Four systematic literature reviews were undertaken to help define best clinical practice in the management of end-stage renal disease (ESRD). Only randomised controlled trials (RCTs) were included. The areas reviewed were (1) Synthetic versus cellulose/modified-cellulose membranes for haemodialysis in ESRD; (2) Bicarbonate versus acetate dialysate for haemodialysis in ESRD; (3) Short versus standard duration dialysis in haemodialysis in ESRD; and (4) Continuous Cyclic Peritoneal Dialysis (CCPD) versus Continuous Ambulatory Peritoneal Dialysis (CAPD) in ESRD. The paucity of trials made it difficult to determine best practice in relation to many outcome measures. The review identified only a modest benefit from synthetic membranes over cellulose membranes in reducing adverse symptoms during dialysis at considerable extra cost. There was good evidence to support the use of bicarbonate in preference to acetate haemodialysis on the basis of greater effectiveness and similar cost. The single study which considered haemodialysis duration did not produce data to support the equal safety of short duration dialysis compared with standard duration. Finally, though the single study identified tended to favour CCPD in preference to CAPD in terms of fewer peritonitis episodes the extra cost involved was considerable. Though approximately 16,000 abstracts were identified by the search strategy only forty-two RCTs met the inclusion criteria for any of the four reviews. Considering the volume of published work and the critical importance of the policy decisions being reviewed, it was disappointing to identify so few. These reviews have highlighted the need for further, large, multi-centre RCTs in nephrology and dialysis. Systematic literature reviews will play a key role in placing the practice of nephrology on a solid foundation of robust scientific evidence. They may also nurture a culture of clinical research in nephrology where the confusion and conflict of many small methodologically week trials is replaced by the scientific clarify of fewer, large, well conducted, methodologically sound RCTs.

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Le bon usage des antibiotiques en réanimation est un véritable défi. Le sepsis et l’épuration extra-rénale peuvent modifier le comportement des anti-infectieux exposant le patient au risque de sous ou de surdosage. Une meilleure compréhension des altérations liées au sepsis et aux défaillances d’organe permet d’adapter les posologies d’antibiotiques. L’augmentation des posologies d’antibiotiques est nécessaire à la phase initiale du sepsis en raison d’un volume de distribution augmenté. Les adaptations posologiques vont ensuite dépendre des propriétés physico-chimiques de l’anti-infectieux plus que du type d’épuration extra-rénale appliquée. La modélisation pharmacocinétique de population couplée à des simulations de Monte Carlo est une approche pharmaco-statistique élaborée permettant de définir pour une population spécifique les paramètres influençant la PK de l’antibiotique et de prendre en considération la variabilité inter-individuelle. Cette analyse permet également de tester différents schémas posologiques pour un antibiotique donné afin de déterminer la posologie optimale en fonction de différentes fonctions d’organe et selon la susceptibilité des germes traités. La prescription individualisée faisant appel à des logiciels de modélisation PK/PD pourrait permettre à l’avenir d’optimiser l’utilisation des antibiotiques tant en terme d’efficacité que de toxicité tout en limitant l’émergence de résistance. / Prescribing antibiotics in an appropriate way is a massive challenge for the intensivists. Sepsis and renal replacement therapy may alter antibiotics pharmacokinetics exposing critically ill patients to under or overdosing. A better understanding of sepsis and organ failure related alterations could help optimizing antibiotic drug dosing. Increased dosing regimens are often necessary at the early phase of sepsis due to increased volume of distribution. Dosing adjustment will then depend on the physicochemical properties of the anti-infective agent rather than renal replacement therapy modalities. A population pharmacokinetic analysis coupled to Monte Carlo simulations consists in a pharmaco-statistic approach aiming to identify covariates influencing antibiotics PK and to consider inter-individual variability. This analysis allows testing different dosing scenarios to determine the optimal dosing regimen according to different levels of organ dysfunction and according to pathogen susceptibility. Individual drug dosing optimisation, using PK/PD modelling software could improve antibiotic efficacy while limiting antibiotic-related toxicity and antimicrobial resistance.

Philosophiae Doctor - PhD / End stage renal disease (ESRD), a more severe form of kidney disease, is considered to be a complex trait that may involve multiple processes which work together on a background of a significant genetic susceptibility. Black Africans have been shown to bear an unequal burden of this disease compared to white Europeans, Americans and Caucasians. Despite this, most of the genetic and epidemiological advances made in understanding the aetiology of kidney diseases have been done in other populations outside of sub-Saharan Africa (SSA). Very little research has been undertaken to investigate key genetic factors that drive ESRD in Africans compared to patients from rest of world populations. Therefore, the primary aim of this Bioinformatics thesis was twofold: firstly, to develop and apply a whole exome sequencing (WES) analysis pipeline and use it to understand a genetic mechanism underlying ESRD in a South African population of mixed ancestry. As I hypothesized that the pipeline would enable the discovery of highly penetrate rare variants with large effect size, which are expected to explain an important fraction of the genetic aetiology and pathogenesis of ESRD in these African patients. Secondly, the aim was to develop and set up a multicenter clinical database that would capture a plethora of clinical data for patients with Lupus, one of the risk factors of ESRD. From WES of six family members (five cases and one control); a total of 23 196 SNVs, 1445 insertions and 1340 deletions, overlapped amongst all affected family members. The variants were consistent with an autosomal dominant inheritance pattern inferred in this family. Of these, only 1550 SNVs, 67 insertions and 112 deletions were present in all affected family members but absent in the unaffected family member. Following detailed evaluation of evidence for variant implication and pathogenicity, only 3 very rare heterozygous missense variants in 3 genes COL4A1 [p.R476W], ICAM1 [p.P352L], COL16A1 [p.T116M] were considered potentially disease causing. Computational relatedness analysis revealed approximate amount of DNA shared by family members and confirmed reported relatedness. Genotyping for the Y chromosome was additionally performed to assist in sample identity. The clinical database has been designed and is being piloted at Groote Schuur medical Hospital at the University of Cape Town. Currently, about 290 patients have already been entered in the registry. The resources and methodologies developed in this thesis have the potential to contribute not only to the understanding of ESRD and its risk factors, but to the successful application of WES in clinical practice. Importantly, it contributes significant information on the genetics of ESRD based on an African family and will also improve scientific infrastructure on the African continent. Clinical databasing will go a long way to enable clinicians to collect and store standardised clinical data for their patients.

This report seeks to describe the status of kidney disease and renal replacement therapy in lower-resource settings, particularly sub-Saharan Africa. Acute kidney injury and transplantation are included on a limited basis because it is impossible consider the renal replacement therapy landscape at the exclusion of either. As in the rest of the developing world, chronic kidney disease and end-stage renal disease place a sizable and rapidly growing burden on sub-Saharan Africa, and Africans face a double-burden of disease from communicable and non-communicable diseases. Meanwhile, renal replacement therapy and the subspecialty of nephrology are expanding in sub-Saharan Africa, from non-existence in many countries to a limited, tentative subsistence, largely with the support of international organizations and the dedication of local nephrologists. Hemodialysis is the most common form of renal replacement therapy in sub-Saharan Africa, but peritoneal dialysis services, particularly for acute kidney injury, are growing and renal transplants are performed in a few sub-Saharan countries. Nonetheless, in the majority of sub-Saharan Africa, maintenance dialysis is still only available to the wealthy urban few. Although peritoneal dialysis may seem more feasible in the developing world than hemodialysis for multiple reasons, it is still fraught with challenges that make widespread implementation presently unadvisable. As renal replacement therapy is costly and currently unaffordable on a large scale for most of these countries, emphasis must be on identifying at-risk populations through screening and low-cost treatment or management of risk factors to mitigate chronic kidney disease.

Introducão - A Terapia Renal Substitutiva (TRS) é utilizada por uma quantidade elevada de pacientes de forma contínua, demandando montantes financeiros crescentes do Sistema Único de Saúde (SUS). Objetivo - explorar e compreender, a partir das contribuições da Economia Política da Saúde (EPS), os processos econômicos, políticos e sociais envolvidos na oferta da Terapia Renal Substitutiva (TRS) no estado de São Paulo. Métodos - a partir do referencial teórico da Economia Política da Saúde (EPS), foi realizado estudo de caso sobre a Terapia Renal Substitutiva (TRS) no estado de São Paulo mediante a investigação da dimensão industrial, da política e a de proteção social. Com relação à dimensão industrial, foram construídos indicadores com base em dados secundários relacionados às Autorizações para Procedimentos de Alta Complexidade, ao Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos, Órteses, Próteses e Meios Auxiliares de Locomoção do SUS e ao Cadastro Nacional de Estabelecimentos de Saúde. A escala da análise foram as 17 redes Regionais de Atenção Saúde em São Paulo. Com relação à dimensão política e social, foram realizadas entrevistas com atores-chaves. Procedeu-se inicialmente à leitura livre da entrevista; na sequência, foram identificados os núcleos temáticos de interesse da pesquisa. Resultados - Na dimensão industrial, foi constatado que, apesar do elevado gasto, a tecnologia na diálise apresenta somente inovações incrementais. A oferta de máquinas, em 2017, por 10000 habitantes, foi superior à do ano de 2008 em todas as regiões de saúde. O gasto para a diálise cresceu no período de 2008 a 2017. Houve crescimento de 37% na produção de procedimentos dialíticos ao longo de 2008 a 2017. Com relação aos turnos, 92% das clínicas operam com menos do que três turnos de atividade, tendo capacidade ociosa. A participação dos prestadores de serviços é de 2% para os prestadores de serviços municipais, 9% para os estaduais, 53% para os privados lucrativos e 35% para os privados sem fins lucrativos (filantrópicos). O custo é de 75% com filtros hemodialisadores importados, tendo elevado impacto no financiamento do SUS. Com a abertura do mercado da saúde ao capital estrangeiro, sancionada pelo governo através da Lei 13.097/2015, identificou-se a compra de clínicas privadas de diálise por empresas estrangeiras que pertencem à cadeia produtiva da diálise, em uma estrutura de mercado oligopolista. Com relação à dimensão política, não se observou a configuração de um conjunto de políticas públicas para o segmento. Por fim, com relação à dimensão de proteção social, há um acesso desigual aos serviços. Conclusões - Verificou-se que a diálise está inserida em um cenário de extrema dependência produtiva para sua operacionalização, sendo que todos os insumos e equipamentos são importados. É notória a presença de empresas multinacionais no segmento da diálise, com maior poder de barganha na composição dos preços dos produtos ofertados ao segmento, delineando-se um processo inflacionário e um forte impacto nos gastos. O SUS financia esta área da saúde; seria importante a indução do parque produtivo nacional para a produção de filtros, no entanto, esse movimento ainda não foi concretizado. Para complementar, as multinacionais começam a adquirir as clínicas, em um processo de liquidação dos serviços de diálise, o que pode ter implicações futuras no acesso aos pacientes SUS dependentes. / Introduction - Renal Replacement Therapy (TRS) is used by a large number of patients in continuous treatment, demanding increasing amounts of the Unified Health System (SUS). Objective - to explore and understand, from the contributions of the Political Economy of Health (EPS), the economic, political and social processes involved in the supply of Renal Replacement Therapy (TRS) in the state of. Methods - A case study on Renal Replacement Therapy (TRS) in the state of São Paulo was carried out using the industrial, political and social protection research, based on the theoretical framework of the Political Economy of Health (EPS). Regarding the industrial dimension, indicators were built based on secondary data related to the Authorizations for High Complexity Procedures, the System of Management of the Table of Procedures, Medications, Orthoses, Prostheses and Auxiliary Locomotion of SUS and to the National Registry of Establishments The scale of the analysis was the 17 Regional Health Care Networks in São Paulo. With regard to the political and social dimension, interviews were conducted with key actors. The free reading of the interview was initially done, in the sequence identified the thematic nuclei of interest of the research. Results - In the industrial dimension, it was observed that despite the high expenditure, dialysis technology presents only incremental innovations. The supply of machines in 2017 per 10,000 inhabitants was higher than in 2008 in all health regions. Dialysis expenditures increased from 2008 to 2017. There was a 37% increase in the production of dialysis procedures from 2008 to 2017. With regard to shifts, 92% of the clinics operate with less than three shifts of activity, taking idle capacity. The share of service providers is 2% for municipal service providers, 9% for state service providers, 53% for profitable private firms and 35% for private non-profit organizations (philanthropic). The cost is 75% with imported hemodialysis filters, having a high impact on the financing of SUS. With the opening of the health market to foreign capital, sanctioned by the government through Law 13.097 / 2015, it was identified the purchase of private dialysis clinics by foreign companies that belong to the dialysis production chain, in an oligopolistic market structure. Regarding the political dimension, the configuration of a set of public policies for the segment was not observed. Finally, with regard to the social protection dimension, there is an unequal access to services. Conclusions - It was verified that dialysis is inserted in a scenario of extreme dependence on production for its operationalization, and all inputs and equipment are imported. The presence of multinational companies in the dialysis segment is notorious, with a greater bargaining power in the composition of the prices of the products offered to the segment, outlining an inflationary process and a strong impact on expenses. The SUS finances this area of health, it would be important to induce the national productive park for the production of filters, but, however, this movement has not yet materialized. In addition, multinationals are beginning to acquire the clinics in a process of settlement of dialysis services, which may have future implications for access to SUS dependent patients.

Made available in DSpace on 2016-04-26T20:48:39Z (GMT). No. of bitstreams: 1 Antonio Pescuma Junior.pdf: 1103497 bytes, checksum: d268bd211e1e7520f8e251d44e3e0ce3 (MD5) Previous issue date: 2013-10-10 / In this research will be an analysis about the problem of financing of SUS throughout its existence, with questions about Desvinculações das Receitas da União(DRU), and the current economic policy. We conducted a study about the financial progress of Fundo Nacional da Saúde (FNS) and Média e Alta Complexidade (MAC) before and after the term of Pacto pela Saúde. It was verified that the MAC block has a financial higher participation compared to other blocks of financing. Finally, it was found that Terapia Renal Substitutiva (TRS) concentrates the most part of the financial resources present in the MAC / Nesta pesquisa, é feita uma análise sobre a problemática do financiamento do SUS ao longo de sua existência, com questionamentos acerca das Desvinculações das Receitas da União (DRU), e sobre a política econômica vigente no Brasil. Realizou-se um estudo sobre a evolução financeira do Fundo Nacional da Saúde (FNS) e sobre o bloco da Média e Alta Complexidade (MAC), antes e após a vigência do Pacto pela Saúde. Foi verificado que o bloco MAC possui uma participação financeira superior em comparação com outros blocos de financiamento. Por fim, constatou-se que a Terapia Renal Substitutiva (TRS) concentra a maior parte dos recursos financeiros presentes no MAC

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