Orientador: Priscylla Tatiana Chalfun Guimarães Okamoto / Resumo: A doença do trato urinário inferior de felinos (DTUIF) corresponde a uma série de afecções que podem acometer a bexiga e a uretra desses animais. A forma obstrutiva é a consequência mais prevalente e mais grave dentre outras DTUIF, podendo levar o animal a azotemia pós-renal, redução da taxa de filtração glomerular (TFG) e a lesão renal aguda (LRA), que caso não seja tratada de forma eficiente, pode evoluir para doença renal crônica (DRC), uma doença frequente na população geriátrica felina. A creatinina sérica (sCr) é o biomarcador de TFG mais utilizado na clínica veterinária, porém apresenta baixa sensibilidade e diversos fatores que podem afetar seus valores. A dimetilarginina simétrica (SDMA) é um biomarcador mais recente na medicina veterinária que vem apresentado maior precocidade na detecção da perda da função renal e menor interferência de fatores extrarrenais, porém poucos são os trabalhos que determinam valores de SDMA em lesão renal de gatos. Este trabalho visou avaliar os valores de SDMA e compará-los com a sCr, ureia, dados hemogasométricos, escore clínico e tempo de obstrução de gatos com DTUIF obstrutiva. Os animais foram alocados em dois grupos experimentais, sendo 17 animais do grupo obstruído (GO) e 13 animais sadios para grupo controle (GC). As amostras foram coletadas antes da desobstrução (M0) e durante o tratamento clínico, nos momentos 12, 24 e 48 horas (M12, M24 e M48). Resultados obtidos demonstraram que no M48 do GO, 50% dos gatos obstruídos apresent... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Feline lower urinary tract disease (FLUTD) is a series of conditions that can affect the bladder and urethra of these animals. The obstructive form is the most prevalent and most serious consequence among other FLUTD, which can lead to post-renal azotemia and reduced glomerular filtration rate (GFR) and acute kidney injury (AKI), which if not treated effectively, can progress to chronic kidney disease (CKD), a common disease in the feline geriatric population. Serum creatinine (sCr) is the biomarker of GFR most commonly used in veterinary pratice, but it has low sensitivity and there are several factors that may affect its values. Symmetrical dimethylarginine (SDMA) is a newer biomarker in veterinary medicine that has been shown to be more precocious in detecting loss of renal function and less interference of extrarenal factors, but there are few studies determining SDMA values in feline kidney injury. This work aimed to evaluate SDMA values and to correlate them with sCr, urea, hemogasometric data, clinical score and duration of obstruction of felines with obstructive DTUIF. The animals were allocated into two experimental groups, 17 animals from the obstructed group (GO) and 13 healthy animals for control group (GC). Samples were collected before clearance (M0) and during clinical treatment at 12, 24 and 48 hours (M12, M24 and M48). The results obtained were that in GO M48, 50% of obstructed cats had SDMA values above normal, while for sCr only 29.41% of cats were elevated... (Complete abstract click electronic access below) / Mestre

Background. This study aims to establish age- and gender-specific cystatin C (CysC) reference values for healthy infants, children, and adolescents and to relate them to pubertal stage, height, weight, and body mass index (BMI). Methods. Serum CysC and creatinine levels of 6217 fasting, morning venous blood samples from 2803 healthy participants of the LIFE Child study (age 3 months to 18 years) were analyzed by an immunoassay. Recruitment started in 2011; 1636 participants provided at least one follow-up measurement. Percentiles for CysC were calculated. Age- and gender-related effects of height, weight, BMI, and puberty status were assessed through linear regression models. Results. Over the first 2 years of life, median CysC levels decrease depending on height (ß = − 0.010 mg/l/cm, p < 0.001) and weight (ß = − 0.033 mg/l/kg, p < 0.001) from 1.06 to 0.88 mg/l for males and from 1.04 to 0.87 mg/l for females. Following the second year of age, the levels remain stable for eight years. From 11 to 14 years of age, there is an increase of median CysC levels in males to 0.98 mg/l and a decrease in females to 0.86 mg/l. The change is associated with puberty (ß = 0.105 mg/l/Tanner stage, p < 0.001 in males and ß = − 0.093 mg/l/Tanner stage, p < 0.01 in females) and in males with height (ß = 0.003 mg/l/cm, p < 0.001). Conclusions. CysC levels depend on age, gender, and height, especially during infancy and puberty. We recommend the use of age- and gender-specific reference values for CysC serum levels for estimating kidney function in clinical practice.:1 Contents ........................................................................................................... 1 2 Introduction ...................................................................................................... 2 GFR measurement ............................................................................................. 2 Technically advanced methods ........................................................................ 2 Serum creatinine................................................................................................ 3 Serum Cystatin C............................................................................................... 3 Current state of research..................................................................................... 5 Reference values of Cystatin C ......................................................................... 5 Cystatin C in healthy test persons .................................................................... 6 Validity of Cystatin C for kidney diseases.......................................................... 6 Post-transplant validity of Cystatin C ............................................................... 7 Validity of Cystatin C in extra-renal diseases .................................................... 7 GFR-equations................................................................................................... 8 Confounders ...................................................................................................... 9 Relevance of the topic ......................................................................................... 11 Hypothesis ........................................................................................................... 13 3 Publication – manuscript................................................................................... 14 4 Summary and interpretation ............................................................................. 16 5 References ........................................................................................................ 20 6 Appendix ........................................................................................................... I 7 Description of the own contributions ................................................................ VII 8 Erklärung über die eigenständige Abfassung der Arbeit .................................. VIII 9 Curriculum vitae ................................................................................................ IX 10 Scientific publications and presentations ....................................................... XI 11 Acknowledgements.......................................................................................... XII

A convolutional deep neural network is employed to assess renal autoregulation using time series of arterial blood pressure and blood flow rate measurements in conscious rats. The network is trained using representative data samples from rats with intact autoregulation and rats whose autoregulation is impaired by the calcium channel blocker amlodipine. Network performance is evaluated using test data of the types used for training, but also with data from other models for autoregulatory impairment, including different calcium channel blockers and also renal mass reduction. The network is shown to provide effective classification for impairments from calcium channel blockers. However, the assessment of autoregulation when impaired by renal mass reduction was not as clear, evidencing a different signature in the hemodynamic data for that impairment model. When calcium channel blockers were given to those animals, however, the classification again was effective.

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Bladder dysfunction is seen as a public health problem with a strongly increasing incidence in older men. Despite this, the man's experience of bladder dysfunction is a topic that has not been researched in the empirical field as much as women’s experiences. Not highlighting the man's experience leads to suffering and constitutes an obstacle to equal care. The aim of this study was to illustrate the man's experience of living with bladder dysfunction. This study is intended to illustrate experiences, therefore it was well suited to make an integrative compilation of qualitative research – inspired by meta-synthesis. Nine qualitative articles that described the man's experiences were analysed schematically and resulted in three themes and six sub-themes. Experiences that were noticed in the man were the impact of the environment in bladder dysfunction which included environmental and health care responses. Emotional impact in bladder dysfunction, which highlighted the experiences that arose in connection with bladder dysfunction. The life adaptations in bladder dysfunction was an experience which described the changes the man made to achieve a normality in everyday life as well as changes to hide the condition. The man used a range of strategies to maintain normality in life and to keep his condition a secret from those around him. This is seen because of the stigmatization that emerged through this study. Healthcare failed to care for the man with bladder dysfunction and was seen as partially responsible for the stigmatization the man experienced.

This systematic review aims to examine the relationship between the social determinants of health that significantly impact the prevalence and progression of chronic kidney disease (CKD) amongst Black Americans. The Black American population has the highest prevalence of CKD in the United States, while concurrently possessing prominent genetic risk factors for this chronic disease. The social determinants: healthcare quality and access (extended to account for health behaviors), social and community context, and economic stability were specifically assessed in this review. Key terms were utilized to search electronic databases PubMed and Web of Science, which yielded 470 unduplicated articles. Twenty-nine articles met the inclusion criteria for this systematic review, with three articles being applicable to the three selected social determinants, six being applicable to social and community context, six being applicable to economic stability, and fourteen being applicable to healthcare quality and access. Major contributors towards CKD incidence and progression amongst Black Americans were identified to be: exposure to discrimination, expectations of discrimination and prejudice, low routine medical care, limited health literacy, distrust of health providers, being of low socioeconomic status, and a lack of engagement in functional health behaviors (fruit/vegetable consumption and CKD screening). Each social determinant was seldom observed to be operating exclusively as a contributing factor towards CKD, exemplifying how the intersectionality of these factors contributes to increased CKD risk and progression. Findings from this systematic review highlight the need for targeted healthcare initiatives for Black Americans to remedy the CKD endemic.

<p>Reduced kidney function around the time of surgery is an important risk factor for postoperative mortality. Despite this there is limited information on how reduced kidney function prior to surgery alters prognosis, what causes sudden decrements in kidney function after surgery (known as acute kidney injury), or how they might be avoided. The studies in this thesis inform these knowledge gaps. Chapter 2 describes the results of a post hoc analysis of the interaction between preoperative estimated glomerular filtration rate, a marker of kidney function, and postoperative cardiac troponin T, a marker of heart damage, for predicting 30-day mortality in a prospective cohort study of patients undergoing noncardiac surgery. Chapter 3 uses administrative and clinical data from a single centre to inform the risk of acute kidney injury after noncardiac surgery by concentrations of preoperative hemoglobin and change in postoperative hemoglobin. Chapter 4 uses the same data to determine a definition of intraoperative hypotension that is prognostic of acute kidney injury, myocardial injury and death. Chapter 5 describes a randomized controlled trial that compares a novel therapeutic procedure called remote ischemic preconditioning to a sham procedure in patients undergoing cardiac surgery.</p> / Doctor of Philosophy (PhD)

Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data. Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome. Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases. Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.

Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT. Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer. Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer. Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour. Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

Background: Peer-to-peer (P2P) support programs have the potential to assist ESRD patients in managing their disease and improve outcomes. Yet, there is little research examining P2P programs’ impact on psychosocial outcomes and disease management behaviors. Methods: A 4-month P2P mentoring intervention was designed and piloted in a facility serving 249 in-center hemodialysis patients in Lynchburg, Virginia. Preceded by a social marketing effort, which included a program naming contest and participant recruitment, the intervention included: (1) mentor training, (2) pairing of mentees and mentors, (3) kick-off social mixers, (4) ongoing meetings between mentees and mentors, (5) mentor training booster, and (6) a final celebration. A single arm quasi-experimental study with repeated measurements at three time points was used with data collection over four months. The hypotheses that the intervention would result in improvements for both mentees and mentors (i.e., self-efficacy, knowledge, perceived social support, dialysis social support (i.e., support from peers within the dialysis setting), and self-management behaviors) were tested using repeated measures ANOVA or the Friedman’s test for nonparametric data. Results: Mentees experienced increases in self-efficacy, F(2,22)=8.15, p<.01; knowledge, F(2,44)=6.62, p<.01; perceived social support, F(2,22)=7.30, p<.01; and dialysis social support, F(2,44)=4.79, p=.01. Mentors experienced increases in knowledge, F(2,22)=11.88, p<.01; dialysis social support, F(2,42)=3.19, p=.05; and dialysis self-management, χ2(2) = 7.65, p =.02. Conclusion: A P2P mentoring program for in-center hemodialysis patients can be beneficial for both mentees and mentors. Future research should focus on larger groups of patients using more rigorous research designs.