Human N-acetyltransferase 2 (NAT2) gene variability in Brazilian populations from different geographical areas.

Introduction: Several polymorphisms altering the NAT2 activity have already been identified. The geographical distribution of NAT2 variants has been extensively studied and has been demonstrated to vary significantly among different ethnic population. Here, we describe the genetic variability of human N-acetyltransferase 2 (NAT2) gene and the predominant genotype-deduced acetylation profiles of Brazilians. Methods: A total of 964 individuals, from five geographical different regions, were genotyped for NAT2 by sequencing the entire coding exon. Results: Twenty-three previously described NAT2 single nucleotide polymorphisms (SNPs) were identified, including the seven most common ones globally (c.191G>A, c.282C>T, c.341T>C, c.481C>T, c.590G>A, c.803A>G and c.857G>A). The main allelic groups were NAT2*5 (36%) and NAT2*6 (18.2%), followed to the reference allele NAT2*4 (20.4%). Combined into genotypes, the most prevalent allelic groups were NAT2*5/*5 (14.6%), NAT2*5/*6 (11.9%) and NAT2*6/*6 (6.2%). The genotype deduced NAT2 slow acetylation phenotype was predominant but showed significant variability between geographical regions. The prevalence of slow acetylation phenotype was higher in the Northeast, North and Midwest (51.3%, 45.5% and 41.5%, respectively) of the country. In the Southeast, the intermediate acetylation phenotype was the most prevalent (40.3%) and, in the South, the prevalence of rapid acetylation phenotype was significantly higher (36.7%), when compared to other Brazilian states (p < 0.0001). Comparison of the predicted acetylation profile among regions showed homogeneity among the North and Northeast but was significantly different when compared to the Southeast (p = 0.0396). The Southern region was significantly different from all other regions (p < 0.0001). Discussion: This study contributes not only to current knowledge of the NAT2 population genetic diversity in different geographical regions of Brazil, but also to the reconstruction of a more accurate phenotypic picture of NAT2 acetylator profiles in those regions.

Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.

BACKGROUND: Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive ß-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the ß-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. METHODS: Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. CONCLUSION: This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension. CLINICAL TRIAL REGISTRATION: The trial protocol was registered at clinicaltrials.gov (NCT04713657).

Sex-age-specific handgrip strength and mortality in an incident hemodialysis cohort: The risk explained by nutrition and comorbidities.

OBJECTIVE:: To investigate associations of sex-age-specific handgrip strength by a dynamometer with all-cause mortality and the percent excess risk explained (%ERE) by comorbidities and nutritional indicators in incident maintenance hemodialysis patients. METHODS:: Prospective cohort of 413 adult patients (165 women, 248 men, 299 <60 years and 114 ⩾60 years) with <6 months (82% <3 months) on dialysis enrolled in PROHEMO in Salvador, Brazil. Low and high handgrip strength groups were based on sex-age-specific cutoffs (17.8 kg for women <60 years, 13.8 kg for women ⩾60 years, 29.5 kg for men <60 years, and 21.9 kg for men ⩾60 years). We used Cox regression to estimate the mortality hazard ratio. The %ERE was determined by the equation (HR1 - HR2)/(HR1 - 1) × 100, in which HR1 represented the hazard ratio in a model with a smaller number of covariates and HR2 represented the hazard ratio in a subsequent model with the inclusion of new covariates plus the variables included in the previous model. RESULTS:: The mortality hazard ratio comparing low and high handgrip strength was 2.58 (95% confidence interval: 1.73, 3.85) in the model with sociodemographic factors and vintage and 2.25 (95% confidence interval: 1.49, 3.43) with addition of comorbidities, corresponding to a %ERE of 21%. The hazard ratio was 1.98 (95% confidence interval: 1.29, 3.06) after addition of nutritional indicators corresponding to %ERE of 38%. Results stratified by age and gender followed similar patterns. CONCLUSION:: These results provide support for the assessment of handgrip strength in all maintenance hemodialysis patients for early identification of those who may require special care to improve nutritional status and survival.

A 3-day diary of dietary protein and calorie intake by serum phosphate concentration and binder use in hemodialysis patients.

INTRODUCTION: The use of phosphate binders to control hyperphosphatemia may allow diets less restricted in protein and calories for maintenance hemodialysis (MHD) patients. The study compared intakes of protein, calorie and phosphate among MHD patients with different serum phosphate concentrations, taking into account binder use. The hypothesis was that low serum phosphate would be associated with low intakes of protein and calories only in patients not on binders. METHODS: A cross-sectional study of 443 patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO) in Salvador, Brazil, with stratified sampling on serum phosphate: ≤3.0 (n = 41), 3.5-5.5 (n = 328) and ≥7.0 mg/dL (n = 74). A 3-day diet diary was used to determine dietary intakes. RESULTS: Approximately 49.0% confirmed binder use. Covariate-adjusted linear regression showed that associations between dietary intakes and serum phosphate were modified by the binder use. In patients not on binders, protein intake was >20% lower for serum phosphate ≤3.0 mg/dL compared to higher concentrations. Also in those not on binders, calorie intake was >30% lower for serum phosphate ≤3.0 mg/dL compared to ≥7.0 mg/dL. Differences in dietary intakes by serum phosphate were virtually absent in patients on binders. CONCLUSIONS: The results are consistent with the hypothesis that low serum phosphate is associated with low protein and calorie intake only among MHD patients not on binders. This study supports recommendations to prevent hyperphosphatemia in MHD patients by adequate combination of binder use and selection of foods restricted in phosphors but not severely restricted in protein and calories.

Associations of physical activity energy expenditure with nutritional-inflammatory markers in hemodialysis patients.

BACKGROUND: Sedentariness, high inflammation status and malnutrition are highly prevalent in end-stage kidney disease patients on maintenance hemodialysis (MHD). This study investigated associations of weekly physical activity energy expenditure (PAEE) with clinical and anthropometric markers of nutrition and inflammation. METHODS: The analysis was performed using baseline cross-sectional data of 640 patients enrolled in the prospective cohort "The Prospective Study of the Prognosis of Patients Treated Chronically by Hemodialysis" (PROHEMO) developed in Salvador, BA, Brazil. The long version of the International Physical Activity Questionnaire was used to determine a summary measure of PAEE, the metabolic equivalent of task (MET), taking into account physical activities related to occupation, recreation, travel, sports, and housework. PAEE was the predictor variable. To assess associations of PAEE with outcomes, the sex-age-specific median MET was used. The malnutrition-inflammation score (MIS) with range of 0 to 30 (higher is worse), conicity index as indicator of abdominal adiposity and C-reactive protein (CRP) were the nutritional-inflammatory outcomes. RESULTS: The mean age of the patients was 48.9 ± 13.8 y, 60.3% were males, 16.7% diabetic, 88.1% nonwhite. In multivariable logistic regression models with adjustments for sociodemographic variables and comorbidities, PAEE ≤median was associated with MIS ≥6 (odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.08, 2.29), conicity index ≥1.3 (OR = 1.52, 95% CI = 1.03, 2.23) and CRP >1.30 mg/dL (OR = 1.69, 95% CI = 1.08, 2.84). CONCLUSIONS: Greater physical activity assessed by PAEE was associated with indicators of better nutritional and inflammation status. These results indicate opportunities for improving outcomes in MHD patients by counseling and treatment intervention.

Coping with fluid restriction and the quality of life in hemodialysis patients with very low or no daily urine output.

PURPOSE: Fluid restriction is crucial to prevent circulatory overload in maintenance hemodialysis (MHD) patients with very low urine volume, but fluid restriction may result in psychological distress. We studied MHD patients with urine volume ≤ 200 ml/day to investigate if their acceptance of fluid restriction was associated with their health-related quality of life (HRQOL). METHODS: Cross-sectional study of 271 Brazilian adult MHD patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO). To assess the acceptance of fluid restriction, patients were asked about the extent of feeling bothered by living on this restriction. The KDQOL was used to determine HRQOL scores. Higher scores indicate better HRQOL with differences of >3.0 points considered clinically significant. RESULTS: 52.4% reported being "moderately to extremely" bothered by fluid restriction and had lower scores for all HRQOL scales than patients less bothered by fluid restriction. The largest covariate-adjusted differences in HRQOL were 19.5 for emotional role (p<0.001), 15.1 for emotional well-being (p<0.001), and 14.1 for vitality (p<0.001). Adjusted differences were larger for mental component (7.53 points, p<0.001) than for physical component (2.07, p = 0.075) summaries. CONCLUSIONS: These results indicate that MHD patients with a lower level of acceptance of fluid restriction have poorer HRQOL, particularly in mental domains of HRQOL. The high prevalence of poor acceptance of fluid restriction in the present study underscores the need for interventions to improve acceptance of fluid restriction and determine if such interventions improve HRQOL of MHD patients with very low urine volume.