Recentemente descrevemos que ratos tratados com o inibidor do sistema NF-?B pirrolidina ditiocarbamato (PDTC) durante a lactação desenvolvem uma hipertensão arterial na fase adulta, sem lesão renal aparente, caracterizando assim um novo modelo hipertensão essencial. No presente estudo, nós investigamos se a Uninefrectomia (UNx) associada a uma sobrecarga salina (SS) na dieta revelaria uma possível disfunção renal, agravando assim a hipetensão arterial e levando a lesões renais. Ratos Munich-Wistar recém-nascidos foram divididos em 2 grupos: Controle, sem qualquer tratamento; e PDTCLact, recebendo PDTC (280 mg/Kg/dia) na água do bebedouro do 0 aos 20 dias após o nascimento. Após 10 semanas de vida, 120 ratos machos submetidos à Uninefrectomia e foram estudados em dois protocolos. No protocolo 1, os ratos machos foram subdivididos em: UNx+NS, ratos Controle recebendo dieta padrão (NS); PDTCLact+UNx+NS, ratos PDTCLact recebendo NS; UNx+SS, ratos Controle recebendo SS; PDTCLact+UNx+SS, ratos PDTCLact recebendo SS. Após 12 semanas, os animais do Grupo UNx+SS apresentaram hipertensão, aumento da albuminúria e lesões renais moderadas. Nos animais do grupo PDTCLact+UNx+SS a hipertensão, esclerose glomerular e a deposição de Colágeno-1 intersticial apresentaram um aumentado exacerbado, juntamente com lesões arteriolares do tipo \"casca de cebola\", estresse oxidativo, ativação do NF-kB, intenso infiltrado de macrófagos, linfócitos e aumento de células positivas para Angiotensina II, mesmo com a renina plasmática reduzida. Para investigar o papel do sistema renina-angiotensina neste modelo, no protocolo 2, 40 ratos foram divididos em: PDTCLact+UNx+SS, como descrito no protocolo 1; PDTCLact+UNx+SS+L, ratos tratados com Losartan (50 mg/kg) na água do bebedouro. O tratamento com Losartan foi capaz de atenuar as lesões glomerulares e a inflamação renal. Esses resultados indicam que a integridade do sistema NF-kB é fundamental para o desenvolvimento adequado do rim e a manutenção da homeostase do sódio na fase adulta. Paradoxalmente, esse mesmo sistema contribui para o desenvolvimento da lesão renal quando a disfunção renal causada por sua inibição durante a nefrogênese é desmascarada por UNx associada ao SS / Recently we described that rats treated with the NF-?B inhibitor pyrrolidine dithiocarbamate (PDTC) during lactation develop high blood pressure hypertensive in adult life, without apparent functional or structural damage to the kidneys, thus providing a new model of essential hypertension. In the present study, we investigated whether uninephrectomy (UNx) associated with saline overload would unveil a possible renal dysfunction, thus aggravating arterial hypertension and leading to hemodynamically mediated renal injury. Munich-Wistar rat pups were divided into 2 groups: Control, receiving no treatment; and PDTCLact, receiving PDTC (280 mg/kg/ day) in the drinking water from 0 to 20 days after birth. At 10 weeks of age, 120 male rats underwent uninephrectomy and were studied in two protocols. In Protocol 1, rats were subdivided into: UNx+NS, control rats receiving normal salt (NS) diet; PDTCLact+UNx+NS, PDTCLact rats receiving NS; UNx+HS, control rats receiving high-salt (HS) diet; PDTCLact+UNx+HS, PDTCLact rats receiving HS. After 12 weeks, the UNx+HS animals were moderately hypertensive and exhibited mild albuminuria and renal injury. By contrast, arterial hypertension, glomerulosclerosis and cortical collagen-1 deposition were exacerbated in the PDTCLact+UNx+HS group, along with \"onion skin\" arteriolar lesions, evidence of oxidative stress, NF-kB activation and intense infiltration by macrophages, lymphocytes and angiotensin II-positive cells, even though circulating renin was depressed. To investigate the role of the renin-angiotensin system in this setting, 40 rats were divided into: PDTCLact+UNx+HS, treated as described before; and PDTCLact+UNx+HS+L, receiving in addition Losartan, 50 mg/kg in drinking water. Losartan treatment strongly atenuated glomerular injury and renal inflammation. The NF-kB system is essential for the kidneys to develop properly and maintain sodium homeostasis in adult life. Paradoxically, this same system contributes to renal injury when renal dysfunction caused by its inhibition during nephrogenesis is unmasked by UNx associated to HS

Introdução: Doença Renal Crônica (DRC) consiste, principalmente, na redução da capacidade dos rins em filtrar substâncias tóxicas, acarretando alterações metabólicas e hormonais. Em fases terminais, a terapia renal substitutiva (TRS) torna-se necessária, e o transplante renal tem sido relatado como a melhor opção terapêutica e de reabilitação para pacientes com DRC. Entretanto a DRC e o transplante renal podem afetar a qualidade de vida relacionada à saúde (QVRS) desses pacientes, podendo ser influenciada por aspectos da saúde física e mental, tais como os sintomas depressivos (SDs). Objetivos: Caracterizar os pacientes com DRC, após transplante renal, em um município do estado de São Paulo quanto aos aspectos sociodemográficos, econômicos e clínicos; descrever a QVRS e os SDs; correlacionar a QVRS e os fatores sociodemográficos, econômicos e clínicos; comparar a QVRS, segundo as dimensões do SF-36, entre os pacientes sem e com SDs e correlacionar a QVRS com os SDs. Material e Método: Trata-se de um estudo transversal, de natureza quantitativa, que incluiu pacientes que realizaram transplante renal entre 6 e 24 meses retroativos da data de início da coleta de dados, maiores de 18 anos e faziam acompanhamento no ambulatório de Transplante Renal do HCFMRP-USP, na cidade de Ribeirão Preto-SP. Foram excluídos os pacientes que apresentavam instabilidade clínica, o que totalizou a inclusão de 60 pacientes no estudo. Os instrumentos utilizados foram: instrumento para caracterização dos participantes, o qual foi adequado ao estudo e submetido à avaliação de conteúdo, Medical OutcomesStudy (MOS SF-36) para avaliação da QVRS e o Inventário de Depressão de Beck (IDB) para avaliar os SDs. Os dados foram obtidos por meio de entrevista individual com o paciente e de consulta ao prontuário. A coleta de dados ocorreu de abril a agosto de 2011. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da Escola de Enfermagem de Ribeirão Preto - Universidade de São Paulo. A análise dos dados constou da análise estatística descritiva; coeficiente de correlação de Pearson (r) para verificar a correlação entre os domínios do SF-36 com o escore total do IBD; análise de variância (ANOVA) para comparar os domínios do SF-36, nos grupos com ausência e com presença de SD; Teste Exato de Fisher para verificar a associação entre as variáveis qualitativas relacionadas ao escore de IDB e às diversas variáveis independentes, além disso, a quantificação da associação foi mensurada por meio de modelos de regressão logística na qual calculamos o OddsRatio Bruto com seus respectivos intervalos de confiança de 95%. Todas as análises estatísticas foram realizadas com a utilização do software estatístico SAS® 9.0. Valores de p menores que 0,05 foram considerados significativos. Resultados: Dos 60 pacientes, 51 eram adultos e 9 idosos; 41 eram homens e 19 eram mulheres. Os domínios do SF-36 que obtiveram menores escores médios foram: aspectos físicos (59,58), capacidade funcional (64,67) e vitalidade (71,42), e os que obtiveram maiores escores médios foram: aspectos sociais (79,79), dor (78,12) e aspectos emocionais (75,56). Quanto aos escores do IDB, 43 pacientes apresentaram ausência de SDs, 12 apresentaram disforia e 5 apresentaram SDs classificados entre leves e moderados. Não possuir trabalho aumentou a chance em 7,7 vezes de ter SDs que ter trabalho. Os pacientes com ausência de SDs apresentaram escores médios mais elevados nos domínios do SF-36, refletindo melhor QVRS, quando comparados aos pacientes com algum grau de SDs, com notória diferença na comparação (p<0,05). Encontramos correlações negativas entre os domínios do SF-36 e os escores do IDB, ou seja, à medida que aumentaram os escores de SDs, decresceram os escores médios nos domínios de QVRS. Tais correlações apresentaram p valor <0,05, exceto para o domínio estado geral de saúde. Conclusão: A presença de SDs se relacionou negativamente com a QVRS dos pacientes transplantados renais, evidenciando a necessidade de incluir a avaliação dos sintomas depressivos e respectivos atendimentos das alterações quando identificadas, na prática clínica que engloba a atuação do enfermeiro, para otimizar a QVRS desses pacientes. / Introduction: Chronic Kidney Disease (CKD) mainly involves the decrease in the kidney\'s ability to filter toxic substances, causing metabolic and hormonal alterations. In terminal stages, renal replacement therapy (RRT) becomes necessary, and kidney transplantation has been reported as the best treatment and rehabilitation option for CKD patients. CKD and the kidney transplantation can affect these patients\' healthrelated quality of life (HRQoL) though, which can be influenced by physical and mental health aspects, including depressive symptoms (DS). Aims: Characterize CKD patients after kidney transplantation in a city in São Paulo State regarding socio-demographic, economic and clinical aspects; describe HRQoL and DS; correlate HRQoL with the socio-demographic, economic and clinical factors; compare HRQoL, according to the SF-36 dimensions, between patients with and without DS and correlate HRQoL with the DS. Material and Method: This quantitative and crosssectional study included patients who underwent a kidney transplantation between 6 and 24 months before the start of data collection, over 18 years of age and monitored at the Kidney Transplantation outpatient clinic of HCFMRP-USP in RibeirãoPreto-SP, Brazil. Clinically unstable patients were excluded, totaling 60 patients included in the study. The following instruments were used: patient characterization instrument, which was adapted to the study and submitted to content assessment, Medical Outcomes Study (MOS SF-36) for HRQoL assessment and Beck\'s Depression Inventory (BDI) for the assessment of DS. Data were collected through an individual interview with the patient and consultation of patient files. Data collection took place between April and August 2011. Approval for the project was obtained from the Institutional Review Board at the University of São Paulo at RibeirãoPreto College of Nursing. Data analysis comprised descriptive statistical analysis; Pearson\'s correlation coefficient (r) to check the correlation between the SF-36 domains and the total BDI score; variance analysis (ANOVA) to compare the SF-36 domains in the groups with and without DS; Fisher\'s Exact Test to verify the association between the qualitative variables related to the BDI score and the different independent variables. In addition, the association was quantified through logistic regression models, in which the Gross Odds Ratio was calculated with its respective 95% confidence intervals. SAS® 9.0 statistical software was used for all statistical analyses. P-values inferior to 0.05 were considered significant. Results: 51 out of 60 patients were adults and 9 elderly; 41 were men and 19 women. The SF-36 domains with the lowest mean scores were: physical aspects (59.58), functional capacity (64.67) and vitality (71.42); while the domains with the highest mean scores were: social aspects (79.79), pain (78.12) and emotional aspects (75.56). As for the BDI scores, 43 patients presented absence of DS, 12 dysphoria and 5 DS classified between mild and moderate. Not having a job increased the chance of DS by 7.7 times. Patients without DS obtained higher mean scores on the SF-36 domains, reflecting a better HRQoL in comparison with patients with some degree of DS, with a statistically significant difference (p<0.05). We found negative correlations between the SF-36 domains and the BDI scores, that is, to the extent that DS scores increased, the mean scores on the HRQoL domains dropped. The p-value for these correlations was <0.05, except for the general health status domain. Conclusion: The presence of DS was negatively related with the HRQoL of kidney transplant patients, evidencing the need to include the assessment of depressive symptoms and attend to the alterations when identified in clinical practice, which includes nursing actions, in order to improve these patients\' HRQoL.

Toute maladie rénale chronique (MRC) se caractérise par le développement de lésions de fibrose rénale et d’une perte de fonction qui peut, à terme conduire vers l’insuffisance rénale chronique terminale. miR-21-5p est un microARN ubiquitaire impliqué dans le processus de fibrose, notamment rénale. Toutefois, des données expérimentales contradictoires suggèrent que miR-21-5p joue un rôle ambivalent dans la constitution des lésions rénales de fibrose.L’objectif de ce travail est de préciser l’implication de miR-21 au cours des lésions rénales aigües, en s’appuyant sur un modèle murin de toxicité rénale du cisplatine, ou chroniques chez l’homme au cours de la néphropahtie à dépôts mésangiaux d’IgA (maladie de Berger).Dans un premier travail, une cohorte rétrospective de patients porteurs d’une néphropathie à dépôts mésangiaux d’IgA a été caractérisée de façon systématique sur le plan clinico-biologique et anatomo-pathologique (classification d’Oxford). L’expression rénale de trois fibromiR (miR-21-5p, miR-199a-5p et miR-214-3p) est associée aux lésions de fibrose rénale (p ≤ 0,02). Parmi ces microARN, miR-21-5p semble le plus pertinent car il présente des amplitudes de variation d’expression plus importantes selon le niveau de fibrose, il est également associé aux lésions de sclérose glomérulaire (p = 0,001) et son niveau d’expression tissulaire rénale est associée à une moins bonne survie rénale.Un second travail a été mené en utilisant un modèle murin d’insuffisance rénale aiguë secondaire à l’injection intra-péritonéale de cisplatine chez des animaux invalidé pour miR-21a-5p. Deux schémas d’injections ont été réalisés afin explorer le rôle de miR-21a-5p au cours de lésions rénales aiguës (injection d’une dose unique de 10mg/kg de cisplatine) ou subaiguës (injections répétées de 7 mg/kg de cisplatine). Les souris ayant reçu une injection unique de cisplatine ne présentent pas de différence significative d’urée sanguine, de marqueurs de souffrance rénale (NGAL, KIM-1), d’inflammation (TNF-α, IL-6) et de stress oxydant (HO-1, NRF2), ni d’activité apoptotique selon leur statut sauvage ou invalidé pour miR-21a-5p. Le modèle d’injections répétées de cisplatine a, quant à lui, permis de mettre en évidence des lésions plus importantes chez les souris miR-21-/-. En effet, les souris miR-21-/- cisplatine présentent une urée sanguine plus élevée (1,92 g/l ±, 0,72 versus 0,66 g/l ± 0,15 p = 0,014) et une expression rénale de NGAL plus importante (RQ = 118,1 ± 44,8 versus RQ = 45,4 ± 37,7, p= 0,018) que le souris sauvages cisplatine. Enfin les lésions rénales de nécrose tubulaire aiguë observées sont plus sévères chez les souris miR-21-/-.Ainsi ces résultats montrent qu’une forte expression rénale de miR-21-5p est associée à la fibrose et au pronostic rénal chez des patients porteurs d’une néphropathie à dépôts mésangiaux d’IgA. Dans notre modèle expérimental, les souris déficientes pour miR-21a-5p présentent une sensibilité variable au développement de lésions rénales induites par le cisplatine en fonction du type d’administration, aigu ou subaigu. Ces résultats confirment que miR-21-5p joue un rôle ambivalent au cours des lésions rénales, protecteur à la phase précoce d’une agression rénale aiguë et délétère lorsque le processus se prolonge dans le temps. miR-21-5p est présent dans les fluides biologiques, et constitue ainsi un candidat potentiel en tant que biomarqueur de la fibrose rénale. De plus, miR-21-5p constitue une cible thérapeutique innovante, ayant montré son efficacité dans différents modèles murins de fibrose rénale. / Independently of the cause, active CKD leads to the development of fibrotic lesions, responsible for a loss of renal function and ultimately, end-stage renal failure. MiR-21-5p is a ubiquitous microRNA involved in the process of fibrosis, especially renal fibrosis. However, contradictory experimental data suggest that miR-21-5p plays an ambivalent role in the regulation of renal fibrosis.The aim of this work was to investigate the involvement of miR-21 in chronic renal lesions based on human renal samples and in acute lesions by using a murine model of renal toxicity induced by cisplatin.In a first part of the work, a retrospective cohort of patients with IgA nephropathy has been systematically characterized clinically, biologically and pathologically (according to Oxford classification). The renal expression of three FibromiRs (miR-21-5p, miR-199a-5p and miR-214-3p) is associated with renal fibrosis lesions (p ≤ 0.02). Among these microRNAs, miR-21 appears to be the most relevant as it displayed larger amplitudes of variation, it was also associated with glomerular sclerosis (p = 0.001) and its strong expression was associated with lower renal survival.A second part of the work was carried out on a murine model of acute renal failure secondary to the intraperitoneal injection of cisplatin. Two injections schemes were established to investigate the role of miR-21-5p in acute renal lesions (injection of a single dose of 10 mg/kg cisplatin) or subacute (repeated injections of 7 mg/kg cisplatin). After a single injection of cisplatin, no significant difference in blood urea, renal (NGAL, KIM-1), inflammation (TNF-α, IL-6) and oxidative stress (HO-1, NRF2) nor apoptotic activity was observed in miR21-/- mice compared to wild-type mice. In a model of repeated injections of cisplatin, we observed more renal lesions in miR-21-/- mice. Indeed, miR-21-/- mice treated with cisplatin exhibited higher blood urea (1.92 g / l ±, 0.72 versus 0.66 g / l ± 0.15 p = 0.014) and an increased renal expression of NGAL (RQ = 118.1 ± 44.8 versus RQ = 45.4 ± 37.7, p = 0.018) compared to wild-type mice.Thus, these results demonstrate that an increased renal expression of miR-21-5p is associated with fibrosis and renal prognosis in patients with IgA nephropathy. In an experimental model, of cisplatin-induced renal injury, mice deficient for miR-21a-5p exhibit a higher sensitivity when cisplatin was administered several times. These results confirm that miR-21-5p plays an ambivalent role in renal lesions and seems to be protective at an early stage, or deleterious when the process is prolonged over time. As miR-21-5p is present in biological fluids, it might be an efficient biomarker of renal fibrosis. Moreover, miR-21-5p is an innovative therapeutic target validated in several murine models of renal fibrosis.

The worldwide population of patients with chronic kidney disease (CKD) is growing, with estimated prevalence at 12-15% of adults. Of particular concern are those with late stage CKD, defined as an estimated glomerular filtration rate (eGFR)of less than 30 ml/min/1.73m2, as they are susceptible to the highest risk of adverse outcomes such as progression to end stage kidney disease (ESKD), cardiovascular disease and all-cause mortality (1, 2). As such, late stage CKD patients are often managed in specialized clinics with set clinical targets, standardized education and multi-disciplinary care(3). A key clinical target for therapeutic intervention and prevention of the progression of CKD is blood pressure (BP) reduction(4). Yet, multiple relevant questions remain regarding the strength and nature of association of BP with clinical outcomes in late stage CKD. As the risks of hypotension-related complications are high in late stage CKD, it remains unclear whether strict BP control delays CKD progression in a real world clinic population(5). Furthermore, it is unclear how to appropriately specify the nature of the longitudinal association between BP and clinical outcomes of ESKD and mortality. The overall objective of this thesis is to examine the longitudinal association of BP and adverse clinical outcomes in a cohort of 1203 patients (mean eGFR 17.8 ml/min/1.73m2; mean of 6.7 BP measures per patient) with late stage CKD. In our first paper we examined the association of repeat measures of BP with CKD progression, defined as a decline in eGFR. When modeling eGFR using longitudinal linear regression, we found that its over-time trajectory was non-linear and that this trajectory was modified by BP; thus, we found a significant time-dependant association between BP and eGFR. When modeling time to eGFR decline ≥ 30% using Cox proportional hazards regression with categorized BP specified as a time-dependent exposure, BP was significantly associated with risk of eGFR decline; in particular, extremes of low and high systolic blood pressure (SBP) and high diastolic blood pressure (DBP) significantly increased the risk of eGFR decline. In our second paper, we examined different methods of modelling longitudinal BP and its association with time to mortality and ESKD. We found that elevations in SBP and DBP, in particular, when expressed as current (most recent visit), lag (previous visit), and cumulative exposure were significantly associated with increased risk of ESKD while low SBP (current, lag and cumulative exposure) was significantly associated with increased risk of mortality. Baseline BP measures were not statistically significantly associated with any outcomes. In patients with more moderate ranges of SBP (121-140) or DBP (60-85) at baseline, a subsequent rise to >160 or > 85 respectively, was associated with an increased risk of ESKD. Thus, longitudinal BP measures in late-stage CKD are significantly associated with adverse outcomes and convey important information beyond baseline BP measures.

Orientadores: Jose Antonio Rocha Gontijo, Sarah Monte Alegre / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T10:43:55Z (GMT). No. of bitstreams: 1 Almeida_AmandaRobertade_D.pdf: 2198169 bytes, checksum: 7c24ef7c416a9b7492db15a314337669 (MD5) Previous issue date: 2013 / Resumo: A obesidade é considerada um importante problema de saúde pública, sendo classificada como uma epidemia global, podendo ser definida como uma doença que pode causar ou exacerbar problemas de saúde. Nos últimos anos, o crescimento do número de indivíduos com sobrepeso e obesidade revela um quadro epidemiológico preocupante. Este aumento de peso causa hipertrofia e/ou hiperplasia dos adipócitos, podendo constituir situações relacionadas à gênese do processo fisiopatológico da obesidade e suas complicações. Dentre as complicações, o aumento na produção de citocinas corrobora para o desenvolvimento de um quadro inflamatório, que está associado à resistência à insulina e hipertensão arterial, caracterizado como Síndrome Metabólica. Este processo inflamatório está também relacionado à função renal, sugerindo que o rim desempenha um papel no clearance das citocinas envolvidas no processo inflamatório. Observa-se também a hiperinsulinemia presente em grande parcela de indivíduos obesos, contribuindo para alterações na função renal. A patologia renal em paciente obeso é conhecida como glomerulopatia relacionada à obesidade. No obeso a taxa de filtração elevada leva a uma vasodilatação da arteríola aferente com consequente elevação da fração de filtração, como resultado de uma hiperfiltração glomerular seguido de dano renal. Este trabalho procurou entender as implicações da obesidade, sem qualquer outra co-morbidade associada, sobre a função tubular renal, a pressão arterial, os perfis metabólico e inflamatório em um grupo de voluntários obesos comparados a um grupo de controles eutróficos. Os voluntários foram submetidos ao clearance de lítio e creatinina, juntamente com o teste de tolerância oral à glicose. Foi avaliada a função tubular renal, os perfis metabólico, lipídico e inflamatório. Os voluntários obesos apresentaram fenótipos diferentes para a resistência à insulina e pressão arterial, contudo, o perfil inflamatório e a função tubular renal foram similares. O perfil insulinêmico mostrou diferença importante entre os grupos de obesos quando comparados ao controle. O presente estudo demonstrou que a obesidade no grupo estudado, pode ocorrer com poucas alterações fisiopatológicas. Nós aventamos a hipótese que estas alterações, particularmente as metabólicas, são acentuadas ou associadas à elevação do status inflamatório dos voluntários obesos, mas por outro lado, são atenuadas possivelmente pela elevada concentração sérica de adiponectina no grupo normo-insulinêmico, quando comparado aos voluntários hiperinsulinêmicos. Assim, é possível, que os indivíduos do grupo obeso normo-insulinêmicos possam tardiamente evoluir para hiperinsulinemia reciprocamente à redução dos níveis de adiponectina / Abstract: Obesity is considered an important public health problem, being classified as a global epidemic, which can be defined as a disease that can cause or exacerbate health problems. In recent years, the growth in the number of individuals with overweight and obesity reveals an epidemiological framework concern. This increase in weight cause hypertrophy and/or Adipocyte hyperplasia and may constitute situations related to the genesis of the pathophysiological process of obesity and its complications. Among its complications, the increase in the production of cytokines supports for the development of an inflammatory process, which is associated with insulin resistance and hypertension, characterized as metabolic syndrome. This inflammatory process is also related to kidney function, suggesting that the kidney plays a role in the clearance of cytokines involved in the inflammatory process. It is also observed hyperinsulinemic present in large proportion of obese individuals, contributing to changes in renal function. Renal changes in obese patient is known as glomerulopathy related to obesity. In the obese high filtration rate leads to vasodilation of the afferent arteriole with consequent elevation of the filtration fraction, as a result of glomerular Hyperfiltration followed by renal damage. Thus, this work sought to understand the implications of obesity, with no other associated co-morbidity, on renal tubular function, blood pressure, and inflammatory and metabolic profiles in a group of obese volunteers compared to a group of eutrophic controls. Obese volunteers showed different phenotypes for insulin resistance, blood pressure, inflammatory profile and renal tubular function were similar. Insulinemia profile showed significant difference for the obese groups compared to controls. The present study showed that obesity, at least in a specific group, can occur without major patho-physiological changes. We may state the hypothesis that these amendments, particularly the metabolic, are accentuated or associated with elevation of inflammatory status of obese volunteers, but on the other hand, are attenuated possibly by the high concentration of serum adiponectin in normo-insulinemic group when compared to the hyperinsulinemic volunteers. Thus, it is possible however, that individuals of the obese group normo-insulinemic can later evolve to hyperinsulinemic reciprocally to reduction of adiponectin levels / Doutorado / Fisiopatologia Médica / Doutora em Ciências

Introdução: O trato gastrointestinal humano é composto por uma comunidade microbiana diversificada que atua no controle da saúde. Estudos recentes demonstraram que o equilíbrio da microbiota intestinal é afetado na doença renal crônica (DRC), ocasionando o quadro de disbiose intestinal. Estes estudos sugeriram uma associação da disbiose intestinal com complicações metabólicas como acúmulo de toxinas urêmicas, progressão da DRC, inflamação e risco cardiovascular. Diante disso, medidas com o objetivo de restaurar o equilíbrio da microbiota intestinal são sugeridas, tais como a ingestão oral de probióticos, mas poucos estudos têm abordado o efeito destes suplementos na progressão da DRC e no risco cardiovascular destes pacientes. Objetivo: Avaliar o efeito do consumo de probióticos em fatores associados com progressão da DRC e risco cardiovascular de pacientes com DRC. Material e métodos: Trata-se de um estudo clínico controlado por placebo registrado no Clinical Trials NCT03400228. O estudo incluiu 30 pacientes adultos com DRC nos estágios 3 a 5 não em diálise, com função renal estável e proteinúria igual ou superior a 500 mg. A coleta de dados ocorreu entre novembro de 2015 até dezembro de 2017. O protocolo do estudo constou de período de washout de 4 semanas e randomização dos pacientes para o grupo de intervenção (GI, suplemento com probiótico) ou para o grupo controle (GC, maltodextrina). Foi realizado avaliação basal e após 24 semanas de consumo de probiótico ou placebo. Todos os pacientes receberam a orientação de consumir 2 sachês por dia do probiótico ou do placebo (maltodextrina). Foram avaliadas variáveis demográficas, clínicas, nutricionais, hábito intestinal e exames laboratoriais com amostras sanguíneas e urinárias. Resultados: Dos 30 pacientes incluídos, 20 completaram as 24 semanas do estudo, sendo 10 no grupo intervenção e 10 no grupo placebo. Após o uso de probiótico houve aumento na taxa de filtração glomerular estimada (p<0,001) e diminuição nos níveis séricos de creatinina (p<0,001), ureia (p=0,015), proteína C reativa (p=0,03), hormônio da paratireóide (p=0,03) e potássio (p=0,012), em comparação ao grupo placebo. Os efeitos positivos do probiótico na taxa de filtração glomerular estimada e na diminuição dos níveis séricos de creatinina e ureia permaneceram após análise de regressão multivariada. Não houveram diferenças significativas nos parâmetros urinários entre os grupos. Sintomas de constipação (p<0,001) e consistência fecal (p=0,016) apresentaram melhora no grupo intervenção versus placebo. Conclusão: A suplementação de probióticos melhorou os marcadores de função renal e reduziu inflamação, além de auxiliar na melhora dos sintomas de constipação intestinal em pacientes com DRC. / Introduction: The human gastrointestinal tract is colonized by a diversified microbial community that acts in control of health. Recent studies have shown that intestinal microbiota balance is affected in chronic kidney disease (CKD) leading to intestinal dysbiosis. These studies have suggested association of intestinal dysbiosis with several metabolic disorders such as accumulation of uremic toxins, progression of CKD, inflammation and cardiovascular risk. Therefore, interventional measurement that improve intestinal microbiota balance are suggested such as supplementation of probiotics, however few studies evaluated the effect of these supplements on the progression of CKD and cardiovascular risk in CKD patients. Aim: The purpose of the study was to evaluate the effects of probiotic supplementation on the factors associated with progression of CKD and cardiovascular risk in patients with CKD. Desing and Methods: This was a randomized, double-blind, placebo-controlled study. Thirty patients with CKD stages 3 to 5 not on dialysis, with stable renal function and protein-creatinine ratio > 0.50 were included. Data collection was between November 2015 and December 2017. Study protocol was 4-week washout period, patients randomized to intervention group (IG, probiotic supplement) or control group (CG, maltodextrin), and follow for 24 weeks. Renal function, C-reactive protein (CRP), bone and mineral metabolism, nutritional, and lipid profile markers and intestinal habit were measured at baseline and 24 weeks of study. Results: From 30 patients included in this study, 20 completed the 24 study weeks, 10 in the TG and 10 in PG. After probiotic supplementation, there was increase in estimated glomerular filtration rate (p<0.001) and decrease in serum creatinine 8 (p<0.001), urea (p=0.015), C-reactive protein (p=0.030), parathyroid hormone (p=0.03), and potassium (p=0.012) levels compared to CG. The beneficials effects of probiotics on estimated glomerular filtration rate and serum creatinine, urea, and Creactive protein remained after multivariate linear regression. There were no significant differences in the urinary parameters between the two groups. Symptoms of constipation (p<0.001) and stool consistency (p=0.016) improved in IG compared to CG. Conclusion: Probiotic supplementation improved markers of renal function and reduced inflammation. In addition, it improved the symptoms of intestinal constipation in patients with CKD.

Bakgrund: Mer än 10% av den västerländska befolkningen lever med kronisk njursvikt. Njurtransplantation är det effektivaste behandlingsalternativet vid svår kronisk njursvikt, och fler än 600 personer står på väntelistan för en ny njure i Sverige. Det är som sjuksköterska viktigt att se patienterna bakom sjukdomen och ha förståelse för deras individuella behov. Genom att få en uppfattning av patienternas livsvärld, har sjuksköterskan möjlighet att främja njurmottagarnas liv efter transplantationen. Syfte: Syftet med litteraturstudien var att belysa njurmottagares erfarenheter av livet efter en transplantation. Metod: En litteraturstudie baserad på 10 vetenskapliga studier med kvalitativ ansats. Studiernas kvalitet granskades med hjälp av SBU:s granskningsmall och analyserades med en innehållsanalys. Resultat: Resultatet presenterades i tre tema och nio undertema. De tema som framkom var: Utmaningar i det dagliga livet, Livsförändringar och Självständighet. Slutsats: Njurmottagarna upplevde många olika känslor efter transplantationen. De kände glädje och tacksamhet, för att de hade fått en ny chans i livet, men också för att de inte längre var beroende av dialysbehandling. De upplevde också känslor av rädsla och oro, som var associerade till risken för njuravstötning och fysiska komplikationer. Dessutom hade anhöriga höga förväntningar som mottagarna inte kunde leva upp till, vilket bidrog till känslor av besvikelse. Genom personcentrerad vård och mycket information från sjuksköterskor, var njurmottagarna mer redo för livet efter transplantationen. / Background: More than 10% of the western population are living with kidney failure. The most effective treatment for severe chronic kidney failure is a kidney transplant, and more than 600 people are waiting for a new kidney in Sweden. It is important as a nurse to see the patient behind the disease and have understanding for their individual needs. By gaining insight of the person’s life-world, can the nurse promote kidney recipients life after a transplant. Aim: The purpose was to explore kidney recipient’s experiences of life after a transplantation. Method: A literature review based on 10 scientific articles with qualitative approach. The quality of the articles was reviewed and analyzed by a content analysis. Results: The results were presented in three themes and nine sub-themes. The themes presented were Challenges in the daily life, Life changes and Independence. Conclusion: The kidney recipients experienced different emotions after the transplant. They felt joy and gratitude, because they had been given a new chance in life, but also because they were no longer dependent on dialysis treatment. They also experienced feelings of fear and anxiety, which were associated with the risk of kidney rejection and physical complications. In addition, relatives had high expectations that the recipients could not live up to, which contributed to feelings of disappointment. The obstacles that the recipients experienced in life after the transplant, could the nurse support them in. Through person centered care and a lot of information from the nurses, were the kidney recipients more ready for life after the transplant.

Die Nierentransplantation stellt aktuell die Therapie der Wahl für Patienten mit terminaler chronischer Niereninsuffizienz dar. Dabei ist die Lebendspende der postmortalen Transplantation vorzuziehen, sofern ein passender Organspender zur Verfügung steht. Welchen Stellenwert einzelne Einflussfaktoren und Aspekte für das körperliche und seelische Wohlbefinden einnehmen, soll in dieser Arbeit an den 1997 – 2014 ope- rierten Patienten des Transplantationszentrums Dresden untersucht werden. Zusammenfassend beschäftigt sich diese Studie mit der gesundheitsbezogenen Lebensqualität von Spendern und Empfängern nach einer Lebendnierentransplantation. Die Ergebnisse sollen dazu beitragen, die perioperative Therapie und Betreuung zu optimieren sowie dem persönlichen Umfeld Hinweise zur Unterstützung ihrer Angehörigen aufzuzeigen.:Inhaltsverzeichnis Abbildungs- und Tabellenverzeichnis Abkürzungsverzeichnis 1. Einleitung 1.1 Funktion der Niere 1.2 Die Niereninsuffizienz 1.3 Nierenersatzverfahren 1.4 Organtransplantation 1.5 Das Transplantationsgesetz 1.6 Lebendnierenspende 1.6.1 Modelle 1.6.2 Voraussetzungen 1.6.2.1 Medizinisch 1.6.2.2 Psychologisch 1.6.2.3 Rechtlich 1.6.3 Durchführung 1.6.4 Vorteile 1.6.5 Risiken 1.6.6 Gesundheitsbezogene Lebensqualität und Transplantation 1.6.6.1 Empfänger 1.6.6.2 Spender 1.7 Entscheidungsfindung 2 Material und Methoden 2.1 Ziele und Fragestellungen 2.2 Durchführung der Datenerhebung 2.3 Beschreibung der Instrumente 2.3.1 BSI-18 2.3.2 Morisky-Score 2.3.3 WHO-5 2.3.4 Beratungsbedarf 2.3.5 LOT-R 2.3.6 BFI-K 2.3.7 F-SozU-22 2.3.8 GBB-24 2.3.9 Item Bundesgesundheitssurvey 2.4 Datenaufbereitung und statistische Auswertung 3 Ergebnisse 3.1 Auswertung nach Spenderstatus 3.1.1 Soziodemographie 3.1.2 Komplikationen 3.1.3 Zufriedenheit 3.1.4 Veränderungen 3.1.5 Psychisches Befinden 3.1.6 Compliance 3.1.7 Lebensqualität 3.1.8 Beratungsbedarf 3.1.9 Persönlichkeit 3.1.10 Soziale Unterstützung 3.1.11 Körperliche Beschwerden 3.2 Auswertung nach Geschlecht 3.2.1 Soziodemographie 3.2.2 Komplikationen 3.2.3 Zufriedenheit 3.2.4 Veränderungen 3.2.5 Psychisches Befinden 3.2.6 Compliance 3.2.7 Lebensqualität 3.2.8 Beratungsbedarf 3.2.9 Persönlichkeit 3.2.10 Soziale Unterstützung 3.2.11 Körperliche Beschwerden 3.3 Auswertung nach Alter 3.3.1 Komplikationen 3.3.2 Zufriedenheit 3.3.3 Veränderungen 3.3.4 Psychisches Befinden 3.3.5 Compliance 3.3.6 Lebensqualität 3.3.7 Beratungsbedarf 3.3.8 Persönlichkeit 3.3.9 Soziale Unterstützung 3.3.10 Körperliche Beschwerden 3.4 Auswertung nach Bildungsstand 3.4.1 Soziodemographie 3.4.2 Komplikationen 3.4.3 Zufriedenheit 3.4.4 Veränderungen 3.4.5 Psychisches Befinden 3.4.6 Compliance 3.4.7 Lebensqualität 3.4.8 Beratungsbedarf 3.4.9 Persönlichkeit 3.4.10 Soziale Unterstützung 3.4.11 Körperliche Beschwerden 3.5 Auswertung nach postoperativem Zeitraum 3.5.1 Komplikationen 3.5.2 Zufriedenheit 3.5.3 Veränderungen 3.5.4 Psychisches Befinden 3.5.5 Compliance 3.5.6 Lebensqualität 3.5.7 Beratungsbedarf 3.5.8 Persönlichkeit 3.5.9 Soziale Unterstützung 3.5.10 Körperliche Beschwerden 3.6 Regressionsanalyse 3.6.1 Zusammenhänge psychische Belastung 3.6.2 Zusammenhänge körperliches Befinden/Beschwerdedruck 3.6.3 Zusammenhänge Lebensqualität 3.6.4 Zusammenhänge soziale Unterstützung 3.6.5 Zusammenhänge Zufriedenheit 3.7 Korrelationsanalyse 4 Diskussion der Studie 4.1 Spender und Empfänger 4.2 Frauen und Männer 4.3 Alter 4.4 Bildungsstand 4.5 Datum der Transplantation 4.6 Studienkritik 4.6.1 Auswahl der Patienten 4.6.2 Durchführung 4.6.3 Auswertung 5 Zusammenfassung 6 Literaturverzeichnis 7 Anhang 7.1 Tabellen 7.2 Fragebogen 7.3 Fragebogen „Nachbefragung“ 7.4 Votum der Ethikkommission 7.5 Anlage 1 7.6 Anlage 2 8 Danksagung

Bakgrund: Njurtransplantation ses som den främsta behandlingsmetoden vid terminal njursvikt, då den ökar både livskvalitet och livslängd för patienten jämfört med dialys. Prevalensen av njursvikt ökar i hela världen och efterfrågan av njurar möter inte behovet. Syfte: Syftet med studien var att belysa patientens upplevelse i väntan på en njurtransplantation. Metod: Studien genomfördes som en litteraturstudie med induktiv ansats, för att bilda en uppfattning om hur forskningsläget ser ut inom valt område. Resultat: Resultatet baseras på nio kvalitativa vetenskapliga artiklar från sju olika länder, där fyra kategorier framkom, Ett liv som begränsar, Förväntningar, Glädje och sorg samt Behov och betydelse av stöd. Gemensamt för samtliga artiklar var att livet begränsades i väntan på en njurtransplantation, vilket påverkade patienterna både emotionellt och fysiologiskt. Ju längre tid som patienterna befann sig på väntelistan minskade hoppet om en ny njure, och känslan av frustration samt oro ökade. Konklusion: Litteraturstudien visar på att behovet av information från sjuksköterskan till patienter som väntade på en njurtransplantation var stort. Information skapade en känsla av delaktighet i vården som i sin tur bevarade patientens hopp, samt minskade upplevelsen av oro. / Background: Kidney transplantation is seen as the main treatment method for terminal kidney failure as it increases both quality of life and longevity of the patient compared to dialysis. The prevalence of kidney failure is increasing worldwide and the demand for kidneys is not meeting the need. Aim: The aim of the study was to highlight the patient's experience while waiting for a kidney transplant. Method: The study was conducted as a literature study with an inductive approach to form an idea of what the research situation looks like in the chosen area. Result: The result is based on nine qualitative articles from seven different countries where four categories emerged: A life that limits, Expectations, Joy and sorrow and Need and importance of support. Common to all articles was that life was limited while waiting for a kidney transplant, which affected the patients both emotionally and physiologically. The longer the patients were on the waiting list, the less hope for a new kidney diminished and the feeling of frustration and anxiety increased. Conclusion: The literature study shows that the need for information from the nurse to patients waiting for a kidney transplant was great. Information created a sense of participation in care which in turn preserved the patient's hope and reduced the experience of anxiety.

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and occurs in up to 40% of patients with diabetes. The standard of care for DKD treatment has not kept up with the current health epidemic, which has led to a heavy economic toll and substantial health burden. Targeting either cell surface (cs)GRP78, activated α2-macroglobulin (α2M*) or preventing their interaction may provide a novel anti-fibrotic therapeutic target for the treatment of DKD and potentially non-diabetic chronic kidney disease (CKD) as well. Previously our lab has shown that HG-induced csGRP78 is a mediator of PI3k/Akt signaling and downstream extracellular matrix (ECM) protein production in glomerular mesangial cells (MC). However, the ligand responsible for activating high glucose (HG)-induced csGRP78 had not yet been determined. We have shown thus far that α2M is endogenously produced, secreted, and activated (denoted α2M*) in HG by MC, which leads to its binding to and activation thereof csGRP78. Further, α2M knockdown or α2M* neutralization attenuated Akt activation, the production of the profibrotic cytokine connective growth tissue factor (CTGF) and ECM proteins fibronectin and collagen IV. We have also shown that integrin β1 (Intβ1), a transmembrane receptor, associated with csGRP78 under HG conditions and likely acts as a tether to present csGRP78 completely extracellularly on MC. Interestingly, Intβ1 activation, even in the absence of HG, was sufficient to induce csGRP78 translocation. Further, inhibition of either csGRP78 or Intβ1 prevented synthesis, secretion and signaling of TGFβ1. This data implicates a role for Intβ1 as a required signaling partner for csGRP78-mediated profibrotic signaling. To further our understanding of csGRP78/ α2M*’s role in DKD, we investigated their ability to mediate TGFβ1 signaling through its non-proteolytic activator thrombospondin-1 (TSP1). Here, HG-induced TSP1 expression, ECM deposition, and activation of TGFβ1 was regulated by the PI3k/Akt pathway via csGRP78/α2M* in MC. Furthermore, we assessed whether this csGRP78/ α2M* axis is relevant to promoting profibrotic signaling in other renal cell types, including proximal tubule epithelial cells (PTEC) and renal fibroblasts (RF), that contribute to the pathogenesis of both later stage DKD and non-diabetic CKD. We show evidence here that HG and direct treatment with TGFβ1, a key pathologic regulator of kidney fibrosis, induce GRP78 surface translocation as well as the endogenous production and activation of α2M in both PTEC and RF. Inhibition of either csGRP78 or α2M* prevented TGFβ1 signaling measured as Smad3 activation as well as downstream ECM production. Interestingly, inhibition of this pathway under direct TGFβ1 treatment did not prevent Smad3 activation, implicating a role for Smad-independent TGFβ1 signaling through this axis. We identified the known noncanonical TGFβ1 signaling partners, yes associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), are mediated by csGRP78 and α2M*. Lastly, we evaluated the potential therapeutic benefit of inhibiting csGRP78/α2M* interaction in the kidney fibrosis model, unilateral ureteral obstruction (UUO). Here, we show evidence that inhibition of this signaling axis using an inhibitory peptide can prevent renal fibrosis. Whether this peptide also prevents fibrosis in DKD is currently being assessed. Together, these studies strongly implicate targeting csGRP78/α2M* interaction as a novel anti-fibrotic therapeutic intervention for early and late stage DKD, as well as a potential role in non-diabetic CKD. / Thesis / Doctor of Philosophy (Medical Science) / Diabetic kidney disease is the leading cause of kidney failure in developed nations. This progressive disease leads to the loss of kidney function due to an accumulation of scar proteins in the kidney over time. High glucose is a major factor that causes this to occur. Our lab studies specific kidney cells called mesangial cells, proximal tubule epithelial cells, and fibroblasts that produce scar proteins in the presence of high glucose. We have shown that when these cells are treated with high glucose, this causes the movement of a protein called GRP78 that normally resides inside the cell to move to the cell’s surface where it can interact with other proteins. My research has established that the proteins alpha 2-macroglobulin (ɑ2M), integrin β1 (Intβ1), and thrombospondin-1 (TSP1) can bind to GRP78 on the cell surface and cause cells to make scar proteins. Preventing ɑ2M or Intβ1 from binding to GRP78 or preventing TSP1 production prevents mesangial cells from making scar proteins when exposed to high glucose. In a mouse model that overproduces these scar proteins, we showed that preventing cell surface GRP78 and α2M interaction prevents scar protein production and is thus a novel potential treatment option for kidney disease.