O emprego do hamsters (Mesocricetus auratus) como modelo biológico experimental para a reprodução da condição de portador renal de leptospiras foi investigado em machos e fêmeas jovens com 80 a 120 g de peso vivo. Os animais foram experimentalmente infectados com estirpe patogênica do sorovar Pomona caracterizada por provocar a morte por leptospirose entre o quinto e o décimo dia pós-infecção. No segundo dia pós-infecção os animais foram tratados com estolato de eritromicina, nas concentrações de 10, 20, 40 e 80 mg/kg de peso vivo. Aos 30 dias, da infecção experimental os sobreviventes foram anestesiados com isofluorano e procedeu-se a colheita de sangue para a determinação dos indicadores da função hepática e renal (Proteínas totais, Albumina, Uréia, Creatinina, Fosfatase Alcalina, Alanina Aminotransferase, Aspartato Aminotransferase, Bilirrubinas Indireta, Bilirrubinas Direta e Bilirrubinas Totais), bem como o titulo de aglutininas pela prova de soro aglutinação microscópica. A seguir, com o aprofundamento da anestesia, os animais foram submetidos a eutanásia e necropsiados para a colheita de tecido renal e hepático destinados aos exames histopatológicos pelas colorações de Hematoxilina - Eosina e Warthin- Starry, bem como do isolamento de leptospiras por cultivo em meio de Fletcher. Houve controles do inóculo infeccioso, do tratamento com antibiótico e do sistema de manejo adotado. O número de DL 50 efetivamente empregadas no inóculo infeccioso foi de 7,11. No grupo controle do antibiótico foi constatado elevação do nível de fosfatase alcalina e degeneração vacuolares dos hepatócitos para as concentrações de 40 a 80 mg de antibiótico. Os portadores renais de leptospira foram obtidos entre os animais tratados com 40 ou 80 mg de estolato de eritromicina, independentemente do sexo; estes animais apresentaram elevação dos níveis séricos de creatinina e proteínas totais já as determinações de albumina, uréia, alanina aminotrasferase, aspartato aminotransferase, bilirrubinas direta, bilirrubinas indiretas e totais foram iguais as encontradas em animais não infectados por leptospiras e não tratados com antibióticos. As alterações histológicas encontradas nos animais portadores de leptospiras foram degeneração vacuolar em hepatócitos, sangue no espaço porta, congestão glomerular. Nos animais induzidos a condição de portadores renais de leptospiras os títulos de anticorpos aglutinantes, para o sorovar homólogo ao da infecção, expressos em logaritmo de base, 10 foram iguais ou superiores a 1,19. / The use of hamsters (Mesocricetus auratus) as experimental model for the reproduction of leptospires kidney carrier condition was investigated on youngs males and females with 80 to 120 g of living weight. The animals were experimentally infected with pathogenic strain of serovar Pomona able of causing the death by leptospirosis between the fifth and the tenth post-infection day. On the second day post-infection the animals were treated with erythromycin estolate at the concentrations of 10, 20, 40 and 80 mg/ kg of living weight. At the 30th day of experimental infection the survivors were anesthetized with isoflurane and blood sample were collected for the determination of kidney and liver functions (Total proteins, Albumin, Urea, Creatinine, Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Indirect Bilirubins, Direct Bilirubins and Total Bilirubins), and the of agglutinine title by the microscopic agglutination test (MAT). The animals were killed whit the reinforcement of the anesthesis, and necropsied for the collection of kidney and liver sample for histopathologic tests by staining of Hematoxylin-Eosina and Warthin-Starry, such as the isolation of leptospiras by cultivation into Fletcher´s medium. There were controls of the infecctious inoculum, antibiotic treatment and of the management system adopted. The number of DL 50 effectively applied in the infectious inoculum was 7,11. The antibiotic controls presented elevation of the alkaline phosphatase level and vacuolar degeneration of hepatocytes at the concentrations of 40 to 80 mg of antibiotic. The leptospire\'s kidney carriers were obtained in the animals treated with 40 or 80 mg of Erythromycin Estolate, regardless of the sex; these animals showed increase in creatinine\'s and total protein serum levels but of albumin, urea, alanine aminotransferase, aspartate aminotransferase, direct bilirubins, indirect bilirubins and total bilirubins were the same as found in animals not infected by leptospires and not treated with the antibiotic. The histological changes found in the animals induced as leptospires carrier were vacuolar degeneration in hepatocytes, blood in the portal tract, and glomerular congestion. The agglutinine titles for the homologous serovar, expressed on base 10 logarithm, were at least 1.19.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2017. / Background Abnormalities of mineral bone disease have been consistently associated with adverse clinical outcomes in patients with chronic kidney disease (CKD). The consequences of these changes have also been shown to differ across races. However, in Africa the impact of derangements of CKD -mineral and bone disorder (CKD-MBD) on patients with CKD is largely unknown. In addition, studies from the USA have reported racial variations in markers of CKD and it remains unclear whether genetic factors may explain this discrepancy in the levels of biochemical markers of CKD-MBD across ethnic groups. Therefore, this study has been conducted to determine the existence of racial differences in the levels of fibroblast growth factor 23(FGF23) and traditional markers of mineral bone metabolism in a heterogeneous African CKD population, and to provide important insights into the pattern and genetic variability of CKD-MBD in sub-Saharan Africa. Methods This was a cross sectional multicenter study carried out from April 2015 to May 2016, involving two hundred and ninety three CKD patients from three renal units in Johannesburg, South Africa. The retrospective arm of this study involved two hundred and thirteen patients undergoing maintenance haemodialysis (MHD) from two dialysis centers in Johannesburg between January 2009 and March 2016. The first part of this study described the pattern of CKD-MBD in MHD patients using traditional markers of CKD-MBD. The second part of the study looked into the spectrum of CKD-MBD and racial variations in markers of CKD-MBD in pre dialysis and dialysis patients. This was followed by the genetic aspect of the study that examined the influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders. Lastly, the study also evaluated the association between markers of CKD-MBD and mortality in MHD patients. Results The prevalence of hyperparathyroidism (iPTH>150 pg/mL), hyperphosphataemia, hypocalcaemia and 25-hydroxyvitamin D deficiency (<30 ng/mL) was 73.4%, 57.0%, 20.3% and 80.7 % respectively in our MHD patients. The combination of markers of bone turnover (iPTH>150 pg/mL and total alkaline phosphatase > 112 U/L) suggestive of high turnover bone disease, was present in 47.3 % of the study population. The odds ratios for developing secondary hyperparathyroidism with hypocalcaemia and hyperphosphataemia were 5.32 (95% CI 1.10 - 25.9, P =0.03) and 3.06 (95 % CI 1.15 - 8.10, P =0.02) respectively. The 293 CKD patients (208 blacks, 85 whites) had an overall mean age of 51.1±13.6 years, and black patients were significantly younger than the white patients (48.4 ±.13.6 versus 57.1±15.5 years; p<0.001). In comparison to whites, blacks had higher median iPTH (498 [37-1084] versus 274[131-595] pg/ml; P=0.03), alkaline phosphatase (122[89-192] versus 103[74-144] U/L; P=0.03) and mean 25- hydroxyvitamin D (26.8±12.7 versus 22.7 ±12.2 ng/ml, P=0.01) levels, while their median FGF23 (100 [34-639] versus 233[80-1370] pg/ml; P=0.002) and mean serum phosphate (1.3±0.5 versus 1.5±0.5, P =0.001) levels were significantly lower. With the exception of vitamin D receptor (VDR) Taq I polymorphism, the distribution of the VDR polymorphisms differs significantly between blacks and whites. In hemodialysis patients, the BsmI Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, P=0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, P=0.03). Patients with high total alkaline phosphatase (TAP) had significantly higher risk of death compared to patients with TAP <112 U/L (hazard ratio, 2.50; 95% CI 1.24–5.01, P = 0.01). Similarly, serum calcium >2.75 mmol/L was associated with increased risk of death compared to patients within levels of 2.10–2.37 mmol/L (HR 6.34, 95% CI 1.40–28.76; P = 0.02). The HR for death in white patients compared to black patients was 6.88; 95% CI 1.82–25.88; P = 0.004. Conclusions Secondary hyperparathyroidism and 25–hydroxyvitamin D deficiency were common in our haemodialysis patients. The study also highlighted the existence of racial differences in the circulating markers of mineral bone disorders in our African CKD population. In addition, the study showed that both moderate and severe secondary hyperparathyroidism are predicted by the BsmI Bb genotype, and the over expression of this genotype in black patients may partly explain the ethnic variations in the severity of secondary hyperparathyroidism in the CKD population. High levels of serum alkaline phosphatase, hypercalcaemia, and white race are associated with increased risk of death in MHD patients. / LG2018

End-stage renal disease (ESRD), or kidney failure, is a serious illness with significant health consequences and high-cost treatment options. Since the early 1980s, the number of Canadians with ESRD has more than quadrupled (CIHI, 2001), leading to questions about the current and future impact of the disease on public health, quality of life, health spending, and patients’ productivity. Using an economic burden of illness approach, this thesis estimates ESRD’s “direct” health care costs and “indirect” costs, such as productivity losses due to premature death and short- and long-term disability. It also projects future results under various alternative assumptions using a multi-state discrete time Markov model. The analysis suggests that, although less than 0.1% of Canadians have ESRD, it generated direct health care costs of $1.3 billion in 2000 or $51,099 per person with ESRD. That compares to $3,183 per capita for Canadians overall (CIHI, 2002b). Adding indirect morbidity and mortality costs brings the total to $1.9 billion. Rising ESRD numbers suggest higher costs in the future. Further analysis explored the effect of various assumptions about drivers of past trends, such as population growth, changes in the age structure, and the prevalence of conditions known to cause ESRD (e.g. diabetes). Projections were most sensitive to assumptions about the rate at which new cases are diagnosed. If current trends continue, the total economic burden of the disease can be expected to reach $7.9 billion by 2015 (year 2000 dollars). On the other hand, if the rate of new cases in 2000 were maintained, the economic burden of illness would be $5.7 billion in 2015. Nevertheless, under this and many other assumptions, there is likely to be a significant gap between available organs for transplant and the demand for transplantation. The likely effects of various options for addressing this gap are also explored. / Thesis / Doctor of Philosophy (PhD)

No description available.

Inappropriate modulation of the renin angiotensin system (RAS) can lead to derangements of blood pressure homeostasis in humans. Cyp1a1-mRen2.F transgenic rats were used to define the renal mechanisms underlying the development of angiotensin II-dependent hypertension. These transgenic rats were previously generated by introducing the mouse Ren2 gene into the rat genome under the control of a Cyp1a1 inducible promoter. The aim of the current investigation was to establish the contribution of renal function to the development of hypertension in the Cyp1a1- mRen2.F transgenic rat. Expression of the mRen2 transgene was induced by daily gavage of indole 3 carbinol (I3C) at the dose of 100mg/kg. Blood pressure was measured in conscious rats after 1, 3 or 7 days of treatment. The control group received the vegetable oil carrier for 7 days. In addition blood pressure, renal haemodynamics and excretory function were measured under thiobutabarbital anaesthesia. Transgene induction caused a progressive increase in blood pressure in a time dependent manner. Neither glomerular filtration rate nor renal blood flow was affected. This indicates proper function of renal autoregulation during the experimental time course. Tubular sodium reabsorption was significantly increased after the first day of transgene induction and this effect was sustained for the duration of treatment. A pharmacological approach was used to localize the increased reabsorption to a specific region of the nephron and was found to reflect increased activity of the thiazide-sensitive cotransporter (NCC). Chronic administration of thiazide significantly blunted the hypertensive response to transgene induction. Similarly AT1 receptor blockade attenuated the hypertensive phenotype and prevented the transgene-induced stimulation of NCC activity. In contrast, mineralocorticoid receptor blockade did not prevent the development of either hypertension or increased NCC activity. The current study suggests that the development of angiotensin II-dependent hypertension is mediated by increased tubular sodium reabsorption. Increased activity of NCC is a key hypertensive mechanism in this model and results directly from the actions of angiotensin II at the AT1 receptor; indirect aldosterone pathways do not play a major role.

Introduction Podocytes are terminally differentiated, highly specialized glomerular cells that form the final barrier to protein loss. Podocyte injury is characterised by proteinuria. Proteinuria is an important prognostic marker in kidney diseases, and lowering proteinuria has become a principal clinical goal. Compelling evidence supports the notion that continuing loss of podocytes plays a major role in the initiation and progression of glomerular diseases. It is my hypothesis that interventions that reduce the disruption by rescuing susceptible podocytes next to injured ones are potential therapies to restore podocyte phenotype and filtration behaviour, thereby protecting the kidney from progressive deterioration. Prevention of this damage, or ways to aid its recovery, could therefore be important to improving the management of human kidney diseases. Methods Transgenic mice expressing the human diphtheria toxin receptor on podocytes had been previously generated in our laboratory. Characterization of two lines showed that graded specific podocyte injury could be induced by single intraperitoneal injection of diphtheria toxin. Eight-week intervention studies involved administration of oral drug in water or food from 24h after toxin injection. Two control groups received no drug or were non-transgenic (wild-type) littermates. Primary endpoints were glomerulosclerosis and kidney function (serum creatinine). Other readouts included blood pressure, albuminuria, serum albumin, podocyte quantification and collagen staining of kidney. The angiotensin converting enzyme inhibitor (ACEi) captopril was tested because of its proven protective effect on renal function in patients with proteinuria. Subsequently another proteinuria-reducing drug, the endothelin receptor A antagonist sitaxsentan was tested alone and in combination with captopril. Results Captopril reduced proteinuria and ameliorated scarring, with matrix accumulation and glomerulosclerosis falling almost to baseline. Podocyte counts were reduced after toxin administration and showed no significant recovery irrespective of captopril treatment. In the following sitaxsentan and captopril combined intervention study, glomerular scarring was significantly reduced in all drug-treated groups either alone or in combination, but only combination drug treatment reduced glomerular damage to levels comparable to wild-type controls, demonstrating a synergistic effect of the two agents. Similarly, serum creatinine was lowered further in combined but not single drug-treated groups. Blood pressure of all drug treated mice was lowered compared to the placebo group. Surprisingly in this second study there were no significant differences in proteinuria between treated and untreated groups. Conclusion These results support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease, and plays a major role in progressive glomerulosclerosis. Both captopril and sitaxsentan alone or in combination provided protection without substantial preservation or restoration of podocyte numbers at the degree of injury induced in these experiments. Combined therapy showed a synergistic effect in protecting the kidney from progressive damage. These results suggest that protection may be at least partly due to change in podocyte phenotype. The model is ideal for studying strategies to protect the kidney from progressive damage following specific podocyte injury. Further elucidations on the mechanism of action of the drugs may aid development of superior future therapeutic treatments in the field of renal diseases.

Context: Albuminuria, a clinical indicator of chronic kidney disease, has a high prevalence among the US population where approximately half of the people with this condition are women. In the US, most participants in food based government assistance programs are women who have food insecurity. Research indicates that obesity and diabetes, known risk factors for chronic kidney disease, are consequences of food insecurity. Aim: The aim of this study is to examine racial-ethnic differences in the relationship between food insecurity and albuminuria in women who participated in the 2011-2012 NHANES. Methods: Odds ratios from racial-ethnic specific multivariate logistic regression were used to determine the associations between food insecurity and albuminuria. Results: Among all participants, black women had the highest rate of food insecurity at 36%. From multivariate analysis, it was determined that among non-Hispanic blacks that having albuminuria was associated (OR= 3.73 95% CI 1.47-9.44) with food insecurity. However, there was no statistically significant association between food insecurity and albuminuria (OR= 1.46 95% CI .501-4.261) for non-Hispanic whites. Discussion: Significant racial-ethnic differences in the association between food insecurity and albuminuria were identified in Non-Hispanic black women. It is recommended that further studies be done to evaluate the biological basis of the relationship between albuminuria and food insecurity in black women. A public health intervention to improve food insecurity may help reduce the risk of albuminuria in black women.

Adult Polycystic Kidney Disease (APKD) is a genetic disease transmitted in an autosomal dominant fashion. There is no cure. Treatment is of the symptoms as they appear usually in adulthood. Patients affected by APKD may receive genetic counselling from renal physicians. The aims of genetic counselling can be described through paradigms which reflect the current understanding of genetics and knowledge of the illnesses. The availability of new diagnostic techniques creates a new paradigm concerned with the ethical issues of genetic testing and counselling. An investigation into patients' knowledge, perceptions and understanding of genetic counselling was undertaken at the Renal Unit of Glasgow Royal Infirmary, prior to the establishment of a screening and counselling service for those at risk for APKD. The main findings of the study were: the majority of patients had received some genetic counselling from renal physicians; the majority of patients had relatively good knowledge of the symptoms of and treatments for APKD; nevertheless patients believed that the two most important items to be included in genetic counselling were information about the symptoms and the treatment of APKD; patients did not fully understand the genetic inheritance of APKD; they described the risk of transmission of APKD (50-50) as a medium risk; almost all patients recommended that their at risk relatives and their children be tested for APKD; prior to the availability of prenatal diagnosis, patients thought that their children should be tested between the ages of 16 and 20. A secondary study, including spouses of those with APKD and also haemophiliacs and their spouses, found that respondents favoured prenatal testing without termination of pregnancy and that both diseases were rated as being of medium severity. These findings raise ethical issues for those giving genetic counselling, and have implications for the content of genetic counselling.

No description available.