A growing number of factors, including the costs, technological advancements, an ageing population, and medical errors are leading industrialised countries to invest in research on alternative solutions to improving their health care systems and increasing patients’ life quality. Personal Health System (PHS) solutions envision the use of information and communication technologies that enable a paradigm shift from the traditional hospital-centred healthcare delivery model toward a preventive and person-centred approach. PHS offers the means to follow patient health using wearable, portable or implantable systems that offer ubiquitous, unobtrusive bio-data acquisition, allowing remote access to patient status and treatment monitoring.Electrical Bioimpedance (EBI) technology is a non-invasive, quick and relatively affordable technique that can be used for assessing and monitoring different health conditions, e.g., body composition assessments for nutrition. EBI technology combined with state-of-the-art advances in sensor and textile technology are fostering the implementation of wearable bioimpedance monitors that use functional garments for the implementation of personalised healthcare applications.This research studies the development of a portable EBI spectrometer that can use dry textile electrodes for the assessment of body composition for the purposes of clinical uses. The portable bioimpedance monitor has been developed using the latest advances in system-on-chip technology for bioimpedance spectroscopy instrumentation. The obtained portable spectrometer has been validated against commercial spectrometer that performs total body composition assessment using functional textrode garments.The development of a portable Bioimpedance spectrometer using functional garments and dry textile electrodes for body composition assessment has been shown to be a feasible option. The availability of such measurement systems bring closer the real implementation of personalised healthcare systems. / 2013-04-29 Licentiatseminarium kl.10-11.30 The presentation will be broadcast using Adobe Connect. For more information contact javier.ferreira@hb.se

Les maladies cardiovasculaires apparaissent précocement au cours de l'insuffisance rénale chronique (IRC) et représentent la première cause de mortalité. La 1ère étape pour apprécier la relation entre risque cardiovasculaire et progression de l'IRC consiste à améliorer l'estimation du débit de filtration glomérulaire (DFG). Nous avons donc évalué l'impact des conditions analytiques de mesure de la créatininémie et de la cystatinémie sur l'estimation du DFG. Les créatinines IDMS traçables (enzymatique et Jaffe compensé) améliorent l'estimation du DFG. Cependant, les méthodes enzymatiques non sensibles aux pseudochromogènes doivent être préférées. Concernant la cystatine C, nos résultats soulignent l'absence de standardisation du dosage. Chez des patients IRC non dialysés (stade I à V), nous avons identifié l'ostéoprotégérine (OPG) comme marqueur biologique de la présence de calcifications vasculaires. In vitro, nous avons démontré que le stress oxydant, majoré en présence de sérum urémique, jouait un rôle clé dans la transdifférenciation des cellules musculaires lisses vasculaires en ost oblastes. La mortalité en dialyse reste élevée et est largement dépendante des maladies cardiovasculaires. Il nous a donc paru nécessaire de rechercher les marqueurs pronostics et/ou d'en suivre l'évolution en transplantation. En dialyse, malgré une épuration significative par hémodiafiltration, les peptides natriurétiques sont des marqueurs du remodelage ventriculaire. La combinaison "NT-proBNP-CRP" est un puissant facteur pronostic de mortalité cardiovasculaire en hémodialyse. Après transplantation rénale, les calcifications vasculaires se stabilisent chez la majorité des patients et les taux d'OPG diminuent précocement. Les taux d'OPG sont significativement plus élevés chez les patients dont les calcifications progressent. Toutefois, seule l'intensité des calcifications avant transplantation permet de prédire la progression / Cardiovascular disease occurs in the early stage of chronic kidney disease (CKD) and is the leading cause of death. The first step, to appreciate the link between cardiovascular risk and CKD progression, is to improve glomerular filtration rate (GFR) estimation. We have therefore evaluated the impact of analytical conditions for creatinine and cystatin C measurement on estimated GFR. New creatinine ID-MS traceable methods (enzymatic and compensated Jaffe) improved estimation of GFR by predictive equations. However, enzymatic methods that are much less susceptible to interfere with non-creatinine chromogens may provide more reliable estimations of GFR. Regarding cystatin C, our results highlighted the lack of standardization. In non dialyzed CKD patients (stage I to V), we identified osteoprotegerin (OPG) as a biomarker for the presence of vascular calcification. In vitro, we demonstrated that oxidative stress, increased in the presence of uremi c serum, played a key role in the transdifferentiation of vascular smooth muscle cells into osteoblast-like cells. In dialysis, mortality is high and largely dependant on cardiovascular disease. We have therefore investigated prognostic markers and/or followed their evolution after transplantation. In dialysis, despite their removal by hemodiafiltration, natriuretic peptides could be potential markers of left ventricular remodelling. In addition, the combination of high CRP and circulating NT-proBNP dramatically impaired the hemodialysis survival rate. After renal transplantation, stabilization of vascular calcification was observed in the majority of patients and OPG levels are dramatically reduced. Despite a higher baseline OPG level in progressors vs. non-progressors patients, post transplant vascular calcification progression was only predicted by baseline score.

Kidney failure is frequently associated with the risk factors linked to metabolic syndrome. Lipopolysaccharide (LPS) is a potent inflammatory molecule, which has increased absorption from the gut into blood circulation following a high fat and high-energy diet. We hypothesized that LPS from a high fat diet can amplify inflammation, thereby exacerbating chronic kidney disease and associated disorders. We have found that adding a high fat diet to renal insufficient mice significantly progressed their kidney disease as well as associated disorders, compared to both a high fat diet and renal insufficiency alone. Additionally, we were able to demonstrate in vitro that the combination of LPS and palmitic acid, a marker of high fat diet, induced inflammatory pathways significantly more than either LPS or palmitic acid alone. These results provide insight into connection between a high fat diet and the progression of chronic kidney disease as well as associated disorders.

L'insuffisance rénale chronique (IRC) est associée à une importante morbidité et mortalité cardio-vasculaire, à laquelle participent la dysfonction endothéliale. Les patients IRC présentent de plus une susceptibilité accrue aux thromboses qu’elles soient veineuses ou artérielles. Les toxines urémiques sont des solutés s'accumulant dans le sérum et les tissus des patients IRC. Parmi elles, les toxines urémiques liées aux protéines ont une toxicité endothéliale démontrée in vitro. Nous avons démontré que l’indoxyl sulfate (IS) et l’indole acetic acide (IAA), deux toxines liées aux protéines provoquent un phénotype pro coagulant de cellules endothéliales en culture via une production accrue de facteur tissulaire (FT). Le facteur tissulaire est un facteur membranaire procoagulant qui initie la cascade de la coagulation en activant le facteur VII via la voie extrinsèque. Nous avons aussi démontré que la production de FT passe par une voie cellulaire préalablement connue pour son implication dans les processus de detoxification : la voie de l’aryl hydrocarbon receptor (AHR). Dans notre travail, nous montrons que l’IS et l’IAA ont un comportement similaire à l’intoxication par la dioxine. Le lien entre FT et AHR n’avait jamais été démontré auparavant. En conclusion, l’IS et l’IAA participent à la dysfonction endothéliale des patients IRC et à la surmortalité cardiovasculaire, en augmentant la production endothéliale de FT et ainsi en provoquant un phénotype pro coagulant des cellules endothéliales. La voie AHR constitue une cible thérapeutique très intéressante dans la problématique de la surmortalité cardiovasculaire des patients IRC. / Chronic kidney disease (CKD) is associated with significant morbidity and cardiovascular mortality, which involves chronic inflammation, oxidative stress and endothelial dysfunction. CKD patients have a higher risk of venous or arterial thrombosis compared to general population. Uremic toxins are molecules that accumulate in the serum and organs of CKD patients. Among them, protein-bound uremic toxins are poorly removed by dialysis, and their endothelial toxicity had been well demonstrated in vitro. In this thesis, we demonstrated that indoxyl sulfate (IS) and indole acetic acid (IAA ), two protein-bound toxins can cause a pro coagulant phenotype of cultured endothelial cells through an increased production of tissue factor (TF ) Tissue factor is a membrane procoagulant factor that initiates the coagulation cascade by activating factor VII via the extrinsic pathway. We also demonstrated that TF increase was produced via a cellular pathway previously known to be involved in the detoxification processes: the aryl hydrocarbon receptor pathway (AHR) . The canonical ligand of AHR is dioxin, well known for its cardiovascular adverse effects. In this work, we showed that IS and IAA had a “dioxin- like effect”. The link between FT and AHR had never been shown earlier. CKD constitutes an endogenous situation similar to dioxin poisoning. In conclusion, the IS and IAA are involved in endothelial dysfunction in CKD patients and cardiovascular mortality by increasing the endothelial production of TF and thus causing a pro- coagulant phenotype of endothelial cells. AHR pathway is a very interesting therapeutic target in the problematic of cardiovascular mortality in CKD patients .

Orientador: Luis Cuadrado Martin / Resumo: Fundamentação: É crescente o número de trabalhos revelando a associação de hiperuricemia assintomática com hipertensão, síndrome metabólica, doenças cardiovasculares e doença renal crônica. Alguns estudos revelam que o tratamento da hiperuricemia assintomática reduz o número de desfechos renais e cardiovasculares. Tal premissa, no entanto, ainda não foi avaliada em uma subpopulação brasileira. Objetivos: Avaliar a associação entre tratamento com alopurinol e ocorrência de desfechos definitivos em portadores de doença renal crônica com hiperuricemia assintomática. Materiais e métodos: Foram avaliados, de forma retrospectiva, pacientes hiperuricêmicos e portadores de doença renal crônica não dialítica, em tratamento no HC-FMB – UNESP, os quais iniciaram acompanhamento no ambulatório de Insuficiência Renal Crônica ou de Nefrologia Geral do HC-UNESP desde janeiro 2002 a dezembro 2017. Com o intuito de avaliar a associação do uso do alopurinol sobre desfechos definitivos (entrada em terapia renal substitutiva, duplicação da creatinina ou morte). Resultados: Foram avaliados 109 pacientes sendo 53 do sexo feminino, cuja média de idade foi de 68 ± 11 anos. Destes, 95 eram brancos, 13 afrodescendentes e um asiático. Vinte e seis pacientes apresentaram o desfecho estudado no período; entre todos os 36 pacientes que iniciaram o uso de alopurinol no primeiro ano seguimento, ocorreram oito desfechos (22%). A proteinúria em 24 h associou-se aos desfechos avaliados Hazzard Ratio de 1,301 (I... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Rationale: There is increasing number of studies revealing an association of hyperuricemia with hypertension, metabolic syndrome, cardiovascular diseases and chronic kidney disease. Some studies have shown that treatment of asymptomatic hyperuricemia reduces the number of renal and cardiovascular outcomes. This premise, however, has not yet been evaluated in a Brazilian subpopulation. Objectives: To evaluate the association between treatment with allopurinol and the occurrence of definitive outcomes in patients with chronic kidney disease with asymptomatic hyperuricemia. Materials and methods: Hyperuricemic patients with chronic non-dialytic kidney disease under treatment at HC-FMB - UNESP who began follow-up at the Chronic Kidney Insufficiency or General Nephrology outpatient clinic at HC-UNESP, were retrospectively evaluated, from January 2002 to December 2017. In order to evaluate the association of the use of allopurinol on definitive outcomes (renal replacement therapy, creatinine doubling or death). Results: A total of 109 patients were evaluated, of which 53 were females, whose mean age was 68 ± 11 years. Of these, 95 were white, 13 Afro-descendants and one Asian. Twenty-six patients presented the outcome studied in the period; among all 36 patients who started using allopurinol in the first year of follow-up, eight outcomes (22%) occurred. Proteinuria at 24 h was associated with the Hazzard Ratio of 1.301 (95% CI: 1.122 -1.508), p: 0.011. In univariate analysis, phosp... (Complete abstract click electronic access below) / Mestre

Descrevemos recentemente um novo modelo de DRC, baseado nos efeitos adversos da administração de L na lactação (LLact). Os objetivos do presente estudo foram; caracterizar os mecanismos patológicos envolvidos com a nefropatia do LLact e investigar se o extraordinário efeito renoprotetor obtido com a associação L+H no modelo NX seria reproduzido no modelo LLact. Utilizamos 20 ratas Munich-Wistar lactantes, com 6 filhotes cada. As matrizes receberam L, 250mg/Kg/d durante a amamentação e a droga atingiu a prole via leite materno. Os filhotes machos foram acompanhados até os 7 meses de vida, quando se verificou; pressão caudal, albuminúria, creatinina sérica, glomerulosclerose, expansão intersticial, proliferação celular, presença de miofibroblastos intersticiais e rarefação capilar. Os animais LLact restantes foram divididos em 3 novos grupos: LLact+V, mantido sem tratamento, LLact+L, LLact+H, e LLact+LH. Os parâmetros foram reavaliados após 3 meses nesses grupos e também em animais controle (C). Os ratos, LLact apresentaram hipertensão, albuminuria, glomerulosclerose (GS) e lesão intersticial com inflamação e fibrose aos 10 meses de vida. O tratamento com L+H na vida adulta limitou a hipertensão, albuminúria, GS, proliferação intersticial e infiltração de miofibroblastos. Porém, a renoproteção obtida pela associação foi moderada em relação aos resultados previamente obtidos com o modelo NX, especialmente no tocante ao comprometimento tubulointersticial / We recently standardized a severe CKD model based on impaired nephrogenesis by suppression of angiotensin II (Ang II) activity during lactation (LLact). In the present study we sought to gain further insight into the mechanisms associated with the LLact model and to verify if the renoprotection obtained with the association of the Ang II receptor blocker, Losartan (L), and Hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, could be also obtained in the LLact model. Twenty Munich-Wistar dams, each nursing 6 pups, received L, 250 mg/kg/d, until weaning. The male LLact offspring remained untreated until 7 months of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (LLactPre), followed no further. The remaining rats were divided in groups: LLact+V, untreated, LLact+L, given L, 50 mg/kg/day, now as a therapy, LLact+H, given H, 6mg/kg/day and LLact+LH, given L and H. All the parameters were reassessed 3 months later in these groups and in agematched controls (C). At this time, LLact rats exhibited hypertension, albuminuria, glomerulosclerosis (GS), interstitial expansion and inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. LH therapy normalized blood pressure, albuminuria, GS, and limited interstitial cell proliferation and -smooth muscle actin (-SMA) accumulation. However, LH renoprotection achieved with the LLact model was only mild if compared previous studies with the 5/6 renal ablation model

Introdução: A nefropatia induzida por contraste iodado (NIC) é um efeito adverso comum em pacientes com doença renal crônica (DRC). Caracteriza-se por uma síndrome de doença renal crônica agudizada. Resultado da vasoconstrição renal, hipóxia, ativação da cascata inflamatória, lesão celular oxidativa, a NIC deteriora a função renal, aumenta os dias de hospitalização, os custos hospitalares e a mortalidade do paciente portador de DRC. Objetivo: Avaliar o efeito renoprotetor do resveratrol, um polifenol com propriedades vasodilatadoras e anti-inflamatórias em ratos com doença renal crônica que receberam contraste iodado. Métodos: Ratos Wistar, machos, adultos randomizados em quatro grupos: SHAM: controle do modelo de doença renal crônica; Nx: ratos com nefrectomia 5/6 (modelo experimental de DRC); Nx+C: ratos Nx que receberam 6 ml/Kg de contraste iodado; Nx+C+R: animais Nx que foram pré-medicados com resveratrol 25 mg/Kg e 6 ml/Kg de contraste iodado. Foram avaliadas a função (clearance de inulina) e hemodinâmica renal (fluxo sanguíneo renal e resistência vascular renal), estresse oxidativo (peróxidos, óxido nítrico e substâncias reativas ao ácido tiobarbitúrico urinário e tióis no tecido renal) e análise histológica. Resultados: O uso de contraste resultou em deterioração da função renal, redução do fluxo sanguíneo renal, aumento da resistência vascular renal, lesão oxidativa e lesão túbulo intersticial dos ratos com DRC. O uso do resveratrol resultou na manutenção da taxa de filtração glomerular, do fluxo sanguíneo e resistência vascular renal, reduziu a lesão oxidativa e a lesão túbulo intersticial após a exposição ao contraste. Conclusões: O resveratrol apresentou efeito renoprotetor, hemodinâmico e antioxidante, na NIC em ratos com doença renal crônica. / Introduction: Contrast-Induced acute kidney injury (CI-AKI) is a common adverse effect in patients with chronic kidney disease (CKD). Result of renal vasoconstriction, hypoxia, activation of inflammatory cascade, oxidative cell damage, CI-AKI promote impaired renal function, increased length of hospitalization, hospital costs and mortality. Objective: This study evaluated the renoprotection of resveratrol, a polyphenol with vasodilating and anti-inflammatory properties in rats with chronic kidney disease receiving iodinated contrast media. Methods: Wistar, adult, male rats randomized into four groups; Sham: control of chronic renal injury model; Nx: rats with 5/6 nefrectomy (experimental model of CKD); Nx+IC: Nx rats that received 6 ml/kg of iodinated contrast; Nx+IC+R: Nx rats that received 6 ml/kg of iodinated contrast and resveratrol 25 mg/Kg. Renal function (inulin clearance), renal hemodynamics (renal blood flow and renal vascular resistance), oxidative profile (peroxides, urinary nitric oxide, reactive substances to thiobarbituric acid in urine, thiols in renal tissue) and histological analysis were evaluated. Results: Iodinated contrast led to impaired renal function, reduced renal blood flow, intensified renal vascular resistance, and promoted oxidative and tubular injury in CKD rats. Resveratrol maintained glomerular filtration rate, renal blood flow and vascular resistance, reduced oxidative and tubular injury after contrast exposition. Conclusion: Resveratrol showed a renoprotective effect, with antioxidant and hemodynamics impact, on CI-AKI in rats with CKD.

Pacientes em hemodiálise (HD) estão sob estresse oxidativo, o que leva à formação de espécies reativas de oxigênio (EROs). Toxinas urêmicas, a própria hemodiálise e o comprometimento do sistema antioxidante induzem a formação de EROs. Dentre os antioxidantes está o Selênio (Se), mineral que a literatura já relata deficiência em pacientes em HD. Considerando a importância da atividade antioxidante nestes pacientes com doença renal crônica (DRC) em HD, o objetivo deste estudo foi avaliar o efeito da suplementação com castanha-do-brasil nos níveis de Se e na atividade da glutationa peroxidase (GSH-Px) em pacientes nestas condições. Foram estudados 81 pacientes em HD (52,0 ± 15,2 anos, tempo média de HD de 82,3 ± 91,4 meses e IMC de 24,4 ± 4,4 kg/(m)2) das clínicas RenalCor e RenalVida do Rio de Janeiro. Os pacientes receberam uma castanha (≈ 5g), cerca 290µg Se, por dia, durante três meses. A concentração de Se foi determinada por espectrometria de absorção atômica com geração de hidretos (HITACHI®, Z-500). A atividade da enzima GSH-Px foi medida usando kit comercial RANDOX®. Os níveis de Se no plasma (18,8 ± 17,4 µg/L) e no eritrócito (72,4 ± 37,4 µg/L) antes da suplementação estavam abaixo da faixa da normalidade (60-120 µg/L no plasma e de 90-190 µg/L no eritrócito) e após a suplementação os níveis plasmáticos e eritrocitários aumentaram para 104,0 ± 65,0 µg/L e 244,1 ± 119,5 µg/L (p< 0,0001), respectivamente. A atividade de GSH-Px também aumentou após a suplementação passando de 46,4 ± 14,9 U/gHb para 55,9 ± 23,6 U/gHb (p< 0,0001). Antes da suplementação 11% dos pacientes apresentaram atividade da GSH-Px abaixo da normalidade (27,5 - 73,6 U/gHb) e, após a suplementação todos pacientes apresentaram atividade da GSH-Px normal. Os resultados mostraram que os pacientes estudados apresentaram Se plasmático e eritrocitário abaixo dos valores normais e o consumo de apenas uma castanha-do-brasil por dia (5g) foi eficaz no aumento da concentração de Se e na atividade da GSH-Px nos pacientes em HD; além disto, ela pode contribuir para a melhora da condição de estresse oxidativo desses pacientes. / Hemodialysis (HD) patients may undergo oxidative damage which causes reactive oxygen species (ROS) formation. Uremic toxins, HD treatment and the decrease in antioxidant system are known to result in the ROS generation. Selenium (Se) has a role as an antioxidant and studies report Se deficiency in these patients. Considering the importance of the antioxidant activity in patients with chronic kidney disease (CKD) in HD, the aim of this work was evaluate the effect of Brazilian nuts (main food source) supplementation on levels of Se and glutathione peroxidase (GSH-Px) activity in HD patients. A total of 81 HD patients (52.0 ± 15.2 years old, average time on dialysis was 82.3 ± 91.4 months and BMI of 24.9 ± 4.4 kg/m2) from RenalCor and RenalVida Clinics in Rio de Janeiro, Brazil were studied. The patients received one nut (≈ 5g), average of 290 µg Se, each day during three months. The Se concentration was determined by atomic absorption spectrophotometry with hydride generation (HITACHI®, Z-500). The levels of GSH-Px were measured by using RANDOX® commercial kits. The Se levels in plasma (18.8 ± 17.4 µg/L) and erythrocyte (72.4 ± 37.9 µg/L) before supplementation were below the normal range (60-120 µg/L for plasma and 90-190 µg/L for erythrocyte) and after nut supplementation, the plasma levels increased to 104.0 ± 65.0 µg/L and erythrocytes to 244.1 ± 119.5 µg/L (p<0.0001). The activity of GSH-Px also increased after supplementation from 46.6 ± 14.9 U/ gHb to 55.9 ± 23.6 U/gHb (p<0.0001). Before supplementation, 11% of patients had activity of GSH-Px below the normal range (27.5 - 73.6 U/gHb) and, after supplementation, all patients showed activity of GSH-Px within the normal range. The data revealed that the investigated patients had erythrocyte and plasma Se levels below the normal values and the consumption of just one Brazil nut each day (5g) was effective to increase on Se concentration and GSH-Px activity of the patients in HD, thus contributing to improve the antioxidant condition of these patients.

INTRODUÇÃO: O Gadolínio (Gd) é um raro metal da classe dos lantanídios usado como meio de contraste devido as suas propriedades paramagnéticas. Após sua descoberta, foi considerado um contraste pouco nefrotóxico em pacientes com doença renal crônica (DRC). Atualmente, existem evidências de que o Gd pode apresentar nefrotoxicidade semelhante aos contrastes iodados. A administração de Gadolínio em ratos com DRC pode levar a piora da função renal aferida por clearance de inulina e mobilização do ferro corporal gerando stress oxidativo. OBJETIVOS: O objetivo do estudo foi avaliar o efeito do Gd na função renal, nos parâmetros de cinética do ferro em ratos com DRC e o possível efeito protetor do anti-oxidante N-Acetilcisteína (NAC). MATERIAIS E MÉTODOS: Ratos Wistar machos foram submetidos à nefrectomia 5/6 (Nx) para induzir DRC. Gadoterate Meglumine, um contraste à base de Gadolínio iônico e macrocíclico foi administrado via intravenosa na dose de 1,5mmol/kg de peso de rato 21 dias após a nefrectomia. Para avaliar o efeito do Gd sobre a função renal, estudos de clearance de inulina foram realizados em 4 grupos de ratos 48 hs após a aplicação do Gd: grupo controle 1- Nx (n=7); 2- Nx+NAC (n=6); 3- Nx+Gd (n=8); 4- Nx+Gd+NAC (n=5). O NAC foi administrado no grupo 4 diluído em água 48 hs antes e 48 hs depois da administração do Gd na dose de 4800mg/l. O grupo 2 recebeu NAC durante o mesmo período de tempo do grupo 4. O Gd também foi administrado em ratos com função renal normal, grupo Normal (n=8) na mesma dose dos grupos nefrectomizados com avaliação da função renal e proteinúria. Além da taxa de filtração glomerular (TFG), foram avaliados: proteinúria de 24hs (ptn), parâmetros de gaiola metabólica, pressão arterial (PA), paramêtros de cinética do ferro representados pelo ferro sérico (Fe), capacidade total de ligação do ferro (CTLF), saturação de transferrina, ferritina sérica e stress oxidativo por meio da dosagem de espécies reativas ao ácido tiobarbitúrico (TBARS). Os dados foram submetidos à análise de variância ANOVA utilizando o programa Graph Prism com nível de significância p<0,05 e erro padrão. RESULTADOS: A aplicação de Gd em ratos nefrectomizados resultou em queda na TFG no grupo 3 em relação ao grupo controle 1 (p<0,01). Houve uma tendência de aumento da ptn no grupo 3 em relação aos demais grupos. O grupo 4 que recebeu tratamento com NAC apresentou TFG e ptn semelhante ao grupo 1 e TFG estatisticamente maior que o grupo 3 (p<0,05). Com relação ao grupo de ratos normais não houve alteração da TFG nem aumento de ptn após a aplicação do Gd em relação à ratos não nefrectomizados que não receberam contraste. Com relação aos parâmetros da cinética do ferro, o grupo 3 apresentou elevação da ferritina e da saturação da transferrina comparados ao grupo 1 (p<0,05) e (p<0,01) respectivamente. Houve diminuição da capacidade total de ligação do ferro (CTLF) no grupo 3 comparado ao grupo 1(p<0,01). O uso profilático do NAC no grupo 4 reverteu todas as alterações descritas anteriormente no grupo 3 com significância estatística (p<0,05), (p<0,01) e (p<0,01) respectivamente. Com relação ao stress oxidativo, o grupo 3 apresentou níveis de TBARS significativamente maiores que o grupo 1 (p<0,05). O grupo 4 apresentou níveis de TBARS semelhantes ao grupo 1 e menores que o grupo 3 (p<0,05). O grupo 2 que recebeu apenas NAC por curto período de tempo apresentou TFG, Ptn e parâmetros de cinética de ferro semelhantes aos grupos 1 e 4. Com relação aos dados de gaiola metabólica e pressão arterial não houve diferença estatística entre os grupos 1,2,3 e 4. CONCLUSÕES: Os resultados mostram que a administração de Gd em ratos nefrectomizados resulta em dimuição da TFG, aumento da proteinúria associado a aumento da ferritina sérica, saturação de transferrina e diminuição da CTLF. Em ratos normais o Gd não mostrou ser nefrotóxico e o uso do NAC isoladamente no grupo 2 por curto período de tempo não demonstrou nenhum efeito, pois todos os parâmetros avaliados foram semelhantes ao grupo controle. Indução de stress oxidativo foi representado pelo aumento do TBARS nos ratos que receberam o Gd. O uso de NAC reverteu todas as alterações provocadas pelo Gd. Concluímos que o NAC pode ser usado como profilaxia da toxicidade associada ao Gd. / INTRODUCTION: Gadolinium (Gd) is a rare class of lanthanide metal used as a contrast agent due to its paramagnetic properties. After its discovery, was considered a bit of contrast nephrotoxicity in patients with chronic kidney disease (CKD). Currently, there is evidence that Gd may present similar to iodine contrast media nephrotoxicity. The administration of Gadolinium in rats with CKD can lead to worsening renal function measured by inulin clearance and mobilization of iron body causing oxidative stress. OBJECTIVES: The aim of this study was to evaluate the effect of Gd on renal function, iron parameters and oxidative stress in rats with CKD and a possible effect of antioxidant N-Acetylcisteine (NAC). MATERIALS AND METHODS: Male Wistar rats underwent nephrectomy 5/6 (Nx) to induce CKD. Gadoterate meglumine, a Gadolinium based contrast ionic and macrocyclic was administrated intravenously at a dose of 1.5 mmol / kg BW of rats 21 days after nephrectomy. To evaluate the effect of Gd on renal function, inulin clearance studies were performed in 3 groups of animals 48 hours (hs) after application of Gd: a control group 1 - Nx (n =7), 2- Nx+NAC (n = 6); 3- Nx+Gd (n=8) e 4- Nx+Gd+NAC (n=5). The NAC was administrated in group 4, diluted with water 48 hs before and 48 hs after administration of gadolinium at a dose of 4800mg / l. Group 2 received NAC four days before clearance study. Gd was also administrated in rats with normal renal function, group normal (n = 8) at the same dose of nephrectomized rats with assessment of renal function and proteinuria. In addition to the glomerular filtration rate (GFR) were evaluated: 24 hours proteinuria (ptn), cage metabolic parameters, blood pressure (BP), serum iron (Fe), total capacity of iron binding (TIBC), transferrin saturation, serum ferritin and oxidative stress through measurement of thiobarbituric acid reactive species (TBARS). Data were submitted to ANOVA using the program Prism Graph with a significance level p <0.05 and standard error. RESULTS: Gd administration to group 3 results in a decrease of GFR compared with group 1 (p<0,01). There was a trend of increase ptn in group 3 compared to other groups. Normal rats treated with the same dose of Gd presented similar GFR and proteinuria when compared with normal controls. In group 3, there was a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS elevation compared with group 1 (p<0,01), (p<0,05), (p<0,01) and (p<0,05) repectively. The treatment with NAC in group 4 reversed the decreased in GFR and proteinuria compared with group 3 (p<0,05) for both variables. Treatment with NAC in group 4 also reversed all alterations in iron parameters and oxidative stress described earlier with statistical significance (p<0,01), (p<0,05), (p<0,01) and (p<0,05) respectively. Group 2 received NAC for a short period of time had GFR, Ptn and kinetic parameters of iron similar to groups 1 and 4. With respect to metabolic cage data and blood pressure showed no statistical difference between groups 1,2,3 and 4.CONCLUSIONS: These results show that Gd administration to nephrectomized rats results in a decrease of GFR and increased proteinuria associated with increased serum ferritin and transferrin saturation with decreased TIBC. In normal rats, Gd was not nephrotoxic. These effects were not due to a possible effect of NAC on Nx, since all parameters measured in group 2 were not different from the group 1. There was induction of oxidative stress represented by the increase in TBARS in rats receiving gadolinium. The use of NAC reversed all these changes caused by Gd. We conclude that the NAC can be used as prophylaxis of toxicity associated with Gd.

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