SILVIA MARIA DE OLIVEIRA TITAN
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- Chronic kidney disease - determinants of progression and cardiovascular risk. PROGREDIR cohort study: design and methods(2017) DOMINGOS, Maria Alice Muniz; GOULART, Alessandra Carvalho; LOTUFO, Paulo Andrade; BENSENOR, Isabela Judith Martins; TITAN, Silvia Maria de OliveiraCONTEXT AND OBJECTIVE: Chronic kidney disease (CKD) has become an important public health issue. The socioeconomic burden of renal replacement therapy (RRT) is very high, as is CKD-related cardiovascular mortality and morbidity. Preventive and therapeutic measures only have modest impact and more research is needed. Few cohort studies have been conducted on populations with CKD. Our aim was to establish a cohort that would include more advanced forms of CKD (stages 3 and 4). Data collection was focused on renal and cardiovascular parameters. DESIGN AND SETTING: Prospective cohort study; Sao Paulo, Brazil. METHODS: Recruitment took place in Hospital das Clinicas, Sao Paulo, from March 2012 to December 2013. Data relating to medical history, food-frequency questionnaire, anthropometry, laboratory work-up, calcium score, echocardiography, carotid intimal-medial thickness, pulse-wave velocity, retinography and heart rate variability were collected. A biobank including serum, plasma, post-oral glucose tolerance test serum and plasma, urine (morning and 24-hour urine) and DNA was established. RESULTS: 454 participants (60% men and 50% diabetics) of mean age 68 years were enrolled. Their mean estimated glomerular filtration rate-CKD Epidemiology Collaboration was 38 ml/min/1.73m(2). Follow-up is ongoing and the main outcomes are the start of RRT, cardiovascular events and death. CONCLUSIONS: The PROGREDIR cohort is a promising prospective study that will allow better understanding of CKD determinants and validation of candidate biomarkers for the risks of CKD progression and mortality.
- Bisphosphonate utilization across the spectrum of eGFR(2020) TITAN, Silvia M.; LAUREATI, Paola; SANG, Yingying; CHANG, Alex R.; EVANS, Marie; TREVISAN, Marco; LEVEY, Andrew S.; GRAMS, Morgan E.; INKER, Lesley A.; CARRERO, Juan-JesusBisphosphonates are the most common treatment for osteoporosis but there are concerns regarding its use in CKD. We evaluated the frequency of BSP by eGFR categories among patients with osteoporosis from two healthcare systems. Our results show that 56% of patients were treated, with reduced odds in those with lower eGFR. Introduction Osteoporosis is common in patients with chronic kidney disease (CKD). Bisphosphonates (BSP) are the most common treatment but there are concerns regarding its efficacy and toxicity in CKD. We evaluated the frequency of BSP use by level of estimated glomerular filtration rate (eGFR) in patients with osteoporosis. Methods We assessed BSP use in patients with incident osteoporosis from the SCREAM-Cohort, Stockholm-Sweden, and Geisinger Healthcare, PA, USA. Osteoporosis was defined as the first encountered ICD diagnosis, and BSP use was defined as the dispensation or prescription of any BSP from 6 months prior to 3 years after the diagnosis. Multinomial logistic regression was used to account for the competing risk of death. Results A total of 15,719 women and 3011 men in SCREAM and 17,325 women and 3568 men in Geisinger with incident osteoporosis were included. Overall, 56% of individuals used BSP in both studies, with a higher proportion in women. After adjustments, the odds of BSP was lower across lower eGFR in SCREAM, ranging from 0.90 (0.81-0.99) for eGFR 75-89 mL/min/1.73m(2) to 0.56 (0.46-0.68) for eGFR 30-44 mL/min/1.73m(2) in women and from 0.72 (0.54-0.97) for eGFR of 60-74 to 0.42 (0.25-0.70) for eGFR 30-44 mL/min/1.73m(2) in men. In Geisinger, odds were lower for eGFR < 30 mL/min/1.73m(2) in both sexes and the frequency of BSP use dropped over time. Conclusion In the two healthcare systems, approximately half of the people diagnosed with osteoporosis received BSP. Practices of prescription in relation to eGFR varied, but those with lower eGFR were less likely to receive BSP.
- Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4(2019) BETONICO, Carolina C.; TITAN, Silvia Maria O.; LIRA, Aecio; PELAES, Tatiana S.; CORREA-GIANNELLA, Maria Lucia C.; NERY, Marcia; QUEIROZ, MarciaPurpose: Glycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time-action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4. Methods: Thirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA(1c)) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA(1)(c) was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring. Findings: After 24 weeks, mean HbA(1c )decreased on glargine U100 treatment (-0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047). (C) 2019 Published by Elsevier Inc.
- 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.
bookPart Nefropatia Diabética(2016) NORONHA, Irene de Lourdes; TITAN, Silvia- Serum RBP4 and CKD: Association with insulin resistance and lipids(2017) DOMINGOS, Maria Alice M.; QUEIROZ, Marcia; LOTUFO, Paulo Andrade; BENSENOR, Isabela Judith; TITAN, Silvia Maria de OliveiraObjective: Serum RBP4 is new adipokine and it has been related to insulin resistance and diabetes risk in animal and clinical studies. However, there is controversy on this relationship among CKD patients. In this study, we evaluated the association of serum RBP4 with insulin resistance and cardiovascular risk factors in CKD. Methods: Baseline data from the PROGREDIR Study (Sao Paulo, Brazil) comprising 454 participants (mainly stages 3 and 4) was analyzed. Results: In univariable analysis, RBP4 was inversely related to renal function, age and HDL, and positively related to other lipids, insulinemia, HOMA, glycemia, albumin, phosphorus and right hepatic lobe diameter. After adjustment for sex, age and eGFR, HOMA and lipids remained associated to RBP4. In multivariable analysis, eGFR and triglyceride remained significantly associated with RBP4, while HOMA showed no longer a significant positive association. An interaction term between RBP4 and eGFR was significantly related to HOMA. Conclusions: Renal function is inversely related to serum RBP4. As GFR decreases, the relationship between RBP4 and HOMA is attenuated. On the other hand, triglycerides remained strongly related to RBP4 and this was not affected by eGFR, suggesting that in the CKD population triglycerides may be a better marker of RBP4-associated metabolic effects.
- Potential Biomarkers of the Turnover, Mineralization, and Volume Classification: Results Using NMR Metabolomics in Hemodialysis Patients(2020) BAPTISTA, A.L.; PADILHA, K.; MALAGRINO, P.A.; VENTURINI, G.; ZERI, A.C.M.; REIS, L.M. dos; MARTINS, J.S.; JORGETTI, V.; PEREIRA, A.C.; TITAN, S.M.; MOYSES, R.M.A.Bone biopsy is still the gold standard to assess bone turnover (T), mineralization (M), and volume (V) in CKD patients, and serum biomarkers are not able to replace histomorphometry. Recently, metabolomics has emerged as a new technique that could allow for the identification of new biomarkers useful for disease diagnosis or for the understanding of pathophysiologic mechanisms, but it has never been assessed in the chronic kidney disease–mineral and bone disorder (CKD–MBD) scenario. In this study, we investigated the association between serum metabolites and the bone TMV classification in patients with end-stage renal disease by using serum NMR spectroscopy and bone biopsy of 49 hemodialysis patients from a single center in Brazil. High T was identified in 21 patients and was associated with higher levels of dimethylsulfone, glycine, citrate, and N-acetylornithine. The receiver-operating characteristic curve for the combination of PTH and these metabolites provided an area under the receiver-operating characteristic curve (AUC) of 0.86 (0.76 to 0.97). Abnormal M was identified in 30 patients and was associated with lower ethanol. The AUC for age, diabetes mellitus, and ethanol was 0.83 (0.71 to 0.96). Low V was identified in 17 patients and was associated with lower carnitine. The association of age, phosphate, and carnitine provided an AUC of 0.83 (0.70 to 0.96). Although differences among the curves by adding selected metabolites to traditional models were not statistically significant, the accuracy of the diagnosis according to the TMV classification seemed to be improved. This is the first study to evaluate the TMV classification system in relation to the serum metabolome assessed by NMR spectroscopy, showing that selected metabolites may help in the evaluation of bone phenotypes in CKD–MBD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
- Parathyroidectomy Improves Survival In Patients with Severe Hyperparathyroidism: A Comparative Study(2013) GOLDENSTEIN, Patricia Taschner; ELIAS, Rosilene Motta; CARMO, Lilian Pires de Freitas do; COELHO, Fernanda Oliveira; MAGALHAES, Luciene Pereira; ANTUNES, Gisele Lins; CUSTODIO, Melani Ribeiro; MONTENEGRO, Fabio Luiz de Menezes; TITAN, Silvia Maria; JORGETTI, Vanda; MOYSES, Rosa Maria AffonsoBackground and objectives: Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery. Methods: This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012. Results: Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group. Conclusions: Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients.
- Association between Dietary Intake and Coronary Artery Calcification in Non-Dialysis Chronic Kidney Disease: The PROGREDIR Study(2018) MACHADO, Alisson Diego; GOMEZ, Luz Marina; MARCHIONI, Dirce Maria Lobo; ANJOS, Fernanda Silva Nogueira dos; MOLINA, Maria del Carmen Bisi; LOTUFO, Paulo Andrade; BENSENOR, Isabela Judith Martins; TITAN, Silvia Maria de OliveiraCoronary artery calcification (CAC) is a widespread condition in chronic kidney disease (CKD). Diet may play an important role in CAC, but this role is not clear. This study evaluated the association between macro-and micronutrient intakes and CAC in non-dialysis CKD patients. We analyzed the baseline data from 454 participants of the PROGREDIR study. Dietary intake was evaluated by a food frequency questionnaire. CAC was measured by computed tomography. After exclusion of participants with a coronary stent, 373 people remained for the analyses. The highest tertile of CAC was directly associated with the intake of phosphorus, calcium and magnesium. There was a higher intake of pantothenic acid and potassium in the second tertile. After adjustments for confounding variables, the intake of pantothenic acid, phosphorus, calcium and potassium remained associated with CAC in the generalized linear mixed models. In order to handle the collinearity between these nutrients, we used the LASSO (least absolute shrinkage and selection operator) regression to evaluate the nutrients associated with CAC variability. In this approach, the nutrients that most explained the variance of CAC were phosphorus, calcium and potassium. Prospective studies are needed to confirmthese findings and assess the role of interventions regarding these micronutrients on CAC prevention and progression.
- ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: a double-blind randomized clinical trial(2011) TITAN, S. M.; VIEIRA JR., J. M.; DOMINGUEZ, W. V.; BARROS, R. T.; ZATZ, R.Objective: The combination of an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for the treatment of diabetic nephropathy (DN), but doubts remain about its efficacy and safety. We compared the effects of combination therapy and ACEI monotherapy on proteinuria and on three urinary inflammatory cytokines (MCP-1, TGF-beta and VEGF). Design and patients: 56 patients with macro-albuminuric DN received 40 mg/d enalapril for 4 months, followed by add-on 100 mg/d losartan or placebo for another 4 months. The primary and secondary endpoints were reduction of proteinuria and cytokine levels, respectively. Results: Proteinuria did not fall in either group. Repeated measures ANOVA revealed no difference between groups. A high side effect rate was observed (28.5%). Finally, unadjusted logistic regression showed no difference between groups, but after adjustments the risk of worsening proteinuria was higher in the combination therapy group (p = 0.04). The same pattern was observed for urinary MCP-1. Conclusion: These results suggest that 1) in advanced DN with severe proteinuria and poor metabolic control, angiotensin II blockade may be less effective than in other groups of CKD patients. 2) In such patients, combination therapy may not afford superior renoprotection compared to enalapril. 3) Urinary MCP-1 is a promising biomarker for the response to ACEI and/or ARB treatment and for the risk of associated unwanted effects.