Proteinuria has been recognized as a common feature in many forms of chronic kidney disease (CKD). As traditional medications for proteinuric nephropathy, such as blockade of the renin-angiotensin system (RAS), has only achieved limited clinical success, more effective renoprotective strategies need to be explored. Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have recently shown promise as a therapeutic tool in acute kidney injury (AKI) models. The therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in proteinuric nephropathy models is unknown. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, I first examined the potential effect of BM-MSCs in albumin-induced pro-inflammatory response and epithelial-to-mesenchymal transition (EMT) in PTECs. The unstimulated BM-MSCs exerted moderate suppressive effect on tubular inflammation as only albumin-induced CCL-2 and CCL-5 expression was attenuated in PTECs. When concomitantly stimulated by albumin excess, however, BM-MSCs remarkably suppressed albumin-induced tubular IL-6, IL-8, TNF-α, CCL-2, and CCL-5 expression, suggesting albumin overloaded milieu to be a prerequisite for them to fully exhibit their anti-inflammatory effects. This effect was mediated via deactivation of tubular NF-κB signaling as BM-MSCs prevented the overexpression of p-IκB and nuclear translocation of NF-κB. In addition, albumin-induced tubular EMT, as shown by the loss of E-cadherin and induction of α-SMA, FN-1 and collagen IV in PTECs, was also prevented by BM-MSC co-culture. To dissect the mechanism of action, I next explored the paracrine factors secreted by BM-MSCs under an albumin-overloaded condition and studied their contribution to the protective effect on tubular inflammation and EMT. Albumin-overloaded BM-MSCs per se overexpressed 34 paracrine factors, of which hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 were regulated by P38 and NF-κB signaling. These paracrine factors suppressed both the proinflammatory and profibrotic phenotypes in albumin-induced PTECs. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. Finally, in albumin-overloaded mice, a well established murine model reminiscent of human CKD, treatment with mouse BM-MSCs markedly reduced BUN, tubular CCL-2 and CCL-5 expression, interstitial macrophage, α-SMA and collagen IV accumulation independent of changes in proteinuria, together with upregulated renal cortical expression of HGF. Exogenous BM-MSCs were detected in their kidneys by PKH-26 staining. Collectively, these in vitro and in vivo data suggest a modulatory effect of BM-MSCs on albumin-induced tubular inflammation and fibrosis and underscore a therapeutic potential of BM-MSCs for CKD in the future. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

Surgical resection is the best option for both liver and kidney cancers, which providing the long term survival. However intraoperative blood loss can be a significant challenge, and is clearly associated with morbidity and mortality. Radiofrequency ablation (RFA) precoagulation has been introduced into liver and kidney surgery. Promising results have already achieved in reduction of intraoperative blood loss. In this thesis, a detailed explanation on precoagulation by RFA has been given. Our group developed a novel bipolar multi-array RFA device ??? InLine (ILRFA). In this thesis, we have investigated the performance in a variety of fields. In the study of ILRFA-assisted laparoscopic liver resection, ILRFA was easily employed through a hand port and achieved significant decrease of blood loss compared to control group (p < 0.05). In the liver trauma study, ILRFA produced a 63.88% reduction of blood loss in peripheral injury and 53.57% in central injury respectively. In postoperative evaluation of ILRFA-assisted liver resection, animals underwent an uneventful recovery, no complications occurred. Histological examination revealed a typical post RFA evolution. In ILRFA-assisted partial nephrectomy, the mean intraoperative blood loss 35 ?? 7 ml in the ILRFA and 152 ?? 94 ml in the control, a 77.0% reduction (P = 0.024). The mean blood loss per centimetre resection area was 2.09 ?? 1.41 ml/cm2 in the ILRFA compared with 12.79 ?? 1.68 ml/cm2 in controls, the reduction was 79.0% (P = 0.019). In ILRFAassisted laparoscopic partial nephrectomy, the mean intraoperative blood loss was 32 ?? 15 ml in the ILRFA and 187 ?? 69 ml in the control group, a 77.0% reduction (P = 0.043). The mean blood loss per centimetre resection area was 2.27 ?? 0.95 ml/cm2 in the ILRFA compared with 26.46 ?? 8.81 ml/cm2 in controls, the reduction was 79.0% (P = 0.047). In the renal trauma experiment, ILRFA also achieved promising results in haemostasis. We believe that ILRFA is a useful device which may help in the treatment of patients with liver and kidney illness.

Idiopathic Membranous nephropathy (MN) is a common cause of nephrotic syndrome in humans, and many patients progress to end-stage kidney disease. The best available animal model of MN is active Heymann nephritis (HN) in which rats are immunized with renal tubular antigen (RTA) in complete Freund's adjuvant (CFA). Rats develop heavy proteinuria, a key measure of glomerular damage, and the disease is histologically identical to human MN. It has been thought that HN is mediated by antibody-based mechanisms. More recent evidence demonstrates a critical role for cytotoxic T cells. This thesis aims to further examine the role of T cell responses in active HN. First, the effect of the anti-CD3 monocIonal antibody (mAb) G4.18 was investigated. Anti-CD3 given 4 weeks after immunization prevented the development of proteinuria, delayed anti-RTA antibody responses, and reduced glomerular infiltration of CD8+ T cells and macrophages, but did not affect glomerular deposition of IgG or complement. Increased mRNA expression of the Th2 cytokines IL-4 and IL-5 was detected in draining lymph nodes. These findings suggest that immune deviation to a Th2 response reduces glomerular injury in HN. Second, the role of CD4+ T cells in immune tolerance was examined. Rats were given RTA in incomplete Freund's adjnvant (lFA) to induce tolerance to RTA, and three weeks later were immunized with RTA in CFA. Anti-CD4 mAb therapy at the time of RTA1IFA treatment had no effect on subsequent proteinuria or anti-RTA autibodies. Third, the role of IL-4 in this model of immune tolerance was examined. Anti-IL-4 mAb therapy blocked the induction of tolerance, and led to the development of proteinuria. Finally, the effect of treatment with IL-4 and IL-5 was examined. Treatment with these cytokines separately or together after immunization blocked the development of proteinuria, without a consistent effect on anti-RTA antibodies. These results demonstrate a central role for T cell regulation in HN, and show that immune deviation to a Th2 response is protective against glomerular injury. The findings may have implications in the future for focused therapeutic intervention in human idiopathic MN.

Bibliography: leaves 331-381 / xxiv, 381 leaves : ill ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

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Made available in DSpace on 2014-06-11T19:25:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-14Bitstream added on 2014-06-13T19:53:34Z : No. of bitstreams: 1 almeida_ctp_me_botfm.pdf: 276795 bytes, checksum: fddc3ed509cbae5fda0d241cbe2c809a (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Pacientes com Lesão Renal Aguda (LRA) em Diálise Peritoneal Contínua (DPC) ou Hemodiálise Diária (HD) podem apresentar alterações da função pulmonar relacionadas à hipóxia, retirada de líquidos ou toxinas uremias e, no caso da DPC, ao aumento da pressão intra-abdominal (PIA). Os objetivos deste estudo foram realizar avaliação respiratória de pacientes com LRA dialítica internados em Unidades de Terapia Intensiva (UTI) em Ventilação Mecânica Invasiva (VMI), submetidos à DPC e ou HD e avaliar a PIA nos pacientes em DPC. Foi realizado estudo prospectivo descritivo em que foram avaliadas complacência estática (Cest, expresso em mL/cmH2O), resistência do sistema respiratório (Rsr, expresso em cmH2O/L/s), relação PaO2/FiO2 e FiO2 (expresso em %) em pacientes submetidos a DPC e HD e PIA (expresso em mmHg) naqueles em DPC. Os pacientes do Grupo DPC foram avaliados nos momentos M0 (pré-diálise/cavidade vazia), M1(pós-infusão do dialisato da 1ª sessão de diálise/cavidade cheia), M2, M3 e M4 (após cada sessão de DP/cavidade vazia) e do Grupo HD nos momentos M1, M3 e M5 (pré-diálise) e M2, M4 e M6 (pós-diálise). Análise Estatística: Para comparar as variáveis de Cest, Rsr, PaO2/FiO2, FiO2 e PIA no tempo foi utilizado o modelo Anova de medidas repetidas e comparações múltiplas ajustado por Tukey ou o modelo de medidas repetidas usando uma distribuição assimétrica (Gama) através do procedimento GENMOD pela opção DIFF. Nível de significância de 5%. NO grupo DPC foram avaliados 20 pacientes em 44 sessões. A média de idade foi de 73,2± 11 anos, o APACHE II foi 24,1±4 e o ATN-ISS foi 0,64±23. A Cest diminuiu após a infusão do dialisato (cavidade abdominal cheia) em relação ao Pré- Diálise/cavidade abdominal vazia (M0= 36± 14,7 e M1= 33,85± 13,8 ml/cmH2O; p=ns) e após as trocas do dialisato... / Acute kidney injury (AKI) patients on continuous peritoneal dialysis (CPD) or daily hemodialysis (HD) may show changes in lung function related to hypoxia or removal of uremic toxins and fluids and in those undergoing PD also due to increased intraabdominal pressure (IAP). Objective of this study was to evaluate respiratory mechanic of critical AKI patients undergoing invasive mechanical ventilation (IMV) and treated by CPD or HD and assessment the IAP in patients on CPD. A prospective descriptive study was performed to determine static compliance (Cest expressed in mL/cmH2O), respiratory system resistance (Rsr expressed in cmH2O/L/s), PaO2/FiO2 ratio and Fi2O (expressed in %) in patients undergoing HD and CPD and PIA (expressed in mmHg) in those on CPD. CPD group was evaluated at M0 (pre dialysis/ empty cavity), M1 (post-infusion of the dialysate / filled cavity), M2, M3 and M4 (after each session of DP / empty cavity ) and the HD group at M1, M3 and M5 (pre-dialysis) and M2, M4 and M6 (post-dialysis). Statistical Analysis: To compare the variables Rsr, PaO2/FiO2, FiO2 and PIA was used ANOVA for repeated measures and Tukey adjusted for multiple comparisons or repeated measures model GENMOD procedure for the DIFF option. Significance level of 5%. Twenty patients (44 sessions) were evaluated in CPD group. Age was 73.2 ± 11 years, APACHE II was 24.1 ± 4 and ATN-ISS was 23 ± 0.64. Cest decreased after infusion of the dialysate (abdominal cavity filled) compared to the Pre-Dialysis / empty abdominal cavity (M0 = M1 and 36 ± 14.7 ± 13.8 mL/cmH2O = 33.85, p = ns) and increased progressively after exchanges of dialysate (empty abdominal cavity) (M2 = 38.42 ± 13.4; M3= 40.6± 13.5; and M4 = 53.4 ± 21.9 mL/cmH2O; M4 vs M0: p = 0.0018; M4 vs M1: p = 0.0004; M4 vs M2: p = 0.0017 M4 vs M3: p = 0.04). PIA... (Complete abstract click electronic access below)

Made available in DSpace on 2015-08-20T17:09:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-27. Added 1 bitstream(s) on 2015-08-20T17:26:09Z : No. of bitstreams: 1 000839885.pdf: 1452908 bytes, checksum: c413ca11c7e981d3f7210ad97232d072 (MD5) / Introdução: A mortalidade de pacientes com sepse e lesão renal aguda (LRA) é inaceitavelmente elevada, com necessidade de medidas de prevenção. Faltam estudos brasileiros que mostrem esta incidência em salas de emergências clínicas (SEC) e identifiquem fatores de risco para o seu desenvolvimento, além de marcadores precoces de diagnóstico e prognóstico. Dentre eles, encontra-se o NGAL, que é um biomarcador sérico e urinário (u) promissor de detecção precoce de LRA. Objetivos: Este trabalho teve como objetivo principal avaliar a eficácia do NGALu como preditor diagnóstico e prognóstico da LRA associada à sepse em pacientes admitidos em SEC. Metodologia: Estudo prospectivo de pacientes admitidos na SEC com diagnóstico de sepse durante o período de 01 de fevereiro de 2013 a 31 de maio de 2014. Para cada paciente foi aplicado um protocolo com dados clínicos e laboratoriais. A avaliação da função renal foi realizada por dosagem de creatinina sérica e verificação de débito urinário desde a admissão até o desfecho do quadro (resolução ou óbito). O NGALu foi dosado nas primeiras 24h de admissão (1), entre 24-48h (2) e no momento do diagnóstico de LRA (3). Os resultados foram apresentados por regressão logística e área sob a curva roc para determinar a capacidade do NGALu discriminar o diagnóstico e prognóstico da LRA. Resultados: Foram incluídos 168 pacientes, sendo que 72% tiveram diagnóstico de LRA. Na regressão logística, a idade >65 anos, choque séptico, necessidade de ventilação mecânica (VM) e o NGALu 2 foram identificados como fatores associados à LRA. Quanto à precisão, NGALu 1 e 2, assim como a relação NGAL/Cru 1 e 2 apresentaram área sob a curva ROC para LRA >0,7, com sensibilidade entre 0,63 e 0,75. Os fatores de risco identificados para o óbito foram choque séptico, presença de LRA AKIN 3 e APACHE II > 20. Como preditores de óbito, NGALu 1 e 2 e a relação NGALu/Cru 1 e 2,... / Background: The mortality of septic patients and AKI is inaceptable high, showing the need for preventive measures. There are few Brazilian studies showing the incidence of AKI in clinical emergencies rooms (ER) and identify risk factors for its development, and early markers of diagnosis of AKI and prognosis of patients. NGAL is a serum and urinary (u) promising biomarker for early detection of AKI. Objectives: This study aimed to evaluate the efficacy of uNGAL as a diagnostic and prognostic predictor of AKI associated with sepsis in patients admitted to the ER. Methodology: We prospectively studied patients admitted to the ER diagnosed with sepsis during the period of February 1, 2013 to May 31, 2014. For each patient, a protocol was developed containing clinical and laboratory data from the patients admission to the discharge of the hospital (resolution or death). The assessment of renal function was performed daily by serum creatinine, urine output, and dosage of uNGAL within the first 24 hours after admission (1), between 24-48 h (2) and at moment of AKI diagnosis (3). The results were presented using descriptive statistics of the study population and different statistical tests according to the study objectives. Logistic regression and ROC area under curve was used to determine the ability of uNGAL to discriminate the AKI diagnosis and prognosis of septic patients. Results: One hundred eight patients were included, of which 72% were diagnosed with AKI. In logistic regression, age> 65 years, septic shock, need for mechanical ventilation (MV) and the uNGAL 2 were identified as factors associated with AKI. Regarding the accuracy, uNGAL 1 and 2, as well as uNGAL / uCr 1 and 2 showed an area under the ROC curve for AKI> 0.7, with sensibility between 0.63 and 0.75. The risk factors identified in the logistic regression for death were septic shock, presence of AKI AKIN 3 and APACHE II> 20. As predictors of death, the precision of uNGAL1, ...

Factors Influencing Women's Adaptation to Hemodialysis When Renal Transplantation is not an Option The intent of this study was to explore and describe factors that influence adaptation from the perspective of women on hemodialysis for whom renal transplantation is not an option. Phenomenology was the research design selected for this study in order to understand the experience of these women clients. Data were collected during audio-taped interviews of eight women and were analyzed concurrently with data collection to identify common themes. Two central themes emerged: the adaptation process and the theme of connectedness. The adaptation process was described as a six-phase process. Connectedness was defined as being connected to others and/or sources of life's energy. Several key factors that either facilitated or interfered with adaptation were identified for each of these two themes. Key factors that facilitated adaptation throughout the adaptation process Included a first run on dialysis, experience with adversity, emotional and instrumental support, coping behaviors such as asserting control and reframing the situation, diversions, adequate rest and confidence in health-care professionals. Factors interfering with adaptation to hemodialysis throughout the adaptation process included the gradual and ambiguous nature of renal disease, increasing dependence, reduced energy, transportation to dialysis, compromised somatic health, difficulty with assertiveness, prolonged stressors and lack of confidence in health-care professionals. Specific factors that influenced connectedness were identified. The facilitating factors identified were satisfactory relationships, nurturing others, normalizing, a harmonious atmosphere on the hemodialysis unit and pleasurable activities. Key factors interfering with adaptation related to the connectedness theme were isolation from others, unsympathetic others, ineffective communication with health-care professionals, and exclusion from activities. The findings relative to the adaptation process were discussed in the light of the literature on adapting to illness and stress. Connectedness was discussed primarily in relation to the literature exploring the socialization of women. Implications for nursing practice, education and research arising from these findings were outlined. / Applied Science, Faculty of / Nursing, School of / Graduate