Cette thèse avait pour but d'illustrer l'intérêt de méthodes statistiques avancées lorsqu'on s'in­ téresse aux associations entre différents facteurs et la progression de la maladie rénale chronique (MRC). Dans un premier temps, une revue de la littérature a été effectuée alin d'identifier les méthodes classiquement utilisées pour étudier les facteurs de progression de la MRC ; leurs limites et des méthodes permettant de mieux prendre en compte ces limites ont été discutées. Notre second travail s'est concentré sur les analyses de données de survie et la prise en compte de la censure par intervalle, qui survient lorsque l'évènement d'intérêt est la progression vers un stade spécifique de la MRC, et le risque compétitif avec le décès. Une comparaison entre des modèles de survie standards et le modêle illness-death pour données censurées par intervalle nous a permis d'illustrer l'impact de la modélisation choisie sur les estimations à la fois des effets des facteurs de risque et des probabilités d'évènements, à partir des données de la cohorte NephroTest. Les autres travaux ont porté sur les analyses de données longitudinales de la fonction rénale. Nous avons illustré l'intérêt du modèle linéaire mixte dans ce contexte et présenté son extension pour la prise en compte de sous-populations de trajectoires de la fonction rénale différentes. Nous avons ainsi identifier cinq classes, dont une avec un déclin très rapide et une autre avec une amélioration de la fonction rénale au cours du temps. Des perspectives de travaux liés à la prédiction permettent enfin de lier les deux types d'analyses présentées dans la thèse. / The objective of this thesis was to illustrate the benefit of using advanced statistical methods to study associations between risk factors and chrouic kidney disease (CKD) progression. In a first time, we conducted a literature review of statistical methods used to investigate risk factors of CKD progression, identified important methodological issues, and discussed solutions. In our sec­ ond work, we focused on survival analyses and issues with interval-censoring, which occurs when the event of interest is the progression to a specifie CKD stage, and competing risk with death. A comparison between standard survival models and the illness-death mode! for interval-censored data allowed us to illustrate the impact of modeling on the estimates of both the effects of risk factors and the probabilities of events, using data from the NephroTest cohort. Other works fo­ cused on analysis of longitudinal data on renal function. We illustrated the interest of linear mixed mode! in this context and presented its extension to account for sub-populations with different trajectories of renal function. We identified five classes, including one with a strong decline and one with an improvement of renal function over time. Severa! perspectives on predictions bind the two types of analyses presented in this thesis.

The progressively increasing prevalence of the Metabolic Syndrome (MetS) has emerged as a major global health concern since the MetS is associated with an increased risk for cardiovascular morbidity and mortality. Central obesity represents a key feature of the MetS and is strongly related to all MetS comorbidities. Dysregulation of adipose tissue-derived proteins, so called adipokines, has been implied to partially contribute to these effects. Recently, fibroblast growth factor-21 (FGF-21) has been introduced as a novel insulin sensitizing and weight reducing adipokine with potential therapeutic properties. However, data on FGF-21 elimination are rather limited. Therefore, FGF-21 regulation in relation to renal function has been investigated in a patient population with chronic kidney disease (CKD, study population 1), as well as one with acute kidney impairment (study population 2). In study population 1 (n = 499), patients were distributed into five CKD subgroups according to estimated glomerular filtration rate (eGFR). Median FGF-21 serum concentrations progressively increased from CKD stage 1 to stage 5 and highest values of FGF-21 were detected in stage 5 (1: 86.4 ng/l; 2: 206.4 ng/l; 3: 289.8 ng/l; 4: 591.3 ng/l; 5: 1918.1 ng/l). Furthermore, eGFR remained the strongest predictor for FGF-21 levels in multivariate analysis. For study population 2 (n = 32), blood samples were obtained before elective unilateral partial or total nephrectomy, as well as within 30 hours after surgery. In this population FGF-21 levels significantly increased after surgery (325.0 ng/l) as compared to before surgery (255.5 ng/l). Furthermore, relative changes of FGF-21 were independently and positively predicted by relative changes of creatinine in this cohort. These results are in accordance with the hypothesis that FGF-21 is eliminated by the kidneys and that the extent of kidney dysfunction substantially contributes to serum FGF-21 levels. However, additional animal experiments and prospective clinical studies are needed to further elucidate the role of the kidneys in FGF-21 physiology.

Chronic kidney disease (CKD) is a life-threating disease which arises as a frequent consequence of diabetes and hypertension. Since it is going on silently, CKD often progresses to the end-stage renal disease. It is therefore necessary to combat this disease especially due to the fact that the world population is growing old. The aim of this work was to determine the contribution of selected vasoactive systems contributing to the maintenance of high blood pressure in the developmental and established phase of CKD. Two models of CKD were used: 5/6 nephrectomy in Ren-2 transgenic rats (TGR) and stenosis of renal artery (2K1C) in Wistar rats. We demonstrated that renin-angiotensin system does not play so important role in blood pressure maintenance in both CKD models. By contrast, a more important role has sympathetic nervous system. During both the developmental and established phase of CKD, vasoconstrictor systems prevail above vasodilator NO-synthase effects. In fact, the role of NO-dependent vasodilation gradually decreased in nephrectomized TGR rats, while it was unchanged in Wistar rats with 2K1C hypertension.

La presente tesis tiene por finalidad identificar los obstáculos excesivos que limitan la importación de dispositivos médicos en la subpartida nacional 90.18.39.00.10 con descripción comercial “los demás conjuntos para hemodiálisis, transfusiones o similares” en el periodo 2019. Los productos comprendidos en la subpartida mencionada están dirigidos al tratamiento de la insuficiencia renal dentro del sistema de salud peruano. En el primer capítulo, se detalla el marco teórico, términos relevantes, los antecedentes de investigación nacionales e internacionales, así como el sustento legal en el cual está enmarcada la presente investigación. En el segundo capítulo, se detalla el plan de investigación, lo cual abarca la realidad problemática, los objetivos e hipótesis principales y específicos. Asimismo, contiene también la justificación de la investigación teórica, práctica y metodológica. El tercer capítulo, detalla la metodología de trabajo. Es decir, el enfoque aplicado, siendo en esta ocasión del tipo cualitativo explicativo. Adicionalmente, se menciona las limitaciones, la población, la muestra, la recolección de datos y los aspectos éticos. En el cuarto capítulo, se lleva a cabo el desarrollo y análisis de resultados. En ese sentido, se detalla la información obtenida mediante la técnica de entrevista de profundidad, manejando un programa de atlas TI. Para el presente documento, se ha elaborado una muestra de las empresas representativas y se ha entrevistado al responsable de comercio exterior y al personal químico farmacéutico. Finalmente, en el quinto, sexto y séptimo capítulo, se presentan la discusión, consideraciones finales y recomendaciones. / The purpose of this thesis is to identify the excessive obstacles that limit the importation of medical devices in the national subheading 90.18.39.00.10 with a commercial description "the other sets for hemodialysis, transfusions or similar" in the period 2019. The products included in the mentioned subheading are aimed at the treatment of kidney failure within the Peruvian health system. In the first chapter, the theoretical framework, relevant terms, the national and international research background are detailed, as well as the legal basis in which this research is framed. In the second chapter, the research plan is detailed, which includes the problematic reality, the main and specific objectives and hypotheses. Likewise, it also contains the justification of the theoretical, practical and methodological research. The third chapter details the work methodology. That is to say, the applied approach, this time being of the qualitative explanatory type. Additionally, the limitations, the population, the sample, the data collection and the ethical aspects are mentioned. In the fourth chapter, the development and analysis of results is carried out. In this sense, the information obtained through the in-depth interview technique is detailed, using an Atlas TI program. For this document, a sample of representative companies has been prepared and the person in charge of foreign trade and the chemical-pharmaceutical staff have been interviewed. Finally, in the fifth, sixth and seventh chapters, the discussion, final considerations and recommendations are presented. / Tesis

Objetivo: Se evaluó la utilidad de la razón TG/HDL-c como factor predictor de eventos cardiovasculares y mortalidad en pacientes adultos con enfermedad renal crónica (ERC) en hemodiálisis. Método: Se llevó a cabo una revisión sistemática en las bases Medline, Scopus, Embase, Web of Science y Pubmed para identificar los estudios tipo cohorte relevantes sobre eventos cardiovasculares y mortalidad en pacientes con ERC sometidos a hemodiálisis y el rol del TG/HDL-c como factor de riesgo. Resultado: Se evaluaron cuatro estudios tipo cohorte, con un total de 52 579 pacientes con ERC en hemodiálisis. De estos, tres estudios conducidos en poblaciones asiáticas asociaron la razón TG/HDL-c elevada como un factor de riesgo para eventos cardiovasculares y mortalidad y un estudio conducido en Estados Unidos de América que poseía el mayor porcentaje de la muestra (50 673 pacientes), asoció el marcador como un factor protector. La razón TG/HDL-c elevada se asocia a una mejor supervivencia en pacientes hemodializados y existe una consistente asociación inversa gradual entre TG/HDL-c y mortalidad en todos los subgrupos de análisis. Encontrándose, en la categorización por deciles de la variable de exposición, una disminución de 21% de riesgo de mortalidad cardiovascular y una disminución del 15% para mortalidad por todas las causas en el decil más alto en comparación con el grupo de referencia. (D10 aHR= 0.79: IC95% (0.69- 0.91) y D10 aHR= 0.85: IC95% (0.78- 0.92). Conclusiones: La razón TG/HDL-c se evidencia como un factor protector para desenlaces cardiovasculares y para mortalidad en la población americana y como un factor de riesgo para los mismos en la población proveniente de Asia. Por lo que, los resultados no son concluyentes para su aplicación en cualquier contexto. / Objective: The usefulness of the TG/HDL-c ratio as a predictor of cardiovascular events and mortality in adult patients with chronic kidney disease (CKD) on hemodialysis was evaluated. Method: A systematic review was carried out in the Medline, Scopus, Embase, Web of Science and Pubmed databases to identify the relevant cohort studies on cardiovascular events and mortality in CKD patients undergoing hemodialysis the role of TG/HDL-c as a risk factor. Result: Four cohort-type studies were evaluated, with a total of 52,579 CKD patients on hemodialysis. Of these, three studies conducted in Asian populations associated the elevated TG/HDL-c ratio as a risk factor for cardiovascular events and mortality, and one study conducted in the United States of America had the highest percentage of the sample (50 673 patients), associated the marker as a protective factor. The elevated TG/HDL-c ratio is associated with better survival in hemodialysis patients, and there is a consistent gradual inverse association between TG/HDL-c and mortality in all analysis subgroups. Finding, in the decile categorization of the exposure variable, a 21% decrease in the risk of cardiovascular mortality and a 15% decrease in all-cause mortality in the highest decile compared to the reference group. (D10 aHR=0.79; 95% CI:0.69-0.91 and D10 aHR=0.85; 95%CI:0.78-0.92. Conclusions: The TG/HDL-c ratio is a protective factor for cardiovascular outcomes and mortality in the American population and a risk factor for them in the population from Asia. Therefore, the results are not conclusive for their application in any context. / Tesis

Avec la croissance continue du nombre de patients souffrant d’insuffisance rénale terminale dans le monde, dans un contexte de ressources limitées des soins de santé, beaucoup d’emphase est mise sur l’importance de favoriser les modalités de dialyse à domicile, soit la dialyse péritonéale et l’hémodialyse à domicile (HDD). Toutefois, l’HDD est encore très peu utilisée, notamment au Canada. Ce mémoire visait à identifier pour qui, pourquoi et comment il est possible de favoriser l'utilisation de l'HDD dans nos milieux cliniques en se basant sur l'expérience de l'Australie et la Nouvelle-Zélande (ANZ), où le recours à l’HDD est le plus haut dans le monde, afin d’en tirer des leçons qui pourraient être transposées au modèle canadien. Ceci pourrait favoriser l’amélioration des soins des patients et, dans un deuxième temps, réduire les besoins en ressources humaines et les coûts associés aux thérapies de remplacement rénal. Le registre Australia and New Zealand Dialysis & Transplantation (ANZDATA) a été utilisé pour évaluer divers aspects de l’HDD en ANZ de 1997 à 2017. Tout d’abord, la présence d’un effet de centre dans le recours à la dialyse à domicile a été identifiée, démontrant que des caractéristiques, tant au niveau des patients que des centres, étaient responsables de la variabilité dans le taux d’utilisation d’HDD notée entre les centres de dialyse. Ensuite, il a été démontré qu’il n’existait pas d’effet de centre dans la durée de traitement d’hémodialyse, tant à domicile qu’en centre, mais que la variabilité de cette durée était principalement due aux caractéristiques propres aux patients, ainsi qu’à des pratiques variant entre les états/pays, et ce, de manière beaucoup plus notable en HDD. En effet, une plus grande flexibilité est offerte par cette modalité, qui est beaucoup moins affectée par la limitation des ressources que l’hémodialyse en centre. Finalement, il a été démontré que l’HDD était potentiellement une alternative équivalente à la transplantation rénale au niveau de la survie des patients dans le cas d’un greffon reçu d’un donneur à critères étendus. / With the continued growth in the number of patients with end-stage renal disease around the world, in a context of limited healthcare resources, much emphasis is being placed on the importance of promoting home dialysis modalities, namely peritoneal dialysis and home hemodialysis (HHD). However, HHD is still underutilized, especially in Canada. This thesis aimed to identify for whom, why and how it is possible to promote the use of HHD based on the experience of Australia and New Zealand (ANZ), where the use of HHD is the highest in the world, to draw lessons that could be transposed to the Canadian model. The Australia and New Zealand Dialysis & Transplantation (ANZDATA) registry was used to assess various aspects of HHD in ANZ from 1997 to 2017. First, the presence of a center effect in the use of home dialysis was identified, demonstrating that both patient- and center-level characteristics were responsible for the variability noted in the rate of HHD use between dialysis centers. We then showed that there was no center effect in the duration of hemodialysis treatment, neither at home nor in center, but that the variability of this duration was mainly due to the characteristics of the patients, as well as to varying practices between states/countries, and this, more notably in HHD. Indeed, greater flexibility is offered by this modality, which is much less affected by the limitation of resources than in-center hemodialysis. Finally, HHD was shown to be potentially an equivalent alternative to kidney transplantation in terms of patient survival in the case of a transplant received from an expanded criteria donor.

Chronic kidney disease (CKD) is defined as glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for 3 months and is characterized by progressive loss of renal function. The second leading cause of CKD is hypertension. More than half of CKD patients also suffer from hypertension. Arteries and arterioles adjust to the fluctuations in the systematic blood pressure through a mechanism called autoregulation. In the kidneys, autoregulation protects the delicate glomeruli capillaries from high blood pressure and occurs through myogenic constriction (MC). MC refers to contraction of arterioles in response to an increase in the blood pressure. Chronically hypertensive individuals and animal models have an enhanced MC, leading to minimal renal injury despite their elevated blood pressure. Experimental and clinical evidence point to a role for the MC in the pathogenesis of the CKD, however, the mechanism through which preglomerular arterial MC contributes to CKD has not been fully elucidated. This thesis showed that augmented MC in chronically hypertensive animal models was due to increased thromboxane A2 prostaglandin that was not released from the endothelium (Chapter 2). Nevertheless, inhibiting MC while also reducing the blood pressure prevented salt-induced renal injury even though the blood pressure was still not normalized compared to the normotensive controls (Chapter 3). The resulting improvement in renal structure and function could be attributed to the reduction in the blood pressure, albumin, and uromodulin (UMOD) excretion (Chapter 3). UMOD is a kidney-specific glycoprotein that, based on a genome-wide association study have the strongest association to CKD (Chapter 3). Comparing two CKD hypertensive animal models further revealed that CKD progression was independent of the blood pressure and strongly associated with UMOD excretion levels (Chapter 4). Collectively, the data discussed in this thesis demonstrates potential therapeutic targets in CKD hypertensive animal models. / Dissertation / Doctor of Philosophy (PhD)

Background: Higher protein diets, especially from animal sources, have seen a rise in popularity due to potential metabolic. This may have consequences for kidney function particularly in rising middle class populations who are allocating more income towards meat. The objective of this systematic review and meta-analysis was to evaluate the effects of higher versus lower protein intake on glomerular filtration rate (GFR) in adult populations without renal impairment. Methods: Search strategies were developed and electronic databases searched: MEDLINE and EMBASE. Data were extracted up until June 3, 2015. The main outcome measure was GFR and a random effect model (Cochrane’s Review Manager Version 5.3) was used to pool mean differences in GFR values. Results: Database searches yielded 25 trials from 1914 articles that were eligible for analysis based on inclusion/exclusion criteria. 12 studies were randomized controlled trials and 11 studies were crossover trials. As a result of data presented, 2 crossover studies were treated as 4 trials to result in 25 total trials. A total of 810 subjects from 25 trials were included in this systematic review and meta-analyses. The age of participants was 24-62 years and their BMI was 21-36 kg/m2. Higher protein compared to lower protein-containing diets were associated with increased GFR values [mean difference (MD): 8.33 ml/min (95% CI 4.87 to 11.79), P < 0.00001] but this was less pronounced when assessing change from baseline GFR values [MD: 4.71 ml/min (95% CI 0.06 to 9.36), P = 0.05]. Moreover, significant heterogeneity was present and funnel plot asymmetry indicated potential publication bias in both meta-analyses. Conclusion: Higher protein diets were associated with increased GFR, however, these results were inconclusive due to significant heterogeneity and overestimation by random effect analyses. There is still no clear evidence that high protein diets negatively impact renal function in healthy populations. / Thesis / Master of Science (MSc) / Globally, the leading causes of mortality in industrialized countries are cardiovascular disease (CVD), stroke, and type 2 diabetes (T2D). Deaths from these chronic diseases now outpace deaths due to malnutrition. Being overweight and obese increases the risk of both morbidity and mortality from CVD, stroke, and T2D. Global rates of overweight and obesity have now reached ‘epidemic’ proportions and the World Health Organization has stated that, “… [a] global epidemic of overweight and obesity – ‘globesity’ – is taking over many parts of the world. If immediate action is not taken, millions will suffer from an array of serious health disorders.” Over the past 20-30 years, the popularity of higher protein energy restricted diets have grown due to the potential benefits regarding weight loss, appetite regulation, and maintenance of lean (muscle) mass. Additionally, the expansion of the global ‘middle-class’ has resulted in families allocating more income towards meat products as a primary protein source in their diet. A health concern is that higher protein intake may have an adverse effect on kidney function. In individuals with chronic kidney disease, higher protein diets have been shown to result in further renal impairment. However, the effects of increased protein intake in healthy populations are unclear. The aim of this systematic review and meta-analysis was to compare higher versus lower protein diets on kidney function in healthy populations based on the literature to date. This was accomplished by looking at changes in glomerular filtration rate (the rate at which kidneys filter blood), which is the ‘gold standard’ marker of kidney function.

A growing number of factors, including the costs, technological advancements, an ageing population, and medical errors are leading industrialised countries to invest in research on alternative solutions to improving their health care systems and increasing patients’ life quality. Personal Health System (PHS) solutions envision the use of information and communication technologies that enable a paradigm shift from the traditional hospital-centred healthcare delivery model toward a preventive and person-centred approach. PHS offers the means to follow patient health using wearable, portable or implantable systems that offer ubiquitous, unobtrusive bio-data acquisition, allowing remote access to patient status and treatment monitoring. Electrical Bioimpedance (EBI) technology is a non-invasive, quick and relatively affordable technique that can be used for assessing and monitoring different health conditions, e.g., body composition assessments for nutrition. EBI technology combined with state-of-the-art advances in sensor and textile technology are fostering the implementation of wearable bioimpedance monitors that use functional garments for the implementation of personalised healthcare applications. This research studies the development of a portable EBI spectrometer that can use dry textile electrodes for the assessment of body composition for the purposes of clinical uses. The portable bioimpedance monitor has been developed using the latest advances in system-on-chip technology for bioimpedance spectroscopy instrumentation. The obtained portable spectrometer has been validated against commercial spectrometer that performs total body composition assessment using functional textrode garments. The development of a portable Bioimpedance spectrometer using functional garments and dry textile electrodes for body composition assessment has been shown to be a feasible option. The availability of such measurement systems bring closer the real implementation of personalised healthcare systems. / <p>QC 20130405</p>

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