Xiao, Kang. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 83-103). / Abstracts in English and Chinese. / Abstract --- p.I / 摘要 --- p.VI / Chapter Chapter 1 --- Background --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Albuminuria --- p.3 / Chapter 1.2.1 --- Definition --- p.3 / Chapter 1.2.2 --- Albuminuria in adolescents/children --- p.6 / Chapter 1.2.3 --- Prevalence of albuminuria in adults and adolescents --- p.8 / Chapter 1.2.4 --- Pathogenesis of albuminuria --- p.10 / Chapter 1.3 --- CVD and risk factors --- p.12 / Chapter 1.4 --- The associations between microalbuminuria and CVD risk factors --- p.17 / Chapter 1.5 --- Heavy metals --- p.18 / Chapter 1.5.1 --- Definition of heavy metals --- p.18 / Chapter 1.5.2 --- Adverse effects of heavy metals --- p.19 / Chapter 1.5.3 --- Heavy metals exposure In Hong Kong population: the local scene --- p.28 / Chapter 1.6 --- MicroRNAs --- p.29 / Chapter 1.6.1 --- The discovery of microRNAs --- p.29 / Chapter 1.6.2 --- The biogenesis of microRNAs --- p.30 / Chapter 1.6.3 --- The function of microRNAs --- p.31 / Chapter 1.7 --- Hypothesis --- p.40 / Chapter Chapter 2 --- Methodology --- p.41 / Chapter 2.1 --- Population --- p.41 / Chapter 2.2 --- Laboratory assays --- p.42 / Chapter 2.3 --- Statistical analysis --- p.44 / Chapter Chapter 3 --- Results --- p.46 / Chapter 3.1 --- Demographic and baseline clinical data --- p.46 / Chapter 3.2 --- Microalbuminuria and cardiovascular risk factors --- p.48 / Chapter 3.3 --- Microalbuminuria and heavy metals --- p.51 / Chapter 3.4 --- Microalbuminuria and miRNAs --- p.54 / Chapter 3.5 --- "Microalbuminuria, miRNAs, heavy metals and cardiovascular risk factors" --- p.57 / Chapter 3.6 --- miRNAs and heavy metals --- p.60 / Chapter Chapter 4 --- Discussion --- p.62 / Chapter 4.1 --- Heavy metals and microalbuminuria --- p.62 / Chapter 4.2 --- Heavy metals and CVD risk factors --- p.68 / Chapter 4.3 --- Microalbuminuria and CVD risk factors --- p.75 / Chapter 4.4 --- miRNAs and Heavy metals --- p.76 / Chapter 4.5 --- miRNAs and microalbuminuria --- p.77 / Chapter 4.6 --- Conclusion --- p.79 / Acknowledgement --- p.82 / References --- p.83

Ioversol and Iomeprol are radiological contrast media commonly used interchangeably in many South African imaging facilities for coronary angiography. Despite differences in chemical composition, they are presumed to have similar renal safety profiles. However, no studies directly compare the renal safety of these two contrast media for coronary angiography in a predominantly healthy population. A systematic review was performed to establish which contrast medium is safer. Articles were sourced from Medline, CINAHL, Scopus, Science Direct, and PubMed Clinical Queries databases. Eligible studies were peer-reviewed articles of coronary angiography examinations carried out on a healthy adult population, where Ioversol or Iomeprol or both were administered, with contrast-induced nephropathy as an end-point. Six articles with a total population of 2431 patients were selected. The Cochrane Risk of Bias Tool was used in evaluating included articles. Pooling studies using the random effects model did not show a statistically significant reduction in contrast-induced nephropathy when Iomeprol was administered (Risk ratio 1.14, 95% confidence interval 0.797-1.643, p = 0.466). Moderate heterogeneity (I2=54.21%) across the studies was observed. Study limitations included potential bias during data extraction because this was performed by a single reviewer, and language restrictions to include only English titles. Iomeprol may be better for use in the clinical setting because of more a predictable renal safety profile. / Health Studies / M. P. H. (Health Studies)

Text in Afrikaans / Summaries in Afrikaans and English / Psigonefrologie behels die studie von psigologiese faktore wat 'n rot speel by eindstadiumnierversaking. Nierversaking word beskou as 'n lewensbedreigende siekte, wat die lewensverwogting von die pasient verkort indien hy nie behandeling ontvang nie. Nierversaking kan ingedeet word in drie stadiums: Die pre-dialise, diatise, en oorplantingstadiums. Die onderskeibaorheid von hierdie stadiums is die gevotg von verski lie in mediese behandelingsmetodes. Nie een hiervon bring genesing nie, maar vertig simptome van die uremiese sindroom, verleng die tewensverwagting von die pasient, en is veronderstel om sy lewenskwaliteit te verbeter. DepresS,ie en angs, is algemene simptome wat by nierpasiente voorkom. Die redes hiervoor, is die pasient se psigologiese reaksie teenoor nierversaking, dialise, en/of 'n oorplanting. Verder moet hy ook die newe-effekte van die mediese behandeling trotseer. Aanpassings moet ook gemaak word in terme von beroep~ en sosiate funksionering. Nie net het eindstodiumnierversaking 'n psigososiate impok op die nierposient nie, maar word die gesonde moat ook daardeur be"invtoed. Daarom ervoar meeste egpore gesamentlik die impok von nierversaking op hulle huwelik- en gesinslewe. Vir optimale oanpassing by nierversaking moet egpore sekere oanpassingstoke bemeester, soos om nierversoking as 'n gedeetde probteem te hanteer, oan te pas by die rot von pasient en versorger. die verskillende behoeftes oan nobyheid en afstand tussen pasient en versorger, en die verwisseting in beroepsrolle hanteer, asook effektiewe kommunikasie met mekoar en die mediese span doarstel, en mekaor deurlopend instrumenteel en emosioneel ondersteun ten einde die huweliksverbintenis in stand te hou. Die resultate von hierdie ondersoek dui doarop dat huweliksverondertikes, soos 'n afnome in ontsponningsaktiwiteite en seksuatiteit, en gelykmakende rolle 'n belangrike rot speel om oanpassing by nierversaking te vergemaklik. Daarmee soam is gevind dat godsdiens 'n belangrike oanpossende funksie vir egpore het. Deurgoans speel'n ondersteuningsisteem, wat uit famitie en vriende, onder nierpasiente, die mediese span en 'n sielkundige bestoan 'n vernome rol om die egpoar met oanpassing te help. Uiteindelik blyk dit moonttik te wees vir egpare om hulle huwetiksverhouding in stand te hou, of setfs konstruktief te herstruktureer, asook groter huwelikstevredenheid te ervoar, ondanks die bedreiging von eindstadiumnierversaking. Meeste egpore ervoar die moeilike tydperk dan ook met 'n verdieping in hulle huwelik- en geloofslewe. / Psychonephrology is the study of psychological factors which are evident in end-stage renal disease (ESRD). ESRD is regarded as a life-threatening disease, which shortens the life-expectancy of a patient if he does not receive treatment. ESRD can be divided into three stages: the pre-dialysis, dialysis and transplant stages. These stages are signified by differences in medical treatment methods. None of these leads to a cure but all alle.viate symptoms of the uremic syndrome, increase the life-expectancy of the patient and are supposed to improve his quality of life. Depression and anxiety are general symptoms found in end-stage renal patients. The reasons for this are the patient's psychological reaction to renal disease, dialysis and/or transplant. Patients must also endure the side effects of medical treatment. Adjustment in vocational and social functioning is also evident. ESRD not only has a psycho social impact on the patient but also affects the healthy spouse. This is why most married couples together experience the impact of ESRD in their marital and family life. For optimal adjustment to ESRD couples need to master certain adaptational tasks, such as treating ESRD as a shared problem, adopt the roles of patient and caregiver, manage the various needs of closeness and distance between patient and caregiver and change of career roles, as well as effectively communicating with each other and the medical team, and instrumentally and emotionally support eac~ other in order to maintain the marital bonds. The results of this investigation show that marital variables, such as a decrease in recreation and sexuality and role equality, are important to ease the adjustment to ESRD. It was also found that religion has an important adaptational function for the married couples. A support system of family, friends, other renal patients, the medical team and a psychologist are also important to aid the couples' adjustment. Lastly it should be possible for renal couples to maintain, or even to positively reconstruct their marital relationship, and to experience marital satisfaction in the face of the threat of ESRD. Apparently most couples experience this ordeal as a time of intensification of their married and spiritual life. / Psychology / D.Litt. et Phil. (Psychology)

La transplantation rénale représente le traitement de choix de l’insuffisance rénale terminale parce qu’il offre une espérance de vie plus longue et une meilleure qualité de vie.<p>Néanmoins, l’accès à la transplantation est limité par la pénurie d’organes et dans certains cas, par la présence d’anticorps anti-HLA avant la greffe.<p>Bien que la présence d’anticorps anti-HLA spécifiques du donneur avant ou après la greffe ait été associée au rejet aigu et à la perte chronique d’allogreffe, un rejet humoral tant aigu que chronique peut survenir sans que ces anticorps soient détectables dans le sérum, suggérant que des réponses autologues ou allo-immunes contre des antigènes dits « mineurs » pourraient jouer un rôle dans le rejet et la perte de greffe.<p>MICA, en raison de son polymorphisme important, est considéré aujourd’hui comme un des systèmes antigéniques mineurs les plus robustes par sa capacité à induire des allo-anticorps. Cependant, un effet pathogène des anticorps anti-MICA sur le greffon rénal demeure à ce jour, non formellement établi.<p>Le but de la présente recherche a été d’étudier l’épidémiologie des anticorps anti-MICA à partir d’une large cohorte de volontaires sains et de patients atteints d’insuffisance rénale chronique terminale, de déterminer les facteurs de risque d’immunisation contre MICA, de spécifier la nature autologue ou allogénique de ces anticorps et d’évaluer au sein des patients ultérieurement transplantés, l’impact de ces anticorps sur le rejet et la survie de greffe. <p>La méthode utilisée pour l’identification des anticorps anti-MICA est la technique Luminex, consistant à faire réagir du sérum avec des billes de polystyrène tapissées par un seul antigène MICA recombinant, l’intensité de la liaison antigène-anticorps étant révélée par un fluorocytomètre suite à l’adjonction d’un second anticorps anti-IgG couplé à une substance fluorescente.<p>Nous avons identifié la grossesse, les transfusions sanguines, la greffe préalable et également l’urémie comme étant des facteurs de risque indépendants d’immunisation contre MICA. <p>Nous n’avons pas observé d’effet délétère des anticorps anti-MICA sur la survie à long terme du greffon rénal alors que les anticorps anti-MICA ont été plus fréquents chez les patients dits «à haut risque immunologique» et en particulier chez les patients immunisés contre le HLA.<p>Nos résultats suggèrent que plutôt d’être pathogènes, les anticorps anti-MICA pourraient être simplement des marqueurs de haut risque immunologique. Ceci remet donc en question l’utilité d’un monitoring des anticorps anti-MICA par la technologie Luminex.<p> <p><p>Renal transplantation represents the treatment of choice of stage V chronic kidney disease by offering a longer life expectancy and a better quality of life than dialysis. Nevertheless, the access to transplantation is limited by the shortage of organs and, in some cases, by the presence of HLA antibodies before transplantation. <p>While the presence of either preformed or post-transplant donor specific anti-HLA antibodies has been associated with acute rejection or chronic graft loss, acute or chronic antibody-mediated injury may also occur in the absence of detectable anti-HLA antibodies, suggesting that autologuous or allo-immune response to other relevant minor or non-HLA antigenic determinants might play a role in rejection and subsequent graft loss. Especially, MHC class I-related chain A (MICA), a highly polymorphic minor antigenic system, is now considered to be the most robust minor antigenic system capable of inducing allo-antibodies. However, the possible deleterious effect of MICA antibodies has not been formerly established yet.<p>The goal of the following work was to determine the risk factors for MICA sensitization, to specify the autologuous or allogeneic nature of MICA antibodies and to assess the impact of preformed and 1 yr post-transplant MICA antibodies on defined renal graft outcomes in large cohorts of patients. The method employed for the identification of MICA antibodies was a Luminex single antigen beads assay. We found that pregnancy, previous blood transfusion, previous graft as well as chronic kidney disease were independent risk factors for MICA sensitization.<p>Even if we had found a higher frequency of MICA antibodies in patients at higher immunological risk and especially, MICA antibodies had been closely associated with HLA sensitization, we showed a lack of a deleterious effect of MICA antibodies on long-term renal graft outcomes. <p>Our findings suggest that MICA antibodies are merely surrogate markers of high immunological risk and really question the monitoring of MICA antibodies by the presently available MICA single antigen flow beads assays. <p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Introduction et buts de la thèse<p>La survie du patient et du greffon se sont nettement améliorées depuis les débuts de la transplantation rénale. Les recommandations de pratiques cliniques basées sur l’évidence aident les cliniciens à améliorer la prise en charge standardisée des patients. Cependant, de nombreux programmes de recherche sont actuellement axés sur la découverte de biomarqueurs qui peuvent prédire les différents résultats chez les patients transplantés rénaux. Ces biomarqueurs sont nécessaires pour personnaliser la gestion et le traitement des patients.<p>Le but des travaux résumés dans cette thèse est d'évaluer l'impact potentiel de plusieurs facteurs biologiques acquis et génétiques spécifiques sur les résultats après la transplantation rénale, en particulier les facteurs de thrombophilie et les polymorphismes génétiques associés au diabète post-transplantation.<p>1. Facteurs de thrombophilie<p>Les patients en insuffisance rénale terminale présentent des anomalies complexes de la coagulation, dont les mécanismes sous-jacents ne sont pas connus à ce jour. La thrombose des vaisseaux du greffon et les événements thromboemboliques comme la thrombose veineuse profonde et / ou l’embolie pulmonaire sont des complications graves, mais relativement rares après transplantation rénale. Au cours de la dernière décennie, plusieurs études ont évalué l'impact des facteurs de thrombophilie sur les résultats après la transplantation rénale, tels que les événements thrombo-emboliques, y compris la thrombose de l’artère ou la veine du greffon, le rejet aigu, les événements cardiovasculaires ou la survie du greffon. Cependant, les limitations méthodologiques et l'hétérogénéité de ces études rendent les conclusions ou les recommandations difficiles. D’autre part, la prévalence exacte des facteurs de thrombophilie dans la population de patients en insuffisance rénale terminale et la correction éventuelle de ces facteurs après transplantation ne sont pas connues. Dans ce contexte, nous avons réalisé une étude prospective afin d’évaluer l’impact d’un panel de 11 facteurs de thrombophilie testés le jour de la transplantation et 1 mois plus tard, sur les événements thrombo-emboliques et le rejet aigu durant la première année de greffe [58]. Nous avons également évalué la prévalence de 7 facteurs de thrombophilie non-génétiques chez les patients en insuffisance rénale terminale et le taux de correction après la transplantation rénale dans une cohorte de 215 patients [59]. <p>2. Diabète post-transplantation<p>Le diabète post-transplantation est une complication métabolique grave et fréquente après la transplantation. Les patients transplantés rénaux souffrant d’un diabète post-transplantation ont un risque plus élevé d'événements cardiovasculaires majeurs, de décès et d’échec de greffe. Une étude prospective rapporte une incidence de 20,5% durant les six premiers mois de greffe rénale, en utilisant les critères stricts de l'ADA (American Diabetes Association). La plupart des facteurs de risque identifiés sont communs avec le diabète de type 2 dans la population générale: l'âge, les antécédents familiaux, l’ethnie (africaine et hispanique), l'indice de masse corporelle élevé, une sérologie hépatite C positive et la présence d’un syndrome métabolique. Certains traitements immunosuppresseurs sont des facteurs de risque de diabète post-transplantation spécifiques et modifiables. Les inhibiteurs de la calcineurine sont diabétogènes et il a été clairement montré que le tacrolimus est plus diabétogène que la cyclosporine. En se basant sur ces données, nous avons remplacé le tacrolimus par la cyclosporine chez une série de patients ayant développé un diabète post-transplantation sous tacrolimus. Nous avons évalué rétrospectivement l’efficacité et la sécurité de cette approche [60]. Nous avons également élaboré des recommandations pour la prise en charge du diabète post-transplantation sur base de notre expérience et des études publiées [62]. <p>La susceptibilité génétique du diabète post-transplantation a été étudiée par des approches «gènes candidats », mais les faibles effectifs et l'absence de réplication dans des cohortes indépendantes rendent les conclusions difficiles. Les études pan-génomiques de type « genome wide association study (GWAS) apportent un éclairage neuf sur les origines génétiques du diabète de type 2. Plus de 10 loci de susceptibilité ont été associés au diabète de type 2 dans la population générale, avec des odds ratio (OR) allant de 1.10 à 1.20, excepté un variant commun du gène TCF7L2 pour lequel le risque de la maladie augmente de 37% par allèle à risque. Nous avons utilisé une approche gène candidat en sélectionnant 11 variants génétiques associés au diabète de type 2 à travers ces GWAS et nous avons évalué leur association avec le risque de diabète post-transplantation durant les 6 premiers mois post-transplantation, dans une large cohorte de Caucasiens (N = 1076) [61].<p>Méthodologie générale<p>L’unité de transplantation rénale de l'Hôpital Erasme (Université Libre de Bruxelles) a créé une base de données clinique incluant les patients transplantés depuis 1964 dans l'institution et une biocollection (ADN et sérum) depuis 2001. En outre, depuis 2007, l'unité de transplantation rénale de l'Hôpital Erasme a développé une collaboration avec d'autres centres européens de transplantation rénale (CHU de Tours, CHU de Limoges, CHU de Brest, CHU de Saint-Étienne, CHRU de Lille, CHU de Poitiers et CHU de Bordeaux actuellement). Nous avons actuellement collecté les données cliniques et l’ADN de plus de 4000 receveurs d'allogreffe rénale.<p>Résultats<p>1. Facteurs de thrombophilie<p>Nous avons enrôlé prospectivement 320 greffes rénales consécutives correspondant à 317 patients greffés dans notre institution entre 2001 et 2006. Onze facteurs de thrombophilie ont étés dosés le jour de la transplantation. Dix patients ont étés exclus en raison de valeurs manquantes pour plus de 3 facteurs. Tous nos patients ont reçu de l’acide acétylsalicylique en prophylaxie, débuté juste avant la greffe. Le taux d'événements thromboemboliques et/ou de rejet aigu durant la première année post-transplantation (critère d’évaluation primaire composite) était de 16,7% chez les patients sans facteur de thrombophilie (N = 60) et de 17,2% chez ceux ayant au moins un facteur de thrombophilie (N = 250) (P=NS) le jour de la greffe. L'incidence du critère d’évaluation primaire était similaire chez les patients sans facteur de thrombophilie et ceux avec au moins deux (N = 135), ou au moins trois (n = 53) facteurs (16,3% et 15,1% respectivement, P=NS) et chez les patients avec au moins un facteur persistant 1 mois après la greffe (15,7%, P=NS). Aucun des facteurs de thrombophilie individuels présents le jour de la transplantation n’était associé au critère d’évaluation primaire. L'incidence des événements cardio-vasculaires à 1 an, la créatinine sérique à 1 an, la survie de greffe actuarielle à 4 ans n’étaient pas influencés par la présence d’au moins un facteur de thrombophilie le jour de la greffe (P= NS).<p>La prévalence des facteurs de thrombophilie était significativement plus élevée chez les patients dialysés que chez les patients non encore dialysés le jour de la greffe (74% vs 52,4%, P =0,03). La prévalence était similaire chez les patients hémodialysés et en dialyse péritonéale (P=NS). Un mois après la transplantation, la prévalence globale des facteurs de thrombophilie a chuté de 74,4% à 44,7% (P <0,001). La plupart des facteurs de thrombophilie avaient disparus après la transplantation. <p>2. Le diabète post-transplantation<p>Nous avons analysé rétrospectivement les paramètres du métabolisme glucidique chez 54 patients greffés rénaux traités par tacrolimus et développant un diabète post-transplantation. Trente-quatre patients ont été convertis à la cyclosporine alors que 20 patients ont poursuivi le tacrolimus (groupe contrôle). Après la conversion, le taux de rémission du diabète post-transplantation était de 42% (IC 95% :24-59%) 1 an après la conversion versus 0% dans le groupe contrôle (P=0,001). La conversion<p>était sûre en termes de fonction du greffon, de rejet aigu, de survie des patients et du greffon.<p>Dans notre étude multicentrique (Hôpital Erasme-Bruxelles, CHU de Tours, CHU de Limoges et CHRU de Lille), nous avons enrôlé 1477 patients greffés successivement. Parmi les 1229 patients éligibles pour l’étude, 1076 étaient Caucasiens (analyses primaires). Un total de 118 patients, soit 11% des Caucasiens ont développé un diabète post-transplantation durant les 6 premiers mois de greffe. En analyse multi-variée, le variant rs7903146 de TCF7L2 était indépendamment associé au diabète post-transplantation (OR = 1,60 pour chaque allèle T, P = 0,002). Les autres facteurs de risque indépendants étaient: l'âge du receveur, l’indice de masse corporelle au moment de la greffe, l'utilisation du tacrolimus et la survenue d'un épisode de rejet aigu traité par corticoïdes.<p>Conclusions<p>Les facteurs de thrombophilie sont très fréquents au stade terminal de l'insuffisance rénale et sont corrigés dans la grande majorité après la transplantation rénale. Cela suggère que la plupart des facteurs sont acquis et associés à l'urémie et / ou la dialyse. En outre, notre étude prospective n’a pas démontré d’impact des facteurs de thrombophilie détectés de manière systématique avant la transplantation sur les résultats après transplantation rénale, dans une population recevant un régime immunosuppresseur moderne et de l’acide acétylsalicylique en prophylaxie.<p>L’effet diabétogène du tacrolimus est réversible. Nos résultats suggèrent une amélioration significative du métabolisme glucidique après la conversion à la cyclosporine chez les patients transplantés rénaux atteints de diabète post-transplantation sous tacrolimus.<p>Le diabète post-transplantation et le diabète de type 2 partagent des facteurs de risque communs, dont un variant du gène TCF7L2. La place de ce type de biomarqueur dans la prédiction de la survenue du diabète post-transplantation et dans les stratégies de modification d’immunosuppression doit faire l’objet d’évaluations prospectives.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Indiana University-Purdue University Indianapolis (IUPUI) / The young field of gene therapy offers the promises of significant progress towards the treatment of many different types of human diseases. Gene therapy has been proposed as an innovative way to treat Acute Kidney Injury (AKI). Through proteomic analysis, the upregulation of two enzymes, IDH2 and SULT1C2, within the mitochondrial fraction has been identified following ischemic preconditioning, a treatment by which rat kidneys are protected from ischemia. Using the hydrodynamic fluid gene delivery technique, we were able to upregulate the expression of IDH2 and SULT1C2 in the kidney. We found that the delivery of IDH2 plasmid through hydrodynamic fluid delivery to the kidney resulted in increased mitochondrial oxygen respiration compared with injured kidneys without gene delivery. We also found that renal ischemic preconditioning altered the membrane fluidity of mitochondria. In conclusion, our study supports the idea that upregulated expression of IDH2 in mitochondria can protect the kidney against AKI, while the protective function of upregulated SULT1C2 needs to be further studied.

Indiana University-Purdue University Indianapolis (IUPUI) / Acute Kidney Injury (AKI) is a prevalent and significant problem whose primary treatment is supportive care. Ischemic preconditioning is a strategy used to protect organs from ischemic injury via a prior injury. Ischemic preconditioning in the kidneys has been shown to confer protection onto kidneys from subsequent ischemic insults with attenuated serum creatinine values in treated rats. In the preconditioned kidneys, the enzyme IDH2 was discovered to be upregulated in the mitochondria. Hydrodynamic fluid delivery to the kidney was found to be a viable technique for delivering this gene to the kidney, resulting in artificially upregulated expression of IDH2. Via a two-pronged effort to discern the functional significance of ischemic preconditioning and hydrodynamic IDH2 fluid injections, we performed mitochondrial oxygen respiration assays on both preconditioned and injected kidneys. We found that renal ischemic preconditioning resulted in no significant difference between sham and preconditioned, subsequently injured kidneys, which is similar to the results from the serum creatinine studies. Hydrodynamically IDH2-injected, and subsequently injured kidneys respire significantly better than vehicle injected, and subsequently injured kidneys, which shows that hydrodynamic injections of IDH2 protects kidneys against injury, and partially mimics the effects of preconditioning.

Thesis (M.Sc. (Physiology)) -- University of Limpopo, 2021 / The purpose of this study was to investigate the effect of cART on renal function and assess the association between renal function and cardiovascular risk factors in a black rural HIV-positive population in Limpopo Province, Mankweng district. We have conducted a cross-sectional study which included both male and female cART-treated patients (n=84), cART-naïve patients (n=27) and HIV-negative controls (n=44). We have measured biomarkers of renal function (plasma cystatin C, clusterin, retinol binding protein 4 [RBP4]) and determined the estimated glomerular filtration rate (eGFR) using the chronic kidney disease-epidemiology collaboration formula (CKD-EPI). We have also measured blood pressure (BP), body mass index (BMI) and fasting blood glucose (FBG). The prevalence of renal dysfunction was similar among the study groups. A significant difference in RBP4 was found among the groups after controlling for covariates (age, gender, alcohol consumption, BMI, systolic blood pressure and FBG) (F (2, 146) = [4.479], p=0.010). The significant difference in RBP4 was specifically observed between the cART-treated and cART-naïve groups (p=0.008). Cystatin C, clusterin and eGFR were not significantly different among the study groups after controlling for the covariates. The cardiovascular risk factors age (β=0.207; p=0.039), CD4+ T-cell count (β=-0.236; p=0.040), and duration of cART (β=0.232; p=0.043) were independently associated with cystatin C. The use of cART independently associated with RBP4 (β=0.282; p=0.004). Age (β=-0.363; p=0.001), CD4+ T-cell count (β=0.222; p=0.034) and duration of cART (β=-0.230; p=0.034) independently associated eGFR. Renal dysfunction is common in this HIV-positive population, with similar rates as the HIV-negative population. Plasma cystatin C as a promising alternative renal biomarker need to be re-evaluated in this HIV-positive population. RBP4 may be a more promising renal function biomarker in the HIV-positive population. Cardiovascular risk factors are associated with renal dysfunction in this rural HIV-positive population and CD4+ T-cell count may be an independent predictor for renal function.

Indiana University-Purdue University Indianapolis (IUPUI) / Polycystic kidney diseases (PKD) are genetic disorders characterized by fluid filled cysts in the kidney tubules and liver bile ducts. There are two forms of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The focus of the studies in this thesis has been on ADPKD. The disease progresses slowly and the fluid-filled cysts grow in size due to increased rates of cell proliferation and fluid secretion into the cyst lumen. The expanding cysts compromise the normal kidney function and result in a decrease of renal function to the point of end-stage renal failure in midlife. Cyst enlargement is due, at least in part, to chloride secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Currently therapy is limited to renal cyst aspiration, dialysis, and eventually renal transplantation after organ failure, thus it has critical to determine possible drug therapies for the treatment of PKD. Previous studies showed that cyst fluid caused a secretory response in cells lining the cysts. We hypothesized that once the cyst have expanded and become so large that they burst or leak, which could also occur due to renal injury or aging, the cyst fluid may stimulate additional cyst growth. Lysophosphatidic Acid (LPA) was determined to be the active component of human cyst fluid, and we investigated the LPA stimulated signaling pathway. Our data suggest that the LPA stimulates chloride and fluid secretion by a combination of CFTR and Calcium-Activated chloride channels (CaCC) and that the two channels may functionally be linked to each other. The secretion is not occurring through a cAMP stimulated pathway, and it is possible that TMEM16A, a CaCC, plays a larger role than previously expected. Previous studies demonstrated that PPARγ agonists, insulin sensitizing drugs used to treat diabetes, inhibit chloride secretion by the collecting duct principal cells by decreasing CFTR synthesis. It was logical therefore to considered PPARγ agonists as long-term treatment for PKD. The first preclinical studied showed that high (20 mg/kg BW) dose pioglitazone, a PPARγ agonist, inhibited cyst growth in the PCK rat model, a slow progressing model, of PKD. To continue to look at the effects of the PPARγ agonists another preclinical study was completed, which tested if there was a class action of PPARγ agonists and if a lower dose was effective in treating the cystic burden. Using the PCK rat model, and another PPARγ agonist, rosiglitazone, a 24 week study was completed using 3 doses (4, 0.4, and 0.04 mg/kg BW). 4 mg/kg BW rosiglitazone is analogous to 20 mg/kg BW pioglitazone. The data indicated that the rosiglitazone is effective in lowering the cystic burden, and importantly the low dose proved to be effective. An additional rat model, the W-WPK rapidly progressing model was used to determine efficacy across multiple models, and to determine if there was a way to track the progress of the disease in a manner analogous to that used in human patients. The animals were treated with pioglitazone using 2 doses (2 and 20 mg/kg BW), and were imaged using CT scans to track the progress of the disease. The data suggest that pioglitazone was not as effective in the W-WPK rat model as it was the PCK rat model. There was a trend however, that low dose PPARγ agonist was as effective ad high dose. Even more important, the CT scans proved to be an effective way to track the progress of the disease in animal models.

末期腎衰竭乃是一種慢性並且會持續惡化的疾病，現時唯一的治療方案便是腎功能替代療法。在香港，一般新發現患有末期腎衰竭的病人，將會被安排進行持續性家居腹膜透析。接受持續性家居腹膜透析的病人均需遵照以下四項治療性方案(包括限制膳食和流質食物，服用處方葯物，及跟從腹膜透析的指引)，以減慢病程的惡化。以往有關病人遵照治療性方案的研究，大多側重於使用血液透析的病人及醫護專業人仕的評估。本研究的目的乃是從現正進行持續性家居腹膜透析的病人的觀點，去明白及解釋病人遵照治療性方案的模式。 / 此硏究採用混合方法硏究設計，並分兩期進行。在第一期的調查，173位病人自我評估其遵照治療性方案中四個環節的程度。調查結果顯示:參加對葯物及腹膜透析的遵照程度，比限制膳食和流質食物的遵照程度為高。再者，男性、較年青、或進行了透析治療一至三年的參加者，自覺其遵照程度比其他參加者為低。此調查結果將指導第二期硏究的最大變化採樣，方法是跟據參加者自我報告其遵照治療性方案的程度分為跟從及不跟從兩組，硏究採用立意取樣方法去選取36位不同性別、年齡、及透析年歷的參加者作第二期硏究的面談。整合第一期的調查及第二期的面談結果後，硏究為參加者遵照治療性方案的模式提供了解釋。 / 結果顯示參加者的遵照模式乃是一個浮動過程，此過程可分為三個階段: 起初的遵照模式、隨後的遵照模式、及長期的遵照模式。在起初的遵照模式階段，參加者嘗試嚴謹地遵照各項治療性方案，但體會到這是不能持久的。在進行了透析二至六個月後，參加進入隨後的遵照模式，透過試驗、監察及不斷的調校，參加者學會選擇性地去遵照某些治療性方案。當參加者接受透析三至五年後，他們開始進入長期的遵照模式，在這階段，參加者已能將自行修改了的治療性方案融入日常的生活當中。 / 參加者遵照治療性方案的浮動過程，乃是受其「抱怨失去自主及常規」和「嘗試挽回自主及常規」所驅使。此浮動情況在每個階段都會發生。除了透析年歷，影響參加者遵照治療性方案的決定性因素乃是其家人及醫護專業人仕的支持。參加並認為醫護專業人仕非常強調其需絶對遵照所有治療性方案，反眏現行以治療為本的照料模式。 / 此硏究在理論及臨床上皆有貢獻。在理論方面，此乃首個硏究確立接受持續性家居腹膜透析的病人，在遵照治療性方案的浮動過程中出現的三個階段。在臨床上，此三個階段的確立可作為策劃護理方案的參照，以幫助病人順利過渡各個階段。硏究的結果亦倡導醫療模式的轉變，即由以治療作主導的模式轉變為以病人為本的照料模式，授權病人在末期腎衰竭的治療過程中參與自我料理。 / End-stage renal disease (ESRD) is a chronic, progressive and debilitating illness with renal replacement therapy (RRT) as the only treatment modality. In Hong Kong, patients newly diagnosed with ESRD who require RRT are generally started on continuous ambulatory peritoneal dialysis (CAPD). Patients receiving CAPD are required to adhere to a renal therapeutic regimen comprising four components (dietary and fluid restrictions, and medication and dialysis prescriptions) to decelerate disease progression. Studies on patients' adherence have mainly focused on those undergoing haemodialysis and are generally from healthcare professionals' perspectives. The aim of this study was to understand and explain adherence from the perspectives of patients undergoing CAPD. / The study employed a mixed-methods design and was conducted in two phases. In phase I, a survey was conducted to examine 173 patients' self-reported adherence to the four components of the therapeutic regimen. Results showed that participants were more adherent to dialysis and medication prescriptions than to fluid and dietary restrictions. Moreover, participants who were male, younger or had received dialysis for 1 to 3 years rated themselves as more non-adherent than other participants. These findings guided the maximum variation sampling of 36 purposively recruited participants of different genders, ages, and duration of dialysis from the adherent and non-adherent groups for the phase II interview. The survey and interview data were merged in the interpretation of findings to provide an understanding of participants' adherence. / Findings indicate that participants' adherence was a dynamic process with three stages: initial adherence, subsequent adherence and long-term adherence. At the stage of initial adherence, participants attempted to follow instructions but found that strict persistent adherence was impossible. After the first 2 to 6 months of dialysis, participants entered the stage of subsequent adherence. Through experimenting, monitoring and making continuous adjustments, they learned to adopt selective adherence. The stage of long-term adherence commenced after participants had received dialysis for more than 3 to 5 years. At this stage, they were able to assimilate the modified therapeutic regimen into everyday life. / The dynamic process of adherence was driven by "grieving for the loss of autonomy and normality" and "attempting to regain autonomy and normality". The process was dynamic as there were fluctuations at each stage of the participants' adherence. In addition to the duration of dialysis, the major determinant influencing the participants' adherence was the support provided by family members and healthcare professionals. Moreover, participants perceived that the focus of care provision was on strict adherence to all components of the therapeutic regimen, reflecting a biomedical model of care. / This study has theoretical and clinical significance. Theoretically, this is the first study that identified three stages in the dynamic process of adherence among patients undergoing CAPD. Clinically, with reference to each stage identified, nursing interventions can be developed to help patients achieve a smooth transition throughout all the stages. The findings also call for a paradigm shift from the biomedical model of care to patient-centred care, so as to empower patients to engage in self-management of their ESRD. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Lam, Lai Wah. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese; some appendixes also in Chinese. / LIST OF TABLES --- p.xv / LIST OF FIGURES --- p.xvi / LIST OF ABBREVIATIONS --- p.xvii / LIST OF APPENDICES --- p.xviii / Chapter CHAPTER ONE --- INTRODUCTION / Introduction --- p.1 / ESRD and its management in the Hong Kong context --- p.2 / The research problem --- p.3 / Aim of the study --- p.6 / Overview of the thesis --- p.6 / Chapter CHAPTER TWO --- LITERATURE REVIEW / Introduction --- p.7 / Literature search strategies --- p.7 / The concept of adherence --- p.8 / Theoretical models used to understand adherence --- p.14 / Health belief model --- p.14 / Locus of control --- p.16 / Self-efficacy --- p.19 / Transtheoretical model --- p.22 / Measurement of adherence --- p.24 / Prevalence of adherence --- p.27 / Patients undergoing HD --- p.28 / Patients undergoing PD --- p.31 / Factors influencing patients’ adherence --- p.34 / Demographic and clinical characteristics --- p.34 / Social support --- p.37 / Knowledge about adherence --- p.39 / Chinese culture --- p.43 / Exploring adherence from patients’ perspectives --- p.47 / Adherence among patients undergoing dialysis in Hong Kong --- p.51 / An introduction to the concept of self-management --- p.52 / Summary --- p.53 / Chapter CHAPTER THREE --- METHODOLOGY / Introduction --- p.56 / Aim --- p.56 / Objectives --- p.56 / Operational definitions --- p.57 / Research design --- p.57 / The paradigm of mixed methods research --- p.58 / Justification for using a mixed methods design --- p.60 / Application of the mixed methods design --- p.61 / Phase I study --- p.67 / Sampling --- p.67 / Setting --- p.67 / Sampling method and sample size --- p.67 / Data collection method --- p.68 / Instrument --- p.68 / Data collection procedures --- p.70 / Data analysis --- p.70 / Pilot Study --- p.71 / Validity and reliability --- p.72 / Phase II study --- p.74 / Sampling --- p.74 / Sample size --- p.74 / Sampling method --- p.75 / Data collection method --- p.80 / Semi-structured interview --- p.80 / Development of the interview guide --- p.81 / Data collection procedures --- p.82 / Making contact with participants --- p.82 / The interviewing process --- p.83 / Data analysis --- p.87 / Pilot study --- p.89 / Rigour of the study --- p.91 / Credibility --- p.91 / Dependability --- p.95 / Confirmability --- p.95 / Transferability --- p.95 / Ethical considerations --- p.96 / Summary --- p.98 / Chapter CHAPTER FOUR --- FINDINGS OF THE PHASE I STUDY / Introduction --- p.99 / Results --- p.99 / Participants --- p.99 / Demographic and clinical characteristics of the participants --- p.100 / Overall adherence to the therapeutic regimen --- p.103 / Number of days non-adherent to the therapeutic regimen --- p.103 / Degree of deviation from the therapeutic regimen --- p.104 / Adherence in relation to demographic and clinical variables --- p.106 / Summary --- p.109 / Chapter CHAPTER FIVE --- FINDINGS OF THE PHASE II STUDY / Introduction --- p.110 / Demographic and clinical characteristics of the participants --- p.110 / Major categories and subcategories identified --- p.115 / Perceptions of adherence --- p.117 / Meaning of adherence --- p.117 / Perceived needs to adhere --- p.118 / Perceived levels of adherence --- p.120 / The process of adherence --- p.123 / Initial adherence --- p.124 / Practising two major types of adherence --- p.124 / Striving to live with strict adherence --- p.124 / Doing what I am told --- p.124 / Trying my best --- p.125 / Exercising self-control --- p.127 / Adopting partial adherence --- p.128 / Recognizing limitations of current types of adherence --- p.129 / Sacrificing freedom for strict adherence --- p.129 / Social restriction --- p.129 / Having nothing to eat --- p.132 / Paying the price of inadequate adherence --- p.133 / Physiological complications --- p.134 / Need for additional treatment --- p.136 / Harsh comments from healthcare professionals --- p.137 / Realizing the need for changes in adherence --- p.139 / Rationalising an easy-going approach to adherence --- p.139 / Seeing the need for stricter adherence --- p.144 / Subsequent adherence --- p.146 / Experimenting with an easy-going approach to adherence --- p.147 / Allowing some slippage --- p.147 / Monitoring indicators of adherence --- p.148 / Making continuous adjustments --- p.149 / Adopting selective adherence --- p.153 / Long-term adherence --- p.158 / Factors influencing the process of living with adherence --- p.159 / Support --- p.159 / Family members --- p.159 / Healthcare professionals --- p.163 / Hope for the future --- p.165 / Situational factors --- p.168 / Dinning out --- p.169 / Employment --- p.171 / Summary --- p.173 / Chapter CHAPTER SIX --- DISCUSSION / Introduction --- p.177 / The dynamic process of adherence --- p.179 / Initial adherence --- p.182 / Following instructions --- p.182 / Grieving for the loss of autonomy and normality --- p.184 / Social restriction --- p.185 / Unmet nutritional and psychosocial needs --- p.187 / Subsequent adherence --- p.193 / Experimenting with an easy-going approach to adherence --- p.193 / Attempting to regain autonomy and normality --- p.198 / Dialysis --- p.199 / Medication --- p.201 / Fluid --- p.204 / Diet --- p.205 / Long-term adherence --- p.209 / Support as a major determinant of adherence --- p.212 / Family --- p.213 / Healthcare professionals --- p.216 / Biomedical model of care --- p.221 / Disease-oriented perspective --- p.222 / One-way paternalistic communication --- p.228 / Summary --- p.232 / Chapter CHAPTER SEVEN --- CONCLUSIONS / Introduction --- p.235 / Limitations of the study --- p.235 / Implications --- p.237 / Implications for clinical practice --- p.237 / Initial stage --- p.237 / Provision of timely appropriate support --- p.238 / Psychological support --- p.238 / On-site support --- p.239 / Adjustment of the CAPD training content --- p.240 / Empowering patients for self-management of their ESRD --- p.241 / Subsequent stage --- p.244 / Long-term stage --- p.245 / Implications for administration --- p.246 / Implications for nursing education --- p.247 / Recommendations for further research --- p.249 / Conclusions --- p.252 / REFERENCES --- p.254