Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-11T14:12:04Z No. of bitstreams: 1 flavioaugustoteixeiraronzani.pdf: 2435727 bytes, checksum: 20f1aa166ba8683a2f2eecf36a3fb8ab (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:09:03Z (GMT) No. of bitstreams: 1 flavioaugustoteixeiraronzani.pdf: 2435727 bytes, checksum: 20f1aa166ba8683a2f2eecf36a3fb8ab (MD5) / Made available in DSpace on 2016-01-25T17:09:03Z (GMT). No. of bitstreams: 1 flavioaugustoteixeiraronzani.pdf: 2435727 bytes, checksum: 20f1aa166ba8683a2f2eecf36a3fb8ab (MD5) Previous issue date: 2015-04-30 / Introdução: Existe interesse crescente no estudo e compreensão de possíveis associações entre calcificação arterial na camada média das artérias, doença renal crônica (DRC) e outras doenças crônicas degenerativas. Calcificações arteriais mamárias (CAM) vistas na mamografia podem ser marcadores de risco subjacente à arteriosclerose acelerada, como aquela decorrente da DRC e outras doenças crônicas degenerativas. Embora a mamografia (MMG) seja utilizada principalmente para detecção de câncer de mama, pode ocasionalmente revelar anormalidades relacionadas a doenças extramamárias. Objetivos: avaliar associação de CAM detectadas à MMG de rotina e analisar possível associação das mesmas com DRC, diabetes mellitus (DM) e doenças cardiovasculares. Método: estudo transversal com usuárias atendidas em ambulatório especializado no atendimento de hipertensas de alto risco, diabéticas usuárias de insulina ou renais crônicas categorias 3b, 4 e 5 e voluntárias que participaram de um estudo para validar e ampliar a tabela Scored (Screening For Occult Renal Disease), método proposto para rastrear DRC junto à população brasileira. As pacientes que preencheram critérios de inclusão (entre 40 e 69 anos, sem história de câncer de mama prévio e com MMG nos últimos dois anos) foram convidadas por telefone. As usuárias incluídas assinaram o TCLE e responderam ao questionário semiestruturado. Mamografias de rotina, realizadas nos últimos dois anos, foram analisadas por pesquisadores que desconheciam fatores de risco para CAM e DRC. Os dados foram inicialmente descritos como média, desvio padrão, mediana (variação interquartil) ou percentagem conforme a característica da variável. Separamos os grupos com CAM e sem CAM e comparamos as variáveis sócio demográficas, clínicas e laboratoriais através do teste qui quadrado para variáveis categóricas ou teste T de Student para variáveis contínuas. Além disto, separamos os grupos DM com e sem CAM e DRC com e sem CAM, comparando as variáveis descritas acima. Realizamos ainda uma análise de sensibilidade e especificidade através da Receive Operator Curve (ROC) e área sob a curva (AUC) tendo como variável preditora o número de calcificações mamárias e variável desfecho a presença de DM e DRC respectivamente. A Taxa de Filtração Glomerular (TFG) foi correlacionada com número de vasos calcificados através da correlação de Pearson. Finalmente realizamos uma Regressão logística binária tendo como variável desfecho a presença/ausência de CAM e variáveis preditoras: idade, HAS, DM e DRC. Foi utilizado o software SPSS 15.0 (Chicago Illinois), considerado um intervalo de confiança de 95% com p de 0,05. Resultados. De um total de 431 pacientes selecionados do SCORED / HIPERDIA, 119 pacientes não foram incluídas por não possuírem mamografias sendo 42 do SCORED e 77 do HIPERDIA, sendo 312 incluídas no estudo. A idade média foi de 55,9 ± 7,4 anos, a cor prevalente branca (64,3%) e metade das participantes eram casadas. A avaliação antropométrica revelou IMC médio de 31,0 ± 6,6, a circunferência abdominal média foi 102,6 cm ± 12,4 e a minoria apresentou hábito de fumar (8,7%). Quanto às comorbidades, a hipertensão arterial foi mais prevalente, seguida pelo Diabetes Mellitus. A análise laboratorial da creatinina revelou valor médio de 1,13 ± 0,7 mg/dL e a média de taxa de filtração glomerular foi de 41,87 ± 6,23 ml/min/1.73m2 . Setenta e uma participantes (22,8%) apresentavam CAM, o número de vasos calcificados variou de 1 a 6,. destas, 52% apresentavam CAM em ambas as mamas. Encontramos associação entre CAM e maior idade, HAS, DM, DRC e TFG. Em análise multivariada, apenas a maior idade e DM persistiram associadas à CAM. O OR para risco de CAM foi maior para a presença de todas as patologias crônicas avaliadas. Conclusão: Houve associação entre calcificação arterial mamária com a maior idade, com TFG e doenças crônicas degenerativas – HA, DM e DRC, chamando a atenção do radiologista/clínico que a presença dessas alterações deve ser relatada e deveríamos pesquisar tais patologias nessas pacientes.

Background: Glomerular filtration rate (GFR) is a clinically important measurement of kidney function and estimating the GFR is of great importance in healthcare. Methods available today either lack in precision or are overly time consuming. Proenkephalin (PENK) has been shown to correlate well with the GFR and has therefore been proposed as a novel biomarker for kidney function. Aim: To evaluate a new point-of-care test for measuring PENK in blood and to assess its correlation to GFR measured by iohexol plasma clearance (mGFRiohexol). Materials and methods: Blood was collected from 21 patients with varying indications for the iohexol plasma clearance test. PENK was measured with IB10 Sphingotest penKid in whole blood, plasma and serum respectively. The concentration was correlated to the mGFRiohexol and results were compared to those from measurement of the routine markers for kidney function, i.e. creatinine and cystatin C. Results: Fourteen men and seven women were included. The median age was 57 years. PENK in plasma correlated weakly with mGFRiohexol (R2=0.22, p=0.042). No significant correlation was shown for PENK in whole blood or serum. Creatinine also showed a weak correlation with mGFRiohexol (R2=0.35, p=0.0046). In contrast, cystatin C was strongly correlated with mGFRiohexol (R2= 0.87, p<0.0001). Conclusion: Our results indicate that PENK is a biomarker of low clinical value for estimating the GFR. However, further studies are needed before this can be assured. Cystatin C, on the contrary, seems to be an accurate biomarker for estimating the GFR.

Unilateral ischemia-reperfusion (UIR) injury leads to progressive renal atrophy and tubulointerstitial fibrosis (TIF) and is commonly used to investigate the pathogenesis of the acute kidney injury-chronic kidney disease transition. Although it is well known that contralateral nephrectomy (CNX), even 2 wk post-UIR injury, can improve recovery, the physiological mechanisms and tubular signaling pathways mediating such improved recovery remain poorly defined. Here, we examined the renal hemodynamic and tubular signaling pathways associated with UIR injury and its reversal by CNX. Male Sprague-Dawley rats underwent left UIR or sham UIR and 2 wk later CNX or sham CNX. Blood pressure, left renal blood flow (RBF), and total glomerular filtration rate were assessed in conscious rats for 3 days before and over 2 wk after CNX or sham CNX. In the presence of a contralateral uninjured kidney, left RBF was lower (P < 0.05) from 2 to 4 wk following UIR (3.6 + 0.3 mL/min) versus sham UIR (9.6 + 0.3 mL/min). Without CNX, extensive renal atrophy, TIF, and tubule dedifferentiation, but minimal pimonidazole and hypoxia-inducible factor-1α positivity in tubules, were present at 4 wk post-UIR injury. Conversely, CNX led (P < 0.05) to sustained increases in left RBF (6.2 ∓ 0.6 mL/min) that preceded the increases in glomerular filtration rate. The CNX-induced improvement in renal function was associated with renal hypertrophy, more redifferentiated tubules, less TIF, and robust pimonidazole and hypoxia-inducible factor-1α staining in UIR injured kidneys. Thus, contrary to expectations, indexes of hypoxia are not observed with the extensive TIF at 4 wk post-UIR injury in the absence of CNX but are rather associated with the improved recovery of renal function and structure following CNX.

Yes / Acute kidney injury (AKI) can occur rarely in patients exposed to iodinated contrast and result in contrast-induced AKI (CI-AKI). A key risk factor is the presence of pre-existing chronic kidney disease (CKD), therefore it is important to assess patient risk and obtain kidney function measurement prior to administration. Point of care (PoC) testing provides an alternative strategy but there remains uncertainty, with respect to diagnostic accuracy and clinical utility. A device study compared three PoC analysers (Nova StatSensor, Abbott i-STAT, Radiometer ABL800 FLEX) with a reference laboratory standard (Roche Cobas 8000 series, enzymatic creatinine). Three hundred adult patients attending a UK hospital phlebotomy department were recruited to have additional blood samples for analysis on the PoC devices. The ABL800 FLEX had the strongest concordance with laboratory measured serum creatinine (mean bias=-0.86, 95% limits of agreement = -9.6 to 7.9) followed by the i-STAT (average bias=3.88, 95% limits of agreement = -8.8 to 16.6) and StatSensor (average bias=3.56, 95% limits of agreement = -27.7 to 34.8). In risk classification, the ABL800 FLEX and i-STAT identified all patients with an eGFR≤30, whereas the StatSensor resulted in a small number of missed high-risk cases (n=4/13) and also operated outside of the established performance goals. The screening of patients at risk of CI-AKI may be feasible with PoC technology. However in this study it was identified that the analyser concordance with the laboratory reference varies. It is proposed that further research exploring PoC implementation in imaging department pathways is needed. / Yorkshire and Humber Academic Health Science Network (Grant Number: YHP0318)

Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum. The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death. This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress. In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease. Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

<p>Endotelin-1 je najpotentniji vazokontstriktorni peptid koji značajno doprinosi funkcionalnim i strukturnim bubrežnim promenama i poslednjih godina se izdvojio kao značajan faktor u razvoju i progresiji dijabetesne nefropatije. Cilj ovog istraživanja bio je odrediti nivo plazmatskog endotelina-1 kod bolesnika sa tipom 2 &scaron;ećerne bolesti u odnosu na zdravu populaciju kao i ispitati odnos plazmatskog endotelina-1 i funkcionog statusa bubrega kod bolesnika sa &scaron;ećernom bolesti tip 2 i dijabetesnom nefropatijom. U istraživanje je uključeno sto dvadeset ispitanika sa tipom 2 dijabetesa i sekundarno inzulin zavisni, koji&nbsp; su podeljeni u dve grupe u odnosu na izmerenu jačinu glomerulske filtracije: Grupa I (n=60) ispitanici sa jačinom glomerulske filtracije većom od 60 ml/min/1.73m2 i grupa II (n=60) ispitanici sa jačinom glomerulske filtracije manjom od 60 ml/min/1.73m2. Kod svih ispitanika izmerena je plazmatska vrednost endotelina-1 i izvr&scaron;ena procena funkcionog statusa bubrega merenjem jačine glomerulske filtracije, efektivnog bubrežnog protoka plazme i ostalih parametara bubrežne funkcije: serumske koncentracije cistatina C, uree, kreatinina, mokraćne kiseline kao i određivanje 24h albuminurije i proteinurije. Dobijeni rezultati upoređivani su sa rezultatima kontrolne grupe ispitanika (n= 30). Postoji statistički značajna razlika u medijanama vrednosti endotelina-1 između ispitivanih grupa (p&lt;0.001). Značajno niže vrednosti plazmatske koncentracije endotelina-1 su imali ispitanici kontrolne grupe (0.80 &plusmn;0.3) u odnosu na ispitanike sa &scaron;ećernom bolesti i JGF&gt;60 ml/min (1.4&plusmn;0.4) kao i u odnosu na dijabetesne bolesnike sa JGF&lt;60ml/min (2.5 &plusmn;0.8). Značajno vi&scaron;e vrednosti endotelina-1 su&nbsp; imali bolesnici sa &scaron;ećernom bolesti i većim stepenom redukcije jačine glomerulske filtracije u odnosu na bolesnike sa manjim stepenom redukcije jačine glomerulske filtracije (p&lt;0.001). U grupi bolesnika sa tipom 2 &scaron;ećerne bolesti postoji statistički značajna inverzna korelacija između plazmatskog nivoa endotelina-1 i izmerene vrednosti jačine glomerulske filtracije i efektivnog bubrežnog protoka plazme (r= -0,75; p=0,000; r= -0,74; p=0,000) odnosno bolesnici sa &scaron;ećernom bolesti kod kojih postoje povi&scaron;ene vrednosti plazmatskog endotelina-1 imaju veći stepen redukcije jačine glomerulske filtracije i efektivnog bubrežnog protoka plazme. Kod bolesnika sa tipom 2 dijabetes melitusa i različitim stepenom bubrežne hipofunkcije endotelin-1 u značajnoj meri utiče na vrednosti jačine glomerulske filtracije i efektivnog bubrežnog protoka plazme ali i druge funkcijske parametre bubrega i samim tim može imati važnu ulogu u nastanku i razvoju dijabetesne nefropatije.</p> / <p>Endothelin-1, potent vasoconstrictor peptide may contribute to the functional and structural renal changes and in recent years emerged as a significant factor in the development&nbsp; and progression of diabetic nephropathy. The aim of&nbsp; this study was to determine the level of plasma endothelin-1 levels in patients with type 2 diabetes and compared to healthy&nbsp; population as well as to examine the relationship of plasma endothelin-1 and the functional status of the kidneys in patients with type 2 diabetes. The study included one hundred&nbsp; and&nbsp; twenty patients&nbsp; with type 2 diabetes and insulin-dependent secondary, which are divided into two groups with respect to the measured GFR: Group I (n = 60) subjects with by glomerular filtration rate greater than 60 ml /min/1.73m2 and group II (n&nbsp; =&nbsp; 60) subjects with by glomerular filtration rate of less than 60ml/min/1.73m2 . Plasma levels of endothelin-1, glomerular filtration rate and effective renal plasma flow were determined using appropriate methods in all subjects. Other renal function parameters such as serum&nbsp; concentrations of cystatin C, urea, creatinine, uric acid, 24h albuminuria and proteinuria were measured additionaly. The results were compared with control groups of subjects (n= 30). There was a statistically significant difference in median values of endothelin-1 between the groups (p&lt;0.001). Significantly lower plasma concentrations of endothelin-1 had control subjects (0.80&nbsp; &plusmn;&nbsp; 0.3) compared to subjects with diabetes and GFR&gt;60 ml/min (1.4 &plusmn; 0.4) and in relation to diabetic patients with GFR &lt;60 ml/min (2.5 &plusmn; 0.8). Significantly higher values of endothelin-1 had patients with diabetes and a higher degree of reduction of glomerular filtration rate compared with patients with a lower degree of&nbsp; reduction of glomerular filtration rate (p &lt;0.001). In the group of patients with type 2 diabetes, there was a statistically significant inverse correlation between plasma levels endothelin-1 and the measured values of glomerular filtration rate and effective renal plasma flow (r= -0.75; p=0.000; r= -0.74; p=0.000) and patients with diabetes who have the higher values of&nbsp; plasma endothelin-1 have a higher degree of reduction of glomerular filtration rate and effective renal plasma flow. In patients with type 2 diabetes mellitus and various degrees of renal hypofunction endothelin-1 significantly affects the value of the glomerular filtration rate and effective renal plasma flow or other parameters of renal function and thus can play an important role in thedevelopment of diabetic nephropathy.</p>

Kollagen IV assoziierte Nephropathien sind hereditäre Erkrankungen, die die glomeruläre Basalmembran betreffen. Homozygote Aberrationen des COL4A3- oder des COL4A4-Gens zeigen wie X-chromosomal dominant vererbte Mutationen des COL4A5-Gens das klinische Bild des Alport-Syndroms mit frühzeitigem terminalem Nierenversagen. Heterozygote COL4A3-Mutationen sind ursächlich für die benigne familiäre Hämaturie. Ein zusätzlicher Polymorphismus in Nphs2, welches das Schlitzmembranprotein Podocin kodiert, könnte hierbei zu einem aggravierten Krankheitsverlauf führen. Um diese These zu überprüfen, ist eine Analyse des glomerulären Filters, bestehend aus glomerulärer Basalmembran, der zwischen den Podozytenfüßen liegenden Schlitzmembran und Kapillarendothel notwendig. Nidogen-2 ist als Verbindungsprotein essenzieller Bestandteil der glomerulären Basalmembran. Die Ergebnisse der Untersuchungen des Proteins in der Basalmembran COL4A3 heterozygoter Mäuse mit zusätzlichem Podocin-Polymorphismus wichen stark von denen bei einfach COL4A3 heterozygoten Tieren ab. Es ergeben sich daher anhand von Nidogen-2 Hinweise, dass eine Mutation in Nphs2 den Krankheitsverlauf Kollagen IV assoziierter Erkrankungen modifizieren könnte.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

<p>Live donor nephrectomy (LDN) is a unique surgical challenge where surgery is performed on healthy individuals. It is of great importance to keep the morbidity of donors as low as possible, as well as harvesting a kidney in optimal condition. Lowering morbidity is the motive for introducing the endoscopic technique in LDN. Oliguria and impaired kidney function can, however, be seen during pneumoperitoneum and endoscopic LDN have been criticized for not yet being proven safe enough.</p><p>The aims of this study were to investigate the changes in renal function during elevated intraabdominal pressure (IAP) in donors and rats and to evaluate donor morbidity and safety of the new endoscopic techniques compared to the open LDN.</p><p>In two studies, a rat model was used. It was found that elevation of IAP diminished glomerular filtration rate (GFR). Cardiac output (CO) and renal blood flow decreased as well. Elevation of IAP activates the renin system and aldosterone was increased. Acute angiotensin II receptor 1 blockade (candesartan) treatment lowered blood pressure significantly and impaired renal function during elevated IAP. Volume expansion prior to, and during, pneumoperitoneum reduces the deleterious effects on renal function.</p><p>Three studies on kidney live donors show that traditional laparoscopic surgery (TLS) takes longer time to perform than open LDN. Hand-assistance facilitates the operation and increases the safety margin as well as shortens the operation by 27% compared to TLS. Evaluation of a hand-assisted retroperitoneoscopy (HARS), performed for the first time ever in Uppsala 2001, show that the operation is short and safe, the donors experience little pain and the renal function is favourable compared to open surgery, TLS and hand-assisted transperitoneal laparoscopic approaches.</p><p>In conclusion, the results indicate that elevated IAP decreases GFR due to decreased CO and activation of the RAAS, which can be avoided with adequate hydration. Endoscopy can be facilitated if hand-assistance is applied and in particular hand-assisted retroperitoneoscopic nephrectomy shows advantages for the donor.</p>

Live donor nephrectomy (LDN) is a unique surgical challenge where surgery is performed on healthy individuals. It is of great importance to keep the morbidity of donors as low as possible, as well as harvesting a kidney in optimal condition. Lowering morbidity is the motive for introducing the endoscopic technique in LDN. Oliguria and impaired kidney function can, however, be seen during pneumoperitoneum and endoscopic LDN have been criticized for not yet being proven safe enough. The aims of this study were to investigate the changes in renal function during elevated intraabdominal pressure (IAP) in donors and rats and to evaluate donor morbidity and safety of the new endoscopic techniques compared to the open LDN. In two studies, a rat model was used. It was found that elevation of IAP diminished glomerular filtration rate (GFR). Cardiac output (CO) and renal blood flow decreased as well. Elevation of IAP activates the renin system and aldosterone was increased. Acute angiotensin II receptor 1 blockade (candesartan) treatment lowered blood pressure significantly and impaired renal function during elevated IAP. Volume expansion prior to, and during, pneumoperitoneum reduces the deleterious effects on renal function. Three studies on kidney live donors show that traditional laparoscopic surgery (TLS) takes longer time to perform than open LDN. Hand-assistance facilitates the operation and increases the safety margin as well as shortens the operation by 27% compared to TLS. Evaluation of a hand-assisted retroperitoneoscopy (HARS), performed for the first time ever in Uppsala 2001, show that the operation is short and safe, the donors experience little pain and the renal function is favourable compared to open surgery, TLS and hand-assisted transperitoneal laparoscopic approaches. In conclusion, the results indicate that elevated IAP decreases GFR due to decreased CO and activation of the RAAS, which can be avoided with adequate hydration. Endoscopy can be facilitated if hand-assistance is applied and in particular hand-assisted retroperitoneoscopic nephrectomy shows advantages for the donor.