LUCIENE MACHADO DOS REIS
Projetos de Pesquisa
Unidades Organizacionais
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
23 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 23
- Disturbances of Wnt/beta-catenin pathway and energy metabolism in early CKD: effect of phosphate binders(2013) OLIVEIRA, Rodrigo B. de; GRACIOLLI, Fabiana G.; REIS, Luciene M. dos; CANCELA, Ana L. E.; CUPPARI, Lilian; CANZIANI, Maria E.; CARVALHO, Aluizio B.; JORGETTI, Vanda; MOYSES, Rosa M. A.Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bonekidneyenergy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway. In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 34 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations. Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels. Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.
- The unexpected presence of iron in bone biopsies of hemodialysis patients(2018) CUSTODIO, Melani R.; ELIAS, Rosilene M.; VELASQUEZ, Wagner D.; REIS, Luciene M. dos; OLIVEIRA, Ivone B.; MOYSES, Rosa M. A.; CARVALHO, Aluizio B.; JORGETTI, VandaPurpose Bone biopsy defines classical diseases that constitute the renal osteodystrophy. There is a recent concern regarding other histological findings that are not appreciated by using the turnover, mineralization, and volume (TMV) classification. Iron (Fe) overload has been considered a new challenge and the real significance of the presence of this metal in bones is not completely elucidated. Therefore, the main goal of the current study was to not only to identify bone Fe, but also correlate its presence with demographic, and biochemical characteristics. Methods This is a cross-sectional analysis of bone biopsies performed in 604 patients on dialysis from 2010 to 2014 in a tertiary academic Hospital. Results Histomorphometric findings revealed the presence of Fe in 29.1%. Fe was associated with higher levels of serum ferritin and serum calcium. No TMV status was related to Fe bone overload. Conclusion Our study has highlighted that the presence of Fe in one-third of bone samples has unknown clinical significance. The lack of other contemporary bone biopsy study reporting Fe prevents us from comparison. The findings presented here should be specifically addressed in a future research and will require attention prior to implementation of any clinical guideline. If any proposed treatment, however, would change the bone Fe-related morbidity is undetermined.
- Parathyroid hormone and phosphorus overload in uremia: impact on cardiovascular system(2012) CUSTODIO, Melani R.; KOIKE, Marcia K.; NEVES, Katia R.; REIS, Luciene M. dos; GRACIOLLI, Fabiana G.; NEVES, Carolina L.; BATISTA, Daniella G.; MAGALHAES, Andrea O.; HAWLITSCHEK, Philippe; OLIVEIRA, Ivone B.; DOMINGUEZ, Wagner V.; MOYSES, Rosa M. A.; JORGETTI, VandaBackground. Cardiac remodeling in uremia is characterized by left ventricular hypertrophy, interstitial fibrosis and microvascular disease. Cardiovascular disease is the leading cause of death in uremic patients, but coronary events alone are not the prevalent cause, sudden death and heart failure are. We studied the cardiac remodeling in experimental uremia, evaluating the isolated effect of parathyroid hormone (PTH) and phosphorus. Methods. Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx); they also received vehicle (V) and PTH at normal (nPTH) or high (hPTH) doses. They were fed with a poor-phosphorus (pP) or rich-phosphorus (rP) diet and were divided into the following groups: 'Sham': G1 (V + normal-phosphorus diet (np)) and 'Nx + PTx': G2 (nPTH + pP), G3 (nPTH + rP), G4 (hPTH + pP) and G5 (hPTH + rP). After 8 weeks, biochemical analysis, myocardium morphometry and arteriolar morphological analysis were performed. In addition, using immunohistochemical analysis, we evaluated angiotensin II, alpha-actin, transforming growth factor-beta (TGF-beta) and nitrotyrosine, as well as fibroblast growth factor-23 (FGF-23), fibroblast growth factor receptor-1 (FGFR-1) and runt-related transcription factor-2 (Runx-2) expression. Results. Nx animals presented higher serum creatinine levels as well as arterial hypertension. Higher PTH levels were associated with myocardial hypertrophy and fibrosis as well as a higher coronary lesion score. High PTH animals also presented a higher myocardial expression of TGF-beta, angiotensin II, FGF-23 and nitrotyrosine and a lower expression of alpha-actin. Phosphorus overload was associated with higher serum FGF-23 levels and Runx-2, as well as myocardial hypertrophy. FGFR-1 was positive in the cardiomyocytes of all groups as well as in calcified coronaries of G4 and G5 whereas Runx-2 was positive in G3, G4 and G5. Conclusion. In uremia, PTH and phosphorus overload are both independently associated with major changes related to the cardiac remodeling process, emphasizing the need for a better control of these factors in chronic kidney disease.
- Serum sclerostin is an independent predictor of mortality in hemodialysis patients(2014) GONCALVES, Flavia Leticia Carvalho; ELIAS, Rosilene M.; REIS, Luciene M. dos; GRACIOLLI, Fabiana G.; ZAMPIERI, Fernando Godinho; OLIVEIRA, Rodrigo B.; JORGETTI, Vanda; MOYSES, Rosa M. A.Background: Sclerostin (Scl) has recently emerged as a novel marker of bone remodeling and vascular calcification. However, whether high circulating Scl is also a risk factor for death is not well established. The purpose of this study was to test whether serum Scl would be associated with mortality. Methods: we measured serum Scl in a hemodialysis patients' cohort, which was followed during a ten-year period. Competing risk regression models were applied, as during the follow-up, patients were exposed to both events kidney transplant and death. Results: Ninety-one patients aged 42.3 +/- 18.8 years (55% of male gender, 15% of diabetes) were included. During the follow-up, 32 patients underwent kidney transplant and 26 patients died. Non-survivals presented higher FGF23, higher Scl and lower creatinine. There was an association between all-cause mortality and higher Scl (HR = 2.2), higher age (HR = 1.04) and presence of diabetes (HR = 2.27), by competing risk analyses. Even including potential markers of mortality, as creatinine, FGF 23, and gender, Scl, age and diabetes remained significantly related to higher mortality. Conclusion: Serum Scl is an independent predictor of mortality in dialysis patients. However, whether clinical interventions to modulate Scl would be able to improve these patients survival needs to be determined.
- High Dialysate Calcium Concentration May Cause More Sympathetic Stimulus During Hemodialysis(2016) JIMENEZ, Zaida N. C.; SILVA, Bruno C.; REIS, Luciene dos; CASTRO, Manuel C. M.; RAMOS, Camila D.; COSTA-HONG, Valeria; BORTOLOTTO, Luiz A.; CONSOLIM-COLOMBO, Fernanda; DOMINGUEZ, Wagner V.; OLIVEIRA, Ivone B.; MOYSES, Rosa M. A.; ELIAS, Rosilene M.Background/Aims: Acute activation of sympathetic activation during hemodialysis is essential to maintain blood pressure (BP), albeit long-term overactivity contributes to higher mortality. Low heart rate variability (HRV), a measure of autonomic nervous system activity, and abnormal ankle-brachial index (ABI) are associated with higher mortality in patients on hemodialysis. In this study, we assessed HRV and ABI pre and post dialysis in incident patients on hemodialysis using high (1.75mmol/l) and low (1.25mmol/l) dialysate calcium concentration (DCa). Methods: HRV was measured as the ratio between low frequency and high frequency power (LF/HF). Thirty patients (age 47 16 years, 67% men) were studied in two consecutive mid-week hemodialysis sessions. Results: Mean BP variation was positive with DCa 1.75 and negative with DCa 1.25 [4.0 (-6.0, 12.2 mmHg) vs. -3.2 (-9.8, 1.3 mmHg); p=0.050]. Reduction of ABI from pre to post HD was related to higher sympathetic activity (p=0.031). The increase in LF/HF ratio was higher with DCa 1.75 (58.3% vs. 41.7% in DCa 1.75 and 1.25, respectively, RR 2.8; p=0.026). Conclusion: Although higher DCa is associated with better hemodynamic tolerability during hemodialysis, this occurs at the expense of increased sympathetic activity. Higher sympathetic activity was associated with a decrease of ABI during hemodialysis. (C) 2016 The Author(s) Published by S. Karger AG, Basel
- Transcription factor HNF4 & alpha;2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy(2023) MARTINEZ-CALLE, Marta; COURBON, Guillaume; HUNT-TOBEY, Bridget; FRANCIS, Connor; SPINDLER, Jadeah; WANG, Xueyan; REIS, Luciene M. dos; MARTINS, Carolina S. W.; SALUSKY, Isidro B.; MALLUCHE, Hartmut; NICKOLAS, Thomas L.; MOYSES, Rosa M. A.; DAVID, Valentin; MARTIN, AlineRenal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4 & alpha; (HNF4 & alpha;), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4 & alpha; expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4 & alpha; resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4 & alpha;1 and Hnf4 & alpha;2, we showed that HNF4 & alpha;2 is the main osseous Hnf4 & alpha; isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4 & alpha;2 prevented bone loss in mice with CKD. Our results showed that HNF4 & alpha;2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.
- The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease(2017) GRACIOLLI, Fabiana G.; NEVES, Katia R.; BARRETO, Fellype; BARRETO, Daniela V.; REIS, Luciene M. dos; CANZIANI, Maria E.; SABBAGH, Yves; CARVALHO, Aluizio B.; JORGETTI, Vanda; ELIAS, Rosilene M.; SCHIAVI, Susan; MOYSES, Rosa M. A.Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated beta-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.
- Comparison of clinical, biochemical and histomorphometric analysis of bone biopsies in dialysis patients with and without fractures(2019) SANTOS, Melissa F. P.; HERNANDEZ, Mariel J.; OLIVEIRA, Ivone B. de; SIQUEIRA, Flavia R.; DOMINGUEZ, Wagner V.; REIS, Luciene M. dos; CARVALHO, Aluizio B.; MOYSES, Rosa M. A.; JORGETTI, VandaChronic kidney disease-mineral bone disorders (CKD-MBD) are associated with increased risk of fracture. Studies report about 3% of fractures in CKD patients, and these occur earlier than in the general population, namely 16 and 13years earlier for men and women, respectively. Better understanding of the pathophysiology offractures would probably contribute to new therapeutic approaches. This study aimed to evaluatereport oflong bone fractures from a bone biopsies bank from patients on hemodialysis and compare clinical and biochemical characteristics, as well as the results of the histomorphometric analysis of trabecular and cortical bone of these patients with a control group (without fractures), paired for age, gender, and time on hemodialysis. Bone proteins (SOST, DMP1 and MEPE) were evaluated by immunohistochemistry. Seventeen patients with fracture and controls were studied. Fracture prevalence was 0.82/1000 patients/year. Serum phosphorus levels were significantly lower in the fracture group. Histomorphometric analysis revealed that all the patients had high turnover disease,and the fracture group had smaller volume and trabecular thickness, greater osteoid surface, smaller eroded surface, smaller mineralizing surface, formation rate and longer mineralization lag time when compared to controls; the DMP1 expression in the cortical bone was smaller and the SOST in the trabecular bone was higher in fractured patients. As conclusion, we found low prevalence of fractures. Both groups had high turnover disease, but the fractured ones presentedmore impairedbone microarchitecture, as well as lower formation and greatermineralization defect. Bone proteins expression correlated with parameters involved in bone remodeling.
- Association of parathormone and alkaline phosphatase with bone turnover and mineralization in children with CKD on dialysis: effect of age, gender, and race(2020) SOEIRO, Emilia M. D.; CASTRO, Lucimary; MENEZES, Rejane; ELIAS, Rosilene M.; REIS, Luciene M. dos; JORGETTI, Vanda; MOYSES, Rosa M. A.Background Studies investigating bone histology in children with chronic kidney disease (CKD) are scarce. Methods Forty-two patients, mean age 11.3 +/- 4.3 years with stage 5 CKD on dialysis, underwent double tetracycline labeling bone biopsy and the relationship between clinical features, biochemical markers, and bone densitometry (DXA) was investigated. Results Low bone turnover was present in 59% of patients, abnormal mineralization in 29%, and low bone volume in 7%. Higher bone formation rate was found in non-Caucasian patients, whereas abnormal mineralization occurred in older and shorter children. We found no impact of gender and etiology of renal disease in our population. Parathormone (PTH) and alkaline phosphatase (AP) showed positive associations with bone turnover. ROC curve analysis showed a fair performance of biomarkers to predict TMV status. PTH < 2 times ULN independently associated with low bone turnover (RR 5.62, 95% CI 1.01-31.24; p = 0.049), in a model adjusted for race, calcitriol dosage, and calcium. It was also associated with abnormal mineralization (RR 1.35, 95% CI 1.04-1.75; p = 0.025), in a model adjusted for BMD scores, AP, age, and calcitriol. PTH and AP significantly predicted turnover and mineralization defect, although with low specificity and sensitivity, reaching a maximum value of 64% and 67%, respectively. Conclusions While PTH and AP were associated with turnover and mineralization, we recognize the limitation of their performance to clearly distinguish high from low/normal bone turnover and normal from abnormal mineralization. Our results reinforce the need to expand knowledge about renal osteodystrophy in pediatric population through prospective bone biopsy studies.
- Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy(2012) SABBAGH, Yves; GRACIOLLI, Fabiana Giorgeti; O'BRIEN, Stephen; TANG, Wen; REIS, Luciene Machado dos; RYAN, Susan; PHILLIPS, Lucy; BOULANGER, Joseph; SONG, Wenping; BRACKEN, Christina; LIU, Shiguang; LEDBETTER, Steven; DECHOW, Paul; CANZIANI, Maria Eugenia F.; CARVALHO, Aluizio B.; JORGETTI, Vanda; MOYSES, Rosa M. A.; SCHIAVI, Susan C.Chronic kidney diseasemineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild-type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-beta-catenin was observed both in mouse and human bones. Overall repression of Wnt/beta-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-?B ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/beta-catenin pathway is involved in the pathogenesis of renal osteodystrophy. (C) 2012 American Society for Bone and Mineral Research.
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