Diss. Stockholm : Karolinska institutet, 2006.

Thesis (Ph. D.)--University of Washington, 1991. / Vita. Includes bibliographical references (leaves [218]-228).

Diss. (sammanfattning) Göteborg : Göteborgs universtiet, 2010. / Härtill 4 uppsatser.

Thesis (M.A.(Theology)--University of Pretoria, 2006. / Includes bibliographical references (leaves 97-101).

Kidney transplantation is a lifesaving treatment for end stage kidney disease that offers considerable benefits to recipients in terms of survival and quality of life. The growing demand for transplants to treat conditions stemming from a rising prevalence of end stage renal disease, diabetes and cardiovascular diseases has to be met increasingly with donors who are older with a high incidence of comorbid conditions. Organs obtained from these higher risk donors are more likely to have either suboptimal short and long-term transplant outcomes or even fail to function altogether. Transplant clinicians, who have to balance the risk of patients dying while waiting for a transplant against the uncertainty of outcomes, often decline organs as transplants. These clinical challenges entail difficult decisions, and more refined tools to assess and quantify the risks of marginal donor organs are lacking. Diagnostic markers of donor kidney quality that can predict transplantation outcomes are highly desirable in order to discriminate the suboptimal from those allografts that will recover and have good long-term function. My doctoral research using donor samples collected within the Quality of Organ Donation (QUOD) programme has shown for first time that it is possible, on the basis of a tissue proteomic profile, to discriminate donor kidneys at the time of retrieval that will have suboptimal allograft function from those kidneys that could recover and have good function at three and 12 months post transplantation. Despite AKIN classification and Remuzzi scoring showing no evidence of acute kidney injury or chronic kidney disease in the analysed biopsies, quantitative mass spectrometry and degredomics experiments with a subsequent validation analysis on an independent cohort of biopsy samples confirmed the increased levels of inflammation and pro-fibrotic proteins in the allografts with suboptimal function, while increased levels of cytoprotective proteins were detected in the kidneys that recovered with a good function one year after transplantation. Furthermore, the kidneys with suboptimal function demonstrated enhanced degradation of cytoskeletal proteins that are vital in sustaining the glomerular basement membrane cytoskeleton. In addition, I conducted a pilot study using proteomic analysis of serum and urine of donors whose kidneys either developed delayed graft function or functioned immediately. This study confirmed that is feasible to identify alterations in the blood and urine proteome that are biologically meaningful. In preparation of the discovery and development of diagnostic biomarkers of long-term outcome after kidney transplantation using QUOD plasma samples, I assessed the pre-analytical variability associated with the processing of whole blood during QUOD sample collection in order to identify a baseline proteomic and peptidomic profile against which candidate protein markers relevant for clinical correlates can be selected. Based on the findings reported in this thesis, future work should aim to identify and develop better diagnostic tools that can more reliably predict donor organ quality. In addition, novel intervention strategies can be explored that either attenuate pro-fibrotic and proteolytic activities or enhance antioxidant and cytoprotective mechanisms in deceased donor kidneys prior to transplantation.

Les infections par cytomégalovirus sont un problème majeur en transplantation rénale du fait de l’augmentation du risque de perte de greffon et de l’augmentation de la morbi-mortalité des patients. Toutefois la mise en place d’un traitement prophylactique par ganciclovir a significativement fait diminuer l’incidence de ces infections. Cette efficacité est toutefois limitée par une importante hématotoxicité notamment des neutropénies. La survenue de cet évènement indésirable conduit à une réduction des doses voire à un arrêt du traitement, favorisant ainsi l’émergence de résistances virales. Ces résistances sont un problème grandissant chez les personnes transplantées du fait du manque de protocole de prise en charge de celles-ci. Dans ce contexte notre objectif était de mieux comprendre la survenue et le mécanisme de cette toxicité. Dans un premier temps nous avons étudié le métabolisme intracellulaire du ganciclovir chez des patients. Nous avons remarqué qu’il y a une forte corrélation entre l’exposition à la forme active du ganciclovir et la diminution du nombre de neutrophiles au 3ème mois de traitement. Nous avons par la suite étudié l’impact de variations génétiques sur des transporteurs. Nous avons remarqué qu’un polymorphisme était fortement associé à une diminution du nombre de neutrophiles et qu’il entrainait également une augmentation de la concentration intracellulaire de ganciclovir à l’aide d’un modèle in vitro. Cette thèse fournit de nouveaux outils d’exploration du métabolisme et de l’accumulation intracellulaire du ganciclovir qui pourraient être utiles pour la prévention de la survenue de neutropénies sous ganciclovir. / Cytomegalovirus infection is a major issue in transplant patients as it affects the graft survival and contributes to patients’ morbi-mortality. The implementation of ganciclovir prophylaxis has significantly decreased its incidence, however GCV frequently induces neutropenia. This adverse effect leads to a decrease in the ganciclovir dose or to a discontinuation of the therapy, thereby favoring viral resistance. Resistance to ganciclovir is a growing problem in solid organ transplantion because of the lack of proper data to support treatment decisions when it is encountered. In this context we aim at better understanding the factors involved in this toxicity. First we explored the intracellular metabolism of ganciclovir in patients’ white blood cells. We found that the active form of ganciclovir is associated with neutrophil toxicity at month 3 of treatment. Then we explored the effect of targeted polymorphisms among transporter genes in two cohorts of renal transplant patients. We found that a single nucleotide polymorphism is strongly associated with a decrease in the neutrophil count and in ganciclovir intracellular accumulation. This thesis provides relevant tools for a deeper exploration of ganciclovir intracellular metabolism and accumulation which might be useful for the prevention of ganciclovir induced neutropenia.

Les hépatectomies majeures et la transplantation hépatique sont des procédures bien codifiées, qui induisent d'importantes modifications hémodynamiques au niveau du territoire splanchnique. Ces modifications surviennent pendant ainsi qu'après l'intervention, conséquence d'une augmentation importante du débit sanguin porte associé à une diminution du lit vasculaire du foie restant, aboutissant au syndrome small-for-size qui peut mettre en jeu le pronostic vital. Le but de ce travail était d'étudier les variations hémodynamiques splanchniques au cours des hépatectomies majeures et de la transplantation hépatique, à partir d'une étude clinique et expérimentale.Sur le plan expérimental, nous avons mis au point 2 modèles porcins d'hépatectomie étendue à 70% et 90% et 1 modèle de transplantation hépatique, ce qui nous a permis d'étudier les variations hémodynamiques splanchniques observées après ces procédures. Nous avons par la suite étudié et démontré les effets potentiellement bénéfiques de la perfusion de somatostatine au cours des hépatectomies étendues. Enfin, nous avons développé une nomenclature standardisée pour les modèles porcins de syndrome small-for-size.Sur le plan clinique, nous avons mis en évidence l'intérêt de l'évaluation peropératoire des variations hémodynamiques splanchniques par débitmétrie au cours de la transplantation hépatique pour la gestion des shunts splanchnico-systémiques. Nous avons développé un protocole de gestion des anomalies Doppler du flux artériel hépatique après transplantation hépatique, consistant en l'administration de vasodilatateurs systémiques chez les patients ayant une baisse des index de résistance hépatiques artériels dans les 6 mois après transplantation. Enfin, nous avons développé un protocole d'étude randomisée visant à évaluer l'intérêt de la somatostatine pour la prévention de la survenue d'ascite après hépatectomie pour carcinome hépatocellulaire / Major hepatectomies and liver transplantation represent well-established procedures, which induce dramatic hemodynamic changes at the splanchnic level. These changes occur during and after the procedure and are related to a major increase of portal blood flow combined with a decrease of downstream vascular bed, resulting in the small-for-size syndrome, which represents a life-threatening issue. The aim of the present work was to study the hemodynamic changes after major hepatectomy and liver transplantation from a clinical and experimental point of view. During our experimental study, we developed 2 porcine models of extended 70% and 90% hepatectomy and 1 model of liver transplant, which allowed us to study the hemodynamic changes that occurred after those procedures. We further studied and showed the potentially beneficial effects of somatostatin infusion after extended hepatectomy. Finally, we developed a standardized nomenclature for porcine models of small-for-size syndrome. During our clinical study, we raised the interest of an intraoperative assessment of splanchnic hemodynamic changes using flowmeter for the management of portosystemic shunts. We also developed a protocol for the management of hepatic arterial flow abnormalities following liver transplantation, consisting of the administration of systemic vasodilators in patients with decreased resistive index within 6 months after transplant. Finally, we developed a randomized trial protocol aiming to assess the interest of somatostatin for preventing postoperative ascites after hepatectomy for hepatocellular carcinoma

No description available.

The aims of the present investigation are fourfold: (i) to review the range of non-invasive methods that may be used to diagnose acute cardiac allograft rejection; (ii) to review the use of the bioptome in sampling the donor heart endomyocardium; (iii) to review the light microscopic and histological grading of acute cardiac rejection; (iv) to characterise the mononuclear populations in endomyocardial biopsy samples and correlate the findings with the light microscopic appearances of the same biopsy specimens.

Thesis (M.Med.(General Surgery)--University of the Witwatersrand, Faculty of Health Sciences, 2014. / Background. Renal insufficiency is increasingly common in end-stage liver disease and allocation of livers to this category of patient has escalated. The frequency of combined liver-kidney transplantation (CLKT) has consequently increased. Indications for CLKT in children differ from those for adults and typically include rare congenital conditions; subsequently limited numbers of this procedure have been performed in paediatric patients worldwide. Scant literature exists on the subject. Methods. Subsequent to institutional approval, a retrospective chart analysis of all paediatric CLKTs performed at the Transplant Unit, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa between January 2005 and July 2013 was conducted. Results. Defining children as younger than 18 years of age, 43 patients had received a liver transplant since 2005, of whom 8 received a CLKT. Indications included autosomal recessive polycystic kidney disease (n=3), primary hyperoxaluria type 1 (n=4) and heterozygous factor H deficiency with atypical haemolytic uraemic syndrome (n=1). Graft combinations included whole liver and one kidney (n=5), whole liver and two kidneys (n=1) and left lateral liver segment and one kidney (n=2), all from deceased donors. Patient age ranged from 4 to 17 years (median 9) and included 4 females and 4 males. Weight ranged from 13 to 42 kg (median 22.5). We describe one in-hospital mortality. The remaining 7 patients were long-term survivors with a survival range from 6 to 65 months. Conclusions. Although rarely indicated in children, CLKT is an effective treatment option, appropriately utilising a scarce resource and significantly improving quality of life in the recipient.