DRC é a condição que descreve alteração irreversível da função renal, desencadeando o desenvolvimento de vários sintomas neurológicos. Dentre as hipóteses estão o estresse oxidativo, a resposta inflamatória e a Klotho envolvidos na patogênese tanto da DRC quanto das lesões relacionadas à Demência Vascular. O objetivo deste trabalho é o de avaliar a ausência e presença de déficit cognitivo (CI) em pacientes com DRC em hemodiálise, bem como em modelo animal de 5/6 de ablação renal (Nx), relacionando a concentração de citocinas e klotho em soro, líquor de rato e homogenato de tecido cerebral e renal de rato. Observamos que os mediadores séricos pró- e antinflamatórios, nos indivíduos DRC e DRC-CI, não apresentaram diferença em relação aos indivíduos do grupo controle. Nos animais Nx, não encontramos correlação entre as alterações séricas de citocinas pró- e antiinflamatórias com CI. Finalmente, observamos redução dos níveis séricos da Klotho nos indivíduos do grupo DRC-CI, assim como nos animais Nx-CI quando comparados com os respectivos grupos Controle e DRC sem CI. / CKD is a condition that describes irreversible alteration of renal function and development of various neurological symptoms. Several hypotheses are described as triggering factors of cognitive impairment (CI) related to CKD, including the linked of oxidative stress, inflammation and Klotho in the pathogenesis of CKD and of injuries related to vascular dementia. The objective of this thesis is to evaluate the presence and absence of CI in patients with CKD on hemodialysis, as well as in a 5/6 renal ablation animal model, linking to citokynes and Klotho levels in plasma, brain and kidney samples and cerebrospinal fluid. Our data showed no differences in serum pro-inflammatory and anti-inflammatory mediators in CKD and CKD-CI groups when compared to the control group as well in the animal model of CKD. Our data also showed a reduction in serum levels of Klotho among individuals with CKD-CI, as well as in animals with CI associated with the animal model of CKD when compared with the respective control groups and CKD without deficit.

Diabetic nephropathy is a common diabetic microvascular disease with a prevalence of about 10% to 42%. Research has shown that neutrophil gelatinase-associated lipocalin (NGAL) levels would increase rapidly in the urine and blood of patients with acute kidney failure. NGAL may represent an early and predictive kidney injury biomarker due to the increase of NGAL occurs earlier than that of molecules (creatinine, cystatin C and £]2-microglobulin) for traditional assessment of renal injury in renal disease samples. To evaluate the association of plasma level of NGAL and £]2-microglobulin with diabetic nephropathy, this study was performed on 21 diabetic patients without nephropathy as the control group and 21 patients with diabetic nephropathy stage 2, 26 patients with stage 3, 9 patients with stage 4 and 16 patients stage 5 as the study group. Collection of blood and measurements of all cases were approved by the ethical committee. The results indicate that the levels of blood urea nitrogen (BUN), creatinine, NGAL, and £]2-microglobulin of study group were significantly higher than control group (P<0.001), while the glomerular filtration rate (GFR) was significantly lower than the control group (P<0.001). Linear regression analysis show that NGAL was positively correlated with white blood cells, BUN, creatinine, £]2-micrglobulin and negatively correlated with GFR; and £]2-micrglobulin was positively correlated with BUN, creatinine, NGAL and negatively correlated with GFR. All results indicate that plasma NGAL levels in diabetic nephropathy were positively correlated with renal function parameters, and closely correlated with kidney injury, suggesting that NGAL may play an important role in the progression of diabetic nephropathy.

Submitted by Marcia Clelia Leite Marcellino (marcia.clelia@terra.com.br) on 2018-06-11T02:33:02Z No. of bitstreams: 1 TESE IMPRESSÃO.pdf: 1297621 bytes, checksum: 72d61d4f45d3f68457e648dba38bd91f (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-06-13T16:42:35Z (GMT) No. of bitstreams: 1 marcellino_mcl_dr_bot.pdf: 1297621 bytes, checksum: 72d61d4f45d3f68457e648dba38bd91f (MD5) / Made available in DSpace on 2018-06-13T16:42:35Z (GMT). No. of bitstreams: 1 marcellino_mcl_dr_bot.pdf: 1297621 bytes, checksum: 72d61d4f45d3f68457e648dba38bd91f (MD5) Previous issue date: 2018-03-29 / A nefropatia diabética é fator de risco para aumento da morbimortalidade em pessoas submetidas à cirurgia. A investigação por tratamentos capazes de exercer proteção renal durante procedimentos anestésico- cirúrgicos tornam-se relevantes. Este estudo avaliou a glicemia, a variação ponderal, a concentração sanguínea de ureia e creatinina, a proteinúria, a microscopia eletrônica dos rins com e sem isquemia e reperfusão, e a proteção renal de ratos Wistar com nefropatia diabética experimental, tratados previamente com a infusão dos frutos da Momordica charantia L.. Utilizamos 26 ratos Wistar, divididos em: Grupo Controle (n=10); Grupo Diabético sem tratamento (n=8) e Grupo Diabético tratados com Momordica charanthia L. (n=8). A determinação da glicemia de ambos os grupos foi feita com glicosimetro e o peso foi mensurado em balança digital no 1º, 15º e 30º dia do experimento. A dosagem da proteinúria foi feita em urina de 24 horas. Previamente a eutanásia, foi realizada a manobra da isquemia por 30 minutos, seguida da reperfusão por 15 minutos, no rim esquerdo, simulando a lesão renal ocorrida em cirurgias. Os rins isquêmicos e não isquêmicos foram encaminhados para microscopia eletrônica. A obtenção do sangue para dosagem de ureia e creatinina foi feita por punção cardíaca. Os resultados obtidos evidenciaram redução significativa da glicemia (p<0,001- Teste Friedman p<0,05) no 15ª dia, nos animais diabéticos tratados com a planta, Não foi evidenciada alterações significativas no peso dos animais. A Momordica charantia L. reduziu significativamente a concentração de creatinina (p=0,022 – Teste T-Student p<0,05) e a proteinúria (p<0,001 – Teste T-Student p<0,05), mas não interferiu na uremia dos animais diabéticos. Na microscopia eletrônica evidenciou-se nos rins isquêmicos e não isquêmicos do grupo diabético tratado, a preservação da membrana basal, podócitos e pedicelos. Estas estruturas foram lesionadas no grupo diabético sem tratamento. Conclui-se que a Momordica charantia L. mostrou-se eficaz na redução da glicemia, no 15º dia de experimentação; reduziu a creatinina e a proteinúria em relação ao grupo diabético sem tratamento e preservou a integridade de estruturas glomerulares, sugerindo renoproteção frente à hiperglicemia persistente e a manobra de isquemia e reperfusão renal. / Diabetic nephropathy is a risk factor for increased morbidity and mortality in people undergoing surgery. The investigation of treatments capable of exerting renal protection during anesthetic-surgical procedures becomes relevant. Diabetic nephropathy is a risk factor for increased morbidity and mortality in people undergoing surgery. The investigation of treatments capable of exerting renal protection during anesthetic-surgical procedures becomes relevant. This study evaluated glycemia, weight variation, blood urea and creatinine concentration, proteinuria, electron microscopy of the kidneys with and without ischemia and reperfusion, and renal protection of Wistar rats with experimental diabetic nephropathy, previously treated with the infusion of the fruits of Momordica charantia L. We used 26 Wistar rats, divided into: Control Group (n = 10); Untreated Diabetic Group (n = 8) and Diabetic Group treated with Momordica charanthia L. (n = 8). The determination of glycemia was done with glycosimetre and the weight was measured in digital scale on the 1st, 15th and 30th day of experimentation. The proteinuria was measured in 24-hour urine. Before euthanasia, the maneuver of the ischemia was performed for 30 minutes, followed by reperfusion for 15 minutes in the left kidney, simulating the renal injury that occurred in surgeries. The ischemic and non-ischemic kidneys were referred for electron microscopy. The blood obtained for urea and creatinine dosing was done by cardiac puncture. The results obtained evidenced a significant reduction of glycemia (p <0.001 Friedman test p <0.05) on the 15th day, in the diabetic animals treated with the plant. No significant changes were observed in the weight of the animals. Momordica charantia L. significantly reduced creatinine concentration (p = 0.022 - Student's T-test p <0.05) and proteinuria (p <0.001 - Student's T-test p <0.05) but did not interfere with uremia of diabetic animals. Electron microscopy revealed preservation of the basement membrane, podocytes and pedicels in the ischemic and non-ischemic kidneys of the treated diabetic group. These structures were injured in the diabetic group without treatment. It was concluded that Momordica charantia L. was effective in the reduction of glycemia, on the 15th day of experimentation; reduced creatinine and proteinuria in relation to the untreated diabetic group and preserved the integrity of glomerular structures, suggesting renoprotection against persistent hyperglycemia and renal ischemia and reperfusion maneuver.

Made available in DSpace on 2014-06-11T19:23:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-23Bitstream added on 2014-06-13T18:19:59Z : No. of bitstreams: 1 brum_am_me_jabo.pdf: 342441 bytes, checksum: 76ea043eafca848acccc425ff6c78e8f (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / A dopamina e um composto endogeno amplamente utilizado em terapia intensiva. Possui um amplo espectro de acoes, tanto sobre o sistema cardiovascular como urinario. Aumento da taxa de filtracao glomerular, do fluxo sanguineo renal e excrecao fracionada de sodio e fosforo sao efeitos renais esperados em individuos normais, porem sao pouco explorados na medicina veterinaria. Com o proposito de testar a hipotese que a dopamina e capaz de aumentar a excrecao fracionada de fosforo em caes nefropatas, este estudo foi conduzido. Diferentes doses de dopamina foram administradas em caes nefropatas. Avaliacoes laboratoriais foram realizadas durante e apos os tratamentos. O clearance de creatinina e a excrecao fracionada de fosforo apresentaram aumento dose-dependente nos caes sadios. Em caes nefropatas, a dose de 1 Êg/kg/min aumentou discretamente a TFG, alem de aumentar o volume urinario e excrecao de fosfato, sem modificar a U-P/C e pressao arterial sistemica, enquanto a dose de 3 Êg/kg/min nao aumentou os beneficios e, ainda, promoveu aumento da excrecao urinaria de proteinas. / Dopamine is a endogenous compound largely used in critical care. It has a large spectrum of actions on cardiovascular and urinary systems. Increases in glomerular filtration rate, renal blood flow and frational excretion of sodium and phosphate are renal effects expected in healthy patient, but there are few reports in veterinary medicine. In order to test the hypothesis that dopamine can increase frational excretion of phosphate in nephropathy dogs this study was conducted. Different dopamine doses were administered in nephropathy dogs. Laboratory evaluations were done during and after treatments. Creatinin clearance and frational excretion of phosphate increases dose-dependent form in healthy dogs. In the nephropathy dogs, the dose of 1ìg/kg/min increased the glomerular filtration rate, urinary volume and phosphate excretion, without modified U-P/C and systemic arterial blood pressure, while the dose of 3ug/kg/min don t increased the benefits and promoted a increase in the urinary excretion of proteins.

DRC é a condição que descreve alteração irreversível da função renal, desencadeando o desenvolvimento de vários sintomas neurológicos. Dentre as hipóteses estão o estresse oxidativo, a resposta inflamatória e a Klotho envolvidos na patogênese tanto da DRC quanto das lesões relacionadas à Demência Vascular. O objetivo deste trabalho é o de avaliar a ausência e presença de déficit cognitivo (CI) em pacientes com DRC em hemodiálise, bem como em modelo animal de 5/6 de ablação renal (Nx), relacionando a concentração de citocinas e klotho em soro, líquor de rato e homogenato de tecido cerebral e renal de rato. Observamos que os mediadores séricos pró- e antinflamatórios, nos indivíduos DRC e DRC-CI, não apresentaram diferença em relação aos indivíduos do grupo controle. Nos animais Nx, não encontramos correlação entre as alterações séricas de citocinas pró- e antiinflamatórias com CI. Finalmente, observamos redução dos níveis séricos da Klotho nos indivíduos do grupo DRC-CI, assim como nos animais Nx-CI quando comparados com os respectivos grupos Controle e DRC sem CI. / CKD is a condition that describes irreversible alteration of renal function and development of various neurological symptoms. Several hypotheses are described as triggering factors of cognitive impairment (CI) related to CKD, including the linked of oxidative stress, inflammation and Klotho in the pathogenesis of CKD and of injuries related to vascular dementia. The objective of this thesis is to evaluate the presence and absence of CI in patients with CKD on hemodialysis, as well as in a 5/6 renal ablation animal model, linking to citokynes and Klotho levels in plasma, brain and kidney samples and cerebrospinal fluid. Our data showed no differences in serum pro-inflammatory and anti-inflammatory mediators in CKD and CKD-CI groups when compared to the control group as well in the animal model of CKD. Our data also showed a reduction in serum levels of Klotho among individuals with CKD-CI, as well as in animals with CI associated with the animal model of CKD when compared with the respective control groups and CKD without deficit.

Lithium is given to millions of bipolar disorder or post-traumatic disorder patients. The recent studies also support a role for lithium in treating neurodegenerative disease such as Parkinson's disease and stroke. Lithium treatment leads to lithium nephropathy, which includes lithium-induced nephrogenic diabetic insipidus (NDI), lithium-induced renal cell proliferation leading to the formation of microcysts in the kidney, and lithium-induced renal fibrosis. However, there is still a gap in understanding the mechanisms and signaling pathways involved in regulating lithium-induced nephropathy. mTOR pathway activation and primary cilia are known to be associated with the abnormal renal cell proliferation and the formation of renal cysts in polycystic kidney disease, a renal disease model similar to our lithium model. The activation of hedgehog pathway is associated with the renal fibrosis observed in the unilateral ureteral obstruction and unilateral ischemia reperfusion injury models of chronic renal injury. Thus, I hypothesize that mTOR signaling pathway, primary cilia and hedgehog pathway may all contribute to lithium-induced nephropathy. To address the hypothesis that the mTOR signaling pathway may be responsible for lithium-induced renal collecting duct proliferation, mTOR pathway activation was assessed in lithium-treated mice and lithium-treated mouse inner medullary collecting duct (mIMCD3) cells. Lithium activated mTOR signaling pathway in renal collecting duct cells both in vivo and in vitro. Rapamycin, an inhibitor of mTOR, blocked lithium-induced renal cell proliferation in renal cortex and medulla in vivo and in renal collecting duct cells in vitro, supporting the hypothesis. However, rapamycin did not improve lithium-induced reduction of urine osmolality, suggesting mTOR signaling pathway may not contribute to lithium-induced NDI. To address the hypothesis that primary cilia may be necessary for lithium-induced mTOR activation and renal cell proliferation, primary cilia deficient cells were used to assess mTOR pathway activation and cell proliferation in response to lithium treatment. The absence of primary cilia abolished lithium-induced activation of mTOR pathway and cell proliferation, which supports the hypothesis. To address the hypothesis that lithium elongates primary cilia length, which is mediated by mTOR signaling pathway, primary cilia length alternation was assessed in the kidney and in mIMCD3 cells in response to lithium treatment. Lithium increased primary cilia length in renal collecting duct cells of cortex, outer medulla, and inner medulla kidney regions in vivo and in mIMCD3 cells in vitro. Rapamycin reversed lithium-induced elongation of primary cilia in renal cortical and outer medullary collecting duct cells in vivo, and blocked the increase of primary cilia length in mIMCD3 cells in vitro, which support the hypothesis. To address the hypothesis that lithium activates the hedgehog pathway in a Smoothened (smo, a key regulator of the hedgehog pathway)-dependent manner in renal collecting duct cells, mIMCD3 cells were treated with lithium or lithium/Smo inhibitor or lithium/Smo activator. Hedgehog signaling pathway is activated by lithium in mIMCD3 cells, which is partially Smo-dependent. However, the role of hedgehog signaling pathway in regulating lithium-induced fibrosis was not assessed in the study. Future studies are required to determine the role of the hedgehog pathway in the lithium model.

Objective: The aim of this study was to determine the prevalence of micro- or macroalbuminuria among type 1 and type 2 diabetic patients and to examine the relationship with diabetes control parameters: haemoglobin A1C (HbA1C), blood pressure (BP) and lipids. Design: Analytical cross-sectional study. Setting and subjects: The study consisted of 754 patients with either type 1 or type 2 diabetes mellitus, attending a diabetic clinic at the Kalafong Hospital in Pretoria, South Africa. Outcome measures: Micro- or macroalbuminuria and estimated glomerular filtration rate (eGFR). Results: Of all patients, 88.9% had HbA1C > 7%, and 81% had low-density lipoprotein (LDL) cholesterol ≥1.8 mmol/l. Overall prevalence of micro- or macroalbuminuria was 33.6%. Logistic regression revealed that HbA1C, duration of diabetes, systolic BP, male sex and triglycerides predicted microalbuminuria. Conclusion: The prevalence of micro- or macroalbuminuria in this study falls within the ranges of what has been previously reported in Africa. In all patients, HbA1C and duration of diabetes were the strongest predictors of microalbuminuria, and age was the strongest predictor of a low eGFR. Diabetes was poorly controlled, making the progression to end-stage renal failure a real concern in these patients. / Dissertation (MPH)--University of Pretoria, 2015. / tm2015 / School of Health Systems and Public Health (SHSPH) / MPH / Unrestricted

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21833号 / 農博第2346号 / 新制||農||1068(附属図書館) / 学位論文||H31||N5205(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 澤山 茂樹, 教授 佐藤 健司 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

IgA nephropathy is the world's most common primary glomerulonephropathy. Recent evidence in a rat model implicated excessive production of oxygen-free radicals in the pathogenesis and suggested that vitamin E-treatment ameliorated progression. We studied this antioxidant therapy on the glomerular filtration rate (GFR), proteinuria and hematuria in biopsy-proven IgA nephropathy in children. The duration of treatment or placebo was 2 years, with vitamin E treatment consisting of 400 IU/day in children weighing <30 kg, and twice that dose for those >30 kg. We measured GFR at entry, midpoint and exit. At baseline and at 4-month intervals after randomization, urinary protein/creatinine ratios and urinalysis were examined. The mixed model procedure with log transformation was used in data analysis to test treatment difference as well as the potential time effect. Fifty-five patients were randomized and 38 completed at least 1 year of follow-up. At entry, the clinical characteristics were not different between the treatment and placebo groups. There was a trend toward better preservation of GFR in vitamin E-treated versus placebo patients, 127±50 vs. 112±31 ml/min/1.73 m2, respectively (P=0.09). The urinary protein/creatinine ratio was significantly lower in the vitamin E-treated group vs. placebo; 0.24±0.38 vs. 0.61±1.37 (P<0.013). However, there was no difference in the prevalence of hematuria between the groups. Vitamin E treatment in our study patients was associated with significantly lower proteinuria, but no effect on hematuria. While there was a trend toward stabilization of GFR in the vitamin E-treated patients, longterm treatment and follow-up are needed to determine whether antioxidant therapy is associated with preservation of renal function in IgA nephropathy.

INTRODUCTION Apixaban has revolutionized anticoagulation in patients with atrial fibrillation in preventing strokes. Anticoagulant-induced nephropathy with warfarin is well known, but nephropathy with apixaban is a rare entity, and here we present a case of Apixaban-induced nephropathy. Case Description A 71-year-old patient with a medical history of persistent atrial fibrillation on apixaban, Ischemic cardiomyopathy, and chronic kidney disease stage (CKD) IIIa presented to the hospital with complaints of dyspnea and hemoptysis and tea-colored urine of three-day duration. On admission, the patient had acute kidney injury (AKI) on CKD, Methicillin sensitive Staphylococcus aureus (MSSA) bacteremia, and elevated international normalized ratio (INR) and apixaban were held. The hemoptysis worsened and prompted bronchoscopy revealing diffuse alveolar hemorrhage. The urinalysis showed gross hematuria with high red blood cell (RBC) count and 1+ proteinuria presumed secondary to MSSA associated glomerulonephritis. Evaluation for coagulopathy with serum mixing studies and autoimmune workup has been unremarkable. The patient's coagulopathy was considered secondary to decreased clearance of apixaban with AKI on CKD. However, the patient's kidney function continued to worsen, needing continuous renal replacement therapy and a kidney biopsy for a definitive diagnosis for his decline in kidney function. Kidney biopsy revealed IgA dominant infection associated glomerulitis with one out of hundred glomeruli with the crescent formation and signs of anticoagulant induced nephropathy with several intratubular RBC casts out of proportion to the degree of glomerular injury causing acute tubular damage. The patient's INR improved on dialysis. However, he continued to be oliguric before being terminally extubated. DISCUSSION With the increasing incidence of atrial fibrillation and the use of oral anticoagulants, it is vital to have anticoagulant induced as a differential in patients presenting with supra therapeutic INR and AKI. Apixaban-induced nephropathy is a subset of anticoagulant-induced nephropathy and an uncommon cause of the acute decline in kidney function needing dialysis. Prompt recognition and treatment will prevent further deterioration in kidney function and possible improvement.