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.

A disfunção renal é uma complicação comum associada a desfechos clínicos negativos em pacientes pediátricos gravemente doentes. Na prática clínica, a medida de creatinina sérica continua sendo o marcador mais usado e aceito para monitoramento da função renal, embora haja várias limitações relacionadas ao seu uso. A cistatina C é uma proteína de baixo peso molecular que apresenta características ideais para um marcador da taxa de filtração glomerular. Neste estudo, nossos objetivos foram descrever e analisar o perfil epidemiológico dos pacientes pediátricos gravemente doentes com lesão renal aguda (LRA); classificar a gravidade da LRA segundo o critério RIFLEp, verificar sua praticabilidade; e avaliar a utilidade da cistatina C sérica em detectar comprometimento da taxa de filtração glomerular e sua associação com a creatinina sérica nos 2 primeiros dias de internação na Unidade de Terapia Intensiva Pediátrica (UTIP). Para a estimativa da taxa de filtração glomerular, foi medido o clearance de creatinina. No estudo epidemiológico, foram analisados 174 pacientes internados na UTIP. LRA foi diagnosticada em 45% dos pacientes. Idade menor ou igual a 12 meses, escore PRISM maior ou igual a 6, hipotensão arterial, sepse, tempo de circulação extracorpórea maior do que 120 minutos, pressão intra-abdominal maior ou igual a 8 mmHg e subnutrição proteico-calórica foram fatores de risco associados à LRA. A presença de LRA foi associada a piores desfechos clínicos como maior tempo de internação na UTIP e maior tempo de uso de ventilação mecânica. Na alta da UTIP, 41% dos pacientes com LRA mantinham função renal alterada. No estudo da cistatina C, foram envolvidos 122 pacientes. Observamos que, no grupo de pacientes com LRA (41,8%) segundo o critério RIFLEp, as medidas de cistatina C foram significativamente mais altas tanto no momento da admissão na UTIP quanto de 24 a 36 h após. O desempenho da cistatina C como biomarcador na análise da curva ROC (AUC=0,77) e dos valores de eficiência diagnóstica foi melhor do que o da creatinina sérica (AUC=0,65) em pacientes pediátricos gravemente doentes. Concluímos que o critério RIFLEp mostrou-se importante na detecção precoce de LRA em pacientes de risco e que a cistatina C é melhor marcador do que a creatinina sérica para detectar LRA em pacientes pediátricos gravemente doentes. / Kidney disfunction is a common complication associated with poor clinical outcomes in critically ill pediatric patients. In the clinical setting, serum creatinine is still the most widely used and accepted biomarker for the assessment of renal function; however, it carries a number of limitations. Cystatin C is a low molecular weight protein that has ideal features for measuring the glomerular filtration rate. The present study aims to describe and analyze the epidemiological profile of critically ill pediatric patients with acute kidney injury (AKI); to classify the severity of AKI according to the pRIFLE criteria; to assess its feasibility; and to evaluate the utility of serum cystatin C in determining the deterioration of glomerular filtration rate and its association with serum creatinine in the first two days following PICU admission. In order to estimate glomerular filtration rate, creatinine clearance was used. The epidemiological study assessed 174 patients admitted to PICU; 45% of these were diagnosed with AKI. Age equal or lower than 12 months, PRISM score equal or higher than 6, hypotension, sepsis, cardiopulmonary bypass time longer than 120 minutes, intra-abdominal pressure equal or higher than 8 mmHg and protein-energy malnutrition were risk factors for AKI. AKI was associated with poorer clinical outcomes, such as PICU inpatient time and prolonged mechanical ventilation. When discharged from PICU, 41% of patients with AKI still had altered renal function status. In the cystatin C study, 122 patients were enrolled. The AKI patients\' subgroup (41.8%), according to pRIFLE, showed significantly higher cystatin C levels, both at the time of PICU admission as well as 24 to 36 hours afterwards. Cystatin C performance as a biomarker in ROC curve analysis (AUC=0,77) and its diagnostic efficiency values were better than serum creatinine (AUC=0,65) in critically ill pediatric patients. We conclude that the pRIFLE criteria is definetely important for the early diagnosis of AKI in risk patients and that cystatin C is a more reliable biomarker than serum creatinine to detect AKI in critically ill pediatric patients.

A disfunção renal é uma complicação comum associada a desfechos clínicos negativos em pacientes pediátricos gravemente doentes. Na prática clínica, a medida de creatinina sérica continua sendo o marcador mais usado e aceito para monitoramento da função renal, embora haja várias limitações relacionadas ao seu uso. A cistatina C é uma proteína de baixo peso molecular que apresenta características ideais para um marcador da taxa de filtração glomerular. Neste estudo, nossos objetivos foram descrever e analisar o perfil epidemiológico dos pacientes pediátricos gravemente doentes com lesão renal aguda (LRA); classificar a gravidade da LRA segundo o critério RIFLEp, verificar sua praticabilidade; e avaliar a utilidade da cistatina C sérica em detectar comprometimento da taxa de filtração glomerular e sua associação com a creatinina sérica nos 2 primeiros dias de internação na Unidade de Terapia Intensiva Pediátrica (UTIP). Para a estimativa da taxa de filtração glomerular, foi medido o clearance de creatinina. No estudo epidemiológico, foram analisados 174 pacientes internados na UTIP. LRA foi diagnosticada em 45% dos pacientes. Idade menor ou igual a 12 meses, escore PRISM maior ou igual a 6, hipotensão arterial, sepse, tempo de circulação extracorpórea maior do que 120 minutos, pressão intra-abdominal maior ou igual a 8 mmHg e subnutrição proteico-calórica foram fatores de risco associados à LRA. A presença de LRA foi associada a piores desfechos clínicos como maior tempo de internação na UTIP e maior tempo de uso de ventilação mecânica. Na alta da UTIP, 41% dos pacientes com LRA mantinham função renal alterada. No estudo da cistatina C, foram envolvidos 122 pacientes. Observamos que, no grupo de pacientes com LRA (41,8%) segundo o critério RIFLEp, as medidas de cistatina C foram significativamente mais altas tanto no momento da admissão na UTIP quanto de 24 a 36 h após. O desempenho da cistatina C como biomarcador na análise da curva ROC (AUC=0,77) e dos valores de eficiência diagnóstica foi melhor do que o da creatinina sérica (AUC=0,65) em pacientes pediátricos gravemente doentes. Concluímos que o critério RIFLEp mostrou-se importante na detecção precoce de LRA em pacientes de risco e que a cistatina C é melhor marcador do que a creatinina sérica para detectar LRA em pacientes pediátricos gravemente doentes. / Kidney disfunction is a common complication associated with poor clinical outcomes in critically ill pediatric patients. In the clinical setting, serum creatinine is still the most widely used and accepted biomarker for the assessment of renal function; however, it carries a number of limitations. Cystatin C is a low molecular weight protein that has ideal features for measuring the glomerular filtration rate. The present study aims to describe and analyze the epidemiological profile of critically ill pediatric patients with acute kidney injury (AKI); to classify the severity of AKI according to the pRIFLE criteria; to assess its feasibility; and to evaluate the utility of serum cystatin C in determining the deterioration of glomerular filtration rate and its association with serum creatinine in the first two days following PICU admission. In order to estimate glomerular filtration rate, creatinine clearance was used. The epidemiological study assessed 174 patients admitted to PICU; 45% of these were diagnosed with AKI. Age equal or lower than 12 months, PRISM score equal or higher than 6, hypotension, sepsis, cardiopulmonary bypass time longer than 120 minutes, intra-abdominal pressure equal or higher than 8 mmHg and protein-energy malnutrition were risk factors for AKI. AKI was associated with poorer clinical outcomes, such as PICU inpatient time and prolonged mechanical ventilation. When discharged from PICU, 41% of patients with AKI still had altered renal function status. In the cystatin C study, 122 patients were enrolled. The AKI patients\' subgroup (41.8%), according to pRIFLE, showed significantly higher cystatin C levels, both at the time of PICU admission as well as 24 to 36 hours afterwards. Cystatin C performance as a biomarker in ROC curve analysis (AUC=0,77) and its diagnostic efficiency values were better than serum creatinine (AUC=0,65) in critically ill pediatric patients. We conclude that the pRIFLE criteria is definetely important for the early diagnosis of AKI in risk patients and that cystatin C is a more reliable biomarker than serum creatinine to detect AKI in critically ill pediatric patients.

Tenofovir (TDF), um antirretroviral análogo nucleotídeo inibidor da transcriptase reversa, indicado para o tratamento da infecção pelo vírus da Hepatite B em indivíduos HBeAg reagentes, não cirróticos, tem sido implicado na ocorrência de Injúria renal aguda (IRA) e lesão do túbulo proximal renal (TPR), com características semelhantes à Síndrome de Fanconi, caracterizada por glicosúria, bicarbonatúria, fosfatúria, uricosúria e proteinúria de baixo peso molecular. Outros trabalhos sugerem que os pacientes em uso de TDF sofram toxicidade aos glomérulos, com uma pequena, porém significante redução da taxa de filtração glomerular. O tempo de uso da droga para que ocorra lesão renal é desconhecido. Entretanto, a maioria dos estudos de investigação de nefrotoxicidade do TDF foi realizada em pacientes portadores de infecção pelo HIV. Especula-se que a nefrotoxicidade desta droga possa ser exacerbada ou reduzida pelo uso de outras medicações, frequentemente usadas por pacientes com HIV, que competem com o transporte tubular ou com sua metabolização, aumentando o seu nível sérico. O objetivo geral deste trabalho é avaliar prospectivamente a incidência de lesão renal pelo uso de TDF em pacientes portadores de hepatite B. Os objetivos específicos deste trabalho são: (1) avaliar incidência de lesão do TPR através da avaliação da excreção urinária de ácido úrico, fósforo e da proteína de baixo peso molecular neutrophil gelatinase associated lipocalin (NGAL); (2) avaliar a incidência de redução aguda da taxa de filtração glomerular (LRA) ou redução crônica da mesma. Métodos: Foram incluídos 24 pacientes portadores de Hepatite B que tiveram indicação de iniciar o uso de TDF com idade superior a 18 anos ou inferior a 75 anos. Neste estudo prospectivo, foi realizado a coleta de dados clínicos (idade, gênero, etnia, tempo de doença, antecedentes pessoais, medicações concomitantes, fator de risco para contaminação do VHB, história familiar de infecção VHB) e a avaliação laboratorial foi feita através da coleta de sangue e urina feitas antes do início do uso do TDF e, posteriormente à sua introdução, semestralmente durante 2 anos. Ao final do seguimento foi avaliada a incidência de lesão renal pelo uso de TDF, através das seguintes dosagens: glicemia, fosfatemia, gasometria, creatinina e Cistatina C séricas, microalbuminúria, proteinúria, proteinúria de baixo peso molecular (NGAL), clearance de creatinina, fosfatúria, uricosúria e urina rotina. Foi feita análise estatística comparativa entre os pacientes que usaram o TDF pré tratamento e pós tratamento para detectar lesão do TPR ou redução da taxa de filtração glomerular ao longo do tempo. Resultados: Não foi identificado aumento significativo da creatinina no decorrer do estudo (p = 0,09; R = 2,4%), entretanto, foi observada uma queda significativa nos valores do clearance de creatinina em 24 horas (p < 0,01; R = 15,8%). Não foi observada tendência de queda da filtração glomerular através das fórmulas MDRD simplificada (p = 0,11), CKD-EPI (p=0,14), CKD-EPI cystatin C (p = 0,23). Em relação à cistatina C sérica também não foi observada sua elevação no decorrer do tempo (p=0,15; R = 2,4%). Não foi observado, utilizando-se modelo de regressão linear, aumento na excreção urinária de albumina no decorrer do estudo (p = 0,97; R = 0,00%), mas houve aumento significativo na proteinúria de 24h (p < 0,01). Foi observada também, redução da uricosúria com o passar do tempo (p = 0,01; R = 6,7%) e houve correlação positiva entre o clearance de creatinina dosado em urina de 24 horas e a excreção de ácido úrico em urina de 24 horas (p=0,01; r = + 0,60). A fração de excreção de fósforo (urina de 24h): não foi observada alteração no decorrer do tempo (p = 0,83; R = 0,5%), porém houve correlação negativa com entre o clearance de creatinina dosado em urina de 24 horas e a fração de excreção de fósforo (FePO4) dosada em urina de 24 horas (p = 0,05; r = - 0,25). A detecção de NGAL na urina foi feita pelo índice UNGAL/Ucreat e não foi observado aumento significativo de sua excreção no decorrer do tempo (p = 0,40, r = 0,8%). Conclusão: em conclusão no presente estudo observou-se desenvolvimento de lesão renal aguda em 10% dos pacientes em uso de tenofovir e redução significativa da filtração glomerular. A fosfatúria e proteinúria observados sugerem que a lesão tenha sido decorrente de tubulopatia proximal e os marcadores mais específicos de lesão renal, cistatina C e NGAL, não foram superiores aos biomarcadores disponíveis na prática clínica na detecção destas alterações. / Tenofovir (TDF) a nucleotide analog reverse transcriptase inhibitor antiretroviral indicated for the treatment of infection with the hepatitis B virus in reagents HBeAg individuals, non-cirrhotic patients, has been implicated in the occurrence of acute kidney Injury (AKI) and the proximal tubule injury kidney (TPR), with similar to Fanconi syndrome characterized by glucosuria, bicarbonatúria, phosphaturia, proteinuria, uricosuria and low molecular weight characteristics. Other studies suggest that patients using TDF toxicity suffer the glomeruli, with a small but significant reduction in glomerular filtration rate. The time of drug use for kidney damage that occurs is unknown. However, most of the research studies of nephrotoxicity TDF was performed in patients with HIV infection. It is speculated that the nephrotoxicity of this drug may be exacerbated or reduced by the use of other medications, often used by patients with HIV, which compete with the tubular transport or metabolism, increasing its serum level. The overall objective of this study is to prospectively evaluate the incidence of renal injury by the use of TDF in patients with hepatitis B. The specific objectives of this work are: (1) assess the incidence of injury TPR by assessment of urinary excretion of uric acid, phosphorus and protein of low molecular weight neutrophil gelatinase associated lipocalin (NGAL); (2) assess the incidence of acute reduction in glomerular filtration rate (IRA) or chronic reduction. Methods: 24 patients with hepatitis B who were advised to initiate the use of TDF over the age of 18 years or below 75 years were included. In this prospective study, the collection of clinical data (age, gender, ethnicity, duration of disease, personal history, concomitant medications, risk factor for HBV infection, family history of HBV infection) and laboratory evaluation was done by collect blood and urine samples taken before initiation of the use of TDF and after its introduction, semiannually for 2 years. At final follow-up the incidence of renal injury by the use of TDF was assessed through the following dosages: glucose, phosphatemia, gases, creatinine and serum cystatin C, microalbuminuria, proteinuria, low molecular weight proteinuria (NGAL), clearance creatinine, phosphaturia, uricosuria and urine routine. The comparative statistical analysis of patients using TDF pre-treatment and post treatment to detect the TPR injury or reduced glomerular filtration rate over time. Results: There was not significant increase in creatinine identified during the study (p = 0.09; R = 2.4%), however, a significant decrease was observed in the values of creatinine clearance at 24 hours (p <0.01; R = 15.8%). No downward trend was observed in glomerular filtration through the simplified MDRD formulas (p = 0.11), CKD-EPI (p = 0.14), CKD-EPI cystatin C (p = 0.23). Regarding the serum cystatin C its elevation was not observed over time (p = 0.15, R = 2.4%). Increased urinary albumin excretion during the study was not observed using a linear regression model (p = 0.97, R = 0.00%), but there was significant increase in 24-hour proteinuria (p <0, 01). And there was a positive correlation between creatinine clearance at 24 hour urine and the excretion of uric acid in 24 hour urine (p = 0.01, R = + 0.60), uricosuria reduction over time was also observed (p = 0.01, R = 6.7%). No change was observed over time in the fractional excretion of phosphorus (24 h urine), (p = 0.83; R = 0.5%), but there was a negative correlation between creatinine clearance urine dosed at 24 hours and fractional excretion of phosphorus (FePO4) measured in 24 hour urine (p = 0.05, r = - 0.25). The detection of NGAL in the urine was taken by UNGAL / Ucreat index and was not observed significant increase in excretion over time (p = 0.40, r = 0.8%). Conclusion: In conclusion at the present study we observed the development of acute kidney injury in 10% of patients using tenofovir and a significant reduction in glomerular filtration. The phosphaturia and proteinuria observed suggest that the injury has been caused by proximal tubulopathy and more specific markers of renal injury as cystatin C and NGAL were not greater than the available biomarkers in clinical practice for their detection.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2018-03-26T12:09:17Z No. of bitstreams: 2 Tese - Saura Nayane de Souza - 2017.pdf: 4815483 bytes, checksum: a9d3c576d6699488befc8fdde284c795 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-03-26T12:11:02Z (GMT) No. of bitstreams: 2 Tese - Saura Nayane de Souza - 2017.pdf: 4815483 bytes, checksum: a9d3c576d6699488befc8fdde284c795 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-26T12:11:02Z (GMT). No. of bitstreams: 2 Tese - Saura Nayane de Souza - 2017.pdf: 4815483 bytes, checksum: a9d3c576d6699488befc8fdde284c795 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-03-06 / The goal of the study was to evaluate cystatin C and other biomarkers as diagnostic tools in canine renal disease. The project was divided in two studies. In the first study renal injury was induced in 6 animals by subcutaneous administration of gentamicin (30mg/kg) for 10 days, and 6 animals were kept as controls. Animals were evaluated for 45 days by the following clinical and laboratorial parameters: physical examination; hemogram and fibrinogen levels; measurement of creatinine, urea, total proteins, albumin, phosphorus, calcium, sodium, potassium, cholesterol levels (biochemical analysis); serum protein electrophoresis; urine sodium, potassium, gamma glutamyl transferase and alkaline phosphatase levels; urinalysis; urine protein / creatinine ratio; hemogasometry and non-invasive systemic arterial pressure. The second study evaluated the level of cystatin C in 58 dogs suffering from different stages (2-4) of chronical renal disease, as defined by International Renal Interest Society (IRIS) guidelines. Six animals presenting acute renal injury induced bygentamicin treatment were also evaluated (for 20 time points upon injury). The results indicated that changes in urine gamma glutamyl transferase and fractional excretion of sodium and potassium were the earliest parameters indicating acute renal injury, even when compared to most common renal disease biomarkers: urea and creatinine. Cystatin C measurement, on the other hand, showed little value for early detection of chronic kidney disease and acute kidney injury in dogs. / O objetivo deste estudo foi avaliar a aplicação dos biomarcadores, em especial da cistatina C, no diagnóstico da doença renal em cães e compreendeu duas etapas. Uma fase constou da avaliação de 12 cães, sendo seis pertencentes ao grupo controle e seis cães pertencentes ao grupo experimental que foram submetidos a um protocolo de indução de injúria renal com 30 mg/kg ao dia de gentamicina, via subcutânea, durante 10 dias. Os cães foram avaliados durante 45 dias por meio de: exame clínico; hemograma e fibrinogênio; bioquímica sérica (ureia, creatinina, proteínas totais, albumina, fósforo, cálcio, sódio, potássio, colesterol e eletroforese das proteínas séricas); bioquímica urinária (sódio, potássio, gama glutamil transferase e fosfatase alcalina); urinálise; determinação da razão proteína/creatinina urinária; hemogasometria e pressão arterial sistólica não- invasiva. A outra fase constou da mensuração da cistatina C sérica em 58 cães com doença renal crônica divididos nos estádios 2, 3 e 4 da IRIS (International Renal Interest Society) e em seis cães com injúria renal aguda induzida por gentamicina, avaliados durante 20 momentos após o início da injúria. Os resultados demonstraram que a enzima gama glutamil transferase urinária e a excreção fracionada de sódio e potássio foram mais precoces em detectar a injúria renal aguda em cães do que outros marcadores mais utilizados na rotina clínica como a creatinina e a ureia. A cistatina C sérica não foi eficiente em detectar de forma precoce a doença renal crônica em cães nos estádios iniciais e a injúria renal aguda, possuindo uma baixa aplicabilidade neste estudo.

<p>The cardiac troponins are the biochemical markers of choice for the diagnosis of acute myocardial infarction (AMI) and risk prediction in patients with acute coronary syndrome (ACS). In this thesis, the role of early serial cardiac troponin I (cTnI) testing was assessed in fairly unselected patient populations admitted because of chest pain and participating in the FAST II-study (n=197) and the FASTER I-study (n=380). Additionally, the importance of cTnI testing in stable post-ACS patients from the FRISC II-study (n=1092) was studied.</p><p>The analyses in chest pain patients demonstrate that cTnI is very useful for early diagnostic and prognostic assessment. cTnI allowed already 2 hours after admission the reliable exclusion of AMI and the identification of low-risk patients when ECG findings and a renal marker such as cystatin C were added as conjuncts. Other biomarkers such as CK-MB, myoglobin, NT-pro BNP or CRP did not provide superior clinical information. However, myoglobin may be valuable in combination with cTnI results for the early prediction of an impending major AMI when used as input variable for an artificial neural network. Such an approach applying cTnI results only may also furthermore improve the early diagnosis of AMI.</p><p>Persistent cTnI elevation > 0.01 μg/L was detectable using a high-sensitive assay in 26% of the stable post-ACS patients from the FRISC II-study. NT-pro BNP levels at 6 months were the most important variable independently associated to persistent cTnI elevation besides male gender, indicating a relationship between adverse left ventricular remodeling processes and cTnI leakage. Patients with persistent cTnI elevation had a considerable risk for both mortality and AMI during 5 year follow-up. </p><p>These analyses thus, confirm the value of cTnI for early assessment of chest pain patients and provide new and unique evidence regarding the role of cTnI for risk prediction in post-ACS populations.</p>

The cardiac troponins are the biochemical markers of choice for the diagnosis of acute myocardial infarction (AMI) and risk prediction in patients with acute coronary syndrome (ACS). In this thesis, the role of early serial cardiac troponin I (cTnI) testing was assessed in fairly unselected patient populations admitted because of chest pain and participating in the FAST II-study (n=197) and the FASTER I-study (n=380). Additionally, the importance of cTnI testing in stable post-ACS patients from the FRISC II-study (n=1092) was studied. The analyses in chest pain patients demonstrate that cTnI is very useful for early diagnostic and prognostic assessment. cTnI allowed already 2 hours after admission the reliable exclusion of AMI and the identification of low-risk patients when ECG findings and a renal marker such as cystatin C were added as conjuncts. Other biomarkers such as CK-MB, myoglobin, NT-pro BNP or CRP did not provide superior clinical information. However, myoglobin may be valuable in combination with cTnI results for the early prediction of an impending major AMI when used as input variable for an artificial neural network. Such an approach applying cTnI results only may also furthermore improve the early diagnosis of AMI. Persistent cTnI elevation &gt; 0.01 μg/L was detectable using a high-sensitive assay in 26% of the stable post-ACS patients from the FRISC II-study. NT-pro BNP levels at 6 months were the most important variable independently associated to persistent cTnI elevation besides male gender, indicating a relationship between adverse left ventricular remodeling processes and cTnI leakage. Patients with persistent cTnI elevation had a considerable risk for both mortality and AMI during 5 year follow-up. These analyses thus, confirm the value of cTnI for early assessment of chest pain patients and provide new and unique evidence regarding the role of cTnI for risk prediction in post-ACS populations.

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.

Antibiotics are among the most commonly prescribed drugs. Although the majority of these drugs were developed several decades ago, optimal dosage (dose, dosing interval and treatment duration) have still not been well defined. This thesis focuses on the development and evaluation of pharmacometric models that can be used as tools in the establishment of improved dosing strategies for novel and already clinically available antibacterial drugs. Infectious diseases are common causes of death in preterm and term newborn infants. A population pharmacokinetic (PK) model for gentamicin was developed based on data from a prospective study. Body-weight and age (gestational and post-natal age) were found to be major factors contributing to variability in gentamicin clearance and therefore important patient characteristics to consider for improved dosing regimens. A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model was also developed, to characterize in vitro bacterial growth and killing kinetics following exposure to six antibacterial drugs, representing a broad selection of mechanisms of action and PK as well as PD characteristics. The model performed well in describing a wide range of static and dynamic drug exposures and was easily applied to other bacterial strains and antibiotics. It is, therefore, likely to find application in early drug development programs. Dosing of antibiotics is usually based on summary endpoints such as the PK/PD indices. Predictions based on the PKPD model showed that the commonly used PK/PD indices were well identified for all investigated drugs, supporting that models based on in vitro data can be predictive of antibacterial effects observed in vivo. However, the PK/PD indices were sensitive to the study conditions and were not always consistent between patient populations. The PK/PD indices may therefore extrapolate poorly across sub-populations. A semi-mechanistic modeling approach, utilizing the type of models described here, may thus have higher predictive value in a dose optimization tailored to specific patient populations.

Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Nitric oxide (NO) has previously been shown to play a vital role in plants that are undergoing oxidative stress arising from abiotic stress. To better understand the role of NO on the antioxidative pathway, the effect of NO on Superoxide Dismutase (SOD) activity was studied during salt stress on soybean nodules. The enzymatic activity of specific MnSOD and FeSOD isoforms increased upon 1 week of exposure of nodules to NO or salt stress, the activity of CuZnSOD isoforms however increased in response to salt stress only. Furthermore, 4 putative FeSOD and MnSOD transcripts were identified and shown to increase in response to NO and salt stress. The promoter sequences of these NO-responsive putative SOD genes were analysed alongside a cystatin (AtCYS-1) which is also NO-inducible. Putative NO-responsive cis-acting elements as well as abiotic stress-responsive cis-acting elements were studied amongst these promoter sequences. The MYCL element and the AtMYB4 binding site were found to occur in all four NO-inducible SOD promoter sequences as well as in the AtCYS-1 promoter sequence. This suggests that NO acts via MYCL and/or AtMYB4 to up-regulate specific FeSODs and MnSODs, causing an increase in the activity of these SOD isoforms, thus reducing oxidative stress and cell death in soybean nodules. Furthermore, NO may also be up-regulating cystatins to inhibit cysteine proteases, thus preventing the onset of programmed cell death (PCD) and subsequently reducing salt stress-induced cell death. / AFRIKAANSE OPSOMMING: Geen opsomming