, CM; MARISCO, NS) SES-SP: 1/1/2005-1/1/2011 (4644 tx performed) Mortality on the WL: 7,22 % per year Median waiting time for a non-sensitized pt: 30 m

In Brazil…(better said in São Paulo)  283 TX (6%): 0 MM (A,B,DR)  25,6% of listed patients with PRA >10%  11,4% of listed patients with PRA >50%  6% of listed patients with PRA > 80% (2051 pts)  2% (741 pt) on priority due to access problems  515 pts. transplanted on priority (13%) SES-SP: 1/1/2005-1/1/2011 (4644 tx performed)

PRA vs Priority vs Transplant access WL (25318 pt)Tx (4277 pt) - 17% PRANo priorityPriorityNo priorityPriority < 10%24867 (74,7%)451 (60,9%)4017 (85,7%)260 (67%),16% 10-49%4544 (13,6%)120 (16%)425 (9,1%)69 (17,7%) 50-79%1803 (5,4%)76 (10,3%)154 (3,3%)35 (8,7%) > 80%2051 (6 %)94 (12,7%)92 (2%)26 (6,6%), 5% SES-SP 1/1/ /1/ % of the WL pts. were transplanted 16% with PRA <10% 5% with PRA > 80% 2 times more priority pts. In PRA > 80%

6y patient survival in non-sensitized patients No impact of sensitization in non-priority patients! 74% (N=384) 80% (N=223) SES-SP 1/1/ /1/2011 %

6y graft survival in non-priority patients 6y GS in O MM (A, B, DR): 72% (NS)

6y patient survival in sensitized patients Strong impact of sensitization in patients on priority! 71% (N=706) 56,5% (N=144) SES-SP 1/1/ /1/2011 % Better transplant priority patients earlier, before they become sensitized!

Patient Survival in sensitized patients (PRA > 50%) - (Thymo induction) P= log-rank Deceased donor Living donor Survival compared to UNOS Living Donor Deceased Donor 1 year 97.6%/98% 81.7%/94% 3 year 95.2%/94% 76.5%/88% 5 year 90.9%/90% 70.7%/82% N=190 (42) (148) Transplants performed between 1996 and FMUSP.

Graft survival censored for death in sensitized patients (PRA > 50%) - FMUSP (Thymo induction) Living donor Deceased donor P= log rank Survival compared to UNOS Living Donor Deceased Donor 1 year 92.7%/95% 83.5%/89% 3 year 76.1%/87% 73.5%/78% 5 year 61.6%/80% 64.2%/67% 5% lower GS for living and deceased donors compared to UNOS N=190 (148) (42)

 To evaluate the risk of staying on dialysis  To evaluate the chances to be transplanted ◦ Donation and transplant rate of the region ◦ Median waiting time ◦ Policy for sensitized patients ( Stimulate the allocation of cross- match negative donor kidneys to these patients).  To evaluate the acceptable immunologic risk (easier w/LD)  To evaluate the transplant possibilities with living and with deceased donors ◦ Resources for desensitization ◦ Resources for support a high-risk patient after Tx ◦ Characteristics of the patient (age, life expectation, clinical condition)

Transplant program/Pt ProtocolPt survival Graft survival AR (%) Mean SCr (mg/dl) Mayo clinic/90 HD IVIG PP/LD IVIG 95% (at 5 yr) 80% (at 5 yr)35 1.6±0.6 (at 5 yr) John Hopkins/90 PP/CMVIG 95% (at 3 yr) 80.9% (at 3 yr) ±0.3 (at 3 yr) CSMC/96 GLOTZ/02 (DD) HD IVIG IVIG 97% (at 5 yr) 85% (at 5 yr) 87% (at 5 yr) 70% (at 5 yr) ±0.4 (at 5 yr) Not related

Montgomery R, NEJM 2011 Jul 28;365(4): Patient Survival (%)

N=457 isolated kidney transplants ( )  Global incidence (85/457): 18,6% - Cell-mediated rejection (55/457): 12% - Antibody-mediated rejection (30/457): 6,6% Rejection at FMUSP

Renal function at 1 year  Without vs with rejection  Cell-mediated rej. Vs Ab-mediated rej. N=42 CMR n=28 (66%) AMR n= 14 (34%) p Last Scr1,57 (0,9-4,8)1,67 (1-5,7)0,70 MDRD (ml/min)48,3 (13-75)40,7 (11,5-81,5)0,82 Last Scr1,3 (0,7-6,4)1,57 (0,9-5,7)<0,001 MDRD (ml/min)57,3 (7,5-104)45 (11,5-81,50<0,0001 N=290Without rejection n=248 (85%) With rejection n=42 (15%) p

 Transplant without knowing the immunological risk  No transplant in sensitized patients  No transplant in patients with DSAs  No transplant in pts.with DSAs and high MFIs  No transplant in positive FCXM  Transplant knowing and accepting the immunological risk (post transplant monitoring)

Before the tx:  Stratify AMR risk  Evaluate treatment risk/advantages After the tx:  Active monitoring and observation  Early AMR diagnosis and treatment Best approach in sensitized patients

 Living donors: ◦ Transplant with DSAs but with a negative T and B FCXM ◦ IS: Thymoglobulin, Tacrolimus and MMF (We would use IVIG!)  Deceased donors: ◦ Transplant sensitized patients with any level of DSAs, with a negative T and CDC-XM ◦ IS: Thymoglobulin, MMF and Tacrolimus (We would use IVIg!) ◦ Perform a Single atg PRA and a renal biopsy during the first week ◦ All patients:  We follow renal function, proteinuria, single atg PRA and FCXM (in LD) during the first months  We perform kidney biopsy with C4d staining when clinically indicated  We treat AMR with PP and Rituximab

 Include patients that have PRA higher than 70%, with more than 2 years on dialysis  Look for a living donor: ◦ Low titers: IVIg (maximum of 6 doses) ◦ High titers: IVIG + Rituximab or IVIG + PF  No living donors: ◦ Transplant priority for vascular access problems: IVIG and if no transplant in 3-6m, IVIG + Rituximab ◦ No transplant priority: any sense to treat without priority? Depends on the number of tested donors.

268 pts. evaluated 60 pts (22%) transplanted 36 (60%) without desensitization 24 (40%) with desensitization 208 (78%) stayed waiting for Tx 50 (24%) deaths on the WL 150 (72%) waiting (30 in desensitization protocols)

24 Tx after desensitization 13 (54%) pts. w/LD (1 AMR – 7%) 2 (15%) graft losses (1 due to pt death) 11(84%) with functioning grafts 11 (46%) pts. w/ DD (4 AMR – 36%) 2 (18%) graft losses (1 due to pt death) 9 (82%) with functioning grafts Hospital Samaritano: 9 pt desensitized (4DD, 5 LD), 2y FUT, 0 graft/pt losses.

 Twenty-four patients transplanted with a previous positive IgG AHG- CDC T or B- cell CM or w/ FCXM higher than 300 channels (6 cases) against their potential donors.  All patients with PRA > than 70% ◦ average 74 months on the waiting list, ◦ 18 with transplant priority due to absence of HD vascular access.  All pts. have been treated with 3-9 monthly courses of 2 g/Kg of IVIg  Resistant cases: Rituximab and or PF addition Desensitization protocol at São Paulo University

 Increasing numbers of sensitized and prioritized patients on the WL  Absence of policies to prevent sensitization (transfusions) and problems with vascular access to dialysis  Absence of programs to evaluate the patient “transplantability”  Absence of a national program for increase transplantability of sensitized patients  No reimbursement for various immunological studies and desensitization strategies  No reimbursement for techniques that could help in the prevention, diagnose and correct treatment of AMR.

The worst policy is to have no policy at all! M. Cristina R. de Castro Thanks!