LUCIA DA CONCEICAO ANDRADE
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/12 - Laboratório de Pesquisa Básica em Doenças Renais, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/12 - Laboratório de Pesquisa Básica em Doenças Renais, Hospital das Clínicas, Faculdade de Medicina - Líder
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- A first report of leptospirosis after liver transplantation(2016) SONG, A. T. W.; ABAS, L.; ANDRADE, L. C.; ANDRAUS, W.; D'ALBUQUERQUE, L. A. C.; ABDALA, E.Leptospirosis has been rarely reported in solid organ transplant recipients. We report the first case to our knowledge of leptospirosis in a liver transplant recipient who developed jaundice and renal insufficiency. We describe his favorable clinical progression and discuss the possible mechanisms involved in the more benign disease course. We also review the previously published cases of leptospirosis in solid organ transplant recipients. Although this disease does not appear to present any particularities in this context, we highlight the importance of clinical suspicion in this setting, particularly after liver transplantation.
- Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury(2016) BRAGANCA, Ana C. de; VOLPINI, Rildo A.; MEHROTRA, Purvi; ANDRADE, Lucia; BASILE, David P.Reductions in renal microvasculature density and increased lymphocyte activity may play critical roles in the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) induced by ischemia/reperfusion injury (IRI). Vitamin D deficiency is associated with tubulointerstitial damage and fibrosis progression following IRI-AKI. We evaluated the effect of vitamin D deficiency in sustained IRI-AKI, hypothesizing that such deficiency contributes to the early reduction in renal capillary density or alters the lymphocyte response to IRI. Wistar rats were fed vitamin D-free or standard diets for 35days. On day 28, rats were randomized into four groups: control, vitamin D deficient (VDD), bilateral IRI, and VDD+IRI. Indices of renal injury and recovery were evaluated for up to 7days following the surgical procedures. VDD rats showed reduced capillary density (by cablin staining), even in the absence of renal I/R. In comparison with VDD and IRI rats, VDD+IRI rats manifested a significant exacerbation of capillary rarefaction as well as higher urinary volume, kidney weight/body weight ratio, tissue injury scores, fibroblast-specific protein-1, and alpha-smooth muscle actin. VDD+IRI rats also had higher numbers of infiltrating activated CD4(+) and CD8(+) cells staining for interferon gamma and interleukin-17, with a significant elevation in the Th17/T-regulatory cell ratio. These data suggest that vitamin D deficiency impairs renal repair responses to I/R injury, exacerbates changes in renal capillary density, as well as promoting fibrosis and inflammation, which may contribute to the transition from AKI to CKD.
- Effects of Continuous Erythropoietin Receptor Activator in Sepsis-Induced Acute Kidney Injury and Multi-Organ Dysfunction(2012) RODRIGUES, Camila E.; SANCHES, Talita R.; VOLPINI, Rildo A.; SHIMIZU, Maria H. M.; KURIKI, Patricia S.; CAMARA, Niels O. S.; SEGURO, Antonio C.; ANDRADE, LuciaBackground: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. Methods: Rats were randomized into three groups: control; CLP; and CLP+CERA (5 mu g/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting-to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-kappa B)-and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1 beta, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Results: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-kappa B was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. Conclusion: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.
- N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation(2012) CAMPOS, Renata; SHIMIZU, Maria Heloisa Massola; VOLPINI, Rildo Aparecido; BRAGANCA, Ana Carolina de; ANDRADE, Lucia; LOPES, Fernanda Degobbi Tenorio Quirino dos Santos; OLIVO, Clarice; CANALE, Daniele; SEGURO, Antonio CarlosCampos R, Shimizu MH, Volpini RA, de Bragan a AC, Andrade L, Lopes FD, Olivo C, Canale D, Seguro AC. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 302: L640-L650, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00097.2011.-Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the alpha-subunit of the epithelial sodium channel (alpha-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, alpha-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.
- Klotho deficiency aggravates sepsis-related multiple organ dysfunction(2019) JORGE, Lecticia B.; COELHO, Fernanda O.; SANCHES, Talita R.; MALHEIROS, Denise M. A. C.; SOUZA, Leandro Ezaquiel de; SANTOS, Fernando dos; LIMA, Larissa de Sa; SCAVONE, Cristoforo; IRIGOYEN, Maria; KURO-O, Makoto; ANDRADE, LuciaSepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti-senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho-haploinsufficient mice and their wild-type littermates (CLP-Kl/+ and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP-Kl/+ mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-KB activation. It is noteworthy that CLP-Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprussidc, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction. Klotho might play a protective role in sepsis, especially in elderly individuals in whom Klotho expression is naturally reduced.
- PATHOPHYSIOLOGY OF LEPTOSPIROSIS(2013) SEGURO, Antonio Carlos; ANDRADE, LuciaLeptospirosis is an acute septicemic illness that affects humans in all parts of the world. Approximately 10% of patients with leptospirosis develop severe disease, the Weil syndrome, with jaundice, acute kidney injury (AKI), and pulmonary hemorrhage. Leptospirosis-induced AKI is typically nonoliguric with a high frequency of hypokalemia. Experimental and clinical studies demonstrated that tubular function alterations precede a drop in the glomerular filtration rate and are mainly in the proximal tubule. Studies in humans and animals have demonstrated a decrease in the expression of proximal sodium (NHE3) and water tubular transporter, aquaporin 1 (AQP1) together with higher renal expression of the Na-K-2Cl cotransporter NKCC2. In an experimental model, at the initial phase of the disease, the expression of AQP2, the water transport of the collecting duct, is decreased, which explains the higher incidence of nonoliguric AKI. During the recovery phase of AKI, AQP2 expression increased in human and animals as a compensatory mechanism. Alveolar hemorrhage, pulmonary edema, acute respiratory distress syndrome, or a combination of these features may accompany AKI and is associated with high mortality. Studies with hamsters demonstrated that in leptospirosis a noncardiogenic pulmonary edema occurs consequently to a decrease in the clearance of alveolar fluid, due to a decrease in sodium transporter in the luminal membrane (ENaC) and an increase in the NKCC1 basolateral membrane transporter. Antibiotic treatment is efficient in the early and late/severe phases and revert all kidney transporters. Early and daily hemodialysis, low daily net fluid intake, and lung-protective strategies are recommended for critically ill patients with leptospirosis.
- Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-kappa B and upregulating endothelial nitric oxide synthase(2012) SOUZA, Ana Carolina C. Pessoa de; VOLPINI, Rildo A.; SHIMIZU, Maria Heloisa; SANCHES, Talita Rojas; CAMARA, Niels Olsen Saraiva; SEMEDO, Patricia; RODRIGUES, Camila Eleuterio; SEGURO, Antonio Carlos; ANDRADE, Luciade Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-kappa B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012; doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-kappa B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP + EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLP + EPO + L-NAME). A fifth group (CLP + EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP + EPO rats presented significantly higher inulin clearance than did CLP and CLP + EPO + L-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP + EPO rats; and inulin clearance was significantly higher in CLP + EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP + EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-alpha activation, NF-kappa B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-kappa B downregulation.
- Hemodiafiltration Decreases Serum Levels of Inflammatory Mediators in Severe Leptospirosis: A Prospective Study(2016) CLETO, Sergio Aparecido; RODRIGUES, Camila Eleuterio; MALAQUE, Ceila Maria; SZTAJNBOK, Jaques; SEGURO, Antonio Carlos; ANDRADE, LuciaBackground Leptospirosis is a health problem worldwide. Its most severe form is a classic model of sepsis, provoking acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), with associated mortality that remains unacceptably high. We previously demonstrated that early initiation of sustained low-efficiency dialysis (SLED) followed by daily SLED significantly decreases mortality. However, the mode of clearance can also affect dialysis patient outcomes. Therefore, the objective of this study was to compare the effects of SLED with traditional (diffusive) clearance, via hemodialysis, and SLED with convective clearance, via hemodiafiltration (SLEDf), in patients with severe leptospirosis. Methods In this prospective study, conducted in the intensive care unit (ICU) from 2009 through 2012, we compared two groups-SLED (n = 19) and SLEDf (n = 20)-evaluating demographic, clinical, and biochemical parameters, as well as serum levels of interleukins, up to the third day after admission. All patients received dialysis early and daily thereafter. Results During the study period, 138 patients were admitted to our ICU with a diagnosis of leptospirosis; 39 (36 males/3 females) met the criteria for ARDS and AKI. All patients were on mechanical ventilation and were comparable in terms of respiratory parameters. Mortality did not differ between the SLEDf and SLED groups. However, post-admission decreases in the serum levels of interleukin (IL)-17, IL-7, and monocyte chemoattractant protein-1 were significantly greater in the SLEDf group. Direct bilirubin and the arterial oxygen tension/fraction of inspired oxygen ratio were significantly higher in the SLED group. We identified the following risk factors (sensitivities/specificities) for mortality in severe leptospirosis: age >= 55 years (67%/91%); serum urea >= 204 mg/dl (100%/70%); creatinine >= 5.2 mg/dl (100%/58%); Acute Physiology and Chronic Health Evaluation II score >= 39.5 (67%/88%); Sequential Organ Failure Assessment score >= 20.5 (67%/85%); and inspiratory pressure >= 31 mmHg (84%/85%). Conclusions The mode of dialysis clearance might not affect outcomes in severe leptospirosis.
- Acute kidney injury in a mouse model of meningococcal disease(2021) KOLBE, Karin R.; SANCHES, Talita R.; FANELLI, Camilla; GARNICA, Margoth R.; CASTRO, Leticia Urbano de; GOOCH, Karen; THOMAS, Stephen; TAYLOR, Stephen; GORRINGE, Andrew; NORONHA, Irene de L.; ANDRADE, LuciaIntroduction Meningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease. Methods Female BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice. Results In the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte-macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm-Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect. Conclusion Our findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.