Law Wai Keung. / Thesis (M.Sc.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 98-108). / Abstracts in English and Chinese. / Abstract --- p.v / 摘要 --- p.viii / Acknowledgement --- p.x / List of Abbreviations --- p.i / Index of tables --- p.xiv / Index of figures --- p.xv / Chapter 1. --- Introduction --- p.1 / Chapter 2. --- Literature review --- p.3 / Chapter 2.1 --- Immunosuppression in Organ Transplantation --- p.3 / Chapter 2.2 --- Mechanism of Graft Rejection --- p.4 / Chapter 2.3 --- Conventional immunosuppressive drugs --- p.4 / Chapter 2.3.1 --- Corticosteriod --- p.6 / Chapter 2.3.2 --- Azathioprine --- p.6 / Chapter 2.3.3 --- Polyclonal antilymphocyte globulin and OKT3 --- p.7 / Chapter 2.4 --- Cyclosporine A (CsA) --- p.8 / Chapter 2.4.1 --- Mechanisms of CsA --- p.8 / Chapter 2.4.2 --- Pharmacokinetics of CsA --- p.10 / Chapter 2.4.2.1 --- Absorption --- p.10 / Chapter 2.4.2.2 --- Distribution --- p.11 / Chapter 2.4.2.3 --- Metabolism and elimination --- p.11 / Chapter 2.4.2.4 --- Toxicity --- p.12 / Chapter 2.4.3 --- Therapeutic drug monitoring of CsA --- p.13 / Chapter 2.4.3.1 --- CsA trough monitoring --- p.13 / Chapter 2.4.3.2 --- Full AUC monitoring --- p.15 / Chapter 2.4.3.3 --- Limited sampling strategy --- p.16 / Chapter 2.4.3.4 --- Two-hour post dose CsA level monitoring --- p.20 / Chapter 2.4.4 --- Conventional techniques of measuring cyclosporine concentration --- p.23 / Chapter 2.4.4.1 --- High performance liquid chromatography --- p.23 / Chapter 2.4.4.2 --- Non-specific immunoassays --- p.25 / Chapter 2.4.4.3 --- Specific radioimmunoassays --- p.26 / Chapter 2.4.4.4 --- Specific fluorescent polarization immunoassay --- p.26 / Chapter 2.4.4.5 --- Enzyme multiplied immunoassay technique --- p.28 / Chapter 2.4.4.6 --- Cloned enzyme donor immunoassay --- p.29 / Chapter 2.4.4.7 --- Summary for conventional techniques --- p.29 / Chapter 2.5 --- Liquid chromatography mass spectrometry for CsA measurement --- p.30 / Chapter 2.5.1 --- Main components of MS --- p.31 / Chapter 2.5.1.1 --- Specific interfaces to LC --- p.31 / Chapter 2.5.1.2 --- Mass analyzer --- p.33 / Chapter 2.5.1.3 --- Electron multiplier --- p.36 / Chapter 2.5.2 --- Sample preparation for LC-MS/MS for CsA measurement --- p.36 / Chapter 2.5.2.1 --- Liquid-liquid extraction --- p.37 / Chapter 2.5.2.2 --- Solid phase extraction --- p.38 / Chapter 2.5.2.3 --- Column switching --- p.39 / Chapter 2.5.2.4 --- Dilute and shoot --- p.40 / Chapter 2.5.3 --- LC-MS/MS for CsA measurement --- p.40 / Chapter 2.6 --- Summary --- p.42 / Chapter 3. --- Aim of study --- p.43 / Chapter 4. --- Materials and methods --- p.44 / Chapter 4.1 --- Materials --- p.44 / Chapter 4.1.1 --- Chemicals --- p.44 / Chapter 4.1.2 --- Equipment --- p.44 / Chapter 4.1.3 --- Reagent preparation for CsA analysis --- p.45 / Chapter 4.2 --- Methods --- p.48 / Chapter 4.2.1 --- Immunoassay --- p.48 / Chapter 4.2.2 --- Operation of tandem mass spectrometer --- p.48 / Chapter 4.2.2.1 --- Optimization of cone voltage --- p.50 / Chapter 4.2.2.2 --- Optimization of collision energy --- p.50 / Chapter 4.2.3 --- Optimization of LC-MS/MS --- p.51 / Chapter 4.2.3.1 --- Deproteinization procedures of whole blood --- p.52 / Chapter 4.2.3.2 --- Optimization of mobile phase flow rate --- p.52 / Chapter 4.2.3.3 --- Optimization of source temperature --- p.53 / Chapter 4.2.3.4 --- Optimization of the drying gas flow rate --- p.53 / Chapter 4.2.4 --- Matrix interference on MS/MS response --- p.53 / Chapter 4.2.5 --- Analytical performance of CsA on LC-MS/MS --- p.54 / Chapter 4.2.5.1 --- Linearity study --- p.54 / Chapter 4.2.5.2 --- Precision performance --- p.54 / Chapter 4.2.5.3 --- Accuracy performance --- p.54 / Chapter 4.2.5.4 --- The lowest detection limit of the CsA analysis --- p.55 / Chapter 4.2.5.5 --- Correlation study of the CsA analysis --- p.55 / Chapter 4.3 --- CsA pharmacokinetic studies in Chinese patients --- p.56 / Chapter 4.3.1 --- Determining the time point of CsA correlating better with AUC --- p.56 / Chapter 4.3.1.1 --- Patient and method --- p.56 / Chapter 4.3.1.2 --- Statistical analysis --- p.57 / Chapter 4.3.2 --- "Intra-individual variability of CO, C1 and C2" --- p.57 / Chapter 4.3.2.1 --- Patient and method --- p.57 / Chapter 4.3.2.2 --- Statistical analysis --- p.57 / Chapter 5. --- Results and discussion --- p.59 / Chapter 5.1 --- Optimization of MS parameters --- p.5 9 / Chapter 5.1.1 --- Optimization of cone voltage --- p.61 / Chapter 5.1.2 --- Optimization of collision energy --- p.63 / Chapter 5.2 --- Optimization of LC-MS/MS --- p.63 / Chapter 5.2.1 --- Optimization of mobile phase flow rate --- p.63 / Chapter 5.2.2 --- Optimization of ion source temperature and drying gas flow rate --- p.67 / Chapter 5.3 --- Matrix interference on MS/MS response --- p.69 / Chapter 5.4 --- Analytical performances of CsA on LC-MS/MS method --- p.71 / Chapter 5.4.1 --- Linearity --- p.71 / Chapter 5.4.2 --- Precision performance --- p.71 / Chapter 5.4.3 --- Accuracy performance --- p.72 / Chapter 5.4.4 --- The lowest limit of detection --- p.73 / Chapter 5.4.5 --- Correlation study of the CsA analysis --- p.80 / Chapter 5.5 --- The correlation between CsA at different point and AUCo-6 --- p.84 / Chapter 5.6 --- "Intra-individual variability of CO, C1 and C2" --- p.88 / Chapter 5.7 --- Therapeutic ranges of C2 --- p.90 / Chapter 5.8 --- Practical consideration for C2 measurement by LC-MS/MS method --- p.94 / Chapter 6. --- Conclusions --- p.97 / References --- p.98

O diabetes mellitus (DM) é a principal causa de doença renal crônica (DRC) em vários países do mundo. Para pacientes diabéticos com DRC estágio 5 e indicação da terapia renal substitutiva, o transplante (Tx) renal representa uma modalidade terapêutica com técnica bem estabelecida e com excelentes resultados. O transplante simultâneo de rim-pâncreas (TSRP), uma alternativa mais recente praticada em um número mais restrito de centros, apresenta resultados positivos adicionais no controle metabólico, na qualidade de vida e nas complicações crônicas do diabetes. Entretanto, está associado a um risco maior de complicações pós-operatórias e maior número de internações. Tanto o transplante renal quanto o TSRP estão associados a melhor sobrevida do paciente em relação à diálise. A escolha da melhor modalidade de transplante para o paciente diabético com DRC ainda não está clara. O objetivo deste estudo foi analisar os resultados de diferentes modalidades de transplante em pacientes diabéticos com DRC estágio 5, realizados em 3 Centros Brasileiros de Transplante. Assim, analisar a sobrevida do paciente e do enxerto renal após 1, 5 e 8 anos em pacientes DM tipo 1 submetidos a TSRP comparados com transplante renal isolado com doador vivo (DM1-DV) ou transplante de renal isolado com doador falecido (DM1-DF) (Estudo de 3 modalidades de Tx em DM tipo1). Além disso, avaliar em pacientes DM tipo 2, os resultados do transplante renal realizado com doador vivo (DM2-DV) ou doador falecido (DM2-DF) comparados com pacientes DM tipo 1 submetidos ao transplante renal com doador vivo (DM1-DV) ou doador falecido (DM1-DF) (Estudo do Tx em DM tipo 2 vs DM tipo1). Os transplantes foram realizados em 3 Centros de Transplante (Hospital Beneficência Portuguesa, Hospital do Rim e Santa Casa de Porto Alegre). No \"Estudo de 3 modalidades de Tx em DM tipo 1\", foram incluídos 372 transplantes, sendo 262 TSRP, 78 DM1-DV e 32 DM1-DF. No \"Estudo do Tx em DM tipo 2 vs DM tipo 1\", foram incluídos 254 transplantes, sendo 78 DM1-DV, 32 DM1-DF, 61 DM2-DV, 83 DM2-DF. As curvas de sobrevida do paciente e do enxerto renal (Kaplan-Meyer) foram calculadas 1, 5 e 8 anos após o transplante. No \"Estudo de 3 modalidades de Tx em DM tipo 1\", a sobrevida do paciente de receptores de DM1-DV foi significativamente superior comparada com a sobrevida dos receptores de DM1-DF e TSRP no 1º ano (98,7%, 87,5% e 83,2%, respectivamente; p < 0,05) e no 5º ano pós-Tx (90,5%, 70% e 77%, respectivamente; p < 0,05). Não foi observada diferença entre a sobrevida dos pacientes do grupo DM1-DV e TSRP em 8 anos. A sobrevida do enxerto renal foi superior nos receptores DM1-DV no 1º ano pós-Tx, quando comparada com a sobrevida dos receptores DM1-DF e TSRP (96,1%, 84,4% e 80,2%, respectivamente; p < 0,05). Após 5 e 8 anos, a sobrevida do enxerto renal foi semelhante entre os grupos. Ocorreram 90 óbitos durante o período de estudo sendo as principais causas, a infecção (50%) e doença cardiovascular (22%). Óbito com enxerto funcionante e nefropatia crônica do enxerto foram as principais causas de perda do enxerto renal. No \"Estudo do Tx em DM tipo 2 vs DM tipo 1\", como esperado, os pacientes DM tipo 1 eram mais jovens em relação aos pacientes DM tipo 2 (mediana 37,5 e 55 anos, respectivamente; p < 0,0001). Os pacientes transplantados com doador falecido permaneceram maior tempo em tratamento dialítico pré-transplante (mediana 36 meses em DM1-DF e 36 meses em DM2-DF) comparados com pacientes transplantados com doador vivo (mediana 14 meses em DM1-DV e 18 meses em DM2-DV; p < 0,0001). Em pacientes com DM tipo 2, a sobrevida do paciente em 1, 5 e 8 anos nos pacientes DM2-DV foi 95,1%, 87,9% e 81,8%, respectivamente, significativamente maior do que nos pacientes DM2-DF (74,7%, 59,4% e 48,5%, respectivamente; p < 0,01). Em pacientes com DM tipo 1, a sobrevida do paciente em 1, 5 e 8 anos foi 98,7%, 90,5% e 82,1%, respectivamente, significativamente maior do que nos pacientes DM1-DV que nos pacientes DM1-DF (87,5%, 70% e 66,3%, respectivamente; p < 0,01). Comparando-se a sobrevida dos pacientes DM tipo 2 em relação aos DM tipo 1 submetidos a transplante com um mesmo tipo de doador, não foi observado diferença estatisticamente significante. Pacientes do grupo DM2-DV e pacientes DM1-DV apresentaram sobrevidas semelhantes. A sobrevida dos pacientes DM2-DF encontrada foi inferior em relação aos pacientes DM1-DF, porém sem diferença estatística. Em pacientes com DM tipo 2, a sobrevida do enxerto renal em 1, 5 e 8 anos nos pacientes DM2-DV foi 91,8%, 81,2% e 75,3%, respectivamente, significativamente maior do que nos pacientes DM2-DF (73,5%, 54,9% e 44.3%, respectivamente; p < 0,01). Em pacientes com DM tipo 1, a sobrevida do enxerto renal em 1, 5 e 8 anos nos pacientes DM1-DV foi 96,1%, 80,8% e 72,3%, respectivamente, significativamente maior do que nos pacientes DM1-DF (84,4%, 66,8% e 59,3%, respectivamente; p < 0,01) apenas no primeiro ano. Ocorreram 52 óbitos em pacientes DM tipo 2 sendo a infecção principal causa de óbito nos pacientes DM2-DF e a doença cardiovascular a principal causa de óbito nos DM2-DV. Ocorreram 23 óbitos no grupo de pacientes DM tipo 1 e a principal causa foi infecção nos pacientes DM1-DF e a doença cardiovascular nos DM1-DV. A principal causa de perda do enxerto renal foi óbito com enxerto funcionante (74%), seguido pela nefropatia crônica do enxerto (15%). Conclusão: Os resultados do \"Estudo de 3 modalidades de Tx em DM tipo1\" mostraram que em pacientes portadores de DM tipo 1 o transplante renal isolado realizado com doador vivo apresentou resultados superiores em relação às outras modalidades de transplante. Entretanto, em longo prazo, a sobrevida dos pacientes submetidos ao transplante renal com doador vivo não foi estatisticamente diferente do TSRP. Os resultados do \"Estudo do Tx em DM tipo 2 vs DM tipo1\" mostraram que o transplante renal com doador vivo é uma boa opção de terapia renal substitutiva para pacientes com DM tipo 2. Entretanto, os resultados observados nesta análise desencorajam a indicação de transplante renal com doador falecido para pacientes portadores de DM tipo 2, devendo ser indicado apenas em casos selecionados / Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in several countries around the world. For diabetic patients with stage 5 CKD with an indication of renal replacement therapy, renal transplantation is a therapeutic modality with well-established technique and with excellent results. The simultaneous kidney-pancreas transplantation (SPK), a more recent modality of treatment, performed in a limited number of centers, presents additional positive results in metabolic control, quality of life, and chronic complications of diabetes mellitus (DM). However, it is associated with an increased risk of postoperative complications and a higher number of hospitalizations. Both renal and SPK transplantation are associated with better patient survival outcomes compared to dialysis. The choice of the best modality of transplantation for diabetic patients with CKD is not yet clear. The aim of this study was to analyze the results of different modalities of transplant for diabetic patients with CKD stage 5, performed in 3 Brazilian Transplant Centers. More specifically, the aim of this study was to analyze the patient and graft survival after 1, 5, and 8 years post-transplantation in type 1 DM patients submitted to SPK compared with diabetic patients submitted to isolated kidney transplant with living donor (DM1-LD) or deceased donor (DM1-DD) (Study of 3 Tx (transplant) modalities in type 1 DM). In addition, the aim of this study was also to evaluate the results of renal transplantation in type 2 DM performed with living donor (DM2-LD) or deceased donor (DM2-DD) compared with kidney transplantation in type 1 DM performed with living donor (DM2-LD) or deceased donor (DM2-DD) (Study of Tx in type 2 DM vs. type 1 DM). The transplants were performed in 3 Transplant Centers (Hospital Beneficência Portuguesa, Hospital do Rim, and Santa Casa de Porto Alegre). In the \"Study of 3 transplant modalities in type 1 DM\", 372 recipients were included, (262 SPK, 78 DM1-LD, and 32 DM1-DD). In the \"Study of Tx in type 2 DM vs. type 1 DM\", 254 transplants were included, 78 DM1-LD, 32 DM1-DD, 61 DM2-LD, 83 DM2-DD. Patient and graft survival distribution estimates were calculated using the Kaplan-Meier method in the 1, 5 and 8 years post-transplantation. In the \"Study of 3 transplant Tx modalities in type 1 DM\", the patient survival of DM1-LD recipients was significantly higher compared with the survival of DM1-DD and SPK at 1 year (98.7%, 87.5% and 83.2%, respectively; p < 0.05), and at 5 years post-transplantation (90.5%, 70% and 77%, respectively; p < 0.05). After 8 years, there was no significant difference between the survival of patients in group DM1-LD and SPK. The kidney graft survival was higher in DM1-LD, at 1 year, compared with survival of DM1-DD and SPK (96.2%, 84.4% and 80.8%, respectively; p < 0.05). After 5 and 8 years, the kidney graft survival was similar between the groups. There were 90 deaths during the study period and infection (50%) and cardiovascular disease (22%) were the major causes. Death with a functioning graft and chronic allograft nephropathy were the main causes of kidney graft loss. In the \"Study of Tx in type 2 DM vs. type 1 DM\", type 1 DM patients were younger compared to type 2 DM patients (median 37.5 and 55 years, respectively; p < 0.0001). Recipients of deceased donor remained longer time on dialysis before transplantation (median 36 months in DM1-DD, and 36 in DM2-DD) compared with patients transplanted with living donor (median 14 months in DM1-LD and 18 months in DM2-LD, p < 0.0001). In type 2 DM, patient survival at 1, 5 and 8 years in the group DM2-LD was 95.1%, 87.9%, and 81.8, respectively, significantly higher than patient survival in DM2-DD recipients (74.7, 59,4, and 48.5; respectively, p < 0.01). In type 1 DM, patient survival at 1, 5 and 8 years in the group DM1-LD was 98.7%, 90.5% and 82.1%, respectively, significantly higher than patient survival in DM1-DD recipients ( 87.5%, 70%, and 48.5%; respectively, p < 0.01). The comparison between patient survival with type 2 DM and type 1 DM undergoing kidney transplantation with the same type of donor, was not statistically different between the groups. Patient survival in group DM2-LD and DM1-LD was not different. Patient survival in the group DM2-DD was inferior to the group DM1-DD but without significant differences. In type 2 DM, kidney survival at 1, 5 and 8 years in the group DM2-LD was 91.8%, 81 2%, and 75.3%, respectively, significantly higher than patient survival in DM2-DD recipients (73.5%, 54.9%, and 44.3%, respectively, p < 0.01). In type 1 DM, kidney survival at 1, 5 and 8 years in the group DM1-LD was 96.1%, 80.8%, and 72.3%,, respectively, significantly higher than patient survival in DM1-DD recipients (84.4%, 66.8%, and 59.3%, respectively, p < 0.01) only in the first year. In these patients the kidney graft survival was superior in the group DM2-LD compared with DM2-DD. In type 1 DM patients kidney graft survival was 96.1%, 80.8% and 72.3% in patients DM1-LD; 84.4%, 66.8% and 59.3% in patients DM1-DD (p < 0.01); respectively. There were 52 deaths in the group of type 2 DM patients. Infection was the main cause of death in the group DM2-DD, and cardiovascular disease was the main cause in DM2-LD. There were 23 deaths in the group of type 1 DM patients and the main cause was infection in the group DM1-DD and cardiovascular disease in the group DM1-LD. The main cause of kidney graft loss was death with a functioning graft (74%), followed by chronic allograft nephropathy (15%). Patients in group DM2-LD showed good survival rates, particularly in the first year. Conclusion: The \"Study of 3 transplant modalities in type 1 DM\" showed better patient and graft survival with isolated kidney transplantation with living donor compared with others transplant modalities. However, at longer follow up (8 years), survival of patients undergoing living donor kidney transplantation was not statistically different to SPK. In the \"Study of Tx in type 2 DM vs. type 1 DM\", renal transplantation performed with living donor is a good option of renal replacement therapy for type 2 DM. The results observed in this analysis discourage the indication of kidney transplantation with deceased donor for patients with type 2 DM, which should be indicated in selected cases

O diabetes mellitus (DM) é a principal causa de doença renal crônica (DRC) em vários países do mundo. Para pacientes diabéticos com DRC estágio 5 e indicação da terapia renal substitutiva, o transplante (Tx) renal representa uma modalidade terapêutica com técnica bem estabelecida e com excelentes resultados. O transplante simultâneo de rim-pâncreas (TSRP), uma alternativa mais recente praticada em um número mais restrito de centros, apresenta resultados positivos adicionais no controle metabólico, na qualidade de vida e nas complicações crônicas do diabetes. Entretanto, está associado a um risco maior de complicações pós-operatórias e maior número de internações. Tanto o transplante renal quanto o TSRP estão associados a melhor sobrevida do paciente em relação à diálise. A escolha da melhor modalidade de transplante para o paciente diabético com DRC ainda não está clara. O objetivo deste estudo foi analisar os resultados de diferentes modalidades de transplante em pacientes diabéticos com DRC estágio 5, realizados em 3 Centros Brasileiros de Transplante. Assim, analisar a sobrevida do paciente e do enxerto renal após 1, 5 e 8 anos em pacientes DM tipo 1 submetidos a TSRP comparados com transplante renal isolado com doador vivo (DM1-DV) ou transplante de renal isolado com doador falecido (DM1-DF) (Estudo de 3 modalidades de Tx em DM tipo1). Além disso, avaliar em pacientes DM tipo 2, os resultados do transplante renal realizado com doador vivo (DM2-DV) ou doador falecido (DM2-DF) comparados com pacientes DM tipo 1 submetidos ao transplante renal com doador vivo (DM1-DV) ou doador falecido (DM1-DF) (Estudo do Tx em DM tipo 2 vs DM tipo1). Os transplantes foram realizados em 3 Centros de Transplante (Hospital Beneficência Portuguesa, Hospital do Rim e Santa Casa de Porto Alegre). No \"Estudo de 3 modalidades de Tx em DM tipo 1\", foram incluídos 372 transplantes, sendo 262 TSRP, 78 DM1-DV e 32 DM1-DF. No \"Estudo do Tx em DM tipo 2 vs DM tipo 1\", foram incluídos 254 transplantes, sendo 78 DM1-DV, 32 DM1-DF, 61 DM2-DV, 83 DM2-DF. As curvas de sobrevida do paciente e do enxerto renal (Kaplan-Meyer) foram calculadas 1, 5 e 8 anos após o transplante. No \"Estudo de 3 modalidades de Tx em DM tipo 1\", a sobrevida do paciente de receptores de DM1-DV foi significativamente superior comparada com a sobrevida dos receptores de DM1-DF e TSRP no 1º ano (98,7%, 87,5% e 83,2%, respectivamente; p < 0,05) e no 5º ano pós-Tx (90,5%, 70% e 77%, respectivamente; p < 0,05). Não foi observada diferença entre a sobrevida dos pacientes do grupo DM1-DV e TSRP em 8 anos. A sobrevida do enxerto renal foi superior nos receptores DM1-DV no 1º ano pós-Tx, quando comparada com a sobrevida dos receptores DM1-DF e TSRP (96,1%, 84,4% e 80,2%, respectivamente; p < 0,05). Após 5 e 8 anos, a sobrevida do enxerto renal foi semelhante entre os grupos. Ocorreram 90 óbitos durante o período de estudo sendo as principais causas, a infecção (50%) e doença cardiovascular (22%). Óbito com enxerto funcionante e nefropatia crônica do enxerto foram as principais causas de perda do enxerto renal. No \"Estudo do Tx em DM tipo 2 vs DM tipo 1\", como esperado, os pacientes DM tipo 1 eram mais jovens em relação aos pacientes DM tipo 2 (mediana 37,5 e 55 anos, respectivamente; p < 0,0001). Os pacientes transplantados com doador falecido permaneceram maior tempo em tratamento dialítico pré-transplante (mediana 36 meses em DM1-DF e 36 meses em DM2-DF) comparados com pacientes transplantados com doador vivo (mediana 14 meses em DM1-DV e 18 meses em DM2-DV; p < 0,0001). Em pacientes com DM tipo 2, a sobrevida do paciente em 1, 5 e 8 anos nos pacientes DM2-DV foi 95,1%, 87,9% e 81,8%, respectivamente, significativamente maior do que nos pacientes DM2-DF (74,7%, 59,4% e 48,5%, respectivamente; p < 0,01). Em pacientes com DM tipo 1, a sobrevida do paciente em 1, 5 e 8 anos foi 98,7%, 90,5% e 82,1%, respectivamente, significativamente maior do que nos pacientes DM1-DV que nos pacientes DM1-DF (87,5%, 70% e 66,3%, respectivamente; p < 0,01). Comparando-se a sobrevida dos pacientes DM tipo 2 em relação aos DM tipo 1 submetidos a transplante com um mesmo tipo de doador, não foi observado diferença estatisticamente significante. Pacientes do grupo DM2-DV e pacientes DM1-DV apresentaram sobrevidas semelhantes. A sobrevida dos pacientes DM2-DF encontrada foi inferior em relação aos pacientes DM1-DF, porém sem diferença estatística. Em pacientes com DM tipo 2, a sobrevida do enxerto renal em 1, 5 e 8 anos nos pacientes DM2-DV foi 91,8%, 81,2% e 75,3%, respectivamente, significativamente maior do que nos pacientes DM2-DF (73,5%, 54,9% e 44.3%, respectivamente; p < 0,01). Em pacientes com DM tipo 1, a sobrevida do enxerto renal em 1, 5 e 8 anos nos pacientes DM1-DV foi 96,1%, 80,8% e 72,3%, respectivamente, significativamente maior do que nos pacientes DM1-DF (84,4%, 66,8% e 59,3%, respectivamente; p < 0,01) apenas no primeiro ano. Ocorreram 52 óbitos em pacientes DM tipo 2 sendo a infecção principal causa de óbito nos pacientes DM2-DF e a doença cardiovascular a principal causa de óbito nos DM2-DV. Ocorreram 23 óbitos no grupo de pacientes DM tipo 1 e a principal causa foi infecção nos pacientes DM1-DF e a doença cardiovascular nos DM1-DV. A principal causa de perda do enxerto renal foi óbito com enxerto funcionante (74%), seguido pela nefropatia crônica do enxerto (15%). Conclusão: Os resultados do \"Estudo de 3 modalidades de Tx em DM tipo1\" mostraram que em pacientes portadores de DM tipo 1 o transplante renal isolado realizado com doador vivo apresentou resultados superiores em relação às outras modalidades de transplante. Entretanto, em longo prazo, a sobrevida dos pacientes submetidos ao transplante renal com doador vivo não foi estatisticamente diferente do TSRP. Os resultados do \"Estudo do Tx em DM tipo 2 vs DM tipo1\" mostraram que o transplante renal com doador vivo é uma boa opção de terapia renal substitutiva para pacientes com DM tipo 2. Entretanto, os resultados observados nesta análise desencorajam a indicação de transplante renal com doador falecido para pacientes portadores de DM tipo 2, devendo ser indicado apenas em casos selecionados / Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in several countries around the world. For diabetic patients with stage 5 CKD with an indication of renal replacement therapy, renal transplantation is a therapeutic modality with well-established technique and with excellent results. The simultaneous kidney-pancreas transplantation (SPK), a more recent modality of treatment, performed in a limited number of centers, presents additional positive results in metabolic control, quality of life, and chronic complications of diabetes mellitus (DM). However, it is associated with an increased risk of postoperative complications and a higher number of hospitalizations. Both renal and SPK transplantation are associated with better patient survival outcomes compared to dialysis. The choice of the best modality of transplantation for diabetic patients with CKD is not yet clear. The aim of this study was to analyze the results of different modalities of transplant for diabetic patients with CKD stage 5, performed in 3 Brazilian Transplant Centers. More specifically, the aim of this study was to analyze the patient and graft survival after 1, 5, and 8 years post-transplantation in type 1 DM patients submitted to SPK compared with diabetic patients submitted to isolated kidney transplant with living donor (DM1-LD) or deceased donor (DM1-DD) (Study of 3 Tx (transplant) modalities in type 1 DM). In addition, the aim of this study was also to evaluate the results of renal transplantation in type 2 DM performed with living donor (DM2-LD) or deceased donor (DM2-DD) compared with kidney transplantation in type 1 DM performed with living donor (DM2-LD) or deceased donor (DM2-DD) (Study of Tx in type 2 DM vs. type 1 DM). The transplants were performed in 3 Transplant Centers (Hospital Beneficência Portuguesa, Hospital do Rim, and Santa Casa de Porto Alegre). In the \"Study of 3 transplant modalities in type 1 DM\", 372 recipients were included, (262 SPK, 78 DM1-LD, and 32 DM1-DD). In the \"Study of Tx in type 2 DM vs. type 1 DM\", 254 transplants were included, 78 DM1-LD, 32 DM1-DD, 61 DM2-LD, 83 DM2-DD. Patient and graft survival distribution estimates were calculated using the Kaplan-Meier method in the 1, 5 and 8 years post-transplantation. In the \"Study of 3 transplant Tx modalities in type 1 DM\", the patient survival of DM1-LD recipients was significantly higher compared with the survival of DM1-DD and SPK at 1 year (98.7%, 87.5% and 83.2%, respectively; p < 0.05), and at 5 years post-transplantation (90.5%, 70% and 77%, respectively; p < 0.05). After 8 years, there was no significant difference between the survival of patients in group DM1-LD and SPK. The kidney graft survival was higher in DM1-LD, at 1 year, compared with survival of DM1-DD and SPK (96.2%, 84.4% and 80.8%, respectively; p < 0.05). After 5 and 8 years, the kidney graft survival was similar between the groups. There were 90 deaths during the study period and infection (50%) and cardiovascular disease (22%) were the major causes. Death with a functioning graft and chronic allograft nephropathy were the main causes of kidney graft loss. In the \"Study of Tx in type 2 DM vs. type 1 DM\", type 1 DM patients were younger compared to type 2 DM patients (median 37.5 and 55 years, respectively; p < 0.0001). Recipients of deceased donor remained longer time on dialysis before transplantation (median 36 months in DM1-DD, and 36 in DM2-DD) compared with patients transplanted with living donor (median 14 months in DM1-LD and 18 months in DM2-LD, p < 0.0001). In type 2 DM, patient survival at 1, 5 and 8 years in the group DM2-LD was 95.1%, 87.9%, and 81.8, respectively, significantly higher than patient survival in DM2-DD recipients (74.7, 59,4, and 48.5; respectively, p < 0.01). In type 1 DM, patient survival at 1, 5 and 8 years in the group DM1-LD was 98.7%, 90.5% and 82.1%, respectively, significantly higher than patient survival in DM1-DD recipients ( 87.5%, 70%, and 48.5%; respectively, p < 0.01). The comparison between patient survival with type 2 DM and type 1 DM undergoing kidney transplantation with the same type of donor, was not statistically different between the groups. Patient survival in group DM2-LD and DM1-LD was not different. Patient survival in the group DM2-DD was inferior to the group DM1-DD but without significant differences. In type 2 DM, kidney survival at 1, 5 and 8 years in the group DM2-LD was 91.8%, 81 2%, and 75.3%, respectively, significantly higher than patient survival in DM2-DD recipients (73.5%, 54.9%, and 44.3%, respectively, p < 0.01). In type 1 DM, kidney survival at 1, 5 and 8 years in the group DM1-LD was 96.1%, 80.8%, and 72.3%,, respectively, significantly higher than patient survival in DM1-DD recipients (84.4%, 66.8%, and 59.3%, respectively, p < 0.01) only in the first year. In these patients the kidney graft survival was superior in the group DM2-LD compared with DM2-DD. In type 1 DM patients kidney graft survival was 96.1%, 80.8% and 72.3% in patients DM1-LD; 84.4%, 66.8% and 59.3% in patients DM1-DD (p < 0.01); respectively. There were 52 deaths in the group of type 2 DM patients. Infection was the main cause of death in the group DM2-DD, and cardiovascular disease was the main cause in DM2-LD. There were 23 deaths in the group of type 1 DM patients and the main cause was infection in the group DM1-DD and cardiovascular disease in the group DM1-LD. The main cause of kidney graft loss was death with a functioning graft (74%), followed by chronic allograft nephropathy (15%). Patients in group DM2-LD showed good survival rates, particularly in the first year. Conclusion: The \"Study of 3 transplant modalities in type 1 DM\" showed better patient and graft survival with isolated kidney transplantation with living donor compared with others transplant modalities. However, at longer follow up (8 years), survival of patients undergoing living donor kidney transplantation was not statistically different to SPK. In the \"Study of Tx in type 2 DM vs. type 1 DM\", renal transplantation performed with living donor is a good option of renal replacement therapy for type 2 DM. The results observed in this analysis discourage the indication of kidney transplantation with deceased donor for patients with type 2 DM, which should be indicated in selected cases