Background: Chronic kidney disease (CKD) affects approximately 20 million Americans and is the cause of significant morbidity and mortality. Anemia, common in CKD, develops early in the disease process. It contributes to increased risk of cardiovascular disease, hospitalization, mortality, and diminishes health-related quality of life. Intravenous iron and Erythropoiesis Stimulating Agents (ESAs) are recommended for anemia management in CKD. The utilization patterns of IV iron and ESA, and their impact on hospital costs and length of stay merits investigation. Objectives: There were five general objectives of this investigation. The rate and extent of utilization of IV iron in anemic CKD patients was quantified across teaching hospitals in the US. Patient characteristics of those receiving IV iron and ESA and ESA alone were evaluated in detail. Predictors of IV iron and ESA use were determined. The impact of IV iron and ESA use was examined separately for total hospital costs and length of stay (LOS) while adjusting for confounding. Methods: This is a retrospective cohort analysis within the University Health System Consortium data warehouse. Eligible patients are those who were admitted to a hospital and received either IV iron and ESA or both at least once during the period of January 1, 2006, and December 31, 2008. Inclusion criteria include age > 18 years old with a primary or secondary diagnosis of CKD. The exposure of interest was IV iron and ESA therapy, and the outcome was the difference in total hospital costs and length of stay between patients only on ESA, and those on ESA and IV iron. A clustered binomial logistic regression using the GEE methodology was used to identify predictors of IV iron utilization. Propensity scores were used to control for confounding. A generalized estimating equations (GEE) model using a gamma distribution and log link was used to determine the adjusted hospital cost and length of stay for the IV iron and ESA and ESA alone therapy groups. Results: During the study period, 82,947 patients met all the inclusion and exclusion criteria. Of the 82,947 CKD patients on ESA therapy, only 8% (n = 6678) patients were on IV iron supplementation. Age, race, primary payer, admission status, severity of illness, dialysis status and physician specialty were identified as strong predictors of IV iron use in CKD patients. According to the multivariate model, the overall mean hospital cost for all 82,947 patients was $31,674. For patients using both IV iron and ESA (n=6678), mean costs were $34,756 compared to $31,404 for ESA users alone (n=76,269) – a difference of $3,352. The overall mean LOS for all patients was 9.75 days. For those using IV iron, the LOS was 10.71 days, and for those only using ESA, the LOS was 9.66 days– a difference of approximately 1 day. Conclusions: This inquiry is the first large multi-center investigation to quantify the impact of IV iron and ESA use on total hospital costs and LOS. Our investigation showed significant reduction in ESA doses with the use of IV iron supplementation, however, the overall prevalence of IV iron usage was low. Intravenous iron users were associated with a higher total hospital cost and longer length of stay than ESA users.

L'insuffisance rénale chronique (IRC) et son stade terminal sont associés à diverses complications, parmi lesquelles de nombreuses modifications du milieu intérieur : urémie, anémie, hyperparathyroïdie, rétention urémique… Les taux d'urée plasmatique ont longtemps été utilisés comme critère diagnostique de l'IRC, malgré l'absence de caractéristiques essentielles à un tel marqueur. Ces caractéristiques ont été discutées au regard de l'utilisation historique des déterminations d'urée. La caractérisation des altérations plasmatiques des patients en IRC est essentielle à la compréhension de la maladie et de leur lien avec la morbi-mortalité. Nous avons alors étendu notre champ d'intérêt à l'ensemble des solutés de rétention urémique, et sommes parvenus à identifier 56 nouveaux solutés à partir des études cliniques récemment publiées. L'évaluation diagnostique s'est poursuivie par l'étude des concentrations plasmatiques et urinaires en acides aminés et de leur association avec le stade d'IRC et ses complications, permettant alors la génération d'hypothèses sur l'origine métabolique de ces altérations. D'autre part, la mise en place d'une méta-analyse à montré une réduction du risque de décès chez les patients traités par dérivés de la vitamine D. La correction des comorbidités (hypovitaminose, perturbations du métabolisme phosphocalcique) et d'autres effets néphroprotecteurs expliqueraient ces bénéfices. Enfin, l'évaluation du protéome urinaire et du score CKD273 qui en résulte s'est avérée très intéressante pour l'identification des patients à risque de progresser, ce qui est un enjeu de santé publique. Ces travaux d'analyse bibliographique et de recherche clinique s'intègrent dans une volonté d'amélioration de la caractérisation de l'IRC et de l'évaluation de sa progression dans le but de prévenir ses complications. Ils sont le socle d'un projet plus large d'observation et d'analyse des caractéristiques des patients en IRC et de leur évolution. / Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with various complications, many of which occur within the internal environment: uremia, anemia, hyperparathyroidism, uremic retention… Plasma urea concentrations have long been used as a diagnostic criterion of CKD, despite the absence of some key characteristics. We discussed these features with regards to the historical uses of urea determinations. It is essential to characterize the plasma changes which occur in CKD to understand the disease and the relationship with comorbidities. We expanded our focus to all of uremic retention solutes, and identified 56 new solutes from recently published clinical studies. The study of plasma and urinary concentrations of amino acids and their association with CKD stage and complications further extended the study of CKD diagnosis, and allowed to generate hypotheses on the metabolic origin of these alterations. On the other hand, by meta-analysis, we showed a reduced risk of death in patients treated with vitamin D derivatives. Correcting comorbidities (hypovitaminosis, disturbances of bone and mineral metabolism) and other renoprotective effects may explain these benefits. Finally, the determination of the urinary proteome and the resulting CKD273 score was proved to be very useful for identifying patients at risk of progression, which is a public health issue. This work based on clinical research and literature analyses is part of an effort to improve the characterization of CKD and the evaluation of progression in order to avoid complications. It is the basis for a wider observational project: analyzing the characteristics of CKD patients and their changes over time.

Chronic kidney disease (CKD), defined as a decrease in renal function, is a global issue. The treatment of CKD and its comorbidities imparts a costly burden on the American healthcare system, therefore the need for therapeutics that prevent the progression of chronic kidney disease is urgent. Microarray studies have shown that the serine protease inhibitor clade A member 3 (SERPINA3) is transcriptionally upregulated in kidney injury. SERPINA3 is an extracellular protease inhibitor that maintains the homeostasis of extracellular matrix proteins. Our lab hypothesizes that SERPINA3 might not only be a transcriptional biomarker for kidney injury, but the SERPINA3 protein might act as a key upstream regulator in the advancement of renal inflammation and fibrosis. Our research characterizes the expression patterns of SERPINA3 in models of acute and chronic kidney injury through immunoblotting and immunohistochemistry. Our unilateral ureteral obstruction (UUO) model of chronic renal injury displays significant glomerular localization of SERPINA3. The adenine diet model of chronic kidney injury and the renal ischemic reperfusion injury (RIRI) model of acute kidney injury both display tubular upregulation of SERPINA3. The DOCA-salt hypertension model of chronic kidney injury was imposed on two strains of mice, C57BL/6 and 129/sv, both of which display tubular and glomerular upregulation of SERPINA3. However, the C57BL/6 strain, which is known for its resistance to glomerular sclerosis, displays higher renal localization of SERPINA3 when exposed to DOCA-salt hypertension, than does the 129/sv strain. In conclusion, our data suggests that SERPINA3 protein is upregulated in both acute and chronic kidney injury. The role of SERPINA3 in these models remains unknown, however, our lab theorizes that SERPINA3 protein may be renoprotective in certain instances of kidney injury. Functional assays must be performed to elucidate the role of SERPINA3 in these models of kidney injury. Characterizing the function of SERPINA3 in chronic and acute kidney injury might aid in the development of novel therapeutics to prevent the advancement of CKD.

A doença renal crônica (DRC) está associada com inibição de sistemas enzimáticos e de transportadores de fármacos. O nebivolol, um bloqueador de terceira geração, seletivo para receptores 1 adrenérgicos e com atividade vasodiladora, é metabolizado principalmente por hidroxilação aromática dependente do CYP2D6, hidroxilação alicíclica e por glicuronidação. O estudo avalia a influência da DRC estágios 3 e 4 e da hemodiálise na farmacodinâmica e na farmacocinética dos isômeros do nebivolol. Os pacientes investigados divididos nos Grupos controle (n=12), DRC estágios 3 e 4 (n=12) e Hemodiálise (n=11) receberam dose única p.o. de 10 mg de nebivolol racêmico. As amostras seriadas de sangue foram coletadas até 48h após a administração do fármaco. Em cada tempo de colheita de sangue, a frequência cardíaca foi avaliada na situação de exercício isométrico durante 2 min com o handgrip, a 30% da contratilidade voluntária máxima. Todos os pacientes foram fenotipados como metabolizadores rápidos do metoprolol, exceto um paciente do Grupo controle fenotipado como metabolizador lento. Os isômeros do nebivolol foram analisados em plasma como concentração total empregando LC-MS/MS e coluna de fase quiral. O método foi linear no intervalo de concentrações de 25-2500 pg de cada isômero do nebivolol/mL de plasma. Os parâmetros farmacocinéticos foram calculados empregando o programa WinNonlin. O teste de Wilcoxon foi empregado para avaliar as razões isoméricas diferentes da unidade (p<0,05) e o teste de Kruskal-Wallis foi empregado para comparar os parâmetros farmacocinéticos entre os três Grupos investigados. A disposição cinética do nebivolol nos pacientes do Grupo controle é enantiosseletiva com acúmulo plasmático (Cmax 1,32 vs 0,88 ng/mL e AUC0-¥ 8,02 vs 4,25 ng.h/mL), menores valores de clearance oral aparente (623,58 vs 1176,40 L/h) e menores valores de volume aparente de distribuição (5383,30 e 6397,70 L) para o isômero lnebivolol. Os parâmetros farmacocinéticos do l-nebivolol e d-nebivolol para os pacientes do Grupo DRC (n=12) permitem inferir, à semelhança do Grupo controle, maiores valores de Cmax e AUC (Cmax 2,40 vs 1,67 ng/mL e AUC0- 10,20 vs 8,37 ng.h/mL) e menores valores de clearance oral aparente (491,51 vs 604,58 L/h) e de volume aparente de distribuição (3527,00 e 5232,50 L) para o isômero l-nebivolol. Semelhante aos Grupos controle e DRC, o Grupo Hemodiálise também apresenta enantiosseletividade com acúmulo acúmulo plasmático (Cmax 1,35 vs 0,78 ng/mL e AUC0- 6,74 vs 4,50 ng.h/mL), menores valores de clearance oral aparente (742,26 vs 1112,10 L/h) e menores valores de volume aparente de distribuição (5704,70 vs 9477,10 L) para o isômero l-nebivolol. A farmacocinética dos isômeros do nebivolol no paciente investigado do Grupo controle, fenotipado como metabolizador lento, difere dos dados apresentados para os pacientes do Grupo controle (n=11), Grupo DRC (n=12) e Grupo Hemodiálise (n=11), fenotipados como metabolizadores rápidos, com observação de razão isomérica de AUC l/d de 4,77 e redução nos valores de clearance oral aparente de ambos os isômeros do nebivolol (67,24 vs 122,07 L/h, respectivamente para os isômeros l-nebivolol e d-nebivolol). Concluindo, a DRC estágios 3 e 4 e a Hemodiálise não alteram a farmacocinética de ambos os isômeros do nebivolol, o volume aparente de distribuição de ambos os isômeros do nebivolol não mostra correlação com o peso dos pacientes, assim como os valores de clearance aparente de ambos os isômeros não mostram correlação com o peso ou com os valores de clearance da creatinina dos pacientes investigados. No entanto, os valores de clearance aparente de ambos os isômeros do nebivolol mostram correlação significativa com a atividade do CYP2D6 avaliada através da RMplasma ix metoprolol/-hidroximetoprolol. A análise PK-PD foi realizada incluindo os 34 pacientes fenotipados como metabolizadores extensivos. O modelo Emax inibitório descreveu a análise PK-PD empregando a variação da frequência cardíaca como parâmetro farmacodinâmico em função das concentrações plasmáticas do d-nebivolol, resultando em valores de Emax de 15,42 bpm e de EC50 de 2,26 ng/mL, seguindo a administração de dose única oral de 10 mg de nebivolol racêmico. / Chronic kidney disease (CKD) is related to inhibition of enzyme systems and drug transporters. Nebivolol, a third generation -blocker, is a selective 1-adrenoceptor antagonist and has vasodilatory properties. It undergoes aromatic hydroxylation through the CYP2D6, alicyclic hydroxylation and glucuronidation. The study evaluates the influence of CKD stages 3 and 4 and hemodialysis on the pharmacodynamics and pharmacokinetics of nebivolol isomers. The investigated patients were divided into 3 groups: control group (n = 12), CKD stages 3 and 4 (n = 12) and hemodialysis (n = 11). They received a single oral dose of 10 mg of racemic nebivolol and serial blood samples were collected up to 48h. At each time of blood sampling, heart rate was assessed in the situation of isometric exercise during 2 min with handgrip at 30% of maximal voluntary contractility. All patients were phenotyped as extensive metabolizers (EM) of metoprolol, except one patient in the control group phenotyped as poor metabolizer (PM). The isomers of nebivolol were analyzed in plasma samples by LC-MS/MS using a chiral phase column. The method was linear over the concentration range of 25-2500 pg of each isomer of nebivolol/mL of plasma. Pharmacokinetic parameters were calculated using the WinNonlin program. The Wilcoxon test was used to assess isomeric ratios different from unit (p <0.05) and the Kruskal-Wallis test was used to compare the pharmacokinetic parameters among the 3 groups investigated. The kinetic disposition of nebivolol was stereoselective in control group with plasma accumulation (Cmax 1.32 vs 0.88 ng/mL and AUC0 0- 8.02 vs 4.25 ng.h/mL), lower values of apparent clearance (623.58 vs 1176.40 L/h) and apparent volume of distribution (5383.30 and 6397.70 L) for the l-nebivolol isomer. The kinetic disposition of nebivolol was also stereoselective in CKD group (n=12) showing higher Cmax and AUC (Cmax 2.40 vs 1.67 ng/mL and AUC0- 10.20 vs 8.37 ng.h/mL) and lower values of apparent clearance (491.51 vs 604.08 L/h) and apparent volume of distribution (3527.00 vs 5232.50 L) for the l-nebivolol isomer. Similarly to CKD and control groups, the Hemodialysis Group showed stereoselectivity with plasma accumulation (Cmax 1.35 vs 0.78 ng/mL and AUC0- 6.74 vs 4.50 ng.h/mL), lower values of apparent clearance (742.26 vs 1112.10 L/h) and apparent volume of distribution (5704.70 vs 9477.10 L) for the l-nebivolol isomer. The pharmacokinetics of nebivolol isomers in the patient phenotyped as PM differed from the data presented to the patients phenotyped as EM, with observation of isomeric ratios AUC l/d of 4.77 and reduced values of apparent clearance of both nebivolol isomers (67.24 vs 122.07 L/h, respectively for l- and d-nebivolol). Concluding, CKD stages 3 and 4 and Hemodialysis did not alter the pharmacokinetics of both nebivolol isomers (Kruskal-Wallis test, p> 0.05), the apparent volume of distribution of both nebivolol isomers showed no correlation with the weight of the patients, the apparent clearance of both isomers also showed no correlation with the weight or with the creatinine clearance of the investigated patients. However, the values for apparent clearance for both nebivolol isomers showed a significant correlation with the CYP2D6 activity evaluated by the metabolic ratios plasma metoprolol/-hidroximetoprolol. PK-PD analysis was evaluated including all the investigated patients phenotyped as EM (n=34). The inhibitory Emax model described the PK-PD analysis using heart rate variation as a pharmacodynamic parameter plotted against the plasma concentrations of the isomer dxi nebivolol, showing Emax values of 15.42 bpm and EC50 of 2.26 ng/mL, following administration of a single oral dose of 10 mg of racemic nebivolol.

Gatos infectados naturalmente pelo vírus da imunodeficiência felina (FIV) desenvolvem uma síndrome semelhante à causada pela infecção pelo vírus da imunodeficiência humana (HIV), sendo a espécie felina um modelo promissor de estudo da infecção pelo HIV. Em humanos a nefropatia associada à infecção pelo HIV é uma causa comum e preocupante de complicação por resultar em insuficiência renal progressiva nos pacientes acometidos. Achados clínico-patológicos identificados em gatos naturalmente infectados pelo FIV também sugerem um envolvimento renal. Com o intuito de determinar a ocorrência de doença renal crônica (DRC) em gatos infectados pelo FIV e uma possível associação entre essas doenças, foi estudada uma população de 44 gatos, sendo 20 animais naturalmente infectados e 24 animais não-infectados, submetidos às mesmas condições higiênico-sanitárias, de dieta e quanto à exposição a agentes infecciosos. Os animais foram acompanhados durante um período de 18 meses, durante o qual foram realizadas dosagens periódicas de creatinina sérica e mensuração da relação proteína:creatinina urinária (RPC-U). A ocorrência de DRC em gatos infectados pelo FIV foi de 45%, maior em comparação aos 25% referentes ao grupo não-infectado, embora não tenha havido diferença estatisticamente significativa entre esses grupos. A proteinúria em pelo menos um momento foi observada em 60% dos gatos infectados pelo FIV e em 26,1% dos gatos não infectados (p= 0,037). Considerando proteinúria persistente como aquela observada em pelo menos 3 momentos consecutivos, os gatos infectados tiveram ocorrência de 30,8% em comparação a 6,7% referente ao grupo não infectado (p> 0,05). Houve associação entre o óbito e a DRC apenas nos gatos infectados (p= 0,02). Concluiu-se que, apesar de a ocorrência de doença renal crônica e de proteinúria não ter sido estatisticamente maior diante da infecção pelo FIV, a associação entre o óbito e a DRC nos animais infectados sugere que o FIV pode contribuir para o agravamento da DRC, levando a rápida deterioração do organismo e considerável diminuição da sobrevida. / Cats naturally infected with the feline immunodeficiency virus (FIV) develop a syndrome that share common characteristics with the human immunodeficiency virus (HIV) infection. For this reason, felines are considered a promising model for the study of HIV infection. HIV associated nephropathy is a common and concerning complication in human beings, resulting in progressive renal insufficiency. Likewise clinico-pathological findings in naturally infected cats suggest a renal involvement. To evaluate the occurrence of chronic kidney disease (CKD) in cats infected with FIV and to verify a possible association between both diseases, a population of 44 cats submitted to the same sanitary handling, diet and exposure to infectious agents was studied. Of these cats, 20 were naturally infected with FIV and 24 were free of FIV infection. Animals were periodically accompanied for a 18-month period through serum creatinine and urinary protein:creatinine ratio measures. The occurrence of CKD in cats infected with FIV was 45%, a value higher than the observed in non-infected cats (25%), but no statistical difference was found. Proteinuria in at least one moment of evaluation was observed in 60% of infected cats and in 26,1% of non-infected cats (p=0,037). Considering the criterion of persistent proteinuria as the observation of urinary protein excretion in at least 3 consecutive moments, infected cats exhibited occurrence of 30,8% compared with 6,7% in the non-infected group (p>0,05). It was observed an association between death and CKD only in the cats infected with FIV (p=0,02). In conclusion, despite occurrence of CKD and proteinuria have not been statistically higher in infected cats than in non-infected one, the association between death and CKD in FIV-infected cats suggests FIV may contribute for the worsening of CKD, resulting in a quicker organic dysfunction and marked reduction of survival.

Bakgrund:Njurarnas huvudfunktioner har en vital roll och är en förutsättning till att upprätthålla kroppens balans. Kronisk njursvikt orsakar en kraftig reducering av funktionerna och i värsta fall kan njurarna helt sluta att fungera. Tillståndet leder till döden om inte dialysbehandling eller njurtransplantation genomförs. Under flera decennier har det skett en ökning av patienter som utvecklar kronisk njursvikt och därmed får dialysbehandling. Att leva med kronisk sjukdom orsakar svårigheter och förändringar i livet. Genom en god vård kan sjuksköterskan främja patientens livskvalitet och välbefinnande trots kronisk njursvikt och ett liv med hemodialys.  Syfte: Syftet med litteraturöversikten var att belysa hur patienter med kronisk njursvikt upplever livet med hemodialys.  Metod: Litteraturöversikten baserades på tolv vetenskapliga originalartiklar som analyserats. Metoden innefattade att identifiera likheter och skillnader som sedan bildade nya teman till litteraturöversiktens resultat. Artiklarna inhämtades från databaserna CINAHL Complete och PubMed.  Resultat: Under analysen identifierades femhuvudteman: En förändrande process, Ett liv som begränsar, Hemodialys som en fängslande frihet, En oförutsägbar framtid och Upplevelsen av vårdmiljö &amp; vårdpersonal. En förändrande process kompletterades med två underteman; Emotionell påverkan och Vägen till acceptans. ÄvenHemodialys som en fängslande frihet kompletterades med två underteman; Dialysmaskinen, en vän eller en fiende? och Kroppsliga förändringar.  Diskussion: Resultatdiskussionen tolkar huvudfynden i en större helhet med hjälp av Katie Erikssons vårdvetenskapliga teori, annan forskning samt författarnas egna reflektioner. / Background: The main functions of the kidneys have a vital role and are essential for maintaining the balance of the body. Chronic kidney disease causes a steep reduction in the kidney´s functions, in the worst-case scenario the kidneys may cease to function entirely. The condition leads to death unless treated with hemodialysis or kidney transplantation. For decades, there has been an increase in patients developing chronic kidney disease and thus receive dialysis treatment. Living with chronic disease causes difficulties and changes in life. Through good care, the nurse can promote the patient´s quality of life and well-being despite of chronic kidney disease and a life with hemodialysis. Aim: The aim was to elucidate how patients with chronic kidney disease experience life with hemodialysis. Method: The literature review was based on twelve scientific original articles that were analyzed. The method involved identifying similarities and differences that then formed new themes for the literature review results. The articles were obtained from the databases CINAHL Complete and PubMed. Results: During the analysis five main themes were identified: A changing process, A life that limits, Hemodialysis as a captivating freedom, An unpredictable future, and Experience of care environment &amp; healthcare staff. A changing process was supplemented with two sub-themes; The emotional impact and Path to acceptance.Additionally, Hemodialysis as a captivating freedom was supplemented by two sub-themes; The dialysis machine, a friend or an enemy? and Bodily changes.  Discussion: The results discussion interprets the main findings in a larger whole with the help of Katie Eriksson´s health science theory, other research, and the author´s own reflections.

A saliva é um fluído produzido e secretado pelas glândulas salivares. Ela desempenha um importante papel na homeostase dos indivíduos. Diversas doenças afetam a produção ou a composição da saliva secretada, dentre elas a doença renal crônica (DRC). A DRC é definida como um dano renal ou diminuição da função renal por um período igual ou superior a três meses. É classificada em estágios, sendo que em seu grau mais avançado existe a necessidade de terapias de hemodiálise ou transplante renal. Muitos são os estudos que buscaram manifestações orais, alterações de fluxo e composição salivares nestes pacientes, contudo quando buscamos na literatura, não encontramos trabalhos que utilizaram um modelo animal para o estudo de parâmetros de composição salivar na doença renal crônica. O objetivo deste estudo foi analisar alterações em alguns componentes na saliva de ratos estimulada por pilocarpina (1mg/Kg) ou isoproterenol (5mg/Kg), em um modelo de 5/6 de nefrectomia (IRC), comparando com um grupo controle positivo (Sham) e outro controle negativo (C) em dois tempos experimentais de 8 e 12 semanas. A nefropatia crônica foi obtida com 5/6 de nefrectomia pela ligadura de dois ramos da artéria renal esquerda e nefrectomia total direita e os grupos Sham foram submetidos à simulação do procedimento cirúrgico. Ao final dos tempos experimentais, amostras de sangue e saliva foram coletadas de todos os grupos e foram analisados: fluxo salivar, concentração de proteína total, atividades das enzimas amilase e peroxidase, ácido siálico livre e total, bem como as dos íons: cálcio, fósforo, sódio, potássio e concentração de ureia salivar. Foram analisadas também as concentrações séricas de ureia e creatinina. Observamos aumento significativo das concentrações séricas de ureia e creatinina e das concentrações salivares de ureia nos grupos IRC em ambos os tempos experimentais; Com estímulo de pilocarpina, observamos que com 8 semanas ocorreu diminuição significativa da atividade da enzima amilase e com 12 semanas ocorrem aumentos significativos da concentração de proteínas totais e atividade da enzima peroxidase. No estímulo com isoproterenol, observamos que com 8 semanas ocorrem diminuições significativas das atividades das enzimas amilase e peroxidase, com 12 semanas ocorreu diminuição significativa do fluxo salivar do grupo IRC em relação ao grupo Sham, aumento significativo da atividade da enzima amilase e diminuição significativa da atividade da enzima peroxidase no grupo IRC em relação aos grupos controle e sham. Concluímos que o período de 12 semanas pós-cirurgia apresentou maiores alterações da saliva coletada tanto pelo estímulo simpático quanto pelo estímulo parassimpático, devendo este período ser utilizado nas futuras análises em glândulas salivares. / Saliva is a fluid produced and secreted by the salivary glands. It plays an important role in the homeostasis of individuals. Several diseases affect the production or composition of saliva secreted, among them chronic kidney disease (CKD). CKD is defined as a kidney damage or decreased kidney function for a three months exceeding period. It is classified in stages, and in its most advanced level there is a need for hemodialysis therapies or kidney transplantation. Many studies have sought oral manifestations, changes in salivary flow and composition in these patients, however when we look at the literature, we did not found studies that used an animal model for the study of salivary composition in chronic kidney disease. The aim of this study was to analyze changes in some components in the saliva of rats stimulated by pilocarpine (1mg/Kg) or isoproterenol (5mg/kg) in a model of 5/6 nephrectomy (CRF), compared with a positive control group (Sham) and a negative control (C) at two time period of 8 and 12 weeks. The chronic nephropathy was obtained with 5/6 nephrectomy by ligation of two branches of the left renal artery and right radical nephrectomy and Sham groups underwent surgery simulation. At the end of the experimental period, blood and saliva samples were collected from all groups and were analyzed: salivary flow rate, total protein concentration, activities of amylase and peroxidase, free and total sialic acid, as well as the ions calcium, phosphorus, sodium, potassium and urea concentration in saliva. We also evaluate the serum concentrations of urea and creatinine. We observed a significant increase in serum urea and creatinine concentrations and salivary urea in IRC groups in both experimental times; Under pilocarpine stimulation, we found a significant decrease in the activity of the enzyme amylase 8 weeks after the surgery. 12 weeks after the surgery increase in the total protein concentration and peroxidase activity were observed; Under stimulation with isoproterenol, we observed decreases in the activities of amylase and peroxidase after 8 weeks; 12 weeks after the surgery we found decrease in salivary flow compared to the sham group, increase in the activity of the enzyme amylase and decrease of the peroxidase activity in CRF group when compared to control and sham groups. We conclude that the period of 12 weeks after surgery showed greater changes in saliva collected both by sympathetic stimulation and by parasympathetic stimulation, and this period should be used in future analyzes in salivary glands.

Vitamin D deficiency in patients with chronic kidney disease, measured by reduced serum concentrations of 25 hydroxy vitamin D, is highly prevalent and associated with both endothelial dysfunction and an increased risk of cardiovascular disease. Observational studies in chronic kidney disease have demonstrated that vitamin D therapy reduces the risk of cardiovascular disease. In patients with chronic kidney disease and concomitant vitamin D deficiency, the effect of vitamin D therapy on endothelial function, which is associated with cardiovascular disease, is poorly understood. The mechanism by which vitamin D affects endothelial function is unclear. Methods Presented in this thesis, two studies have addressed these issues: 1. A double blind, randomized controlled trial evaluating the effect of ergocalciferol compared to placebo on microcirculatory endothelial function in patients with non-dialysis chronic kidney disease and concomitant vitamin D deficiency 2. In vitro and in vivo experiments to determine the mechanistic effect of ergocalciferol on endothelial function in an experimental model of uraemia. Results In the clinical study, ergocalciferol increased vitamin D serum concentrations and improved microcirculatory endothelial function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Oxidative stress measured by skin autofluorescence for advanced glycation end products did not change in the ergocalciferol group but increased significantly in the placebo group. Ergocalciferol increased endothelial nitric oxide synthase expression and activity in cultured human endothelial cells and improved endothelial function in an in vivo model of mild uraemia. The findings from the in vivo and clinical studies occurred independently of changes in blood pressure, conduit artery function, serum calcium, phosphate and parathyroid hormone supporting in vitro findings that ergocalciferol acts directly on the endothelium. Conclusion Ergocalciferol improved endothelial function in both rodent and human subjects with chronic kidney disease. Experimental evidence suggests this effect occurs through an endothelium dependent mechanism involving changes in the upregulation and function of endothelial nitric oxide synthase.

Orientador: Bárbara Perez Vogt / Resumo: INTRODUÇÃO: Atualmente, várias sociedades internacionais reconhecem a presença da sarcopenia nas doenças catabólicas, como a doença renal crônica. Sarcopenia afeta qualidade de vida e atividades diárias dos indivíduos. O objetivo deste trabalho foi avaliar o diagnóstico, prevalência e associação de parâmetros clínicos e nutricionais com a sarcopenia em pacientes em diálise peritoneal (DP). MÉTODOS: Realizado busca ativa da sarcopenia em pacientes prevalentes em DP maiores de 18 anos. Avaliação da massa muscular pelo índice de massa apendicular (IMMA) e da função muscular pela força de preensão manual (FPM) foram realizadas. Diagnóstico de sarcopenia foi realizado de acordo com o European Working Group on Sarcopenia in Older People (EWGSOP) e sua gravidade foi avaliada por teste de velocidade de marcha (VM). Para análise estatística, foi utilizado teste Kolmogorov-Smirnov, seguido de qui quadrado ou exato de Fisher, Mann-Whitney ou Teste t de Student, de acordo com a distribuição dos dados. Posteriormente, foi realizada regressão logística multivariada. As variáveis com significância <0,1 na análise univariada foram incluídas no modelo de regressão. RESULTADOS: Foram incluídos cinquenta indivíduos em DP, média de idade de 55,74±16,22 anos, 52% eram mulheres. A prevalência de sarcopenia em DP foi de 10% (n=5), sendo 8% (n=4) considerados com sarcopenia severa. Comparando os grupos de pacientes de acordo com a presença de sarcopenia, foram encontradas diferenças significativas c... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: INTRODUCTION: Currently, several international societies recognize the presence of sarcopenia in catabolic diseases, such as chronic kidney disease. Sarcopenia affects quality of life and daily activities of individuals. The aim of this study was to evaluate the diagnosis, prevalence and association of clinical and nutritional parameters with sarcopenia in patients on peritoneal dialysis (PD). METHODS: Screening for sarcopenia was performed in prevalent patients in PD older than 18 years. Muscle mass by appendicular skeletal muscle mass index (ASMMI) and muscle function by handgrip strength (HGS) were evaluated. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People (EWGSOP) and its severity was assessed by gait speed (GS). For statistical analysis, Kolmogorov-Smirnov test was used, followed by Chi-square or Fisher's exact test, Mann-Whitney or Student´s t Test, according to data distribution. Later, binary logistic regression was performed. Variables with significance <0.1 in the univariate analysis were included in the binary logistic regression model. RESULTS: Fifty subjects on PD were included, mean age 55.74±16.22 years, 52% female. Sarcopenia prevalence was 10% (n=5), and 8% (n=4) were classified as severe sarcopenia. Comparing the groups of patients according to the presence of sarcopenia, significant differences were found regarding body weight (55.34±7.01kg vs 70.78±15.60kg, p=0.003), body mass index (BMI) (22.75±1.45kg/m² vs 2... (Complete abstract click electronic access below) / Mestre

Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD). For patients who recover from AKI, there is a 25% increase in the risk of CKD, and a mortality rate of up to 50% after 10 years. Nuclear factor kappa-B (NF-κB) is a family of transcription factors that regulates the transcription of many proteins that play a key role in inflammation. Inhibitor of IκB kinase (IKK) is directly upstream of NF-κB. My aim was to investigate a) the role of IKK in the progression of AKI to CKD, and b) whether its inhibition attenuates renal fibrosis. In this thesis I used a model of unilateral renal ischaemia-reperfusion injury with contralateral nephrectomy, to firstly map the acute time course of AKI. From the data generated from the time course, I decided to treat the animals at 24 h post reperfusion with the IKK inhibitor, IKK16, as i) this was at the peak of renal dysfunction (24 h post reperfusion), and ii) prior to the activation of NF-κB (48 h post reperfusion). The inhibition of IKK at 24 hours post reperfusion, as a delayed treatment, successfully attenuated renal dysfunction, NF-κB activation and renal structural damage. I subsequently increased the recovery time after ischaemia-reperfusion in my rat model to 28 days to study the development of fibrosis post AKI. The inhibition of IKK at 24 hours post reperfusion successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components at 28 days post reperfusion. In addition, the delayed inhibition of IKK at days 7-13 post unilateral ureteral obstruction in a rat model, successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components. These data indicate that the activation of the IKK complex drives tubulointerstitial fibrosis, and suggests that the inhibition of IKK could be a useful pharmacological tool for the creation of therapies to combat AKI and the subsequent development of fibrosis, via the reduction of both inflammation and the prevention of the expression of pro-fibrotic markers.