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      Efeito da terapia de indução em pacientes sensibilizados: análise dos riscos e benefícios Translated title: Effect of induction therapy in kidney transplantation in sensitive patients: analysis of risks and benefits

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          Abstract

          Resumo Introdução: A sensibilização está associada a piores desfechos clínicos após o transplante renal (TxR), incluindo maior incidência de função tardia, rejeição aguda e perda do enxerto. Objetivos: Avaliar os desfechos de eficácia e segurança de 1 ano de receptores de TxR com doador falecido sensibilizados induzidos com globulina antitimócito (ATG) e compará-las aos de pacientes não sensibilizados. Métodos: Receptores de TxR com doador falecido entre janeiro de 1998 e dezembro de 2009 foram divididos em 5 grupos: grupo controle 1 - n = 89, PRA negativo, sem indução; grupo controle 2 - n = 94, PRA negativo, indução com basiliximabe; grupo controle 3 - n = 81, PRA negativo, indução com ATG; grupo teste 4 - n = 64, PRA 1-49%, indução com ATG; grupo teste 5 - n = 118, PRA ≥ 50%, indução com ATG. Resultados: Não houve diferença na incidência de rejeição entre pacientes sensibilizados e não sensibilizados, exceto pelo grupo 1, que apresentou a maior incidência de rejeição aguda comprovada por biópsia (20,2%, p = 0,006 vs. grupo 4 e p = 0,001 vs. grupo 5). Os pacientes sensibilizados induzidos com ATG apresentaram maior incidência de infecção por citomegalovírus quando comparados aos pacientes do grupo 2 (26,6% e 14,4% vs. 2,1%). Não houve diferença nas sobrevidas do enxerto e do paciente. Na análise multivariada, PRA > 50% e uso de ATG não foram associados à perda, perda com óbito censorado ou óbito. Conclusão: Os pacientes sensibilizados induzidos com ATG apresentaram incidência de rejeição semelhante ou inferior à de pacientes não sensibilizados não induzidos. Estes pacientes apresentaram sobrevidas do enxerto e do paciente semelhantes em 1 ano e comparável perfil de segurança.

          Translated abstract

          Abstract Introduction: Sensitization is associated with worse clinical outcomes after kidney transplantation (KT), including increased incidence of delayed graft function, acute rejection (AR) and graft loss. Objectives: To evaluate 1-year efficacy and safety outcomes in sensitized KT recipients receiving antithymocyte globulin (ATG) induction and compare them to non-sensitized patients. Methods: Deceased donors KT recipients transplanted between January 1998 and December 2009 were divided into 5 groups: control group 1 -n = 89, PRA negative, without induction therapy; control group 2 - n = 94, PRA negative, basiliximab induction; control group 3 - n = 81, PRA negative, ATG induction; test group 4 - n = 64, PRA 1-49%, ATG induction; test group 5 -n = 118, PRA ≥ 50%, ATG induction. Results: There was no difference in the incidence of AR among patients sensitized and non-sensitized, except for group 1, with highest incidence of AR (20.2%, p = 0.006 vs. Group 4 and p = 0.001 vs. group 5). Sensitized patients induced with ATG had higher incidence of citomegalovirus infection when compared with group 2 (26.6% and 14.4% vs. 2.1%). There were no differences in graft and patient survivals. In multivariable analysis, PRA > 50% and ATG induction were not associated with graft loss, death or death-censored graft loss. Conclusion: Sensitized patients induced with ATG presented similar or lower incidence of AR when compared with non-sensitized patients not induced. Besides, these patients had similar safety profile and graft and patient survivals at 1 year.

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          Most cited references34

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          The Banff 97 working classification of renal allograft pathology.

          Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.
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            Rabbit antithymocyte globulin versus basiliximab in renal transplantation.

            Induction therapy reduces the frequency of acute rejection and delayed graft function after transplantation. A rabbit antithymocyte polyclonal antibody or basiliximab, an interleukin-2 receptor monoclonal antibody, is most commonly used for induction. In this prospective, randomized, international study, we compared short courses of antithymocyte globulin and basiliximab in patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor. Patients taking cyclosporine, mycophenolate mofetil, and prednisone were randomly assigned to receive either rabbit antithymocyte globulin (1.5 mg per kilogram of body weight daily, 141 patients) during transplantation (day 0) and on days 1 through 4 or basiliximab (20 mg, 137 patients) on days 0 and 4. The primary end point was a composite of acute rejection, delayed graft function, graft loss, and death. At 12 months, the incidence of the composite end point was similar in the two groups (P=0.34). The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P=0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P=0.005). The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss (9.2% and 10.2%, respectively), delayed graft function (40.4% and 44.5%), and death (4.3% and 4.4%). Though the incidences of all adverse events, serious adverse events, and cancers were also similar between the two groups, patients receiving antithymocyte globulin had a greater incidence of infection (85.8% vs. 75.2%, P=0.03) but a lower incidence of cytomegalovirus disease (7.8% vs. 17.5%, P=0.02). Among patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graft function. Patient and graft survival were similar in the two groups. (ClinicalTrials.gov number, NCT00235300 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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              Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies.

              The presence of panel-reactive antibodies (PRA) against HLA antigens before transplantation is associated with early rejection of kidney grafts from cadaver donors. Transplants from HLA-identical sibling donors do not provide a target for antibodies to HLA antigens and should therefore not be affected by PRA. Data from the Collaborative Transplant Study were used to examine the influence of PRA on graft survival. Uncensored graft survival and death-censored graft survival were calculated, and the data were analysed by multivariate Cox's regression methods. Among recipients of HLA-identical sibling transplants, 3001 patients with no PRA had significantly higher 10-year graft survival (72.4% [SE 1.1]) than 803 patients with 1-50% PRA (63.3% [2.5]; p=0.0006) or 244 patients with more than 50% PRA (55.5% [4.0]; p<0.0001). The effect of PRA became apparent after the first post-transplant year and was, therefore, strikingly different from the early steep decline in graft survival during the first year associated with PRA in recipients of cadaver kidneys. We could not discern whether graft loss was a direct effect of non-HLA humoral sensitisation or whether PRA served as an indicator of heightened immunity against non-HLA transplantation antigens. PRA reactivity is strongly associated with long-term graft loss in kidney transplants from HLA-identical sibling donors. Our findings suggest that non-HLA immunity has a much stronger role in clinical transplantation than previously thought. In contrast to immunity against HLA mediated by antibodies present before transplantation, which leads to early acute graft rejection, non-HLA immunity is associated with chronic graft loss. The possibility of identifying recipients at increased risk of late graft loss before transplantation could be used to devise specific immunosuppressive strategies for these patients.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                jbn
                Jornal Brasileiro de Nefrologia
                J. Bras. Nefrol.
                Sociedade Brasileira de Nefrologia
                2175-8239
                March 2016
                : 38
                : 1
                : 82-89
                Affiliations
                [1 ] Hospital do Rim Brazil
                Article
                S0101-28002016000100082
                10.5935/0101-2800.20160013
                a38d078c-7619-40e6-bf63-75e9849fe6d3

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0101-2800&lng=en
                Categories
                UROLOGY & NEPHROLOGY

                Urology
                rejeição de enxerto,quimioterapia de indução,sobrevivência,transplante de rim.,graft rejection,immunosuppression,kidney transplantation,survival

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