The increased prevalence of chronic kidney disease (CKD) has become a major global health burden. This increase in CKD burden parallels the increase in hypertension prevalence. In addition, increasing evidence suggest that genetics play a strong role in the susceptibility for renal disease. Inbred mouse strains C57BL/6 and 129S6SvEv differ in their susceptibility to kidney disease when subjected to hypertension using the DOCA/salt uninephrectomy model of hypertension. Similar to others, we found the 129S6SvEv mice to be susceptible to develop severe glomerulosclerosis, whereas the C57BL/6 mice are comparatively resistant. To identify new candidate genes that are involved in the pathogenesis of glomerular disease, we used microarray technology to compare the glomerular transcriptome of both strains and determine changes in glomerular gene expression when subjected to the DOCA/salt uninephrectomy model of systemic hypertension. This approach was accompanied with ultrastructural analysis and glomerular stiffness measurements to identify corresponding structural changes. Here, we have identified novel genes associated with strain differences and hypertension, and we used immunohistochemistry to validate their expression in podocytes and glomerular arterioles in murine and human kidneys. The increased understanding of the molecular mechanisms underlying hypertension-associated podocyte injury and glomerular damage which will result from these studies, will ultimately lead to identification of novel pharmacologic targets or therapeutic strategies for patients with hypertension and renal disease. / 2017-11-02T00:00:00Z

Patients with chronic kidney disease are at increased risk of cardiovascular disease. These patients are often excluded in randomized controlled trials of treatments for cardiovascular disease, leading to greater uncertainty behind treatment effects in this population. Further, patients with kidney disease experience unique complications from accepted therapies for the general population, e.g.; long-term anticoagulation may be result in further kidney injury called anticoagulation-related nephropathy. However, incidence and magnitude of this acute kidney injury are not adequately measured in past randomized controlled trials of anticoagulation. Chapters in this thesis aim to increase our understanding the relationship between cardiac and kidney disease. Chapters 2 and 3 focus on the optimal prosthetic valve in dialysis patients requiring valve replacement surgery. Chapter 2 is a systematic review and meta-analysis comparing the short and long-term outcomes of two prosthetic valves implanted in dialysis patients. Chapter 3 is a survey of physicians aiming to understand the current practice of nephrologists, cardiologists, and cardiac surgeons caring for dialysis patients requiring valve replacement surgery and their preference for either prosthetic valve based on patient factors. Chapter 4 explores the interaction between an individual’s baseline kidney function and the effect on stroke reduction of occluding the left atrial appendage. This is accomplished by a secondary analysis of the Left Atrial Appendage Occlusion Study 3 (LAAOS III). Chapter 5 is a rationale and study design of LIMIT-Renal, a substudy of Low INR to Minimize Bleeding with Mechanical Valves Trial (LIMIT). This substudy aims to validate the existence of anticoagulation-related nephropathy, a form of acute kidney injury in patients receiving long-term anticoagulation, and its magnitude on renal health. Chapter 6 is the conclusion of the thesis and discusses key findings, strengths and limitations, future directions, and potential obstacles. / Thesis / Doctor of Science (PhD) / Individuals with chronic kidney disease are at an increased risk of heart disease and those receiving treatment for heart disease may be at an increased risk of developing kidney disease. Chapters in this thesis investigate the understudied interplay of heart disease and renal disease, for which an overview is presented in chapter 1. Chapter 2 addresses the uncertainty surrounding an optimal prosthetic valve in dialysis patients requiring surgical valve replacement surgery. Chapter 3 aims to understand the perceptions and preferences of physicians caring for dialysis patients needing valve replacement surgery. Chapter 4 explores the interaction between occluding the left atrial appendage and baseline kidney function on stroke reduction using data from the Left Atrial Appendage Occlusion Study 3 (LAAOS III). Chapter 5 is the design and rationale for a substudy of Low INR to Minimize Bleeding with Mechanical Valves Trial (LIMIT) exploring a form of acute kidney injury in patients receiving blood-thinning medications. Chapter 6 discusses the key findings from each chapter, their strengths and limitations, future directions, and potential obstacles.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2017. / Background Abnormalities of mineral bone disease have been consistently associated with adverse clinical outcomes in patients with chronic kidney disease (CKD). The consequences of these changes have also been shown to differ across races. However, in Africa the impact of derangements of CKD -mineral and bone disorder (CKD-MBD) on patients with CKD is largely unknown. In addition, studies from the USA have reported racial variations in markers of CKD and it remains unclear whether genetic factors may explain this discrepancy in the levels of biochemical markers of CKD-MBD across ethnic groups. Therefore, this study has been conducted to determine the existence of racial differences in the levels of fibroblast growth factor 23(FGF23) and traditional markers of mineral bone metabolism in a heterogeneous African CKD population, and to provide important insights into the pattern and genetic variability of CKD-MBD in sub-Saharan Africa. Methods This was a cross sectional multicenter study carried out from April 2015 to May 2016, involving two hundred and ninety three CKD patients from three renal units in Johannesburg, South Africa. The retrospective arm of this study involved two hundred and thirteen patients undergoing maintenance haemodialysis (MHD) from two dialysis centers in Johannesburg between January 2009 and March 2016. The first part of this study described the pattern of CKD-MBD in MHD patients using traditional markers of CKD-MBD. The second part of the study looked into the spectrum of CKD-MBD and racial variations in markers of CKD-MBD in pre dialysis and dialysis patients. This was followed by the genetic aspect of the study that examined the influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders. Lastly, the study also evaluated the association between markers of CKD-MBD and mortality in MHD patients. Results The prevalence of hyperparathyroidism (iPTH>150 pg/mL), hyperphosphataemia, hypocalcaemia and 25-hydroxyvitamin D deficiency (<30 ng/mL) was 73.4%, 57.0%, 20.3% and 80.7 % respectively in our MHD patients. The combination of markers of bone turnover (iPTH>150 pg/mL and total alkaline phosphatase > 112 U/L) suggestive of high turnover bone disease, was present in 47.3 % of the study population. The odds ratios for developing secondary hyperparathyroidism with hypocalcaemia and hyperphosphataemia were 5.32 (95% CI 1.10 - 25.9, P =0.03) and 3.06 (95 % CI 1.15 - 8.10, P =0.02) respectively. The 293 CKD patients (208 blacks, 85 whites) had an overall mean age of 51.1±13.6 years, and black patients were significantly younger than the white patients (48.4 ±.13.6 versus 57.1±15.5 years; p<0.001). In comparison to whites, blacks had higher median iPTH (498 [37-1084] versus 274[131-595] pg/ml; P=0.03), alkaline phosphatase (122[89-192] versus 103[74-144] U/L; P=0.03) and mean 25- hydroxyvitamin D (26.8±12.7 versus 22.7 ±12.2 ng/ml, P=0.01) levels, while their median FGF23 (100 [34-639] versus 233[80-1370] pg/ml; P=0.002) and mean serum phosphate (1.3±0.5 versus 1.5±0.5, P =0.001) levels were significantly lower. With the exception of vitamin D receptor (VDR) Taq I polymorphism, the distribution of the VDR polymorphisms differs significantly between blacks and whites. In hemodialysis patients, the BsmI Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, P=0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, P=0.03). Patients with high total alkaline phosphatase (TAP) had significantly higher risk of death compared to patients with TAP <112 U/L (hazard ratio, 2.50; 95% CI 1.24–5.01, P = 0.01). Similarly, serum calcium >2.75 mmol/L was associated with increased risk of death compared to patients within levels of 2.10–2.37 mmol/L (HR 6.34, 95% CI 1.40–28.76; P = 0.02). The HR for death in white patients compared to black patients was 6.88; 95% CI 1.82–25.88; P = 0.004. Conclusions Secondary hyperparathyroidism and 25–hydroxyvitamin D deficiency were common in our haemodialysis patients. The study also highlighted the existence of racial differences in the circulating markers of mineral bone disorders in our African CKD population. In addition, the study showed that both moderate and severe secondary hyperparathyroidism are predicted by the BsmI Bb genotype, and the over expression of this genotype in black patients may partly explain the ethnic variations in the severity of secondary hyperparathyroidism in the CKD population. High levels of serum alkaline phosphatase, hypercalcaemia, and white race are associated with increased risk of death in MHD patients. / LG2018

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-06T17:58:43Z No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-08T14:41:23Z (GMT) No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) / Made available in DSpace on 2016-06-08T14:41:23Z (GMT). No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) Previous issue date: 2013-08-02 / Introdução: O Serviço social entra oficialmente para o rol de profissões da saúde com a resolução do ministério da saúde nº 218/97. Esse reconhecimento da profissão perpassa um processo histórico, marcado pelas condições históricas nas quais a saúde pública se desenvolveu no Brasil e pelo reconhecimento social da profissão. Dentro da intervenção do Serviço Social na saúde, encontramos um novo campo de atuação que é o da nefrologia, uma atuação que, nos centros de Terapia Renal Substitutiva (TRS), possui um respaldo legal, sendo um reconhecimento da importância dos assistentes sociais na composição das equipes mínimas de atenção ao usuário com Doença Renal Crônica (DRC) em TRS. A associação entre fatores socioeconômicos e incidência e prevalência de DRC está bem determinada na literatura. Indubitavelmente, a etnia é o fator social mais estudado no que diz respeito à incidência e prevalência da DRC. Apenas recentemente, fatores educacionais têm sido abordados com relação à DRC, analisando a importância do autoconhecimento da patologia e a melhora dos desfechos. Um problema frequentemente abordado é a dificuldade de acesso aos serviços de saúde, tanto em países desenvolvidos, com modelos de sistemas de saúde que não são universais, como nos Estados Unidos, quanto em países em desenvolvimento, com populações com baixo nível socioeconômico, como o Brasil. Fatores como o gênero também tem sido abordados em poucos estudos, com mulheres tendo maior incidência de DRC. Quando avaliamos a influência desses mesmos fatores na progressão da DRC, há apenas escassos e fragmentados estudos que avaliam a questão, e vemos claramente que os estudos que avaliam a progressão da DRC abordam prioritariamente fatores biológicos. O objetivo deste estudo foi caracterizar o perfil social dos usuários com doença renal crônica pré-dialítica nos estágios 3, 4 e 5, como também avaliar o impacto das variáveis socioeconômicas na progressão da DRC pré-dialítica nos estágios estudados. Usuários e Métodos: Foi feito um estudo de coorte retrospectivo, período de acompanhamento de janeiro de 2002 a dezembro de 2009. As variáveis analisadas foram sociodemográficas, clínicas e laboratoriais. Os critérios de inclusão: usuários com mais de 18 anos de idade, DRC estágios 3A, 3B, 4 e 5, acompanhados por mais de três meses. Análise Estatística: Os usuários foram divididos de acordo com a vulnerabilidade social (VS). Para calcular a VS, foram utilizadas três técnicas estatísticas em seqüência, análise fatorial, análise de cluster (Cluster) e análise discriminante. Os dados sociodemográficos, clínicos e laboratoriais foram avaliados para cada grupo de VS. Foi realizada uma análise descritiva dos dados, expressos em média ± desvio padrão, mediana ou percentagem, de acordo com a característica da variável. Para avaliar a normalidade, utilizamos o teste de Kolmogorov-Smirnov. Diferenças entre os grupos foram analisadas pelo teste t para amostras independentes ou o teste de Wilcoxon para as comparações não-paramétricas. Um teste de χ2 foi usado para variáveis categóricas. A sobrevida foi analisada com curvas de sobrevida de Kaplan-Meier. O desfecho foi mortalidade ou iniciar a terapia renal substitutiva (TRS), analisadas por uma regressão de Cox. Resultados: Foram avaliados 209 usuários, acompanhados por um período de 7 anos, 29,4% foram classificados como vulneráveis. Não observamos diferença na mortalidade entre os usuários vulneráveis e não vulneráveis (log rank: 0,23), o que também ocorreu quando o resultado foi TRS (log rank: 0,17). No modelo de regressão de Cox, risco relativo (RR) e intervalo de confiança (IC) para o impacto da VS sobre a mortalidade, não ajustado foi RR: 1,87 (IC: 0,64-5,41) e, após RR ajustado: 1,47 (C1: 0,35-6,0). Quando analisamos o impacto da VS em TRS, observamos o R RR não ajustado: 1,85 (IC: 0,71-4,8) e RR ajustado: 2,19 (CI :0.50-9 0,6). Conclusão: A VS não apresentou impacto nos desfechos óbito e TRS. O acesso aos cuidados de saúde, no Brasil, apesar de suas características universais, tem barreiras sociais no acesso ao tratamento especializado. Acreditamos que os usuários passaram pelas barreiras sociais impostas para o 7 acesso a cuidados especializados (viés de seleção). Nosso estudo apresenta limitações, já que não nos permite comprovar a eficácia de uma intervenção interdisciplinar, uma vez que o desenho do estudo adotado (coorte retorspectiva) não nos permite avaliar o impacto da aborgadem interdisciplinar, pois a coleta dos dados ocorreu após a intervenção da equipe.No entanto, o presente estudo é o primeiro a avaliar a VS em usuários com DRC em pré-diálise, por um período de acompanhameto de sete anos. / Introduction: The Social Work officially enter the ranks of health professions with the resolution of the Ministry of Health No. 218/97. This recognition of the profession goes through a historical process marked by the historical conditions in which public health was developed in Brazil and the social recognition of profession. Inside Social Service Health, found a new playing field that is nephrology, a performance that, in the centers of Renal Replacement Therapy (RRT), has a legal backing, and a recognition of the importance of social workers in the composition teams minimal attention to patient with Chronic Kidney Disease (CKD) in TRS. The association between socioeconomic factors and incidence and prevalence of CKD is well established in the literature. Undoubtedly, the ethnicity is the most studied social factor with regard to the incidence and prevalence of CKD. Only recently, educational factors have been addressed with respect to CKD, analyzing the importance of self-pathology and improves outcomes. An issue often discussed is the difficulty of access to health services, both in developed countries, with models of health systems that are not universal, as in the United States and in developing countries with populations with low socioeconomic status, as Brazil. Factors such as the genre has also been addressed in a few studies, with women having higher incidence of CKD. When we evaluated the influence of these same factors in the progression of CKD, there is only scarce and fragmented studies evaluating the issue, and we see clearly that studies evaluating the progression of CKD deal primarily biological. The aim of this study was to characterize the social profile of users with chronic kidney disease pre-dialysis stages 3, 4 and 5, as well as assess the impact of socioeconomic variables on the progression of CKD pre-dialysis stages studied. Patients and Methods:: We conducted a retrospective cohort study, follow-up period from January 2002 to December 2009. The variables were sociodemographic, clinical and laboratory. Inclusion criteria: users over 18 years of age, CKD stages 3A, 3B, 4 and 5, accompanied by more than three months. Statistical Analysis: The users were divided according to social vulnerability (SV). To calculate the VS, we used three statistical techniques in sequence, factor analysis, cluster analysis (Cluster) and discriminant analysis. The demographic data, clinical and laboratory data were evaluated for each group of VS. We performed a descriptive analysis of the data, expressed as mean ± standard deviation, median, or percentage, according to the characteristic of the variable. To assess normality, we used the Kolmogorov-Smirnov test. Differences between groups were analyzed by t test for independent samples or the Wilcoxon test for nonparametric comparisons. A χ2 test was used for categorical variables. Survival was analyzed with survival curves of Kaplan-Meier. Cox regression was performed to examine the impact of SV on the outcomes. Results. We evaluated 209 patients cared for a period of 7 years, 29.4% were classified as vulnerable. There were no differences in mortality among the vulnerable and non-vulnerable users (log rank: 0.23), which also occurred when the result was TRS (log rank: 0,17). In the Cox regression model, hazard ratio (HR) and confidence interval (CI) for the impact of VS on mortality was not adjusted HR: 1.87 (CI: 0.64 to 5.41) and after adjusted HR: 1.47 (C1: 0.35 to 6.0). When we analyze the impact of VS on TRS, observe the HR and CI, unadjusted HR: 1.85 (CI: 0.71 to 4.8) and adjusted HR: 2.19 (CI:0.50-9 0.6) . Conclusion: VS showed no impact on mortality outcomes and TRS. Access to health care in Brazil, despite its universal features, have social barriers in access to specialized treatment. We believe that users spent by social barriers imposed for access to specialized care (selection bias). Our study has limitations, as it does not allow us to prove the effectiveness of an interdisciplinary intervention, since the method adopted (retrospective cohort) did not allow us to evaluate the impact of an interdisciplinary approach, because data collection occurred 9 after the intervention team. However, the present study is the first to evaluate the VS in users with CKD pre-dialysis, for a follow-up period of seven years.

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.

In 2008, El Salvador registered the world's highest mortality rate from kidney failure, with more than 2500 deaths annually in Central America's smallest country. El Salvador is the ground zero of a new form of Chronic Kidney Disease (CKD) that has become an epidemic among otherwise healthy agricultural workers and rural residents in lowland Central America in the past three decades. While the epidemic is believed to stem from some combination of agro- chemical exposure and/or dehydration, research on the disease remains embroiled in controversy, policy changes few, and medical support for affected individuals challenging. Foucaultian theorizations of 'discursive materiality' provide insights into the ways in which–even as the science remains inconclusive–understandings, discussions, and research on CKD in El Salvador are having material effects on individuals' bodies and health statuses. Based on fieldwork in El Salvador in summer 2014, this thesis uses the lens of Salvadorian CKD to explore the workings of biopower in settings of industrial agricultural production. Focusing on the Bajo Lempa region of El Salvador, in particular, the thesis examines the discourses, materialities, and practices through which CKD has "come to matter" as a medical and political phenomenon in relation to the agriculture through which affected Salvadorians make their living. Thinking through the discursive materialities of CKD alongside the production of spaces of health and agriculture, this thesis provides insights for the growing field of the political ecology of health by investigating the wider socio-political and environmental processes that make CKD management such a challenge in a Central America.

Renal replacement therapy, in the form of dialysis or transplantation, is the cornerstone of management for end-stage renal disease. UK renal registry shows nearly half of those needing renal replacement therapy are treated by dialysis – predominantly by haemodialysis. Patients on renal replacement therapy have increased mortality risk compared to age matched general population. Moreover, some specific subgroups of patients on haemodialysis have increased risk of mortality than expected. The survival benefit seen in women in the general population is attenuated resulting in similar survival for men and women on haemodialysis therapy. In addition, obese individuals and those of non-Caucasian origin have better survival outcome. Though the underlying reason for these findings is not clear and is likely to be multi-factorial, it has been hypothesised that this paradox could be due to the current practice of normalising dialysis dose to total body water. A number of metabolic factors – body surface area, resting energy expenditure and total energy expenditure – have been proposed as alternative to total body water for scaling dialysis dose. There were two overarching aims of this work – one was to study the effect of declining renal function on resting and total energy expenditure and to study the influence of various energy expenditure measures on uraemic toxin generation. The second was to study the impact on survival outcome of using these alternate parameters for normalising dialysis dose and to derive dialysis dose adjustments based on these metabolic parameters. In order to study these aims, studies were designed to explore different aspects of energy expenditure measures along with a longitudinal study to examine the impact of these parameters on survival outcome. The relationship between energy metabolism, body composition and uraemic toxin generation was studied with a retrospective analysis of 166 haemodialysis patients in whom urea generation rate was used as surrogate marker of uraemic toxin generation. It was found that total energy expenditure and fat-free mass predicted uraemic toxin generation after adjustment for other relevant variables. This study provided the preliminary data which was useful in designing further studies for this work. The effect of renal function on resting and total energy expenditure was studied in 80 patients with varying stages of chronic kidney disease who were not on renal replacement therapy. Resting and total energy expenditures were measured directly using gold-standard methods. It was found that declining renal function did not have a significant influence on either of these measures. This supports the hypothesis that metabolic rate is the driving force for glomerular filtration rate and not vice-versa. The directly measured energy expenditure measures were also found to have a moderately strong relationship with urea generation rate in these patients not on renal replacement therapy. The impact of physical activity on uraemic toxin generation, and thereby dialysis requirement, was studied in a prospective cross-sectional study of 120 haemodialysis patients in whom the physical activity was measured by an accelerometer device. Results from the study showed physical activity level to be a significant predictor of uraemic toxin generation after adjustment for gender and body size differences. This study results stressed the importance of adjusting dialysis dose based on individual’s physical activity level. To study the impact of using metabolic factors as normalising parameter for scaling dialysis dose on survival outcome, a large-scale longitudinal study was conducted with 1500 maintenance haemodialysis patients recruited for the study. Dialysis dose-related parameters and survival outcomes were collected at baseline and at various time points during the follow-up period of 18 months. Study results were analysed in two parts - the theoretical basis for using these metabolic factors as scaling parameters was explored which showed that current minimum target dialysis dose risks under-dialysis in certain subgroups of patients and using these alternative parameters may provide a more equivalent dialysis dose across individuals of different body sizes and gender. With these results arguing for potential use of the alternative parameters, the impact on survival of using them were examined. It was found that all three parameters performed better than the current parameter (total body water) with regards to predicting mortality. Total energy expenditure was found to be the best parameter with the lowest hazard ratio for risk of death. The study data was also analysed to derive an algorithm for adjustment of minimum target dialysis dose based on body size and physical activity level. This newly derived minimum dose target was also shown to impact on survival with those underdialysed based on this criteria having poorer survival outcomes. To understand the impact of whole body protein turnover on resting energy expenditure and uraemic toxin generation, a cross-sectional study was conducted on 12 patients with advanced CKD – 6 each in pre-dialysis CKD and haemodialysis group. It was found that haemodialysis patients had higher rate of protein turnover compared to pre-dialysis patients. Whole body protein turnover was found to contribute significantly to resting energy expenditure and had a moderately strong relationship with urea generation rate. In the course of these studies, two questionnaire tools have been validated for use for clinical and research purposes – one is a self-report comorbidity questionnaire and the other, the Recent Physical Activity Questionnaire. The comorbidity questionnaire was developed as part of this work and was validated against Charlson Comorbidity Index. The Recent Physical Activity Questionnaire was validated for physical activity data collection and energy expenditure calculation against the gold-standard doubly labelled water method. In conclusion, it has been demonstrated that metabolic factors such as body surface area, resting energy expenditure and total energy expenditure are more closely related to uraemic toxin generation compared to total body water. It has also been demonstrated that physical activity contributes to metabolic waste production and may necessitate changes in dialysis requirement. It has been shown that these metabolic factors, when used as scaling parameter for dialysis dosing, may predict survival better than the current parameter in use. The algorithm for dialysis dose adjustment and the questionnaires validated in this work have provided novel tools for further research studies and clinical practice. The central hypothesis of this work is that some metabolic factors may be better markers of uraemic toxin generation compared to total body water. It is hypothesised that modifications in dialysis practice based on these factors may improve the quality of haemodialysis and favourably impact on survival outcome for patients with end-stage renal disease. The work presented here largely supports this hypothesis.

Background: Chronic kidney disease (CKD) affects approximately 26 million individuals in the United States and is a top priority in the objectives for Healthy People 2020. Despite efforts to improve awareness, discussion of CKD is often minimal or ineffective in the primary care setting. This leads to a lack of patient awareness and knowledge of self-care skills to prevent or slow progression of the disease. A lack of communication of has been attributed to the provider's lack of confidence and knowledge to discuss CKD and to avoid unnecessary stress. Purpose: The purpose of the DNP project is to provide a systematic review of patient-provider communication processes used to influence self-management or behavioral change in primary care and propose a tool to enhance communication and slow progression of CKD. Methods: A systematic review was conducted following the method guidelines of the Cochrane Collaboration. Six electronic databases were searched. Inclusion criteria were adult humans, primary research studies, systematic and literature reviews, focus on communication of self-management or behavioral change strategies, primary outcomes of improving self-management and/or patient outcomes and availability of full-text online or by request. Outcomes: Of the 5765 articles initially identified, 28 studies met inclusion criteria. The studies revealed a lack of evidence directed towards CKD and communication was not directly addressed in a majority of the studies. Interventions most successful in improving patient outcomes were individualized, elicited collaboration or interaction with the patient and provider, were motivational or encouraging and aided in barrier identification and problem solving. A communication tool was developed from the evidence in order to stimulate more meaningful conversation between the patient and provider.

Chronic kidney disease (CKD) is associated with a complex state of immune dysfunction characterised by immune depression, which predisposes CKD patients to infections, and by immune activation resulting in inflammation, which is associated with cardiovascular disease among these patients. It has been suggested that regular moderate exercise may enhance immune function and exert anti-inflammatory effects. However, such effects are still unclear in CKD. Therefore, we investigated the effects of acute and regular (1-month and 6-months) moderate intensity aerobic exercise (walking) on measures of immunity and inflammation in pre-dialysis CKD patients. A single bout of walking exercise induced an overall immune and inflammatory response that was comparable to that observed in healthy individuals, with no indication of harmful effects to patients underlying state of immune dysfunction. Acute exercise induced a normal pattern of mobilisation of immune cells. Concerning immune cell function, acute exercise had no effect on T lymphocyte and monocyte activation, while it actually improved neutrophil responsiveness to a bacterial challenge in the recovery period. In addition, acute exercise induced a systemic anti-inflammatory environment, evidenced by the marked elevation in plasma IL-10 levels after exercise, which was most likely mediated by the observed increase in plasma IL-6 levels. Regular walking exercise exerted anti-inflammatory effects, with no apparent detrimental effects to patients immune and inflammatory status. Regular exercise led to improvements in the systemic inflammatory status (ratio of pro-inflammatory IL-6 to anti-inflammatory IL-10 cytokine levels) that were accompanied, and most likely mediated, by the observed down-regulation of T lymphocyte (only evident at 6-months) and monocyte activation. In addition, a reduction in IL-6 production in PBMC and whole blood cultures was also observed (only assessed at 1-month). Regular exercise had no effect on circulating immune cell numbers and neutrophil degranulation responses. These findings provide compelling evidence that walking exercise is safe from an immune and inflammatory perspective and has the potential to be an effective anti- inflammatory therapy in pre-dialysis CKD patients.

Background In patients with diabetes mellitus (DM) or chronic kidney disease (CKD), established cardiovascular disease (CVD) is associated with an increased risk of recurrent events and poor outcome. Ischemic stroke after an acute myocardial infarction (AMI) is a devastating event that carries high risks of decreased patient independence and death. Among patients with DM or CKD, the risk of an ischemic stroke within a year following an AMI is not known. Improved risk factor control is required to reduce the likelihood of CVD recurrence. Guidelines recommend target lipid profile and blood pressure values; however, data show that these targets are often not met. Therefore, there remains an urgent need for improved cardiovascular secondary preventive follow- up. Aims The aims of the present studies were to define trends in the incidence and predictors of ischemic stroke after an AMI in patients with DM or CKD. Furthermore to assess whether secondary preventive follow-up with nurse-based telephone follow-up including medication titration after CVD improves risk factor values in patients with DM or CKD and to investigate if this method performs better than usual care to implement a new treatment guideline in diabetic patients. Methods To assess the risk of post-AMI ischemic stroke, patient data were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). In separate studies, we compared a total of 173 233 AMI patients with and without DM, and 118 434 AMI patients with and without CKD. Within the nurse-based age-independent intervention to limit evolution of disease (NAILED) trial, we investigated a nurse-based cardiovascular secondary preventive follow-up protocol. Patients with acute coronary syndrome, stroke, or transient ischemic attack were randomized to receive either nurse-based telephone follow-up (intervention) or usual care (control). Low-density lipoprotein (LDL-C) levels and blood pressure (BP) were measured at 1 month (baseline) and 12 months post- discharge. Intervention patients with above-target baseline values received medication titration to achieve treatment goals, while the measurements for control patients were forwarded to their general practitioners for assessment. We calculated the changes in LDL-C level and BP between baseline and 12 months post-discharge, and compared  these changes between 225 intervention patients and 215 control patients with concurrent DM or CKD. During the course of the NAILED trial, new secondary preventive guidelines for DM patients were released, including a new LDL-C target value. To assess adherence to the new guidelines within the NAILED trial, we compared LDL-C levels in the 101 intervention patients and 100 control patients with DM. Results Ischemic stroke after AMI The rates of ischemic stroke within one-year after admission for an AMI decreased over time, from 7.1% in 1998–2000 to 4.7% in 2007–2008 among DM patients, and from 4.2% to 3.7% during the same time periods for non-diabetic patients. Lower stroke risk was associated with percutaneous coronary intervention (PCI) and initiation of secondary preventive treatments in-hospital. In-hospital ischemic stroke occurred in 2.3% of CKD patients and 1.2% of non-CKD patients, with no change in these incidences over time. The rates of one-year post- discharge ischemic stroke decreased between 2003–2004 and 2009–2010 from 4.1% to 2.5% among CKD patients, and from 2.0% to 1.3% among non-CKD patients. Lower rates of post-discharge stroke were associated with PCI and statins. Cardiovascular secondary preventive follow-up Among DM and CKD patients with above-target baseline values in the NAILED trial, the median LDL-C value at 12 months was 2.2 versus 3.0 mmol/L (p&lt;0.001) and median systolic BP was 140 versus 145 mmHg (p=0.26) for intervention and control patients, respectively. Before the guideline change, 96% of the intervention and 70% of the control patients reached the target LDL-C value (p&lt;0.001). After the guideline change, the corresponding respective proportions were 65% and 36% (p&lt;0.001). Conclusion Ischemic stroke is a fairly common post-AMI complication among patients with DM and CKD. This risk of stroke has decreased during recent years, possibly due to the increased use of evidence-based therapies. Compared with usual care, cardiovascular secondary prevention including nurse-based telephone follow-up improved LDL-C values at 12 months after discharge in patients with DM or CVD, and led to more efficient implementation of new secondary preventive guidelines.