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.
- 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.
- 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.
- GlycA, a marker of protein glycosylation, is related to albuminuria and estimated glomerular filtration rate: the ELSA-Brasil study(2017) TITAN, Silvia M.; PECOITS-FILHO, Roberto; BARRETO, Sandhi M.; LOPES, Antonio Alberto; BENSENOR, Isabela J.; LOTUFO, Paulo A.Background: Systemic inflammation has been implicated in several chronic diseases. GlycA is a new nuclear mass resonance (NMR) spectroscopy-derived biomarker of systemic inflammation that reflects protein glycosylation. We evaluated the association of GlycA with albuminuria and eGFR in the ELSA-Brasil Study. Methods: The cross-sectional association between GlycA (automated NMR LipoProfile (R) test spectra, LabCorp, Raleigh, NC), and overnight 12 h-albuminuria and CKD-EPI eGFR was evaluated among 5050 participants. Results: GlycA was higher among older, women, smokers, alcohol abstemious, obese and in those with diabetes, hypertension or dyslipidemia. In addition, both eGFR and albuminuria were associated to GlycA. In linear regression, GlycA was independently associated with log albuminuria (B 0.03; 95% CI 0.02-0.04, P < 0.0001, per 1sd increase) and inversely related to eGFR (B -0.53; 95% CI -0.99 -0.07, P < 0.02), even after adjustments including hsCRP. In logistic regression, GlycA was independently related to the risk of A2 or A3 albuminuria (OR 1.42, 95% CI 1.27-1.57, p < 0. 0001, per 1sd increase), of having an eGFR < 60 ml/min/1.73m(2) (OR 1.26, 95% CI 1.12-1.41, p = 0.0003, per 1 sd) or of a combined diagnosis of both conditions (OR 1.35, 95% CI 1.23-1.46, p < 0.0001, per 1 sd). In the ROC curve, GlycA had a higher AUC in comparison to hsCRP (AUC 0.67 vs. 0.62, p = 0.06) for the association with albuminuria A2 or A3. Conclusions: The present study demonstrates that GlycA is associated with albuminuria and eGFR, independently of major risk factors for CKD progression, including (and with a stronger association than) hsCRP. GlycA should be further evaluated in CKD progression.
- Dietary intake of non-dialysis chronic kidney disease patients: the PROGREDIR study. A cross-sectional study(2018) MACHADO, Alisson Diego; ANJOS, Fernanda Silva Nogueira dos; DONNINGOS, Maria Alice Muniz; MOLINA, Maria del Carmen Bisi; MARCHIONI, Dirce Maria Lobo; BENSENOR, Isabela Judith Martins; TITAN, Silvia Maria de OliveiraBACKGROUND: Despite evidence that diet is very important in relation to chronic kidney disease (CKD) progression, studies in this field are scarce and have focused only on some specific nutrients. We evaluated the energy, macronutrient and micronutrient intakes and dietary patterns of non-dialysis CKD participants in the PROGREDIR study. DESIGN AND SETTING: Cross-sectional study; CKD cohort, Sao Paulo, Brazil. METHODS: Baseline data on 454 participants in the PROGREDIR study were analyzed. Dietary intake was evaluated through a food freguency questionnaire. Dietary patterns were derived through principal component analysis. Energy and protein intakes were compared with National Kidney Foundation recommendations. Linear regression analysis was performed between energy and nutrient intakes and estimated glomerular filtration rate(eGFR), and between sociodemographic and clinical variables and dietary patterns. RESULTS: Median energy and protein intakes were 25.0 kcal/kg and 1.1 g/kg, respectively. In linear regression, protein intake (beta = -3.67; P = 0.07) was related to eGFR. Three dietary patterns (snack, mixed and traditional) were retained. The snack pattern was directly associated with male gender (beta = 0.27; P = 0.006) and inversely with diabetes (p = -0.23; P = 0.02). The traditional pattern was directly associated with male gender (beta = 0.27; P = 0.007) and schooling (beta = 0.40; P < 0.001) and inversely with age (p = -0.01; P = 0.001) and hypertension (beta = -0.34; P = 0.05). CONCLUSIONS: We identified low energy and high protein intake in this population. Protein intake was inversely related to eGFR. Dietary patterns were associated with age, gender, schooling level, hypertension and diabetes.
- Thyrotropin levels are associated with chronic kidney disease among healthy subjects in cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)(2017) MIRANDA, Erique Jose F. Peixoto de; BITTENCOURT, Marcio Sommer; GOULART, Alessandra C.; SANTOS, Itamar S.; TITAN, Silvia Maria de Oliveira; LADEIRA, Roberto Marini; BARRETO, Sandhi Maria; LOTUFO, Paulo A.; BENSENOR, Isabela Judith MartinsFew studies have evaluated a possible relationship between thyrotropin levels and glomerular filtration rate (GFR) and albumin/creatinine ratio in euthyroid subjects. We aimed to analyze this association using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Cross-sectionally, we included subjects with normal thyroid function and with subclinical hypothyroidism (SCH). We excluded individuals using medications that affect thyroid function. Linear and logistic regression models evaluated GFR estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and albuminuria/creatinine ratio as dependent variables and thyrotropin quartiles in individuals with euthyroidism and SCH as independent variables, adjusted for demographical characteristics and diseases related to CKD. We included 13,193 subjects with a median age of 51 years [interquartile range, (IQR): 45-58], 6840 (51.8%) women, 12,416 (94.1%) euthyroid, and 777 (5.9%) with SCH. SCH subjects were characterized by higher age, triglycerides, frequency of white race, cardiovascular disease, CKD, and former smokers. In adjusted models, log-transformed TSH in euthyroid subjects was inversely and strongly associated with CKD (beta = -2.181, 95% CI -2.714 to -1.648), P < 0.0001 for glomerular filtration rate and 4.528 (1.190-7.865) for albuminuria/creatinine ratio. Multivariate logistic models for euthyroid subjects showed an OR of 1.45 (95% CI 1.15-1.83) for GFR and of 1.95 (95% CI 1.08-3.54) for albuminuria/creatinine ratio in the fourth quartile of TSH using the first as the reference. Thyrotropin levels are independently associated with CKD in euthyroid subjects.
- Dietary acid load and the risk of events of mortality and kidney replacement therapy in people with chronic kidney disease: the Progredir Cohort Study(2024) MACHADO, Alisson Diego; MARCHIONI, Dirce Maria; LOTUFO, Paulo Andrade; BENSENOR, Isabela Martins; TITAN, Silvia MariaBackground/ObjectivesThe association between dietary acid load (DAL) and chronic kidney disease (CKD) progression remains controversial. Also, there is a gap in the literature on the association between DAL and mortality. In this study, we evaluated the association between NEAP (net endogenous acid production) and PRAL (potential renal acid load) and the risk of events of all-cause mortality and kidney replacement therapy (KRT) in people with CKD.Subjects/MethodsWe included 442 patients (250 diabetics) from the Progredir Cohort Study, based in Sao Paulo, Brazil. We estimated NEAP and PRAL from dietary intake. Events of death before KRT and KRT were ascertained after a median follow-up of 5.8 and 5.1 years, respectively. Cox proportional hazards regression, Weibull regression, and competing risk models were performed.ResultsMedian NEAP and PRAL were 49.5 and 4.8 mEq/d. There were 200 deaths and 75 KRT events. Neither NEAP nor PRAL were associated with mortality or KRT when all participants were analyzed. After stratification for diabetes, both estimates were positively related to the risk of KRT even after adjustment for age, sex, weight status, glomerular filtration rate, serum bicarbonate, and intakes of protein, phosphorus, and energy (HR 1.31; 95% CI 1.07, 1.60 for NEAP, and HR 1.27; 95% CI 1.04, 1.57 for every 10 mEq/d increments). Competing risk analyses confirmed these findings.ConclusionsDAL estimates were associated with the risk of KRT in people with CKD and diabetes but not in non-diabetics. There was no association between all-cause mortality and DAL.
- Urinary Retinol-Binding Protein: Relationship to Renal Function and Cardiovascular Risk Factors in Chronic Kidney Disease(2016) DOMINGOS, Maria Alice Muniz; MOREIRA, Silvia Regina; GOMEZ, Luz; GOULART, Alessandra; LOTUFO, Paulo Andrade; BENSENOR, Isabela; TITAN, SilviaThe role of urinary retinol-binding protein (RBP) as a biomarker of CKD in proximal tubular diseases, glomerulopathies and in transplantation is well established. However, whether urinary RBP is also a biomarker of renal damage and CKD progression in general CKD is not known. In this study, we evaluated the association of urinary RBP with renal function and cardiovascular risk factors in the baseline data of the Progredir Study, a CKD cohort in Sao Paulo, Brazil, comprising 454 participants with stages 3 and 4 CKD. In univariate analysis, urinary RBP was inversely related to estimated glomerular filtration rate (CKD-EPI eGFR) and several cardiovascular risk factors. After adjustments, however, only CKD-EPI eGFR, albuminuria, systolic blood pressure, anemia, acidosis, and left atrium diameter remained significantly related to urinary RBP. The inverse relationship of eGFR to urinary RBP (beta-0.02 +/- 95CI -0.02; -0.01, p<0.0001 for adjusted model) remained in all strata of albuminuria, even after adjustments: in normoalbuminuria (beta-0.008 +/- 95CI (-0.02; -0.001, p = 0.03), in microalbuminuria (beta-0.02 +/- 95CI (-0.03; -0.02, p<0,0001) and in macroalbuminuria (beta-0.02 +/- 95CI (-0.03; -0.01, p<0,0001). Lastly, urinary RBP was able to significantly increase the accuracy of a logistic regression model (adjusted for sex, age, SBP, diabetes and albuminuria) in diagnosing eGFR<35 ml/min/1.73m(2) (AUC 0,77, 95% CI 0,72-0,81 versus AUC 0,71, 95% CI 0,65-0,75, respectively; p = 0,05). Our results suggest that urinary RBP is significantly associated to renal function in CKD in general, a finding that expands the interest in this biomarker beyond the context of proximal tubulopathies, glomerulopathies or transplantation. Urinary RBP should be further explored as a predictive marker of CKD progression.
- Metabolites related to eGFR: Evaluation of candidate molecules for GFR estimation using untargeted metabolomics(2019) TITAN, S. M.; VENTURINI, G.; PADILHA, K.; TAVARES, G.; ZATZ, R.; BENSENOR, I; LOTUFO, P. A.; RHEE, E. P.; I, R. Thadhani; PEREIRA, A. C.Background: Metabolomics can be used to identify novel metabolites related to renal function and that could therefore be used for estimating GFR. We evaluated metabolites replicated and related to eGFR in 3 studies (CKD) and general population). Methods: Metabolomics was performed by GC-MS. The Progredir Cohort (n = 454, class 3 and 4 CKD) was used as the derivation study and adjusted linear regression models on eGFR-CKDEPI were built. Bonferroni correction was applied for selecting metabolites to be independently validated in the Diabetic Nephropathy Study (n = 56 macroalbuminuric DN) and in the Baependi Heart Study (BHS, n = 1145, general population). Results: In the Progredir Cohort, 72 metabolites where associated with eGFR. Of those, 11 were also significantly associated to eGFR in the DN Study and 8 in the BHS. Four metabolites were replicated and significantly associated to eGFR in all 3 studies: D-threitol, myo-inositol, 4-deoxierythronic acid and galacturonic acid. In addition, pseudouridine was strongly correlated to eGFR only in the 2 CKD populations. Conclusions: Our results demonstrate metabolites that are potential biomarkers of renal function: D-threitol, myo-inositol, 4-deoxierythronic acid, galacturonic acid and pseudouridine. Further investigation is needed to determine their performance against otherwise gold-standard methods, most notably among those with normal eGFR.
- Metabolomics biomarkers and the risk of overall mortality and ESRD in CKD: Results from the Progredir Cohort(2019) TITAN, Silvia M.; VENTURINI, Gabriela; PADILHA, Kallyandra; GOULART, Alessandra C.; LOTUFO, Paulo A.; BENSENOR, Isabela J.; KRIEGER, Jose E.; THADHANI, Ravi I.; RHEE, Eugene P.; PEREIRA, Alexandre C.Introduction Studies on metabolomics and CKD have primarily addressed CKD incidence defined as a decline on eGFR or appearance of albuminuria in the general population, with very few evaluating hard outcomes. In the present study, we investigated the association between metabolites and mortality and ESRD in a CKD cohort. Setting and methods Data on 454 participants of the Progredir Cohort Study, Sao Paulo, Brazil were used. Metabolomics was performed by GC-MS (Agilent MassHunter) and metabolites were identified using Agilent Fiehn GC/MS and NIST libraries. After excluding metabolites present in <50% of participants, 293 metabolites were analyzed. An FDR q value <0.05 criteria was applied in Cox models on the composite outcome (mortality or incident renal replacement therapy) adjusted for batch effect, resulting in 34 metabolites associated with the outcome. Multivariable- adjusted Cox models were then built for the composite outcome, death, and ESRD incident events. Competing risk analysis was also performed for ESRD. Results Mean age was 68 +/- 12y, mean eGFR-CKDEPI was 38.4 +/- 14.6 ml/min/1.73m(2) and 57% were diabetic. After adjustments (GC-MS batch, sex, age, DM and eGFR), 18 metabolites remained significantly associated with the composite outcome. Nine metabolites were independently associated with death: D-malic acid (HR 1.84, 95% CI 1.32-2.56, p = 0.0003), acetohydroxamic acid (HR 1.90, 95% CI 1.30-2.78, p = 0.0008), butanoic acid (HR 1.59, 95% CI 1.17-2.15, p = 0.003), and docosahexaenoic acid (HR 0.58, 95% CI 0.39-0.88, p = 0.009), among the top associations. Lactose (SHR 1.49, 95% CI 1.04-2.12, p = 0.03), 2-O-glycerol-alpha-D-galactopyranoside (SHR 1.76, 95% CI 1.06-2.92, p = 0.03), and tyrosine (SHR 0.52, 95% CI 0.31-0.88, p = 0.02) were associated to ESRD risk, while D-threitol, mannitol and myo-inositol presented strong borderline associations. Conclusion Our results identify specific metabolites related to hard outcomes in a CKD population. These findings point to the need of further exploration of these metabolites as biomarkers in CKD and the understanding of the underlying biological mechanisms related to the observed associations.