Os imunossupressores tacrolimo (Tac) e sirolimo (Srl) são amplamente utilizados no transplante renal. Estes medicamentos apresentam estreita faixa terapêutica e estão associados a uma vasta gama de efeitos colaterais. Polimorfismos de nucleotídeo único (SNP) parecem ter um impacto significativo sobre a farmacocinética dos imunossupressores. Com o objetivo de avaliar a associação de SNP nos genes PPP3CA e MTOR com a resposta farmacológica dos imunossupressores tacrolimo e sirolimo foram selecionados 156 indivíduos indicados para transplante renal entre os pacientes atendidos no Hospital do Rim e Hipertensão da UNIFESP. Esses indivíduos foram tratados com esquema imunossupressor baseado em tacrolimo ou convertido para sirolimo. Amostras de sangue foram coletadas antes do transplante para extração de DNA. As determinações das concentrações sanguíneas de Tac foram determinadas por chemiluminescent microparticle immunoassay (CMIA) e as concentrações sanguíneas de Srl foram obtidas pela técnica de HPLC (High- Performance Liquid Chromatography). Os polimorfismos do MTOR (c.1437T>C, T c.2997C>T e c.4731G>A) e PPP3CA (c.249G>A) foram identificados por PCR em tempo real. O polimorfismo PPP3CA c.246G>A não foi associado à dose diária de tacrolimo ou sirolimo. Já a concentração sanguínea de tacrolimo foi menor nos portadores do alelo A no terceiro dia e terceiro mês de estudo. Os polimorfismos do MTOR foram relacionados à concentração sanguínea corrigida pela dose de tacrolimo. Os portadores dos alelos raros G, T e C dos polimorfismos c.4731G>A, c.14337T>C e c.2997C>T, respectivamente, apresentaram valores de Co/Do de tacrolimo menores em relação aos não portadores destes alelos. As diferenças significativas ocorreram principalmente nos primeiros três meses de estudo. A concentração sanguínea de tacrolimo foi no geral menor nos portadores dos alelos raros, sendo significativamente menor no décimo quarto dia. Doses maiores de tacrolimo foram associadas aos alelos T do c.14337T>C e C do c.2997C>T. No sexto mês de estudo, os portadores dos alelos raros receberam doses de sirolimo significativamente maiores do que os não portadores. O alelo T do polimorfismo c.1437T>C foi associado a menores valores de Co/Do de sirolimo. Os SNPs c.2997C>T e c.1437T>C do MTOR encontram-se em desequilíbrio de ligação (D\'=0,981; r2=0,690). Nos três primeiros meses de estudo, os portadores do haplótipo TC receberam doses menores de tacrolimo e apresentaram a melhor relação Co/Do. Foi possível observar que após a randomização, o haplótipo TC continuou associado a menores doses de tacrolimo e de sirolimo e manteve a tendência de melhores índices de Co/Do de ambos os fármacos. Os polimorfismos c.1437T>C e c.4731G>A foram associados a parâmetros de função renal no grupo TAC. O alelo G do SNP c.4731G>A relacionou-se a valores menores de ureia no pré-Tx, menor redução de ureia e creatinina entre o pré-Tx e o sexto mês de estudo. O alelo T do SNP c.1437T>C também foi relacionado a menores valores de ureia no pré-Tx e menor redução de creatinina. No grupo TAC, o alelo raro do SNP PPP3CA c.249G>A foi relacionado a menores valores de triglicérides no pré-Tx e no grupo SRL uma menor variação de LDL-colesterol. Os portadores do alelo C do SNP c.2997C>T apresentaram menor aumento de colesterol total e LDL colesterol entre o pré-Tx e o sexto mês de estudo, maiores valores de HDL colesterol no pré-Tx e menores valores de triglicérides no sexto mês de estudo. Os portadores do alelo T do SNP c.1437T>C apresentaram menor aumento de colesterol total, LDL colesterol, VLDL colesterol e triglicérides. No sexto mês de estudo apresentaram menores valores de triglicérides em relação aos não portadores deste alelo. Os portadores do alelo G do SNP c.4731G>A tiveram variação menor de colesterol total, VLDL colesterol e triglicérides. Não foi encontrada relação dos polimorfimos estudados e a rejeição aguda comprovada por biópsia ou com a nefropatia crônica do enxerto. Esses resultados são sugestivos de que os polimorfismos do MTOR e PPP3CA estão associados com a dose e concentração sanguínea dos imunossupressores tacrolimo e sirolimo, assim como um perfil lipídico menos aterogênico. / The immunosuppressant tacrolimus (Tac) and Sirolimus (Srl) are widely used in renal transplantation. These drugs have a narrow therapeutic range and are associated with a wide range of side effects. Single nucleotide polymorphisms (SNPs) have a significant impact on the pharmacokinetics of immunosuppressants. In order to evaluate the association of SNPs in genes MTOR and PPP3CA with the pharmacological response of immunosuppressive drugs tacrolimus and sirolimus were selected 156 individuals referred for kidney transplantation among patients treated in the Hospital do Rim e Hipertensão, UNIFESP. These individuals were treated with tacrolimus-based immunosuppressive regimen or converted to sirolimus. Blood samples were collected before transplantation for DNA extraction. Determinations of blood concentrations of Tac were determined by Chemiluminescent microparticle immunoassay (CMIA) and blood concentrations Srl were obtained by the technique of HPLC (High-Performance Liquid Chromatography). Polymorphisms of MTOR (c.1437T>C, T c.2997C>T and c.4731G>A) and PPP3CA (c.249G>A) were identified by real-time PCR. The Polymorphism PPP3CA c.246G>A was not associated with the daily dose of tacrolimus or sirolimus. The blood concentration of tacrolimus was lower in carriers of the allele on the third day and third month of study. The Polymorphisms of MTOR were related to blood concentration corrected by the dose of tacrolimus. The carriers of rare alleles G, T and C polymorphisms c.4731G> A, c.14337T> C and c.2997C> T, respectively, had values of Co/Do tacrolimus lower than the non-carriers of these alleles. Significant differences occurred mainly during the first three months of study. The blood concentration of tacrolimus was generally lower in carriers of the rare alleles being significantly lower on the fourteenth day. Higher doses of tacrolimus were associated with alleles c.14337T T>C and C c.2997C>T. In the sixth month of study, the carriers of rare alleles received doses of sirolimus significantly higher than non-carriers. SNPs c.2997C>T and c.1437T>C MTOR are in linkage disequilibrium (D \'= 0.981; r2 = 0.690). In the first three months of study, carriers of the TC haplotype received lower doses of tacrolimus and presented the best value for Co/Do. It was observed that after randomization, the TC haplotype remained associated with lower doses of tacrolimus and sirolimus and continued the trend of higher rates of Co/Do of both drugs. Polymorphisms c.1437T>C and c.4731G>A were associated with renal function parameters in the TAC group. The G allele of SNP c.4731G> A was related to lower levels of urea in the pre-Tx, a smaller reduction of urea and creatinine between the pre-Tx and sixth months of study. The T allele of SNP c.1437T>C was also related to lower levels of urea in the pre-Tx and a smaller reduction of creatinine. In the TAC group, the rare allele of SNP PPP3CA c.249G>A was related to lower levels of triglycerides in the pre-Tx and the SRL group a smaller variation of LDL-cholesterol. The C allele of the SNP c.2997C>T showed a lower increase in total cholesterol and LDL cholesterol between pre-Tx and sixth months of study, higher HDL cholesterol in pre-Tx and lower levels of triglycerides in the sixth month of study. The T allele of SNP c.1437T>C showed a lower increase in total cholesterol, LDL cholesterol, VLDL cholesterol and triglycerides. In the sixth month of the study, they had lower triglyceride levels compared to non-carriers of this allele. The G allele of SNP c.4731G>A change had lower total cholesterol, VLDL cholesterol and triglycerides. There was no relationship between the studied polymorphisms and biopsy-proven acute rejection or chronic allograft nephropathy. These results suggest that MTOR and PPP3CA polymorphisms are associated with dose and blood concentration of immunosuppressants tacrolimus and sirolimus, as well as a less atherogenic lipid profile.

No description available.

Background: Persistent anemia has been described in kidney transplant (KTx) recipients with parvovirus B19 virus infection. However, the epidemiology of parvovirus B19 and parvovirus B19-related anemia after KTx remains unclear. We conducted this systematic review (1) to investigate the incidence of parvovirus B19 infection after KTx and (2) to assess the incidence of parvovirus B19 among KTx patients with anemia. Materials and Methods: A systematic review was conducted in EMBASE, MEDLINE, and Cochrane databases from inception to March 2019 to identify studies that reported the incidence rate of parvovirus B19 infection and/or seroprevalence of parvovirus B19 in KTx recipients. Effect estimates from the individual studies were extracted and combined using random-effects, generic inverse variance method of DerSimonian and Laird. The protocol for this systematic review is registered with PROSPERO (no. CRD42019125716). Results: Nineteen observational studies with a total of 2108 KTx patients were enrolled. Overall, the pooled estimated seroprevalence of parvovirus B19 immunoglobulin G was 62.2% (95% confidence interval [CI]: 45.8%-76.1%). The pooled estimated incidence rate of positive parvovirus B19 DNA in the 1st year after KTx was 10.3% (95% CI: 5.5%-18.4%). After sensitivity analysis excluded a study that solely included KTx patients with anemia, the pooled estimated incidence rate of positive parvovirus B19 DNA after KTx was 7.6% (95% CI: 3.7%-15.0%). Among KTx with anemia, the pooled estimated incidence rate of positive parvovirus B19 DNA was 27.4% (95% CI: 16.6%-41.7%). Meta-regression analysis demonstrated no significant correlations between the year of study and the incidence rate of positive parvovirus B19 DNA (P = 0.33). Egger's regression asymmetry test was performed and demonstrated no publication bias in all analyses. Conclusion: The overall estimated incidence of positive parvovirus B19 DNA after KTX is 10.3%. Among KTx with anemia, the incidence rate of positive parvovirus B19 DNA is 27.4%. The incidence of positive parvovirus B19 DNA does not seem to decrease overtime.

Die Hyperlipidämie wird als Risikofaktor für die Nierentransplantatfunktionsverschlechterung und den -verlust diskutiert. Wir untersuchten den Zusammenhang zwischen Lipidstoffwechsel und Nierentransplantatfunktion und ihre Beziehungen zu Immunsuppression, Rejektionen, Transplantatalter und Dialysedauer. Im 1. Quartal 1996 wurde allen nierentransplantierten Patienten der Ambulanz die Bestimmung eines umfassenden Lipidstatus (Cholesterine (HDL, LDL, VLDL), Triglyzeride, Apolipoproteine A1, A2, B, Lp(a) und Apo E-Genotyp) angeboten. Die ermittelten Laborwerte wurden zum klinischen Verlauf der Patienten in Beziehung gesetzt. Es wurden 201 Patienten in die Studie eingeschlossen, deren mittleres Alter bei 46,2 ± 11,4 Jahren lag. Die Transplantation lag bei den 146 Männer (72,6 %) und 55 Frauen (27,4 %) 7,7 ± 4,9 Jahre zurück. Eine auf Cyclosporin A basierende Immunsuppression erfolgte bei 143 Patienten (71,1 %), 87 Patienten (43,3 %) erhielten eine lipidsenkende Therapie. Kreatinin 122 ± 86,9 µmol/l; Cholesterin 253,6 ± 52,9 mg/dl; atherogene Risikoratio (Chol/HDL) 5,3 ± 2,3. Das Kreatinin korreliert signifikant mit dem Cholesterin (p < 0,001) und der atherogenen Risikoratio (p < 0,001) - auch in der Untergruppe ohne lipidsenkende Therapie (p = 0,001 bzw. p < 0,001), ebenso LDL, Triglyzeride, VLDL und Apo B. Die Rejektionshäufigkeit war bei Patienten mit und ohne Fettstoffwechselstörung nahezu gleich. Der Apo E-Genotyp scheint keinen Einfluss auf den Lipid- und Nierenstoffwechsel zu haben. Die Lipidparameter unserer Patienten korrelieren in der Querschnittsuntersuchung signifikant mit der Nierentransplantatfunktion, scheinen aber keinen Einfluss auf die Rejektionshäufigkeit zu haben / Hyperlipidemia is discussed as a risk factor for deterioration of the renal transplant function and the graft loss. We examined the relations between the lipid metabolism and renal transplant function and their connections to factors like immunsuppression, rejections, transplant age und time of dialysis. In the first months of 1996 all patients having a renal transplant were offered an extensive blood control including cholesterol, HDL, LDL, VLDL, triglycerides, apolipoproteins A1, A2, B, Lp(a) und Apo E-Genotype. Afterwards the lipid parameters were put into relation to the clinical course of each patient. We included 201 patients in our study, they were 46,2 ± 11,4 years old. The renal transplantation was in 146 men (72,6 %) und 55 women (27,4 %) 7,7 ± 4,9 years ago. 143 patients got a Cyclosporin A based immunsuppression (71,1 %), 87 patients (43,3 %) were set on lipid lowering therapie. Creatinin 122 ± 86,9 µmol/l; cholesterol 253,6 ± 52,9 mg/dl; Chol/HDL-quotient 5,3 ± 2,3. Creatinin correlates significantly with cholesterol (p < 0,001) and the Chol/HDL-quotient (p < 0,001) - even in the group of patients without lipid lowering therapie (p = 0,001 and p < 0,001) - and LDL, Triglyzeride, VLDL and Apo B. The frequency of rejections did not differ between patients with and without hyperlipidemia. The Apo E-Genotype seems to have no influence on the lipid- and renal metabolism. The lipid parameters our patients correlate in our study significantly with the renal transplant function, but seem to have no influence on the frequency of rejections.

A literatura apresenta vários artigos que estudam o tipo e a frequência de alterações bucais em pessoas transplantadas renais, mas é escassa em pesquisas que proporcionem evidências científicas sobre o risco de tratamento odontológico invasivo induzir infecção local ou à distância em receptores de transplante. A escassez de estudos que abordam manejo clínico em procedimentos odontológicos invasivos em pacientes transplantados reflete o empirismo e a falta de homogeneidade nas recomendações das equipes transplantadoras em relação ao manejo odontológico ideal do indivíduo receptor de transplante renal. Este volume apresenta um compilado de três trabalhos científicos que abordaram manejo do indivíduo transplantado renal e a avaliação do desfecho clínico após procedimentos odontológicos invasivos. As pesquisas foram executadas no Centro de Atendimento a Pacientes Especiais (CAPE) da Faculdade de Odontologia da USP. Todas tiveram aprovação do comitê de ética em pesquisa. A primeira pesquisa buscou conhecer, por meio de questionário, as condutas dos cirurgiões dentistas frente ao tratamento odontológico de pacientes transplantados renais. O segundo estudo avaliou retrospectivamente a incidência de complicações após exodontias em pacientes transplantados renais, realizadas no CAPE, por diferentes dentistas, que foram precedidas ou não por antibioticoterapia profilática. O terceiro estudo teve por objetivo avaliar a reparação alveolar após extrações de dentes erupcionados de forma prospectiva, em pacientes transplantados e controles, sem receberem antibioticoterapia profilática. Os resultados mostraram que a maioria dos dentistas entrevistados se sentem inseguros em realizar tratamento odontológico em pacientes transplantados renais e prescrevem antibiótico profilático excessivamente, e com posologia empírica. Foi constatado por meio do estudo retrospectivo que o uso ou não de antibiótico profilático antes de exodontias em indivíduos transplantados renais não afeta o desfecho pós-operatório. Por fim, os resultados do terceiro estudo evidenciaram que não há diferença na epitelização e no reparo alveolar pós-exodôntico entre indivíduos transplantados renais e não transplantados, quando submetidos à exodontias simples, sem o uso de antibiótico profilático. / The literature presents several papers regarding type and frequency of oral manifestations in renal transplant recipients, but there is a lack of studies that give scientific evidence about the risk of invasive dental treatment to induce local or distant site infection in renal transplant individuals. The lack of studies that focus on clinic management in invasive dental procedures reflects the empiricism and lack of standardization on the recommendations given by the transplant team regarding the ideal dental management of the renal transplant recipient. This volume presents a compilation of three scientific papers that approach the management of renal transplant recipient and the assessment of clinical outcomes after invasive dental procedures. The researches were performed at the Special Care Dentistry Center (SCDC), of School of Dentistry, University of Sao Paulo. All studies had ethical approval. The first study sought to know, through a questionnaire, the conducts of dentists regarding dental treatment on renal transplant recipients. The second was a retrospective study, that assessed post-operative complications following dental extractions performed at SCDC, that was preceded or not by antibiotic prophylaxis. The third was a prospective study, which assessed the socket healing after dental extractions of erupted teeth, on renal transplant recipients and control individuals, without antibiotic prophylaxis. The results show that most dentists interviewed feel insecure on performing dental treatment on renal transplanted patients as these practitioners prescribe prophylactic antibiotics excessively and based on empirical therapeutic posology. It was verified through the retrospective study that the antibiotic prophylactic prescription or non-prescription preceding an invasive dental procedure does not affect the post-operative outcome for renal transplant recipients. Finally, the results of the third study evidenced that there is no difference in post-extraction epithelization and thus healing between renal transplant recipients and non-transplanted individuals, without using antibiotic prophylaxis.

Introdução: O transplante renal é amplamente reconhecido como a melhor forma de tratamento para os pacientes que necessitam de terapia de substituição renal, e isso o torna vítima de seu próprio sucesso. Apesar de ser considerado um triunfo clínico-cirúrgico, é igualmente uma fonte de frustração, pela carência de doadores de órgãos e pelo crescimento das listas de espera. Há necessidade do desenvolvimento de estratégias que tornem maior o número de rins disponíveis para transplante. A idade do doador, o tempo de isquemia fria (TIF) e o HLA (antígeno leucocitário humano de histocompatibilidade) são fatores que estão relacionados à sobrevida do enxerto e, desta forma, envolvidos na diminuição da demanda e no aumento da oferta de órgãos. Objetivos: Avaliar o impacto das variáveis, idade do doador, compatibilidade HLA e tempo de isquemia fria, na sobrevida do enxerto de pacientes submetidos à alotransplantes renais com doador cadáver. Materiais e Métodos: Foram analisados retrospectivamente 454 pacientes submetidos a transplantes renais com doadores cadáveres realizados de abril de 1987 a dezembro de 2003, no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP). Resultados: Das variáveis analisadas, a idade do doador foi a de maior impacto estatístico na sobrevida dos transplantes renais estudados. A sobrevida dos enxertos oriundos de doadores com idade de 16 a 40 anos (143,30 meses em média), foi significativamente maior em comparação com a sobrevida nos grupos com doadores acima de 40 anos (66,46 meses) (p= 0,005) e nos doadores de 0 a 10 anos de idade (63,29 meses) (p= 0,01). A compatibilidade HLA e o TIF não interferiram de modo significativo na sobrevida dos transplantes estudados (p= 0,98 e p= 0,16 respectivamente). Conclusões: O tempo de isquemia fria (TIF) e a compatibilidade HLA não apresentaram impacto na sobrevida dos transplantes renais analisados. Os doadores cadáveres com idade de 16 a 40 anos podem ser considerados ideais, uma vez que demonstraram, de modo estatisticamente significativo, impacto favorável na sobrevida dos rins por eles doados. / Introduction: Renal transplantation is world wide recognized as the best therapy for patients that need kidney substitution treatment. It can be considered a clinical and surgical triumph and at the same time, its a form of frustration by the few organs donations available and by the growth of the waiting lists. New strategies are needed to be developed to increase the numbers of kidneys for transplantation. Donors aged, cold ischemia time (CIT) and human leukocyte antigen (HLA) compatibility are correlated with graft survival and consequently, with a diminished organs demand. Objectives: To study the impacts of donors age, cold ischemia time and HLA compatibility, on graft survival patients submitted to cadaver kidney allograft transplantation. Materials and Methods: Records from 454 patients, submitted to cadaver kidneys allograft transplantations between April/1987 and December/2003 by Division of Urology of the Clinical Hospital of Ribeirao Pretos School of Medicine at Sao Paulo University, were analyzed. Results: The age of kidneys donors was the most statistically significant data in the survival graft rate. Donors between 16 and 40 years old had a median survival rate about 143.30 months, that was significantly higher when compared with aged donors above 40 years (66.46 months) (p= 0.005) and below 10 years old (63,29 months) (p= 0.01). In our study, HLA compatibility and cold ischemia time didnt have statistically significant impact on renal allograft survival rate (p= 0.98 and p= 0.16, respectively). Conclusions: HLA compatibility and cold ischemia time didnt have significantly impact on renal allograft survival rate. Donors between 16 and 40 years old can be considered the ideal donors age, since they demonstrated statistically a favorable impact on grafts survival rate.

Devido à complexidade da insuficiência renal crônica e do seu tratamento, o transplante renal é, para a maioria dos pacientes, um acontecimento muito desejado. Atualmente, com o aumento do número de transplantes, observa-se também, com maior freqüência, o paciente que vivencia a experiência de ter que retornar ao tratamento dialítico após a perda do enxerto renal. O presente trabalho tem como proposta focalizar a pessoa com insuficiência renal crônica que já tenha realizado o transplante renal e, por algum motivo, tenha perdido o enxerto deparando-se, novamente, com a necessidade de realizar a hemodiálise para sobreviver. O objetivo é compreender, a partir da experiência vivida pelo paciente, como é para ele retornar a conviver com o tratamento dialítico após ter vivenciado um período sem necessitar desse tratamento. O trabalho fundamenta-se no método de pesquisa qualitativa de inspiração fenomenológica em Psicologia, que investiga a experiência humana vivida, e parte de uma questão orientadora: Como é para o paciente ter que retornar ao tratamento dialítico após ter ficado algum tempo transplantado e fora do programa de hemodiálise. Para tanto, foram entrevistados todos os oito pacientes que vivenciaram tal situação e que realizavam hemodiálise no Instituto de Hemodiálise da Santa Casa de Franca, SP. Por intermédio de entrevista fenomenológica, buscou-se chegar à experiência de cada paciente e apreender os significados atribuídos às suas vivências. Um diário de campo foi utilizado como fonte subsidiária de informação. As entrevistas foram analisadas por meio do método fenomenológico. Após a leitura atentiva de cada entrevista para apreensão de unidades de significado e, a partir das convergências dessas, foram desveladas as seguintes categorias: o transplante, subdividida em: o transplante como possibilidade: sonho e realidade, o transplante como experiência: a facticidade; a perda do transplante, que se subdividu em: o impacto da perda, a busca do sentido, a constatação da aprendizagem através da experiência; a volta a hemodiálise com as subcategorias: o começar de novo. a retomada do projeto existencial; e as fontes de apoio. Após a análise, foi realizada uma síntese compreensiva das vivências dos pacientes e, posteriormente, uma compreensão dessas vivências à luz da Psicologia Fenomenológica. Uma reflexão a respeito do cuidado a essas pessoas, levando em conta a dimensão subjetiva existencial que este olhar possibilita ftnalizou o presente estudo. / Due to the complexity of the chronic renal failure and its treatment, renal transplantation is, for the majority of patients, an event very desired. Currently, with the increase of the number of transplants, it is also observed, more frequently, the patient who lives the experience of having to return to the dialysis treatment dialítico after the loss of the renal graft. This work has the proposal focuses on the person with chronic renal failure who has already completed the renal transplantation and, for some reason, has lost the graft encountering, again, with the need to perform hemodialysis to survive. The objective is to understand, starting from the experience lived by the patient, as it is for him to return to live together with the treatment dialítico after having lived a period without needing of that treatment. The work is based on qualitative research method of phenomenological inspiration in Psychology, which investigates the human experience lived, and part of a guiding question: What is it like for the patient to have to return to dialysis treatment after having been a time transplanted and outside the hemodialysis program? For this, all of the eight patients, who experienced this situation and accomplished hemodialysis at the Institute of Hemodialysis of the Holy House of France, SP, were interviewed. By means of phenomenological interview, we tried to get the experience of each patient and apprehend the meanings attributed to their existences. A field diary was used as subsidiary source of information. The interviews were analyzed by means of the phenomenological method. After a careful reading of each interview for apprehension of units of meaning, and from the convergence of these, were discussed the following categories: the transplant, subdivided into: the transplant as a possible: dream and reality, the transplant as experience: the facticity; the loss of the transplant, which is subdivided into: the impact of the loss, the search for the sense, the verification of the learning through experience; the return to the hemodialysis with the subcategories: beginning again, the retaking of the existential project; and the support sources. After the analysis, a comprehensive synthesis of the patients\' existences was accomplished and, posteriorly, an understanding of these existences in the light of Phenomenological Psychology. A reflection on the care to these people, taking into account the subjective dimension existential that this look allows, concluded the present study.

Introdução - As doenças renais terminais têm elevada prevalência. O transplante renal é sabidamente a melhor opção de tratamento, porém há considerável carência de rins de cadáver. A doação intervivos é uma alternativa que propicia redução do tempo em fila de espera, aliada a outras vantagens, contudo, com riscos para o doador. Prefere-se o rim esquerdo por ter veia renal mais longa que o rim contralateral. O rim direito pode ser utilizado em determinados casos, apesar dos riscos impostos pela menor extensão da sua veia. Objetivou-se avaliar as perdas de extensão de veia renal com os métodos de clampeamento mais freqüentemente utilizados, assim como a comparação entre os comprimentos obtidos das veias renais direita e esquerda, antes do seu clampeamento e secção e após. Métodos - Por meio de dissecção de cadáveres, avaliou-se o comprimento da veia renal direita, antes de ser clampeada e seccionada e após, utilizando-se três métodos de clampeamento: com pinça vascular Satinsky, com sutura mecânica (Stapler) e clipe vascular Hem-o-lok®. Empregaram-se os testes Qui-quadrado, T-pareado e ONEWAY-ANOVA para a análise estatística dos dados obtidos. Resultados - Verificou-se que a veia renal direita é significativamente menor que a veia renal esquerda, considerandose o seu comprimento útil em todas as condições. Dentre os três métodos utilizados, evidenciou-se maior comprimento da veia renal direita com o emprego da pinça vascular Satinsky. Não houve diferença estatisticamente significativa entre Stapler e Hem-o-lok®, apesar de o primeiro ter mostrado valores maiores em relação ao segundo. Conclusões - Concluiu-se que a veia renal direita é significativamente menor que a veia renal esquerda, considerando-se o seu comprimento útil. A veia renal direita é 13,7% menor que a veia renal esquerda e não há diferença estatisticamente significativa quando comparadas as medidas entre os três métodos de clampeamento vascular. / Introduction - End-stage renal diseases have high incidence. Renal transplantation is the best approach to such conditions. Live donor transplants offer shorter waiting times, and less surgical stress, but pose risks to the donor. The left kidney is preferred because the left renal vein is longer. The right kidney may be used in selected cases, in spite of the risks due to its shorter vein. The preferred clamping method to minimize right renal vein length waste has not been defined. Methods - The length of the right renal vein was assessed in cadavers, before and after clamping and section, with comparison of three clamping methods: Satinsky vascular clamp; Stapler; and Hem-o-lock® vascular clip. The chi-squared, paired t, and ONEWAY ANOVA tests were used for statistical analysis. Results - The right renal vein was found to be significantly shorter than the left one. The Satinsky method produced the greatest length of the right renal vein. The Stapler and Hem-o-lock® methods did not significantly differ, although the former produced values constantly higher than the latter. Conclusions - The right renal vein is significantly shorter (13.7%) than the left one, and the measures obtained with the three vascular clamping methods did not statistically differ

Aims There are few proven therapies that can protect against the inevitable ischaemia reperfusion injury (IRI) that occurs during renal transplantation. IRI increases the likelihood of delayed graft function (DGF), which negatively impacts on the long-term survival of a transplanted kidney. One enzyme of interest, heme oxygenase-1 (HO-1), degrades heme and protects against the oxidative stress that occurs secondary to IRI. Clinical renal recipients with higher HO-1 levels have improved graft function post transplant. Heme arginate (HA), a form of hemin, which has been used to treat porphyria for over 30 years, has repeatedly been shown to induce HO-1 in in vivo and in vitro macrophages. It is one of the few HO-1 inducers approved for clinical use and healthy volunteer studies confirmed that HA could also safely induce HO-1 in humans. Prior to the formal start of the MD, the University of Edinburgh successfully applied to NHS Blood and Transplant for funding to investigate whether giving HA to recipients of deceased donor renal grafts prior to transplant could upregulate HO-1 and whether this had any effect on the function and health of the grafts. This MD aims to explain the background behind the proposed study, the process of study approval, planning and trial logistics and protocol. This thesis then describes the methods of sample analysis, the results and future directions for the HOT (Heme Oxygenase-1 in renal Transplantation) study. Methods The HOT study planning and approval process took eight months and the first participant was randomised in January 2012. The study was sponsored by ACCORD, a joint company from University of Edinburgh and NHS Lothian, and recruited patients from the Edinburgh Royal Infirmary Transplant Unit. The protocol was followed to ensure that 40 recipients were randomised blind to either active (two doses 3mg kg-1 HA: pre-operatively, day 2) or placebo (NaCl: same schedule). To ensure that the primary outcome was fulfilled, recipient blood was taken daily for peripheral blood mononuclear cells (PBMC) extraction. After further blinding steps, the PBMCs were analysed for HO-1 protein and mRNA. The secondary outcome measures involved collecting urine for analysis of urinary biomarkers (KIM-1 and NGAL), taking renal graft biopsies pre-op and day 5 for renal HO-1 analysis and collecting renal function data. DGF was calculated daily. To ensure that all adverse event data was captured, the recipients were closely reviewed for 7 days and their renal function was monitored for 90 days. Results The final participant was recruited in May 2013 within the predicted timescale and to budget. This participant completed follow-up in August 2013. Of the 40 participants, three received the infusion but did not receive a transplant and therefore could not give primary outcome data. The remaining 37 did and this was analysed. Adverse events were equivalent between groups and there were no adverse reactions to HA. HA upregulated PBMC HO-1 protein at 24 hours compared to placebo: HA 11.1ng/ml (1.0- 37.0) vs. placebo 0.14ng/ml (-0.7- 0.3)(p= < 0.0001). PBMC HO-1 mRNA was also increased: HA 2.73 fold (1.8- 3.2) vs. placebo 1.41 fold (1.2- 2.2) (p=0.02). HA increased HO-1 protein immunopositivity in day 5 renal tissue compared with placebo: HA 0.21 (-24- 0.7) vs. placebo -0.03 (-76- 0.15) (p=0.02) and the percentage of HO-1 positive renal macrophages also increased: HA 50.8 cells per HPF (40.0- 59.8) vs. placebo 22.3 (0- 34.8) (p=0.012). Renal HO-1 mRNA was also increased in HA group: 2.02 (0.20- 4.03) fold increase compared to 1.68 (0.75- 10.39) fold in the placebo group but it was not significant (p= 0.451). Urinary biomarkers were reduced after HA but not significantly so. Histological injury and DGF rates were similar between the groups. Conclusion HA is safe and effective in renal transplant recipients as reported in this phase II, randomised, placebo controlled, blinded, single-centre study. The primary outcome was achieved and demonstrated for the first time that HA induces HO-1 in peripheral and renal macrophages in kidney transplant recipients. There was also evidence that HA increased HO-1 expression in renal tissue. There was no evidence that HA improved renal function or reduced injury as seen in animal models but it is recognised that the sample size was small and the study was not powered to these endpoints. Larger studies are planned to determine the impact of HO-1 upregulation on clinical outcomes and evaluate the benefit to patients at risk of IRI. The plans for HOT2 are expanded in this thesis.

This work represents a significant contribution to the body of knowledge in the area of renal transplantation as it brings together the research related to policy analysis, empirical research, and cultural and religious issues related to organ donation and transplantation among South Asians in the UK. The candidate's work in this area is the first in the UK to systematically document and map a national picture of kidney transplant waiting lists and to identify and examine the complex reasons underlying how and why patient ethnicity impacts upon the likelihood of receiving a kidney transplant. The candidate has also developed a new evidence-base exploring the adequacies of the existing procurement arrangements and the implications of introducing any alternative policies within the context of a multi-ethnic and multifaith UK. Finally, the candidate's work has focused on developing an evidence-base of the public perceptions, attitudes, and religious viewpoints towards organ donation and transplantation among a cross-section ofthe South Asian population. The candidate's published works have been the foundation blocks for stimulating and informing the debate on the provision of renal transplant services for minority ethnic groups through the generation of an empirical evidence-base in a subject area which has traditionally relied upon anecdotal evidence. The evidence-base illuminates a very complex issue which has multi-faceted solutions that need to be addressed in different settings.