No description available.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

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.