LUCIENE MACHADO DOS REIS
Projetos de Pesquisa
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LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
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- 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.
- Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function(2012) CANCELA, Ana Ludimila; SANTOS, Raul Dias; TITAN, Silvia Maria; GOLDENSTEIN, Patricia Taschner; ROCHITTE, Carlos Eduardo; LEMOS, Pedro Alves; REIS, Luciene Machado dos; GRACIOLLI, Fabiana Giorgetti; JORGETTI, Vanda; MOYSES, Rosa MariaHigh serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m(2). Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score <= 10 (3.63 +/- 0.55 versus 3.49 +/- 0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6 +/- 0.5 versus 3.5 +/- 0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score ( p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.
- Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease(2015) OLIVEIRA, Rodrigo A. de; BARRETO, Fellype C.; MENDES, Monique; REIS, Luciene M. dos; CASTRO, Joao Henrique; BRITTO, Zita Maria L.; MARQUES, Igor D. B.; CARVALHO, Aluizio B.; MOYSES, Rosa M.; JORGETTI, VandaChronic kidney disease-mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/beta-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high-and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25-hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients.
- 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.
- Lanthanum carbonate, like sevelamer-HCl, retards the progression of vascular calcification and atherosclerosis in uremic apolipoprotein E-deficient mice(2012) NIKOLOV, Igor G.; JOKI, Nobuhiko; Thao Nguyen-Khoa; GUERRERA, Ida Chiara; MAIZEL, Julien; BENCHITRIT, Joyce; REIS, Luciene Machado dos; EDELMAN, Aleksander; LACOUR, Bernard; JORGETTI, Vanda; DRUEEKE, Tilman B.; MASSY, Ziad A.Atherosclerosis and vascular calcification (VC) progression in chronic kidney disease is favored by disturbances of mineral metabolism. We compared the effect of phosphate binder lanthanum (La) carbonate with sevelamer-HCl on atherosclerosis, VC and bone structure and function in mice with chronic renal failure (CRF). Apolipoprotein E-deficient (apoE(-/-)) mice were randomized to one non-CRF and three CRF groups, fed with standard diet (one non-CRF and one CRF) or diet supplemented with either 3% lanthanum carbonate (La3%) or 3% sevelamer-HCl (Sev3%). Both La3% and Sev3% supplemented CRF mice displayed a decrease of serum phosphorus, calcification at both intimal and medial aortic sites and atherosclerosis. This was associated with a reduction of plaque Type I collagen expression by both binders and of positive nitrotyrosine staining in response to sevelamer-HCl only. Increased mineral apposition and bone formation rates in unsupplemented CRF mice were reduced by Sev3% but not by La3%. The beneficial effects of La carbonate and sevelamer-HCl on the progression of VC and atherosclerosis in CRF mice could be mainly due to a decrease in phosphate retention and likewise a reduction of arterial Type I collagen expression. The effect of La carbonate differed from that of sevelamer-HCl in that it did not appear to exert its vascular effects via changes in oxidative stress or bone remodeling in the present model.
- Biopsy vs. peripheral computed tomography to assess bone disease in CKD patients on dialysis: differences and similarities(2017) MARQUES, I. D. B.; ARAUJO, M. J. C. L. N.; GRACIOLLI, F. G.; REIS, L. M. dos; PEREIRA, R. M.; CUSTODIO, M. R.; JORGETTI, V.; ELIAS, R. M.; DAVID-NETO, E.; MOYSES, R. M. A.Results from bone biopsy and high-resolution peripheral quantitative computed tomography (HR-pQCT) were compared in 31 CKD patients. There was an agreement mainly for cortical compartment that may represent a perspective on the fracture risk assessment. HR-pQCT also provided some clues on the turnover status, which warrants further studies. Chronic kidney disease (CKD) patients are at high risk of bone disease. Although bone biopsy is considered the best method to evaluate bone disease, it is expensive and not always available. Here we have compared, for the first time, data obtained from bone biopsy and HR-pQCT in a sample of CKD patients on dialysis. HR-pQCT and dual-energy X-ray absorptiometry (DXA) were performed in 31 CKD patients (30 on dialysis). Biopsies were analyzed by quantitative histomorphometry, and classified according to TMV. We have found an inverse correlation between radius cortical density measured by HR-pQCT, with serum, as well as histomorphometric bone remodeling markers. Trabecular density and BV/TV measured through HR-pQCT in the distal radius correlated with trabecular and mineralized trabecular bone volume. Trabecular number, separation, and thickness obtained from HR-pQCT and from bone biopsy correlated with each other. Patients with cortical porosity on bone histomorphometry presented lower cortical density at the distal radius. Cortical density at radius was higher while bone alkaline phosphatase was lower in patients with low turnover. Combined, these parameters could identify the turnover status better than individually. There was an agreement between HR-pQCT and bone biopsy parameters, particularly in cortical compartment, which may point to a new perspective on the fracture risk assessment for CKD patients. Besides classical bone resorption markers, HR-pQCT provided some clues on the turnover status by measurements of cortical density at radius, although the significance of this finding warrants further studies.
- FGF-23 as a Predictor of Renal Outcome in Diabetic Nephropathy(2011) TITAN, Silvia M.; ZATZ, Roberto; GRACIOLLI, Fabiana G.; REIS, Luciene M. dos; BARROS, Rui T.; JORGETTI, Vanda; MOYSES, Rosa M. A.Background and objectives Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). Design, setting, participants, & measurements DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. Results At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteirturia, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7 +/- 10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P = 0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. Conclusions FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention. Clin J Am Soc Nephrol 6: 241-247, 2011. doi: 10.2215/CJN.04250510
- Effect of parathyroidectomy on bone tissue biomarkers and body composition in patients with chronic kidney disease and secondary hyperparathyroidism(2021) SIQUEIRA, Flavia Ramos de; OLIVEIRA, Karin Carneiro de; DOMINGUEZ, Wagner Vasques; TRUYTS, Cesar Augusto Madid; MOYSES, Rosa Maria Affonso; REIS, Luciene Machado dos; JORGETTI, VandaBackground/objective Loss of renal function may induce secondary hyperparathyroidism (s-HPT), which triggers several complications leading to an extreme decline in quality of life and increased mortality in affected patients. We evaluated whether parathyroidectomy (PTx), as surgical treatment for s-HPT, modifies body composition, and hormones involved in the protein-energy metabolism of affected patients. Subjects/methods Overall, 30 s-HPT patients were evaluated at two times, before PTx (pre PTx) and 6 months after PTx (post PTx). Patients were evaluated by biochemistry analysis, anthropometry, electrical bioimpedance (BIA), food intake diary, handgrip strength, and modified global subjective nutritional assessment (SGA). Results After PTx, patients showed decreased serum levels of total and ionic calcium, as well as decreased alkaline phosphatase and PTH, and increased 25 (OH) vitamin D. These results demonstrate that PTx was efficient to correct part of the mineral disorder. We also observed an increase in caloric intake, body weight, body mass index (BMI), phase angle, handgrip strength, SGA score, and a decreasing in the percentage of weight loss. The osteocalcin concentration of both carboxylated (cOC) and undercarboxylated form was diminished post PTx. The cOC correlated with bone metabolism markers and SGA score. Conclusions PTx modified body composition improving nutritional status and preventing the progression of weight loss with increased of energy intake, BMI, handgrip strength, phase angle of BIA, and SGA score. The present study also suggests an association of cOC with bone markers and SGA score. Further studies are needed to better clarify these associations with larger sample size.
- Parathyroidectomy in patients with chronic kidney disease: Impacts of different techniques on the biochemical and clinical evolution of secondary hyperparathyroidism(2018) ALBUQUERQUE, Roxana de Fatima Camelo; CARBONARA, Cinthia Esbrile Moraes; MARTIN, Rita de Cassia T.; REIS, Luciene Machado dos; NASCIMENTO JUNIOR, Climerio Pereira do; ARAP, Sergio Samir; MOYSES, Rosa M. A.; JORGETTI, Vanda; MONTENEGRO, Fabio L. M.; OLIVEIRA, Rodrigo Bueno deBackground. Parathyroidectomy (PTx) decreases the mortality rate of refractory secondary hyperparathyroidism (rSHP) due to chronic kidney disease. A consensus regarding which techniques of PTx are associated with better outcomes is not available. The aims of this study are to evaluate the clinical and laboratory evolution of 49 hemodialysis patients with rSHP who underwent PTx using different techniques. Methods. Patients underwent subtotal PTx (sub-PTx) or total PTx with autotransplantation (AT) of 45 (PTx-AT(45)) or 90 parathyroid fragments (PTx-AT(90)) and were followed for 12 months. We analyzed the expression of proliferating cell nuclear antigen (PCNA), calcium-sensing receptor (CasR), vitamin D receptor (VDR), fibroblast growth factor receptor-1 (FGFR1), sodium-dependent phosphate cotransporter-1 (PIT1), and Klotho in parathyroid glands. Results. Baseline median serum intact parathyroid hormone (iPTH) levels were 1,466 (1,087-2,125) pg/mL; vascular calcification scores correlated with serum iPTH (r = 0.529; P=.002) and serum phosphate levels (r = 0.389; P=.028); and Klotho expression was negatively correlated with serum phosphate levels (r=-0.4; P=.01). After 12 months, serum iPTH and alkaline phosphatase levels were significantly controlled in all groups, as was bone pain. The proportions of patients with serum iPTH levels within the ranges recommended by Kidney Disease: Improving Global Outcomes were similar among the treatment groups. During the hungry bone disease (HBS), patients received 3,786 g (1,412-7,580) of elemental calcium, and a trend toward a positive correlation between the cumulative calcium load at the end of follow up and VC score post-PTx was noted (r = 0.390; P=.06). Two cases evolved to clinically uncontrolled hyperparathyroidism in the sub-PTx group. The expression patterns of PCNA, VDR, CasR, PIT1, FGFRI, and Klotho in parathyroid glands did not correlate with serum systemic iPTH levels or the duration of HBS. Conclusions. All 3 operative techniques were effective at controlling rSHP, both in clinical and laboratory terms. Neither the quantity nor quality of parathyroid fragments influenced serum systemic iPTH and AT-iPTH levels. The cumulative calcium load appeared to correlate with the VC score and may have affected its progression. The effects of phosphate restriction on Klotho expression in human parathyroid glands and the subsequent decrease in FGF23 resistance must be addressed in further studies.
- Renal osteodystrophy in the obesity era: Is metabolic syndrome relevant?(2017) MARTINS, Janaina Da Silva; CASTRO, Joao Henrique; RUEDA, Nestor A. Sainz; REIS, Luciene Machado dos; JORGETTI, Vanda; MOYSES, Rosa Maria Affonso; CARAMORI, Jacqueline TeixeiraBackground Observational studies have shown a beneficial effect of obesity on bone health; however, most of those studies were not based on bone biopsies. Metabolic syndrome (MetS) could have an effect on bone remodeling. However, there are no data on the effects of MetS in the presence of renal osteodystrophy. Objective The aim of this study was to investigate associations between MetS and renal osteodystrophy using the bone histomorphometric turnover-mineralization-volume (TMV) classification. Design, setting, participants & measurements This observational cross-sectional study included 55 hemodialysis patients (28 women/27 men) who were evaluated for MetS and bone histomorphometry. Biochemical parameters included calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, free serum leptin, fibroblast growth factor 23 (FGF23), intact osteocalcin, sclerostin (Scl), glucose, insulin, and thyroid hormones. Robust models of multivariate linear regressions were used for the statistical analyses. Results Females had higher iPTH levels (1,143 vs. 358, p = 0.02). Patients with normal bone volume (BV/TV) had a higher prevalence of MetS (73.6% vs. 41.7%, p = 0.02) and higher serum phosphorus, C-terminal FGF23 and insulin levels. The multivariate regression analysis showed that low-density lipoprotein cholesterol (LDL) was positively correlated with bone formation rate (BFR/BS) and negatively associated with mineralization lag time. Bone volume was negatively associated with age but positively associated with MetS. Body mass index (BMI) was not correlated with any of the bone histomorphometric parameters. Conclusion Our results suggest that MetS is not a risk factor for low bone volume in hemodialysis patients. Furthermore, BMI alone was not related to bone volume in this population.