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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- Vitamin D Deficiency Aggravates Chronic Kidney Disease Progression after Ischemic Acute Kidney Injury(2014) GONCALVES, Janaina Garcia; BRAGANCA, Ana Carolina de; CANALE, Daniele; SHIMIZU, Maria Heloisa Massola; SANCHES, Talita Rojas; MOYSES, Rosa Maria Affonso; ANDRADE, Lucia; SEGURO, Antonio Carlos; VOLPINI, Rildo AparecidoBackground: Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-beta 1 (TGF-beta 1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). Methods: Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-beta, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and alpha-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. Results: IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and alpha-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-beta 1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion: Through inflammatory pathways and involvement of TGF-beta 1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.
- Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial(2019) SILVEIRA, Marcelo Augusto Duarte; TELES, Flavio; BERRETTA, Andressa A.; SANCHES, Talita R.; RODRIGUES, Camila Eleuterio; SEGURO, Antonio Carlos; ANDRADE, LuciaBackgroundChronic kidney disease (CKD) is a public health problem worldwide, and proteinuria is a well-established marker of disease progression in CKD patients. Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory, immunomodulatory, and anti-oxidant properties, as well as having been shown to have an antiproteinuric effect in experimental CKD. The aim of this study was to evaluate the impact of Brazilian green propolis extract on proteinuria reduction and the changes in the estimated glomerular filtration rate (eGFR).MethodsThis was a randomized, double-blind, placebo-controlled study including patients with CKD caused by diabetes or of another etiology, 18-90years of age, with an eGFR of 25-70ml/min per 1.73m(2) and proteinuria (urinary protein excretion >300mg/day) or micro- or macro-albuminuria (urinary albumin-to-creatinine ratio>30mg/g or>300mg/g, respectively). We screened 148 patients and selected 32, randomly assigning them to receive 12months of Brazilian green propolis extract at a dose of 500mg/day (n=18) or 12months of a placebo (n=14).ResultsAt the end of treatment, proteinuria was significantly lower in the propolis group than in the placebo group695mg/24h (95% CI, 483 to 999) vs. 1403mg/24h (95% CI, 1031 to 1909); P=0.004independent of variations in eGFR and blood pressure, which did not differ between the groups during follow-up. Urinary monocyte chemoattractant protein-1 was also significantly lower in the propolis group than in the placebo group58pg/mg creatinine (95% CI, 36 to 95) vs. 98pg/mg creatinine (95% CI, 62 to 155); P=0.038.ConclusionsBrazilian green propolis extract was found to be safe and well tolerated, as well as to reduce proteinuria significantly in patients with diabetic and non-diabetic CKD.Trial Registration.(ClinicalTrials.gov number NCT02766036. Registered: May 9, 2016).
- N-Acetylcysteine Protects Rats with Chronic Renal Failure from Gadolinium-Chelate Nephrotoxicity(2012) PEREIRA, Leonardo Victor Barbosa; SHIMIZU, Maria Heloisa Massola; RODRIGUES, Lina Paola Miranda Ruiz; LEITE, Claudia Costa; ANDRADE, Lucia; SEGURO, Antonio CarlosThe aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic - cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd-chelate administration: 1 - Nx (n = 7); 2 - Nx+NAC (n = 6); 3 - Nx+Gd (n = 7); 4 - Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (mu g/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (mu g/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.
- High Cholesterol Feeding May Induce Tubular Dysfunction Resulting in Hypomagnesemia(2012) FAVARO, Vanessa F.; OSHIRO-MONREAL, Fabiola M.; BRAGANCA, Ana Carolina de; ANDRADE, Lucia; SEGURO, Antonio Carlos; HELOU, Claudia M. B.Background/Aims: Hypomagnesemia may induce hypercholesterolemia, but the contrary has not been described yet. Thus, magnesium homeostasis was evaluated in rats fed a cholesterol-enriched diet for 8 days. This study has a relevant clinical application if hypomagnesemia, due to hypercholesterolemia, is confirmed in patients with long-term hypercholesterolemia. Methods: Both hypercholesterolemic (HC) and normocholesterolemic rats (NC) were divided into sets of experiments to measure hemodynamic parameters, physiological data, maximum capacity to dilute urine (C-H2O), variations (Delta) in [Ca2+](i) and the expression of transporter proteins. Results: HC developed hypomagnesemia and showed high magnesuria in the absence of hemodynamic abnormalities. However, the urinary sodium excretion and C-H2O in HC was similar to NC. On the other hand, the responses to angiotensin II by measuring Delta [Ca2+](i) were higher in the thick ascending limb of Henle's loop (TAL) of HC than NC. Moreover, high expression of the cotransporter NKCC2 was found in renal outer medulla fractions of HC. Taken together, the hypothesis of impairment in TAL was excluded. Actually, the expression of the epithelial Mg2+ channel in renal cortical membrane fractions was reduced in HC. Conclusion: Impairment in distal convoluted tubule induced by hypercholesterolemia explains high magnesuria and hypomagnesemia observed in HC.
conferenceObject VITAMIN D DEFICIENCY AGGRAVATES TENOFOVIR INDUCED METABOLIC SYNDROME AND RENAL FAILURE(2013) CANALE, Daniele; BRAGANCA, Ana Carolina de; GONCALVES, Janana; SHIMIZU, Maria Helosa M.; VOLPINI, Rildo A.; ANDRADE, Lucia; SEGURO, Antonio CarlosIntroduction and Aims:Vitamin D deficiency (VDD) is highly prevalent among HIV-infected individuals. Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, has been associated with comorbidities, some of which have been attributed to renal toxicity and metabolic syndrome. The aim of the study was to investigate the effect of VDD on TDF treated rats. Methods:Wistar rats were randomly divided into four groups: control (C, n = 9), receiving a standard diet for 60 days; VDD (n = 6), receiving a free-vitamin D diet for 60 days; TDF (n = 9), receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+TDF (n = 7) received a free-vitamin D diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days. We measured inulin clearance (GFR, mL/min/100g); blood pressure (BP, mmHg), renal blood flow and calculated renal vascular resistance (RVR, mmHg/mL/min); serum levels of 25-hydroxyvitamin D (25(OH)D, ng/mL), cholesterol (mg/dL) and triglycerides (mg/dL); urinary sodium excretion (UVNa,mEq/24h). In renal tissue, we immunoblotted for angiotensin II (AII), endothelial nitric oxide synthase (eNOS) and vitamin D receptor (VDR). Data are expressed as mean ± SEM. Results:Vitamin D levels were similar in C (15.4±1 ng/mL) and TDF (14.8±1.3 ng/mL) groups and <1.5 ng/mL in VDD groups. Body weight, water intake and food ingestion were not different among the 4 groups. Treatment with TDF led to impaired renal function, hypertension, higher RVR and dyslipidemia. Administration of TDF also increased protein expression of AII and VDR. Association of TDF and VDD exacerbates TDF nephrotoxicity, as well as metabolic syndrome. Furthermore, VDD+TDF group showed urinary sodium retention. The increased VDR protein expression in TDF groups may represent a compensatory effect to decrease renal injury. Conclusions:VDD aggravates renovascular effects and TDF-induced renal failure at least in part due to the involvement of renin-angiotensin-aldosterone system. Therefore, the assessment of vitamin D is important in HIV patients receiving TDF.- 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.
- Chronic Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis (SIAD) in an Adult Woman with Corpus Callosum Agenesis (CCA)(2018) SILVEIRA, Marcelo Augusto Duarte; SEGURO, Antonio Carlos; SILVA, Jukelson Barbosa da; OLIVEIRA, Marcia Fernanda Arantes de; SEABRA, Victor Faria; REICHERT, Bernardo Vergara; RODRIGUES, Camila Eleuterio; ANDRADE, LuciaObjective: Rare co-existance of disease or pathology Background: Corpus callosum agenesis (CCA) is one of the most common congenital brain abnormalities, and is associated with neurodevelopmental and neuropsychiatric disorders. In CCA, defects in osmoregulation have been reported. This report presents a rare case of chronic hyponatremia associated with the syndrome of inappropriate antidiuresis (SIAD) in a woman with CCA. Case Report: A 41-year-old woman presented to the renal unit with symptomatic hyponatremia. In her past medical history, she had a four-year history of systemic arterial hypertension and Sjogren's syndrome, and a three-year history of systemic lupus erythematosus (SLE), which was treated with cyclophosphamide. She had CCA but with irregular neurological follow-up. During the previous eight years, her plasma sodium levels ranged from between 118-134 mEq/L. On this hospital admission, she had plasma hypo-osmolality, measured in milli-osmoles per kilogram of H2O (mOsm/kg H2O), of 251 mOsm/Kg H2O, and a urinary hyper-osmolality of 545 mOsm/Kg H2O, and increased level of plasma antidiuretic hormone (ADH) (1.8 pg/ml). Bone densitometry was consistent with osteoporosis. The patient remained asymptomatic during her hospital stay. Chronic hyponatremia associated with the SIAD was diagnosed. Water restriction and increased protein intake resulted in a partial improvement in the serum sodium level (128-134 mEq/L). The patient was discharged from the hospital with outpatient follow-up. Conclusions: A rare case of chronic hyponatremia due to the SIAD associated with CCA is reported that demonstrates the importance of correct diagnosis, management, and clinical follow-up of the SIAD, including bone densitometry.
conferenceObject NATURAL TRIGGERING OF P21 PROTEIN UPREGULATION IS INHIBITED IN VITAMIN D-DEPLETED RATS WITH ISCHEMIC ACUTE KIDNEY INJURY(2012) BRAGANCA, Ana Carolina De; CANALE, Daniele; GONCALVES, Janaina Garcia; BRANDAO, Thais Prevital Bastos; SHIMIZU, Maria Heloisa Massola; VOLPINI, Rildo Aparecido; SEGURO, Antonio Carlos; ANDRADE, LuciaIntroduction and Aims: Renal ischemia/reperfusion injury (IRI), a common cause of acute kidney injury (AKI), activates pathways of cell proliferation and cell death. AKI induces normally quiescent renal cells to enter the cell cycle and triggers the induction of cell cycle inhibitors, including the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1), which is protective against AKI. In mice lacking the p21 gene, AKI is more severe and the resulting renal cell death is more widespread. The potent immunomodulatory and antiproliferative properties of 25-hydroxyvitamin D [25 (OH)D] suggest that it plays a role in the pathophysiology of renal and cardiovascular disease. By altering the levels of several key cell cycle regulators and arresting cells in G0/G1, 25(OH)D can control renal inflammation. It is known that p21, which also arrests cells in G1, is a genomic target of 25(OH)D in many cell types. Prior vitamin D deficiency (VDD) is a major predictor of mortality in critically ill patients. Here, we evaluated the effect of VDD in IRI-induced AKI, hypothesizing that VDD decreases p21 expression and would thus be harmful in AKI. Methods: Wistar rats were fed 25(OH)D-depleted or normal diets for 30 days. On day 28, some rats were induced to IRI by 45-min clamping of both renal arteries. We studied four groups: C (control, n = 7); VDD (n = 5); IRI (n = 7); and VDD+IRI (n = 8). At 48 h after IRI, we measured inulin clearance (CIn); proteinuria; serum levels of 25(OH)D, Ca, and P; urinary volume and osmolality; and fractional excretion of phosphate (FEP). Immunoblotting for p21 and aquaporin 2 (AQP2) was performed in kidney tissue. Data are expressed as mean ± SEM. Results: VDD, IRI and VDD+IRI rats showed higher urine output, higher water intake and lower urinary osmolality. Renal function was impaired in IRI rats. AKI was more severe in VDD+IRI rats, as evidenced by proteinuria and lower CIn. p21 expression was higher in IRI rats than in control rats (134 ± 13.7 vs. 100 ± 1.0%; P < 0.05); in IRI rats than in VDD+IRI and VDD rats (134 ± 13.7 vs. 85.5 ± 1.9 and 64.4 ± 1.7%; P < 0.01); and in control rats than in VDD rats (100 ± 1.0 vs. 64.4 ± 1.7%; P < 0.05). In VDD rats, markedly increased urine output and decreased urinary osmolality were accompanied by decreased AQP2 expression (26.2 ± 0.6; P < 0.001 vs. controls), which was also lower in VDD+IRI rats than in IRI rats (25.2 ± 0.8 vs. 49 ± 1.0; P < 0.001). Conclusions: In otherwise healthy individuals with VDD, renal expression of p21 is downregulated more than usual. This appears to prevent the natural triggering of p21 upregulation in AKI, thereby increasing its severity. VDD might also cause tubular dysfunction (urinary concentrating defect). Further studies are needed in order to determine whether the correction of VDD provides clinical benefits in AKI.- Vitamin D Deficiency Aggravates Nephrotoxicity, Hypertension and Dyslipidemia Caused by Tenofovir: Role of Oxidative Stress and Renin-Angiotensin System(2014) CANALE, Daniele; BRAGANCA, Ana Carolina de; GONCALVES, Janaina Garcia; SHIMIZU, Maria Heloisa Massola; SANCHES, Talita Rojas; ANDRADE, Lucia; VOLPINI, Rildo Aparecido; SEGURO, Antonio CarlosVitamin D deficiency (VDD) is prevalent among HIV-infected individuals. Vitamin D has been associated with renal and cardiovascular diseases because of its effects on oxidative stress, lipid metabolism and renin-angiotensin-aldosterone system (RAAS). Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, can induce renal injury. The aim of this study was to investigate the effects of VDD on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; VDD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+ TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of angiotensin II and AT1 receptor. TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and VDD aggravated renovascular effects and TDF-induced nephrotoxicity due to changes in the redox state and involvement of RAAS.
- 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.