UNIVERZITA KARLOVA V PRAZE FAKULTA TĚLESNÉ VÝCHOVY A SPORTU The effect of physical activity and nutrition interventions on physical fitness and quality of life during the first year after kidney transplantation Abstract of disertation Zpracovala: Mgr. Klára Švagrová Školitel: Prof. Ing. Václav Bunc, CSc. Školící pracoviště: Laboratoř sportovní motoriky Praha, 2012 ABSTRACT Kidney transplantation is the best known treatment of chronic kidney failure. However, it is often accompanied by a number of health complications. The transplantation itself positively affects both physical fitness and quality of life during the first year after the transplant surgery which are seriously diminished when compared to the healthy population. This improvement can be even enhanced by appropriate physical activity and nutrition interventions otherwise both the physical fitness and quality of life would start declining after the first post-transplant year again. The aim of this study was to confirm a positive effect of a long-term physical activity and nutrition interventions on health-related physical fitness and health-related quality of life in a representative sample of individuals in the first year after the kidney transplantation. At the same time it was fundamental to verify that the experimental trial can be...

Background: Despite recent advances and refinements in perioperative management of simultaneous pancreas–kidney transplantation (SPKT) early pancreatic graft dysfunction (ePGD) remains a critical problem with serious impairment of early and long-term graft function and outcome. Hence, we evaluated a panel of classical blood serum markers for their value in predicting early graft dysfunction in patients undergoing SPKT. Methods: From a prospectively collected database medical data of 105 patients undergoing SPKT between 1998 and 2018 at our center were retrospectively analyzed. The primary study outcome was the detection of occurrence of early pancreatic graft dysfunction (ePGD), the secondary study outcome was early renal graft dysfunction (eRGD) as well as all other outcome parameters associated with the graft function. In this context, ePGD was defined as pancreas graft-related complications including graft pancreatitis, pancreatic abscess/peritonitis, delayed graft function, graft thrombosis, bleeding, rejection and the consecutive need for re-laparotomy due to graft-related complications within 3 months. With regard to analyzing ePGD, serum levels of white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), pancreatic lipase as well as neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) were measured preoperatively and at postoperative days (POD) 1, 2, 3 and 5. Further, peak serum levels of CRP and lipase during the first 72 h were evaluated. Receiver operating characteristics (ROC) curves were performed to assess their predictive value for ePGD and eRGD. Cut-off levels were calculated with the Youden index. Significant diagnostic biochemical cut-offs as well as other prognostic clinical factors were tested in a multivariate logistic regression model. Results: Of the 105 patients included, 43 patients (41%) and 28 patients (27%) developed ePGD and eRGD following SPKT, respectively. The mean WBC, PCT, NLR, PLR, CRP and lipase levels were significantly higher on most PODs in the ePGD group compared to the non-ePGD group. ROC analysis indicated that peak lipase (AUC: 0.82) and peak CRP levels (AUC: 0.89) were highly predictive for ePGD after SPKT. The combination of both achieved the highest AUC (0.92; p < 0.01) in predicting ePGD. Concerning eRGD, predictive accuracy of all analyzed serological markers was moderate (all AUC < 0.8). Additionally, multivariable analysis identified previous dialysis/no preemptive transplantation (OR 2.4 (95% CI: 1.41–4.01), p = 0.021), donor age (OR 1.07 (95% CI: 1.03–1.14), p < 0.010), donor body mass index (OR 1.32 (95% CI: 1.01–1.072), p = 0.04), donors cerebrovascular cause of death (OR 7.8 (95% CI: 2.21–26.9), p < 0.010), donor length of ICU stay (OR 1.27 (95% CI: 1.08–1.49), p < 0.010), as well as CIT pancreas (OR 1.07 (95% CI: 1.03–1.14), p < 0.010) as clinical relevant prognostic predictors for ePGD. Further, a peak of lipase (OR 1.04 (95% CI: 1.02–1.07), p < 0.010), peak of CRP levels (OR 1.12 (95% CI: 1.02–1.23), p < 0.010), pancreatic serum lipase concentration on POD 2 > 150 IU/L (OR 2.9 (95% CI: 1.2–7.13), p = 0.021) and CRP levels of ≥ 180 ng/mL on POD 2 (OR 3.6 (95% CI: 1.54–8.34), p < 0.01) and CRP levels > 150 ng/mL on POD 3 (OR 4.5 (95% CI: 1.7–11.4), p < 0.01) were revealed as independent biochemical predictive variables for ePGD after transplantation. Conclusions: In the current study, the combination of peak lipase and CRP levels were highly effective in predicting early pancreatic graft dysfunction development following SPKT. In contrast, for early renal graft dysfunction the predictive value of this parameter was less sensitive. Intensified monitoring of these parameters may be helpful for identifying patients at a higher risk of pancreatic ischemia reperfusion injury and various IRI- associated postoperative complications leading to ePGD and thus deteriorated outcome.

Os doentes transplantados renais têm alto risco para desenvolver queratoses actínicas e câncer de pele. Para verificar o efeito quimioprofilático da acitretina estudamos a evolução de 13 doentes transplantados renais com queratoses actínicas múltiplas e história de carcinomas cutâneos submetidos a tratamento por 12 meses (20mg/dia). Fez-se a avaliação clínica e laboratorial regularmente em todo o período do estudo. Realizou-se exame histopatológico, demonstração imuno-histoquímica de sub-populações de linfócitos T (CD4, CD8), células natural killer e células de Langerhans, sua quantificação e comparação em biopsias de pele, sem lesão, de área exposta e protegida do sol antes, após seis e 12 meses de tratamento. Observou-se melhora das lesões cutâneas e ausência de aparecimento de novos tumores em 12 dos 13 pacientes. Não ocorreram alterações laboratoriais relacionadas a função renal, hepatotoxicicidade e hiperlipidemia. Não houve diferenças significativas histopatológicas e da população de linfócitos T e células natural killer da pele exposta e protegida do sol com o tratamento. Verificou-se aumento numérico de células de Langerhans epidérmicas aos 12 meses quando comparado aos da pele antes e após seis meses de tratamento (p = 0,002 e p = 0,003). Em nossa casuística o uso de acitretina em doses baixas foi útil para melhorar o aspecto cutâneo e prevenir lesões cutâneas pré-cancerosas e carcinomas. O aumento das células de Langerhans epidérmicas estaria relacionado ao efeito imunomodular da acitretina. / Renal transplant recipients have an increased incidence of actinic keratosis and skin cancer. In order to examine the chemoprophylatic effects of low-dose acitretin on skin cancer development we submitted 13 renal transplanted patients to acitretin therapy (20 mg/day) for 12 month. The patients were assessed at monthly intervals during the first 6 months and every two months until the 12th month for new skin lesions and for acitretin toxicity. Normal skin biopsies of sun exposed and sun protected area were taken for histopathological exam and submitted to immunohistochemistry technique to demonstrate CD4+ and CD8+ T lymphocytes, natural killer cells and Langerhans cells wich were counted and compared in the beginning, after 6th month and 12th month of the treatment. There was an improvement of actinic keratosis and all patients but one did not develop new skin cancer. Side-effects were well-tolerated and no significant biochemical effects were observed. Although there were no differences in the microscopic aspects of the skin and in the number of CD4+ and CD8+ T lymphocytes and natural killer cells, there was a significant increase in the number of epidermal Langerhans cells after 12 months of acitretin therapy. The data obtained permit us to conclude that low dose acitretin therapy is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients. The increase in epidermal Langerhans cells observed may be an expression of the immunomodulatory effect of acitretin.

Problématique : La pénurie d’organes qui sévit actuellement en transplantation rénale incite les chercheurs et les équipes de transplantation à trouver de nouveaux moyens afin d’en améliorer l’efficacité. Le Groupe de recherche transdisciplinaire sur les prédicteurs du risque immunologique du FRSQ travaille actuellement à mettre en place de nouveaux outils facilitant la quantification du risque immunologique global (RIG) de rejet de chaque receveur en attente d’une transplantation rénale. Le calcul du RIG s’effectuerait en fonction de facteurs scientifiques et quantifiables, soit le biologique, l’immunologique, le clinique et le psychosocial. La détermination précise du RIG pourrait faciliter la personnalisation du traitement immunosuppresseur, mais risquerait aussi d’entraîner des changements à l’actuelle méthode de sélection des patients en vue d’une transplantation. Cette sélection se baserait alors sur des critères quantifiables et scientifiques. L’utilisation de cette méthode de sélection possède plusieurs avantages, dont celui d’améliorer l’efficacité de la transplantation et de personnaliser la thérapie immunosuppressive. Malgré tout, cette approche soulève plusieurs questionnements éthiques à explorer chez les différents intervenants œuvrant en transplantation rénale quant à sa bonne utilisation. Buts de l’étude : Cette recherche vise à étudier les perceptions de néphrologues transplanteurs et référents de la province de Québec face à l’utilisation d’une méthode de sélection des patients basée sur des critères scientifiques et quantifiables issus de la médecine personnalisée. Les résultats pourront contribuer à déterminer la bonne utilisation de cette méthode et à étudier le lien de plus en plus fort entre science et médecine. Méthodes : Des entretiens semi-dirigés combinant l’emploi de courtes vignettes cliniques ont été effectués auprès de 22 néphrologues québécois (transplanteurs et référents) entre juin 2007 à juillet 2008. Le contenu des entretiens fut analysé qualitativement selon la méthode d’analyse de Miles et Huberman. Résultats : Les résultats démontrent une acceptation généralisée de cette approche. La connaissance du RIG pour chaque patient peut améliorer le traitement et la prise en charge post-greffe. Son efficacité serait supérieure à la méthode actuelle. Par contre, la possible exclusion de patients pose un important problème éthique. Cette nouvelle approche doit toutefois être validée scientifiquement et accorder une place au jugement clinique. Conclusions : La médecine personnalisée en transplantation devrait viser le meilleur intérêt du patient. Malgré l’utilisation de données scientifiques et quantifiables dans le calcul du RIG, le jugement clinique doit demeurer en place afin d’aider le médecin à prendre une décision fondée sur les données médicales, son expertise et sa connaissance du patient. Une réflexion éthique approfondie s’avère nécessaire quant à l’exclusion possible de patients et à la résolution de la tension entre l’équité et l’efficacité en transplantation rénale. / Background: The overwhelming scarcity of organs within renal transplantation forces researchers and transplantation teams to seek new ways to increase efficacy. The Groupe de recherche transdisciplinaire sur les prédicteurs du risque immunologique is attempting to put in place a scientifically precise method for determining the global immunological risk (GIR) of rejection for each patient waiting for a renal transplant. The quantification of the GIR is based on scientific factors, such as biological, immunological, clinical and psychosocial. The precise and global determination of the GIR could change the way patients are selected for renal transplantation. This selection will be based thus on scientific and quantifiable criteria. The advantages of the use of this method for selecting potential allograft recipients could be improvement in the efficacy of the process and the individualization of immunosuppressive therapy. In spite of these numerous advantages, this approach raises several ethical questions to explore with nephrologists working in kidney transplantation. Aims of the study: The aims of this study is to explore the views of transplant and referring nephrologists on the use of personalized medicine tools to develop a new method for selection potential recipients of a renal allograft. The results of this research could contribute to determine the acceptable use of this method in renal transplantation and to study the link between science and medicine. Methods: Twenty-two semi-directed interviews, using short clinical vignettes, were conducted with nephrologists in the province of Quebec between June 2007 and July 2008. The semi-directed interviews were analyzed qualitatively using the content and thematic analysis method described by Miles and Huberman. Results: The results demonstrate a general acceptance of this approach amongst the participants. Knowledge of each patient’s immunological risk could improve treatment and the post-graft follow-up. On the other hand, the possibility that patients might be excluded from transplantation poses a significant ethical issue. It could be more effective than the method presently used. The method must be validated scientifically, and must leave a role for clinical judgment. Conclusions: The use of personalized medicine within transplantation must be in the best interests of the patient. However, in spite of the use of such scientific data, a place must be retained for the clinical judgment that allows a physician to make decisions based on medical data, professional expertise and knowledge of the patient. An ethical reflection is necessary in order to focus on the possibility of patients being excluded, as well as on the resolution of the equity/efficacy dilemma.

Foram coletados prospectivamente os dados das primeiras nefrectomias totalmente laparoscópicas (NTL) de doadores renais vivos realizadas no Hospital das Clínicas da Universidade Federal de Pernambuco (HCFMUFPE) e comparadas com os dados recentemente publicados do Hospital das Clínicas da Universidade de São Paulo (HCFMUSP). Da mesma forma, a função renal, a taxa de necrose tubular aguda e rejeição e a taxa de complicações dos receptores também foram analisadas e comparadas. Entre Janeiro e Outubro de 2003, foram realizadas 11 NTL de doadores vivos (4 mulheres e 7 homens) no HCFMUFPE. A idade média foi de 31.5 ± 8 anos e o índice de massa corpórea (IMC) de 20,1 ± 4,1 kg/m2. Em todos os casos, o lado esquerdo foi o escolhido para doação. O tempo cirúrgico até a retirada do rim da cavidade abdominal, o tempo cirúrgico total, o tempo anestésico total e o tempo de isquemia quente (TIQ), foram 189 ± 36 minutos (min), 231 ± 39 min, 299 ± 43 min e 289 ± 111s, respectivamente. A perda sanguínea foi de 214 ± 98mL. Em 2 casos, foi observada, no trans-operatório, a presença de vasos supranumerários: 01 caso- 02 veias; 01 caso- 02 artérias. O pedículo renal foi considerado de bom padrão em todos os enxertos, assim como o comprimento e vascularização ureteral. O controle vascular do pedículo renal foi feito com clips metálicos e de polímero (Hem-O-Lok®, Weck Closure Systems, Research Triangle, CA). Houve uma complicação trans-operatória considerada maior (sangramento do coto da artéria renal), levando à uma conversão urgente para o procedimento aberto (9,1%). Nenhum caso necessitou hemotransfusão. A dose média de dipirona no período pós-operatório e o tempo para realimentação foram de 5,1 doses (2-12) e 15,4 horas (12-24), respectivamente. No período pós-operatório, 04 doadores tiveram 6 complicações menores: 01 caso - úlcera duodenal; 01 caso - distensão muscular da parede abdominal esquerda; 01 caso - cervicalgia, enfisema subcutâneo e infecção de ferida operatória e; 01 caso - infecção de ferida operatória por pseudomonas aeruginosa. Houve uma complicação considerada maior (9.1%), pois acarretou na necessidade de laparotomia exploradora no 11º dia de pós-operatório (DPO): hematoma subaponeurótico ao nível da incisão de Pfannenstiel com rompimento interno, levando a abdome agudo. Estas complicações foram tratadas adequadamente, obtendo bom resultado. O tempo médio de alta hospitalar e retorno às atividades habituais foi 2,8 (2-5) e 19,7 dias (12-30), respectivamente. Todos os enxertos foram considerados de bom padrão e funcionaram de imediato após o implante, com exceção de um caso, o qual demorou 09 horas para iniciar diurese (fez uma sessão de hemodiálise pós-operatória). Este atraso foi atribuído a uma complicação transoperatória no receptor (sangramento agudo de ramo venoso da veia ilíaca interna). Entre os receptores houve 02 óbitos (18.2%). O nono receptor foi a óbito no 5º DPO devido a uma ruptura parcial da anastomose arterial, levando ao choque hipovolêmico, refratário a todas as medidas tomadas, inclusive o tratamento cirúrgico emergencial. O segundo óbito foi observado no décimo receptor, devido a uma encefalite provocada por ciclosporina. Nenhuma complicação ureteral foi observada. A taxa de necrose tubular aguda e de rejeição foi 27.3% (3 casos). Houve uma transplantectomia devido a infecção do enxerto por Pseudomonas aeruginosa (9.1%). A creatinina média dos receptores no 1º, 3º, 5º, 10º e 30º DPO foi de 4.0 ± 2.2, 1.9 ± 0.9, 1.8 , 1.7 e 1.2 ng/dl, respectivamente. Comparando a série dos doadores do HCFMUFPE com à do HCFMUSP, observou-se diferença estatisticamente significante em todos os dados trans-operatórios: tempo cirúrgico até a retirada do rim da cavidade abdominal (189 ± 36 min versus 144 ± 32 min, p ....), tempo cirúrgico total (231 ± 39 min versus 179 ± 30 min, p ....), tempo anestésico total (299 ± 43 min versus 223 ± 31 min, p ....), TIQ (289 ± 111 versus 199 ± 95 seg, p .....) e perda sanguínea (214 ± 98 versus 141 ± 82 ml, p..... ). Houve uma complicação transoperatória considerada maior em cada grupo (9.1% e 2%, respectivamente) e uma conversão para procedimento aberto no grupo do HCFMUFPE (9.1%). Para fins de análise estatística, o quadragésimo sétimo caso do grupo do HCFMUSP foi excluído, pois apresentou uma complicação trans-operatória maior, a qual acarretou em longo tempo de isquemia quente e conseqüente taxa de função renal alterada no receptor. No período pós-operatório dos doadores, houve diferença estatisticamente significante exclusivamente na escala subjetiva de dor no período pós-operatório imediato (POI): 4.3 ± 2.2 e 2.4 ± 2.3 (p ....), no HCFMUFPE e HCFMUSP, respectivamente. Houve um óbito (2%) na série do HCFMUSP. Em média, houve economia de R$ 3.985,00 no procedimento cirúrgico adotado no HCFMUFPE, pois grampeadores vasculares e sacos extratores não foram utilizados. Entre os receptores, a taxa de diurese imediata após o implante do enxerto, bem como a taxa de necrose tubular aguda e rejeição, foram semelhantes em ambos os grupos: 91% versus 92% e 27.3% versus 30%, no HCFMUFPE e HCFMUSP, respectivamente. Houve uma transplantectomia no grupo do HCFMUFPE (9.1%) e duas no grupo do HCFMUSP (4%). Ocorreram quatro complicações ureterais nos receptores do HCFMUSP (8%) e nenhuma nos receptores do HCFMUFPE. Não houve diferença significativamente estatística na taxa de função renal (creatinina) entre o grupo do HCFMUFPE e HCFMUSP, no 1º, 3º, 5º, 10º e 30º dias de pós-operatório: 4.0 ± 2.2 versus 4.0 ± 3.0, 1.9 ± 0.9 versus xxxxxx, 1.8 versus 3.4, 1.7 versus 2.6 e 1.2 versus 1.57, respectivamente. Os dados obtidos evidenciam que o grupo do HCFMUFPE ainda não ultrapassou a curva de aprendizado em nefrectomia laparoscópica do doador renal vivo (NLDV), não obstante não houve prejuízo à integridade dos doadores ou à função renal dos enxertos, após implante nos receptores. A ocorrência de complicações graves obtidas em ambos os grupos, inclusive com um óbito no grupo do HCFMUSP demonstram que a NLDV é um procedimento cirúrgico de alta complexidade, na qual é necessário aprimoramento dos cuidados perioperatórios nos doadores, na tentativa de minimizar tais complicações. A técnica cirúrgica desenvolvida pelo grupo do HCFMUFPE demonstrou ser segura e eficaz, apresentando resultados funcionais semelhantes à técnica utilizada pelo grupo do HCFMUSP, com a vantagem de ter um custo financeiro menor. / Data of the first 11 laparoscopic live donor nephrectomy performed at Clinics Hospital of Federal University of Pernambuco (HCFMUFPE) between January and October, 2003 were prospectively recorded and compared with the first 50 laparoscopic live donor nephrectomy performed at Clinics Hospital of State University of São Paulo (HCFMUSP) between April, 2000 and August, 2003. Overall operative time (231 ± 39 min versus 179 ± 30 min, p ....), overall anesthesia time (299 ± 43 min versus 223 ± 31 min, p ....), average warm ischemia time (289 ± 111 versus 199 ± 95 seg, p .....) and blood loss (214 ± 98 versus 141 ± 82 ml, p..... ) were considered statistically significant better for the HCFMUSP group when compared with the HCFMUFPE group. One major complication was observed in each group (HCFMUFPE- 9.1% and HCFMUSP- 2%) and only one open conversion in the HCFMUFPE group (9.1%). Postoperatively, only pain scale at immediate post-operative day had statistically significant difference: 4.3 ± 2.2 versus 2.4 ± 2.3 (p ....). The HCFMUFPE group saved about R$ 3.985,00 per procedure due to the lack of use of disposable equipments. There were no statistically significant difference in time to initiate diuresis after graft implant (91% versus 92%) and acute tubular necrosis (27.3% versus 30%), with or without acute or chronic rejection, between the HCFMUFPE and HCFMUSP groups, respectively. One graft loss occurred in the HCFMUFPE group (9.1%) and two in the HCFMUSP group (4%). Four ureteral complications were seen in the HCFMUSP group (8%) whereas none in the HCFMUFPE group. No statistical difference was observed related to the recipient renal function after transplantation at 1º, 3º, 5º, 10º e 30º post operative days: 4.0 ± 2.2 versus 4.0 ± 3.0, 1.9 ± 0.9 versus xxxxxx, 1.8 versus 3.4, 1.7 versus 2.6 e 1.2 versus 1.57, respectively. In conclusion, the HCFMUFPE data shows that the learning curve is still to be overcome. Nonetheless, there were no major problems for the donors and no loss of renal graft function after transplantation. The occurrence of major complications in both groups and one death in the HCFMUSP group, highlight the complexity of this procedure. Finally, the HCFMUFPE surgical technique showed to be a safe, cheap and an attractive procedure to be used in undeveloped countries.

Im ersten Teil der Arbeit (Kapitel 2) wird über den Versuch berichtet, die Steroidtherapie nach erfolgreicher Pankreas- und Nierentransplantation (PTX/NTX) zu beenden, um steroidassoziierte Nebenwirkungen zu reduzieren. Alle 32 in dieser Studie untersuchten Patienten wurden initial mit Anti-T-Zell Globulin (ATG), Tacrolimus (Tac), Mycophenolat Mofetil (MMF) und Steroiden behandelt. Von einem erfolgreichem Absetzten der Steroide wurde ausgegangen, wenn die Steroidtherapie innerhalb der ersten 15 Monate nach PTX/NTX beendet werden konnte. Dieses Ziel konnte bei 72% (23/32) bzw. 56% (18/32) der Patienten 1 bzw. 4 Jahre nach der PTX/NTX erreicht werden. Der häufigste Grund für ein nicht fristgerechtes Absetzen der Steroide waren MMF-assoziierte Nebenwirkungen, die eine Reduktion oder das Absetzen des MMF erforderlich machten, so dass die Steroidtherapie fortgeführt werden musste. Das 1- und 4-Jahres-Patienten-, Pankreastransplantat- und Nierentransplantat- Überleben war mit 100/97/100% und 97/87/91% exzellent, wobei kein Unterschied zwischen Patienten mit fristgerecht und nicht fristgerecht beendeter Steroidtherapie beobachtet wurde. Auch unterschieden sich die Parameter des Glukose- und Fettstoffwechsels nicht zwischen den beiden Patientengruppen. Die akuten Rejektionen erwiesen sich bei den Patienten, bei denen das Steroid nach der PTX/NTX erfolgreich abgesetzt werden konnte, im Vergleich zu den Patienten, bei denen dies nicht der Fall war, häufiger als steroidsensibel und führten häufiger zu einer Normalisierung der Transplantatfunktion. Weitere Vorteile, die in der Gruppe der Patienten mit erfolgreichem Absetzten des Steroids beobachtet wurden, waren eine geringere Inzidenz von CMV-Infektionen trotz Einnahme einer höheren MMF-Dosis und ein niedrigerer arterieller Blutdruck. Operationspflichtige Komplikationen traten in dieser Gruppe jedoch häufiger auf. Diese über einen so langen Nachbeobachtungszeitraum erhobenen Daten zeigen erstmals, dass, bei Anwendung des o. a. immunsuppressiven Schemas, ein großer Teil der PTX/NTX Patienten erfolgreich und langfristig ohne Steroide weiterbehandelt werden konnten. Der Benefit der Beendigung einer Steroidtherapie muss jedoch in größeren, vergleichenden und prospektiven Studien mit langer Laufzeit bestätigt werden. Im zweiten Teil der Arbeit (Kapitel 3) wird ein Vergleich der immunsuppressiven Potenz der Calcineurininhibitoren Ciclosporin-A (CyA) und Tacrolimus (Tac) bei Patienten mit PTX/NTX im Rahmen einer randomisierten, prospektiven multizentrischen Studie vorgenommen. Insgesamt wurden 205 Patienten randomisiert und erhielten entweder CyA oder Tac sowie ATG, MMF und Steroide. Nach einem Jahr befanden sich noch 77% der mit Tac und 47% der mit CyA behandelten Patienten in der Studie (p / The first part (Chapter 2) is focussing on the attempt to withdraw steroids after successful simultaneous pancreas and kidney transplantation (SPK) in order to reduce steroid induced side effects. All 32 SPK-patients of this study received Anti-T Cell-Globulin (ATG), Tacrolimus (Tac), Mycophenolate Mofetil (MMF) and Steroids as initial immunosuppression. Successful steroid withdrawal was defined as cessation of steroids within 15 months after SPK. This aim could be achieved in 72% (23/32) and 56% (18/32) of the patients 1 and 4 years after SPK, respectively. The main reason not to withdraw steroids in time was caused by MMF-associated adverse effects which required a reduction or termination of the MMF therapy, thus preventing the discontinuation of the steroid therapy. On the other hand rejection episodes were the only reason for a resumption of the steroid therapy. The 1- and 4 year survival of patients, pancreas and kidney transplants was 100/97/100% and 97/87/91%, respectively. No difference was observed in patients with and without successful steroid withdrawal concerning patient and transplant survival as well as parameters of the lipid and glucose metabolism. Acute rejection episodes in patients with successful steroid withdrawal were more often steroid sensitive and showed a higher frequency of normalised transplant function as compared to acute rejections in patients under continuing steroid medication. Further advantages which could be observed in the group of patients with successful steroid withdrawal were a lower incidence of CMV-infection despite intake of higher doses of MMF and a lower arterial blood pressure; the frequency of surgical complications, however, was higher in this group. This long term observation showed for the first time that under the above mentioned immunosuppression scheme the majority of SPK patients could be successfully and lastingly withdrawn from steroids. However, the benefits of steroid withdrawal in SPK will need to be confirmed in larger, prospective and comparative studies with long observation periods. In the second part (Chapter 3) of this paper, the immunosuppressive potency of the calcineurininhibitors Ciclosporin A (CyA) and Tacrolimus (Tac) in SPK patients is compared in a randomised prospective multicentre trial for the first time. A total of 205 patients were randomised to receive CyA or Tac along with a combined scheme consisting of ATG, MMF, and steroids. After 1 year, 77% of the Tac- and 47% of the CyA-groups remained in the study (p

Made available in DSpace on 2016-01-26T12:51:21Z (GMT). No. of bitstreams: 1 ledaravagnani_dissert.pdf: 406508 bytes, checksum: 8f26d3c0c1b70a9355d7d3bcc7052283 (MD5) Previous issue date: 2002-10-07 / A qualidade de vida tem sido freqüentemente estudada em pacientes crônicos e as estratégias por eles utilizadas para lidar com a doença e tratamento parecem influenciar seu bem estar geral. Este estudo teve como objetivo comparar a percepção do paciente sobre qualidade de vida em dois momentos diferentes, pré e pós-transplante renal, e identificar as estratégias de enfretamento utilizadas por ele após o transplante. Foram objetivos específicos do estudo: 1. Caracterizar pacientes submetidos à transplante renal; 2. Comparar qualidade de vida de pacientes transplantados com enxerto funcionante nos pré e pós cirurgia; 3. Identificar principais estressores e estratégias de enfretamento nesses pacientes. Métodos: no período de outubro de 1999 a janeiro de 2002, foram estudados 17 pacientes (nove do sexo feminino), com idade entre 23 e 55 anos (im: 38 anos; dp: 8,12), submetidos a transplante renal (doadores vivos e cadáver) que evoluíram com enxerto funcionante, com segmento no período de 3 m- 29 meses. Nota de Resumo Foram utilizados na avaliação o inventário de qualidade de vida sf-36, inventário de enfretamento e um roteiro de entrevista (pré pós-transplante). Resultados: não houve diferença significante entre avaliação de qualidade de vida nos períodos pré pós-transplante para as variáveis investigadas pelo sf-36. Os principais fatores de estresse/preocupações foram: efeitos colaterais das medicações, consulta médica, alterações da imagem corporal e o tempo de hospitalização. Os pacientes tiveram tendência a utilizar mais estratégias de enfrentamento centradas na emoção, isto é, formas mais subjetivas de lidar com as dificuldades. Reavaliação positiva da situação foi a estratégia de enfretamento mais utilizada. As menos utilizadas foram fugas e esquiva do problema. Conclusão: o transplante renal não pareceu influenciar a qualidade de vida dos pacientes, havendo indicação que a qualidade de vida pode ser comprometida mesmo após o transplante, pelo estresse em relação à saúde e aos efeitos colateria do tratamento.

The use of quality-of-life as an outcome measure provides detailed information about the effectiveness of medical treatments than morbidity or mortality rates alone. The use of quality-of-life data in the clinical setting can inform patients regarding treatment options, treatment benefits and costs. In competing health care markets, outcome measurement is regarded as important as it is concerned with the impact of health care practice and affects health policy decisions. Doessel (1978) conducted the first Australian study on the cost-effectiveness analysis of renal replacement therapies. The study was based on Klarman, Francis & Rosenthal's (1968) the study, where the output was measured in terms of the number of life years gained from kidney transplantation, and a twenty-five percent weight was allocated in an attempt to capture quality-of-life from kidney transplantation. Doessel (1978) used two sources of data: Australian data (Disney 1974) and European data (Gurland et al. 1973; Shiel et al. 1974). The study measured life years gained, and agreed with the Klarman et al. (1974) findings that transplantation is the most effective way to increase life expectancy of persons with chronic renal disease (Butler & Doessel 1989). The outputs of the alternative treatments were not reported in monetary terms; the study focused on life years gained as the output measure. Hence the importance of this current study, which includes a cost-effectiveness analysis for cadaver liver, and living kidney transplantation for end-stage liver and kidney disease patients. Calls to respect patient autonomy and to produce patient-centered outcomes have recently brought the patient’s point of view back into the center of clinical medicine (Sullivan 2003). Survival rates indicate one measure of outcome however they do not reflect patients’ perceptions of health benefit or experiences. Noting that patients’ psychosocial effect on functioning is of more concern to them than their physical Thesis Preamble iii ability, that more accurate knowledge of patients’ conditions be measured prior to transplantation (Tarter et al. 1991). Recently researchers advocated investigating transplant patients' states of health to assess the social benefit of these expensive health care services from their perspective (Joralemon & Fujinaga 1997). The current study's mixed method, bridges the gaps in treatment outcome measurements, as the mixed method applied (Creswell 1994; Sim & Sharp 1998) prospectively measured quality-oflife, determined health utility, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). The study reported the living donors experience of the donation process, described their needs; expressed using a new psychosocial model supporting future living kidney donor's during the donation process.

Problématique : La pénurie d’organes qui sévit actuellement en transplantation rénale incite les chercheurs et les équipes de transplantation à trouver de nouveaux moyens afin d’en améliorer l’efficacité. Le Groupe de recherche transdisciplinaire sur les prédicteurs du risque immunologique du FRSQ travaille actuellement à mettre en place de nouveaux outils facilitant la quantification du risque immunologique global (RIG) de rejet de chaque receveur en attente d’une transplantation rénale. Le calcul du RIG s’effectuerait en fonction de facteurs scientifiques et quantifiables, soit le biologique, l’immunologique, le clinique et le psychosocial. La détermination précise du RIG pourrait faciliter la personnalisation du traitement immunosuppresseur, mais risquerait aussi d’entraîner des changements à l’actuelle méthode de sélection des patients en vue d’une transplantation. Cette sélection se baserait alors sur des critères quantifiables et scientifiques. L’utilisation de cette méthode de sélection possède plusieurs avantages, dont celui d’améliorer l’efficacité de la transplantation et de personnaliser la thérapie immunosuppressive. Malgré tout, cette approche soulève plusieurs questionnements éthiques à explorer chez les différents intervenants œuvrant en transplantation rénale quant à sa bonne utilisation. Buts de l’étude : Cette recherche vise à étudier les perceptions de néphrologues transplanteurs et référents de la province de Québec face à l’utilisation d’une méthode de sélection des patients basée sur des critères scientifiques et quantifiables issus de la médecine personnalisée. Les résultats pourront contribuer à déterminer la bonne utilisation de cette méthode et à étudier le lien de plus en plus fort entre science et médecine. Méthodes : Des entretiens semi-dirigés combinant l’emploi de courtes vignettes cliniques ont été effectués auprès de 22 néphrologues québécois (transplanteurs et référents) entre juin 2007 à juillet 2008. Le contenu des entretiens fut analysé qualitativement selon la méthode d’analyse de Miles et Huberman. Résultats : Les résultats démontrent une acceptation généralisée de cette approche. La connaissance du RIG pour chaque patient peut améliorer le traitement et la prise en charge post-greffe. Son efficacité serait supérieure à la méthode actuelle. Par contre, la possible exclusion de patients pose un important problème éthique. Cette nouvelle approche doit toutefois être validée scientifiquement et accorder une place au jugement clinique. Conclusions : La médecine personnalisée en transplantation devrait viser le meilleur intérêt du patient. Malgré l’utilisation de données scientifiques et quantifiables dans le calcul du RIG, le jugement clinique doit demeurer en place afin d’aider le médecin à prendre une décision fondée sur les données médicales, son expertise et sa connaissance du patient. Une réflexion éthique approfondie s’avère nécessaire quant à l’exclusion possible de patients et à la résolution de la tension entre l’équité et l’efficacité en transplantation rénale. / Background: The overwhelming scarcity of organs within renal transplantation forces researchers and transplantation teams to seek new ways to increase efficacy. The Groupe de recherche transdisciplinaire sur les prédicteurs du risque immunologique is attempting to put in place a scientifically precise method for determining the global immunological risk (GIR) of rejection for each patient waiting for a renal transplant. The quantification of the GIR is based on scientific factors, such as biological, immunological, clinical and psychosocial. The precise and global determination of the GIR could change the way patients are selected for renal transplantation. This selection will be based thus on scientific and quantifiable criteria. The advantages of the use of this method for selecting potential allograft recipients could be improvement in the efficacy of the process and the individualization of immunosuppressive therapy. In spite of these numerous advantages, this approach raises several ethical questions to explore with nephrologists working in kidney transplantation. Aims of the study: The aims of this study is to explore the views of transplant and referring nephrologists on the use of personalized medicine tools to develop a new method for selection potential recipients of a renal allograft. The results of this research could contribute to determine the acceptable use of this method in renal transplantation and to study the link between science and medicine. Methods: Twenty-two semi-directed interviews, using short clinical vignettes, were conducted with nephrologists in the province of Quebec between June 2007 and July 2008. The semi-directed interviews were analyzed qualitatively using the content and thematic analysis method described by Miles and Huberman. Results: The results demonstrate a general acceptance of this approach amongst the participants. Knowledge of each patient’s immunological risk could improve treatment and the post-graft follow-up. On the other hand, the possibility that patients might be excluded from transplantation poses a significant ethical issue. It could be more effective than the method presently used. The method must be validated scientifically, and must leave a role for clinical judgment. Conclusions: The use of personalized medicine within transplantation must be in the best interests of the patient. However, in spite of the use of such scientific data, a place must be retained for the clinical judgment that allows a physician to make decisions based on medical data, professional expertise and knowledge of the patient. An ethical reflection is necessary in order to focus on the possibility of patients being excluded, as well as on the resolution of the equity/efficacy dilemma.

Os doentes transplantados renais têm alto risco para desenvolver queratoses actínicas e câncer de pele. Para verificar o efeito quimioprofilático da acitretina estudamos a evolução de 13 doentes transplantados renais com queratoses actínicas múltiplas e história de carcinomas cutâneos submetidos a tratamento por 12 meses (20mg/dia). Fez-se a avaliação clínica e laboratorial regularmente em todo o período do estudo. Realizou-se exame histopatológico, demonstração imuno-histoquímica de sub-populações de linfócitos T (CD4, CD8), células natural killer e células de Langerhans, sua quantificação e comparação em biopsias de pele, sem lesão, de área exposta e protegida do sol antes, após seis e 12 meses de tratamento. Observou-se melhora das lesões cutâneas e ausência de aparecimento de novos tumores em 12 dos 13 pacientes. Não ocorreram alterações laboratoriais relacionadas a função renal, hepatotoxicicidade e hiperlipidemia. Não houve diferenças significativas histopatológicas e da população de linfócitos T e células natural killer da pele exposta e protegida do sol com o tratamento. Verificou-se aumento numérico de células de Langerhans epidérmicas aos 12 meses quando comparado aos da pele antes e após seis meses de tratamento (p = 0,002 e p = 0,003). Em nossa casuística o uso de acitretina em doses baixas foi útil para melhorar o aspecto cutâneo e prevenir lesões cutâneas pré-cancerosas e carcinomas. O aumento das células de Langerhans epidérmicas estaria relacionado ao efeito imunomodular da acitretina. / Renal transplant recipients have an increased incidence of actinic keratosis and skin cancer. In order to examine the chemoprophylatic effects of low-dose acitretin on skin cancer development we submitted 13 renal transplanted patients to acitretin therapy (20 mg/day) for 12 month. The patients were assessed at monthly intervals during the first 6 months and every two months until the 12th month for new skin lesions and for acitretin toxicity. Normal skin biopsies of sun exposed and sun protected area were taken for histopathological exam and submitted to immunohistochemistry technique to demonstrate CD4+ and CD8+ T lymphocytes, natural killer cells and Langerhans cells wich were counted and compared in the beginning, after 6th month and 12th month of the treatment. There was an improvement of actinic keratosis and all patients but one did not develop new skin cancer. Side-effects were well-tolerated and no significant biochemical effects were observed. Although there were no differences in the microscopic aspects of the skin and in the number of CD4+ and CD8+ T lymphocytes and natural killer cells, there was a significant increase in the number of epidermal Langerhans cells after 12 months of acitretin therapy. The data obtained permit us to conclude that low dose acitretin therapy is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients. The increase in epidermal Langerhans cells observed may be an expression of the immunomodulatory effect of acitretin.