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Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Despite the high prevalence of chronic kidney disease, renal narratives are under-reported. Much of what is written on kidney failure is written by health care professionals for health care professionals and about patients. While medical experts and health care practitioners have one type of knowledge, their patients have another type of knowledge acquired through their experience of their own condition. From within the disability and patients’ rights movements urgent calls have been made for the authentic voices of disabled people and patients to be heard without the mediation of professional lenses. In response to this my dissertation combines personal and academic writing to explore my own experience of end-stage renal disease, dialysis, transplantation and the life after transplant. I have used autoethnography as a methodology. Autoethnography is a relatively new, somewhat postmodern form of inquiry that developed from the reflexive turn in anthropology and narrative studies in the latter part of the twentieth century. It is very useful in writing about the experience of illness and reflecting on illness narratives because, in autoethnographic writing, the observer and observed, the narrator and narrated, insider and outsider are the same person. This allows scope for exploring the problematics of representation and for finding alternatives to already existing ways of telling certain stories. Engaging with autoethnography’s postmodern aspects has allowed me to conceptualize experiences that, until I undertook this research, I have never been able to articulate, because the traditional (static) illness narrative forms did not speak to my experience or my understanding of my condition. The central issue in my dissertation lies in the question: How do I tell the story of chronic illness once I have had an organ transplant? Flowing from this are a number of sub-issues: Can my story change? How do I describe myself: The well, the ill, the impaired, the disabled, the afflicted? Do I describe myself living in no man’s land? In my narrative, do I oscillate between being well and ill, or do I occupy another territory entirely? And if I do, what is it? My study shows that writing the story (or stories) of chronic kidney disease is complex, nuanced and dynamic and that, far from being an extended liminal experience, kidney disease is littoral. This distinction is important in coming to narrative terms with an identity that is not damaged so much as different. Through this I hope to demonstrate to both outsiders and insiders, who often submit to narratives that are forced on them, that more satisfying alternatives can be found. / AFRIKAANSE OPSOMMING: Ondanks die hoë voorkomssyfer van chroniese nierkwale word nierverhale nie genoeg aangemeld nie. Die meerderheid van dit wat oor nierversaking geskryf word, word deur gesondheidsorgdeskundiges vir gesondheidsorgdeskundiges en oor pasiënte geskryf. Terwyl mediese deskundiges en gesondheidsorgpraktisyns een soort kennis het, het hulle pasiënte ’n ander soort kennis op grond van hulle ervaring van hulle eie toestande. Van binne die gestremdheid en pasiënteregte-bewegings het ’n dringende oproep weerklink vir die outentieke stemme van mense met gestremdhede en pasiënte om gehoor te word sonder die tussenkoms van professionele perspektiewe. In reaksie hierop kombineer my verhandeling persoonlike en akademiese beskrywings om my eie ervaring van eindstadium- nierkwale, dialise, oorplanting en die lewe na oorplanting te verken. Ek het outo-etnografie as metodologie gebruik. Outo-etnografie is ’n relatief nuwe, ietwat postmoderne vorm van ondersoek wat in die tweede deel van die twintigste eeu uit die refleksiewe wending in antropologie en narratiewe studies ontwikkel het. Dit is baie bruikbaar wanneer oor die belewenis van siekte en besinning oor siekte-narratiewe geskryf word aangesien die waarnemer en die waargeneemde, die verteller en dit wat vertel word, die ingewyde en die buitestander in outo-etnografiese skryfwerk dieselfde persoon is. Dit laat meer ruimte vir verkenning van die problematiek van voorstelling en vir die opspoor van alternatiewe vir reeds bestaande wyses om sekere stories te vertel. My bemoeienis met postmoderne aspekte van outo-etnografie het dit vir my moontlik gemaak om ervaringe wat ek tot en met hierdie navorsing nooit kon artikuleer nie, te konseptualiseer, aangesien die tradisionele (statiese) vorme van siekte-narratiewe nie tot my ervaring of my begrip van my toestand gespreek het nie. ‘Hoe vertel ek die storie van chroniese siekte nadat ek ’n orgaanoorplanting gehad het?’ is ’n sentrale vraagstuk in my verhandeling. Hieruit spruit ’n aantal newevraagstukke voort: Kan my storie verander? Hoe beskryf ek myself: Die gesonde persoon, die sieke, die verswakte, die gestremde, die aangetaste? Hoe beskryf ek myself wat in ’n niemandsland woon? Fluktueer ek in my narratief tussen gesond wees en siek wees of betrek ek ’n geheel ander gebied? En indien wel, wat is dit? My studie toon dat, om die storie (of stories) van chroniese niersiekte te skryf, kompleks, genuanseerd en dinamies is en dat niersiekte glad nie ’n uitgebreide liminale ervaring is nie, maar eerder littoraal is. Dit is belangrik wanneer daar tot ’n narratiewe verstandhouding gekom moet word met ’n identiteit wat nie soseer beskadig is nie, maar eerder anders. Hierdeur hoop ek om aan beide buitestanders en ingewydes, wat dikwels voor narratiewe wat op hulle afgedwing word, moet buig, te wys dat daar meer bevredigende alternatiewe gekry kan word.

There is limited research on music therapy for transplant recipients, yet board-certified music therapists working in medical settings often encounter individuals from the transplant population. The purpose of this study was to examine the current practices of music therapists working with bone marrow and organ transplant recipients. A total of 68 board-certified music therapists completed an online survey, providing information related to goal areas addressed in music therapy sessions and interventions frequently used with bone marrow and organ transplant patients. The most frequently reported goal areas included: coping skills, mood, and self-expression. The most frequently reported interventions included: singing, songwriting, and improvisation. Survey respondents also shared opinions related to the need for additional resources for music therapists working with transplant recipients, as well as the most rewarding and challenging aspects of working with transplant patients. Study limitations, suggestions for future research, and implications for clinical practice are included.

Background: When a person suffers from organ failure, an organ transplantation can save life. Persons on the waiting list often have mixed feelings like uncertainty and hope for the future. Even the time after transplantation is described like a period of physical and mental challenges during the recovering. Aim: The aim of this study was to highlight persons´ experiences after an organ transplantation. Method: The method used was a literature-based study based on qualitative articles. A total of eight articles were analyzed with a Qualitative content analysis. Results: The results from the study showed that people experienced mixed feelings after transplantation and these were described in three main themes: A new reality, New strategies and Emotional roller coaster. Conclusion: People who have undergone an organ transplant experience both physical and mental stress during recovery. / Personer som drabbas av svikt i ett eller flera organ kan bli aktuella för en organtransplantation. Det är en medicinsk behandlingsmetod som kan rädda liv men samtidigt innebära många omställningar i personens liv. När personerna stod på väntelistan för organtransplantation hade de olika tankar inför sin kommande transplantation och förhoppningar inför livet som transplanterade. Studiens syfte var att belysa personers upplevelser av att ha genomgått en organtransplantation. Åtta artiklar valdes sammanlagt till studien. I resultatet framkom att personerna upplevde fysiska och psykiska påfrestningar efter operationen. Utifrån det formades tre teman En ny verklighet, Nya strategier och Känslomässig bergodalbana. Upplevelserna efter transplantationen hade både positiv och negativ karaktär. Personerna kände skuld, rädsla, tacksamhet och tillit över att ha mottagit ett organ från en avliden person. Chansen till ett nytt liv var något som många ville förvalta på bästa sätt. Personerna upplevde även förändrade roller i familjen och med vänner. De kunde återuppta sina intressen och sina roller som make/maka, förälder och vän. Personerna upplevde även begränsningar i sitt nya liv genom restriktioner i form av infektionskänslighet och medicinering. De flesta fick hjälp och stöttning från familj och upplevde att det och adekvat information från sjukvården gav dem trygghet i sitt tillfrisknande. Sjuksköterskan har en betydande roll i omhändertagandet av personer som genomgått en organtransplantation. Det framkom att många negativa upplevelser som personerna genomgick hade kunnat förhindras med hjälp av information. Genom ett personcentrerat förhållningssätt där varje person bemöts utefter deras förutsättningar och behov går det att förbättra omhändertagandet av personer som genomgått en transplantation och minska deras negativa upplevelser.

Background: Abdominal solid organ transplantation has evolved from an experimental procedure to a well-established therapy within a few decades. This success is largely due to the introduction of calcineurin inhibitor immunosuppression. Tacrolimus is the most widely used calcineurin inhibitor but has a narrow therapeutic range which requires close drug monitoring to prevent both toxicity and inadequate immunosuppression. Previous studies in renal transplantation have shown that genetic polymorphisms, CYP3A5, CYP3A4*22 and ABCB1 can influence the bioavailability and pharmacokinetics of tacrolimus. These polymorphisms are closely linked to ethnicity and have never been studied in a Scottish population before. Additionally, increasing evidence suggests that high variability of tacrolimus is linked to increased graft loss in kidney transplant patients. Methods: 5889 subjects were genotyped for the genetic polymorphisms CYP3A5 A > G allele transition, CYP3A4*22 C > T and ABCB1 C > T transition. This included 4899 healthy individuals from Generation Scotland bio-resource and 990 patients who underwent renal, liver, or simultaneous pancreas kidney transplants or were organ donors. Tacrolimus dose, trough level and renal function were measured at 11 time points from date of transplant up to and including 12 months post-transplant. Clinical data including episodes of acute rejection, graft and patient survival were compared between the different genotypes. Separate analyses were undertaken for kidney, SPK transplants, as well as liver transplants, the latter looking at recipient and liver donor genotype. A separate cohort of 103 renal transplant patients converted from twice-daily to once-daily tacrolimus had their tacrolimus variability calculated and compared with graft survival. Results: The distribution of the 3 different genotypes of CYP3A5, CYP3A4*22 and ABCB1 were comparable with other Caucasian populations studied previously. In renal transplant recipient expression of the A allele (GA/AA) led to significantly increased dose requirements of tacrolimus and initially lower tacrolimus trough levels. The different genotypes of ABCB1 had no effect. Expression of a CYP3A4*22 T allele trended towards a lower tacrolimus dose requirement but this was not significant. There was no difference in renal function, graft survival or patient survival with any of the polymorphisms. SPK patients had comparable results. In the liver transplant patients, the donor genotype had a greater influence than the recipient one. The donors with CYP3A5 A allele expression had significantly higher tacrolimus dose requirements and lower initial tacrolimus levels. This was apparent to a lesser extent with the recipient expression of CYP3A5 and did not reach statistical significance at all time points. There was no significant difference in tacrolimus dose requirements or level with either donor or recipient expression of ABCB1 or CYP3A4*22. There was a significantly higher incidence of acute rejection in donor CYP3A5 A allele expressers of liver transplant patients in univariate and multivariate analysis. There was no significant different in acute rejection with ABCB1 or CYP3A4*22 genotype. No differences in graft or patient survival with either donor or recipient genotype of any of the 3 polymorphisms were noted. Conversion from twice-daily to once-daily tacrolimus in the first 12 months post-transplant reduced tacrolimus variability. Patients with high tacrolimus variability pre and post conversion had significantly greater graft loss than patients with low tacrolimus variability. Conclusion: CYP3A5 expression results in increased tacrolimus requirements to achieve adequate immunosuppression in renal transplant and SPK patients. Donor rather than recipient CYP3A5 expression is relevant for liver transplantation and dose requirements. There may be an association with donor CYP3A5 expression in liver transplant patients and acute rejection which needs further evaluation. ABCB1 and CYP3A4*22 do not appear to have a significant impact in any of the organ transplants. High tacrolimus variability is associated increased graft loss in renal transplant patients.

This thesis sought to improve our understanding of how kidneys become injured as a consequence of organ donation, with the aim of improving the outcomes of transplantation. Every year, hundreds of patients on the waiting list die whilst awaiting a kidney transplant. With an ever-increasing demand for suitable organs, supply cannot keep up with the pressures on the transplant waiting list. As a consequence the transplant community are forced to use organs that previously would not have been considered suitable for transplant, including from older donors with additional comorbidities. This thesis aimed to develop an understanding as to how the kidney becomes injured during the donation process, identifying which key cellular homeostatic processes are disturbed as a consequence of donation. The thesis outlines the experimental development of rodent models of organ donation replicating the donation process for donation after brain death (DBD) and donation after circulatory death (DCD) donors and also the development of a kidney ischaemia reperfusion injury (IRI) model. Proteomics was subsequently used to identifying global protein alterations in the kidney as a consequence of brain death and ischemia reperfusion injury using bioinformatics tools to identify involvement of cellular pathways. The results indicated alterations in mitochondrial function and metabolic homeostasis occurring following brain death. Alterations in cellular metabolism and mitochondrial function were then confirmed using metabolomics and mitochondrial functional assays. I subsequently evaluated how alterations in cellular hypoxia and the hypoxia inducible factor system is altered in the brain dead organ donor kidney and aimed to target this system as a means of conditioning the brain dead organ donor to prevent mitochondrial and metabolic mediated injury to kidney cells following brain death. This involved exploring the role of prolyl hydroxylase inhibitors, including dimethyloxalylglycine, on mitochondrial function and whether this could be a therapeutic target in organ donation. This thesis provides important insights into the mechanism of injury of kidneys following brain death, providing evidence that even before procurement and preservation in the DBD donor alterations in mitochondrial function and metabolic homeostasis occur. I provide preliminary data on the use of prolyl hydroxylase inhibitors in altering mitochondrial function. I also outline my involvement in other ongoing projects in organ donation and machine perfusion that also aim to improve the outcomes of deceased donor kidney and liver transplantation.