Thesis (M.S.)--University of Wisconsin-Madison, 1992. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 77-84).

Thesis (M.S.)--University of Wisconsin-Madison, 1993. / Typescript. Appendix B in Chinese. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-78).

Orthotopic liver transplantation is the treatment of choice for many patients with end-stage liver disease. Despite advances in immunosuppression, acute rejection remains common (up to 70%) and results in significant patient morbidity. It is frequently difficult to distinguish abnormal liver function due to rejection from that due to infection, biliary obstruction or ischaemic injury without performing invasive procedures such as a liver biopsy or angiography which may be Clinically, the diagnosis of rejection is usually once the immunological process is already hazardous. made late, established. In this study, we evaluated standard biochemical parameters and cytokine concentrations (IL-1, IL-6 and TNF-alpha) in serial samples of bile obtained post-operatively via the Ttubes of patients following orthotopic liver transplantation in order to determine whether there are any biochemical or immunological pointers to the early diagnosis of rejection which would enable earlier administration of appropriate antirejection therapy. Biliary cytokines did not prove to be useful and reliable markers of early rejection. Serial measurement of biliary bilirubin levels showed an early and significant decrease a few days prior to rejection, and were a more sensitive marker of graft function than serum bilirubin levels.

The lymphatic system plays an important role in both tissue homeostasis and inflammation. During the surgical procedure there is complete disruption of lymphatic drainage of the allograft kidney. The time course and nature of lymphatic reconnection following transplantation is poorly understood. In addition to the extra-renal lymphangiogenesis required for lymphatic reconnection, some patients may develop de novo lymphatic vessels within the renal parenchyma during acute rejection or chronic allograft damage. This work sought to examine the time course and mechanism of lymphangiogenesis and the role of macrophages in this process. Injection of carbon black and Evan’s blue into the rat kidney resulted in rapid transit to the draining hilar renal lymph node. Surgical disruption of the lymphatic drainage of the kidney prevented trafficking of carbon black to the renal lymph node at 24 hours. At day 6 there was macroscopic and microscopic evidence of carbon black localisation in the renal lymph node suggesting functional reconnection. Careful histological analysis of hilar renal tissue indicated that the large lymphatic trunks were replaced by a network of small proliferating lymphatic vessels. Assessment of intra-renal lymphangiogenesis was undertaken in 2 distinct experimental models of renal transplantation. In a murine model of acute allograft rejection there was no evidence of increased lymphatic vessel number at day 7. In a collaboration with Sheffield University, tissue from a rat model of interstitial fibrosis and tubular atrophy was examined. The rat tissue exhibited a prominent macrophage and T-cell infiltration at 12 months but there was no difference in the number of perivascular lymphatic vessels. In contrast, there were numerous lymphatic vessels evident in the interstitium that were absent in control isograft tissue. Interestingly, the number of lymphatic vessels correlated with the extent of fibrosis. Analysis of vascular endothelial cell growth factor-C (VEGF-C) mRNA expression did not show any increase in allografts. The model of unilateral ureteric obstruction (UUO) was employed as a model of rapidly progressive inflammatory fibrosis. UUO was associated with rapid and prominent interstitial lymphangiogenesis. This was associated with a marked increase in macrophage and T-lymphocyte infiltration and increased whole kidney mRNA expression of VEGF-C. The role of macrophages in lymphangiogenesis was explored by administration of macrophage depleting liposomal clodronate. No effect upon lymphangiogenesis was found but liposomal clodronate failed to deplete ED-1 positive macrophages in the kidney. A macrophage isolation strategy was thus employed using the myeloid CD11b marker cells and flow cytometric cell sorting and immunomagnetic bead sorting. Although gene expression studies demonstrated increased ED1 mRNA expression by CD11b enriched cells, no difference in VEGF-C mRNA expression between CD11b cells obtained from obstructed kidneys versus cells from sham controls was evident. Lastly, despite extensive efforts, immunostaining for VEGF-C was unsuccessful. In summary, lymphangiogenesis can reconstitute the lymphatic drainage of the kidney and is prominent in both chronic allograft injury and the acutely obstructed kidney in the rat. Although VEGF-C is the likely driver of lymphangiogenesis direct evidence of macrophage VEGF-C production was not found.

Post-transplant malignancies cause significant morbidity and mortality. In this thesis we investigated malignancies in renal transplanted patients from a clinical viewpoint. The use of regional tumour registries considerably improved identification of pre- and post-transplant malignancies, which are generally underreported in transplant registries. Despite previously adequate cancer treatments with favourable prognosis, patients with pre-transplant malignancies showed higher incidence of post-transplant cancer and reduced survival compared to a 1:3 ratio matched control group of patients without a previous cancer from the Collaborative Transplant Study in Europe. A careful oncological surveillance pre-transplant and post-transplant is recommended. A multidisciplinary team evaluated the immunosuppressive and oncological treatment in a clinical prospective observational study of 120 renal transplanted patients with post-transplant malignancies. In two-thirds of the patients immunosuppression was possible to change to mTOR inhibitors with anti-tumour effects. Oncological treatment was adjusted in 50% of patients with solid or haematological tumours. MDT assessments are essential for optimizing treatment of post-transplant malignancies. Number of previous cutaneous squamous cell carcinoma (SCC) posed the most significant risk variable in predicting subsequent SCCs during a two-years study of 73 transplanted patients with at least one SCC. Incidence of transplant-derived tumours is 5 times higher than anticipated. Three of eleven cancers in urinary tract and two of four cancers in the transplants were transplant-derived. Five of eleven cancers of the urinary tract were BK-virus positive. Allograft immune response against these tumours offer new options for cancer treatment such as immunomodulatory or anti-viral treatment in combination with modified immunosuppression.

Bakgrund: Organtransplantation betyder att ett friskt organ överförs från en person till en annan och detta används som en livräddande behandling eller också som en behandling vid funktionssvikt. I Sverige transplanterades under 2015 organen njurar, lever, hjärta, lungor, bukspottkörtel, tarmar och cellöar. Syfte: Syftet med litteraturstudien var att undersöka patienternas upplevelser i väntan på ett nytt organ. Metod: Litteraturstudien grundar sig i en kvalitativ ansats baserad på tio vetenskapliga originalartiklar. Artiklarna analyserades med hjälp av en innehållsanalys (Lundman & Graneheim, 2012). Resultat: Fyra kategorier och sju underkategorier framkom efter analys och presenterade resultatet. Upplevelsen av att befinna sig på väntelistan, att få en andra chans, att tappa kontrollen över livet, att leva i väntan. Upplevelsen av att livet förändras, livet stannar upp, förlust av det tidigare livet. Upplevelsen av stöd, stöd från sjukvårdspersonal och stöd från familj, vänner och andra som befunnit sig i samma situation. Känslor gentemot donatorn och donatorns familj. Slutsatser: Väntan på ett nytt organ var en påfrestande tid för patienterna som präglades av emotionella upp och nedgångar. Patienterna behövde stöd från både sjukvårdspersonal och anhöriga för att klara tiden i väntan på ett nytt organ och samtidigt uppleva hälsa och välbefinnande.

published_or_final_version / Pathology / Master / Master of Philosophy

published_or_final_version / Anatomy / Master / Master of Research in Medicine

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

abstract / Orthopaedics and Traumatology / Doctoral / Doctor of Philosophy