Mutation distributions among patients with congenital adrenal hyperplasia from five regions of Brazil: a systematic review

ABSTRACT Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations' distribution among Brazilian regions.Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.

Mutation distributions among patients with congenital adrenal hyperplasia from five regions of Brazil: a systematic review.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations' distribution among Brazilian regions. Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.

Women's experiences of early pregnancy assessment unit services: a qualitative investigation.

OBJECTIVE: To explore the experiences of women who had used an Early Pregnancy Assessment Unit (EPAU) service in the UK and make recommendations for their improvement. DESIGN: Qualitative interview study. SETTING: Early Pregnancy Assessment Units in the UK. SAMPLE: A maximum variation sample of women who had consented to be interviewed having attended one of 26 EPAUs involved in the VESPA study in 2018. METHODS: In-depth telephone interviews with 38 women. A thematic framework analysis was conducted, with a focus on how experiences varied according to EPAU service configuration and clinical pathway. MAIN OUTCOME MEASURES: Women's experiences of EPAU services. RESULTS: We found that EPAUs are highly valued, and women's experiences were generally positive. However, women reported a range of issues that negatively affected their experience. These included difficulties accessing the service, insensitive management of the investigation and treatment options of pregnancy loss, poor communication, insufficient information and a lack of support for their psychological health. These issues were not strongly associated with EPAU configuration or clinical pathway. CONCLUSIONS: Recommendations to improve women's experiences include the separation of EPAUs from general maternity services, and we make suggestions on how to remove barriers to access by reviewing opening hours, how to provide sensitive patient management, such as automatically cancelling appointments and scans following pregnancy loss, and how to improve communication, both with women and their partners as well as with other parts of the health service. TWEETABLE ABSTRACT: Early Pregnancy Assessment Units are highly valued by women but aspects of their care experiences, particularly around sensitive management of pregnancy loss, could be improved.

Análise da permanência em maternidade hospitalar / Analysis of staying in hospital maternity

Pesquisa documental, descritiva e quantitativa que objetivou identificar a permanência de pacientes hospitalizadas na maternidade de um hospital universitário público...

Documentary, descriptive and quantitative research that aimed to identify the permanence of hospitalized patients in the maternity hospital of a public university hospital...

Investigación documental, descriptiva y cuantitativa que objetivó identificar la permanencia de pacientes hospitalizados en la maternidad de un hospital universitario público...

Perfil sociodemográfico, clínico-obstétrico e taxa de parto cesáreo em hospital universitário público / Socio-demographic, clinical-obstetric profile and cesarean delivery rate in hospital public university

Pesquisa documental, descritiva e quantitativa que objetivou identificar o perfil de pacientes atendidas em um centroobstétrico de hospital universitário público e determinar a taxa de parto cesáreo. Foi realizada com uso de planilhas preenchidas pelaequipe de enfermagem do serviço, em recorte temporal que compreendeu mais de três meses de análise entre 2015 e 2016. Às variáveissociodemográficas, clínico-obstétricas e de motivos de parto cesáreo coletadas e tabuladas eletronicamente, procedeu-se análiseestatística descritiva. As pacientes (n=592) eram adultas jovens (55%), em união estável (61,8%) e possuíam ensino médio (62,4%).Realizaram de 6 a 20 consultas pré-natais (78%) e estavam na primeira gestação (37,2%). Houve pouco registro (n=50) de diagnósticosmédicos de patologias nas mulheres. A taxa de parto cesáreo foi de 47,7%, entre diversos (n=36) motivos de indicação. Concluiuseque o perfil é muito bem delimitado e a taxa de cesariana foi alta, o que fornece subsídio para o (re) planejamento do serviço.

Clinical course of 822 children with prenatally detected nephrouropathies.

BACKGROUND AND OBJECTIVES: With the advent of fetal screening ultrasonography, the detection of congenital anomalies of the kidney and urinary tract (CAKUT) in utero has permitted early management of these conditions. This study aims to describe the clinical course of a large cohort of patients with prenatally detected nephrouropathies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective cohort study, 822 patients were prenatally diagnosed with CAKUT and systematically followed up at a tertiary Renal Unit for a median time of 43 months. Variables included in the analysis were sex, laterality, fetal ultrasonography (isolated versus associated hydronephrosis), and presence/absence of nephrouropathies. The events of interest were urinary tract infection, surgical interventions, hypertension, CKD, and death. Survival analyses were performed to evaluate time until occurrence of the events of interest. RESULTS: Urinary tract infection occurred in 245 (29.8%) children, with higher risk in females (hazard ratio=1.30, 95% confidence interval=1.02-1.70, P=0.05); 22 patients (2.7%) had hypertension, and 49 (6%) patients developed CKD. The risk of CKD was greater in patients with associated hydronephrosis (hazard ratio=5.20, 95% confidence interval=2.90-9.30, P<0.001). Twelve patients (1.5%) died during follow-up. Death was significantly associated with being born during the first period of the study (hazard ratio=6.00, 95% confidence interval=1.60-22.50, P<0.001), associated hydronephrosis (hazard ratio=9.30, 95% confidence interval=2.90-29.30, P<0.001), and CKD (hazard ratio=170.00, 95% confidence interval=41.00-228.00, P<0.001). CONCLUSIONS: In our series, the clinical course of prenatally detected CAKUT was heterogeneous, and those infants with associated hydronephrosis at baseline were identified as a high-risk subgroup.

Behavioral disorders and low quality of life in children and adolescents with chronic kidney disease.

Recent years has seen an increasing interest in the quality of life (QOL) of children with chronic kidney disease (CKD). The objective of this cross-sectional study was to investigate the prevalence of behavioral disorders and to assess the health-related QOL (HRQOL) in 136 patients with CKD. To estimate the prevalence of behavior disorders and analyze HRQOL, we used the Strengths and Difficulties Questionnaire (SDQ) and Pediatric Inventory of Quality of Life (PedsQL) Core Scales as assessment tools for both the patients and caregivers. When compared to healthy controls, the CKD group had significantly lower scores in almost all PedsQL domains. After adjustment, only absence of religion/other religions remained significantly associated with a lower global HRQOL score [odds ratio (OR) 6.2, P=0.009]. Among the parents, two factors remained significantly associated with a lower global HRQOL score: patients' age >10 years (OR 5.4, P=0.033) and absence of religion/other religions (OR 3.2, P=0.038). The CKD group demonstrated a higher proportion of behavioral and emotional disorders in all SDQ domains. There was a negative correlation between the presence of behavior and emotional disorders and HRQOL score (r= -0.552, P<0.001). Our findings suggest the importance of evaluating behavioral and social repercussions of CKD in order to improve the life quality of this pediatric population.

Risk factors for recurrent urinary tract infections in a cohort of patients with primary vesicoureteral reflux.

BACKGROUND: Knowledge of risk of urinary tract infection (UTI) recurrence in vesicoureteral reflux (VUR) can help clinicians make therapeutic decisions. The aim of this retrospective cohort study was to identify risk factors associated with recurrent urinary tract infection in children with VUR. In addition, a risk score that might predict the chance of UTI recurrence was also proposed. METHODS: Between 1970 and 2007, 740 patients were diagnosed with VUR and were systematically followed up at a single tertiary Renal Unit. Recurrent UTI was defined as more than 1 episode during follow-up. A binary logistic regression model was applied to identify variables independently associated with recurrent UTIs. RESULTS: During follow-up, information was obtained on 58,856 person-months. Recurrent UTIs occurred in 120 (16.2%) patients. The overall incidence rate of UTI was 8.4 episodes per 1000 person-months (95% CI, 7.7, 9.2). After adjustment by multivariable analysis, 5 variables were independent predictors of recurrent UTI: UTI as clinical presentation, age < 6 months, female gender, dysfunctional elimination syndrome, and severe grade of reflux. The risk for recurrent UTI was classified as low in 24% of children, medium in 42%, and high in 34%. UTI incidence rates per 1000 person-months were 4.3 (95% CI, 3.2, 5.6), 7.9 (95% CI, 6.7, 9.1), and 11.3 (95% CI, 9.9, 12.8) for low-, medium-, and high-risk groups, respectively. CONCLUSION: The prediction model of recurrent UTI allows an early recognition of patients at risk for long-term morbidity and might contribute to the formulation of therapeutic strategies.

Independent risk factors for renal damage in a series of primary vesicoureteral reflux: a multivariate analysis.

AIM: The aim of this study was to investigate risk factors associated with different extents of renal parenchyma involvement in a paediatric series of primary vesicoureteral reflux (VUR). METHODS: A total of 549 patients with VUR were analyzed. The variable of interest was renal scar, assessed by technetium-99m dimercaptosuccinic acid scan, and classified into three subtypes: focal scar, multiple cortical scarring and diffuse scars with a contracted renal unit. The multinomial regression model was applied to identify independent variables associated with each subtype of renal damage. RESULTS: After adjustment, four variables remained independently associated with a contracted renal unit: reflux grades III-V (odds ratio (OR)=9.7; 95% confidence interval (CI) = 4.1-21.0), age at diagnosis (OR=3; 95% CI=1.6-5.1), unilateral reflux (OR=2.1; 95% CI=1.2-3.8), and male sex (OR=2; 95% CI=1.1-3.8). Two variables were associated with multiple scars: reflux grades III-V (OR=13.8; 95% CI=7.4-26.0) and age at diagnosis (OR=1.9; 95% CI=1.2-3.0). Two variables were associated with a focal scar: reflux grades III-V (OR=7.9, 95% CI CI=3.8-16.4) and male sex as a protective factor (OR=0.5; 95% CI=0.25-1.0). CONCLUSION: Our findings suggest that the development of a contracted renal unit is probably due to congenital malformation, more commonly observed in male infants with high-grade reflux.

Predictive factors of progression to chronic kidney disease stage 5 in a predialysis interdisciplinary programme.

BACKGROUND: The clinical course of chronic kidney disease (CKD) in children is heterogeneous and has not been fully established. The aim of this retrospective cohort study was to identify predictive factors associated with the progression of CKD among the children and adolescents admitted to a Predialysis Interdisciplinary Management Programme (PDIMP). METHODS: We analysed the following variables at admission: age, gender, race, blood pressure, primary renal disease, Z-scores for weight and height, CKD stage and degree of proteinuria. Two time-dependent covariates were considered: hypertension and proteinuria. CKD stage 5 was assigned as a dependent variable. Time-fixed and time-dependent Cox regression analyses were applied to evaluate renal survival. RESULTS: One hundred and seven patients with CKD stage 2-4 were followed up for a median time of 94 months. Fifty-seven patients (53.3%) progressed to CKD stage 5. After adjustment for time-fixed model, three baseline variables were found to be independent predictors of CKD stage 5: glomerular disease (hazard ratio, HR = 3.0, P = 0.015), CKD stage 4 (HR = 2.6, P = 0.001) and severe proteinuria (HR = 4.1, P = 0.006). After adjustment for the time-dependent model, three variables were found to be independent predictors of CKD stage 5: proteinuria as time-dependent covariate (HR = 1.9, P = 0.041), CKD stage 4 (HR = 2, P = 0.0086) and baseline serum albumin <3.5 g/dl (HR = 2.6, P = 0.0015). CONCLUSIONS: Taking into account manageable factors, further prospective controlled studies are necessary to assess intervention measures in order to possibly modify the clinical course of CKD in children.

Clinical outcome of children with chronic kidney disease in a pre-dialysis interdisciplinary program.

The purpose of this retrospective cohort study was to describe the outcome of 107 patients with chronic kidney disease (CKD) admitted to a pre-dialysis interdisciplinary management program from 1990 to 2006. The events of interest were progression to CKD stage 5 (renal survival), patient survival, hypertension, and somatic growth. Survival was studied by the Kaplan-Meier method. Patients were classified into four groups according to their primary renal disease: congenital nephro-uropathies; glomerular diseases; cystic disease, and miscellaneous. Median follow-up time was 94 months [Interquartile (IQ) range 38-145]. The probability of reaching CKD stage 5 was estimated to be 36% by 5 years after admission. As a whole, the mean estimated glomerular filtration rate (GFR) decrease per year was 5.8 ml/min per 1.73 m(2) body surface area [standard deviation (SD) 12.4]. The glomerular diseases group showed a median rate of GFR deterioration of 10 ml/min per 1.73 m(2) per year (IQ range -24 to -5.7), whereas the median rate of GFR deterioration for the groups with cystic diseases, congenital nephro-uropathies, and miscellanea were 2.5 ml/min (IQ range -10 to +0.34), 2.2 ml/min (IQ range -5.0 to -0.52), and 0.36 ml/min (IQ range -2.5 to +2.6), respectively (P < 0.001). The results of this study support the view that children and adolescents with glomerular diseases present a faster deterioration of renal function. Therefore, patients with glomerular diseases need to be referred early to a pediatric nephrology center so that suboptimal pre-dialysis care might possibly be avoided.

Risk of hypertension in primary vesicoureteral reflux.

The aim of this report was to estimate the risk of hypertension in children with primary vesicoureteral reflux (VUR). Between 1970 and 2004, 735 patients were diagnosed with VUR at a single tertiary renal unit. Of 735 patients, 664 (90%) were systematically followed and had multiple measurements of blood pressure. Hypertension was defined as values persistently above 95th for age, sex, and height in three consecutive visits. Risk of hypertension was analyzed by the Kaplan-Meier method. Of 664 patients followed, 20 (3%) developed hypertension. The estimated probability of hypertension was 2% (95%CI, 0.5%-3%), 6% (95%CI, 2%-10%), 15% (95%CI, 11%-20%) at 10, 15, and 21 years of age, respectively. The prevalence of hypertension has increased with age: it was 1.7% for patients with 1 yr-9.9 yr, 1.8% for adolescents with 10 yr-14.9 yr, 4.7% for patients with 15-19.9 yr, and 35% for patients>20 years at the end of the follow-up (P<0.001). It was estimated by survival analysis that 50% of patients with unilateral and bilateral renal damage would have sustained hypertension at about 30 and 22 years of age, respectively. Hypertension increased with age and was strongly associated with renal damage at entry in an unselected population of primary VUR.

Circulating renin Angiotensin system in childhood chronic renal failure: marked increase of Angiotensin-(1-7) in end-stage renal disease.

The aim of the present study was to evaluate plasma renin activity (PRA) and Angiotensin (Ang) levels [Ang I, Ang II and Ang-(1-7)] to examine the circulating Renin-Angiotensin System (RAS) in renal disease among children with different forms and stages of chronic renal failure (CRF). Subjects were divided as follows: 32 normotensive healthy subjects, 23 normotensive CRF subjects, 34 hypertensive CRF subjects and 21 subjects with end-stage renal disease (ESRD). Radioimmunoassays for PRA (ngAngI/mL/h) and angiotensin (pg/mL) measurements were performed on all subjects. PRA, Ang I, Ang II and Ang-(1-7) levels were significantly higher in hypertensive CRF subjects when compared with normotensive CRF and healthy subjects (p < 0.05 for all comparisons). No differences were observed between normotensive CRF and healthy subjects. ESRD subjects exhibited a dramatic increase in Ang-(1-7) (25-fold higher than control values). In hypertensive CRF subjects, treatment with angiotensin-converting enzyme inhibitors (ACEi) increased (1.4-fold) plasma Ang-(1-7) and decreased (2.4-fold) Ang II. In ESRD, the use of ACEi produced a similar (1.5-fold) elevation of Ang-(1-7), but no changes in plasma Ang II. Our data showed different circulating RAS profiles between hypertensive and in normotensive CRF subjects. Marked changes in plasma Ang-(1-7) were associated with the presence of hypertension and progression of kidney dysfunction.

Predictive factors of resolution of primary vesico-ureteric reflux: a multivariate analysis.

OBJECTIVE: To identify independent factors predicting the resolution of primary vesico-ureteric reflux (VUR) in a cohort of medically managed children. PATIENTS AND METHODS: Between 1977 and 2003, 506 children were diagnosed with VUR and were conservatively managed and prospectively followed. All of the children were maintained on antibiotic prophylaxis. Follow-up imaging consisted of voiding cysto-urethrography (VCUG) or a direct isotope cystogram at intervals of 2-3 years. The predictive factors used are based on the patient data at the time of entry in the protocol. The dependent variable was VUR resolution. The criterion for resolution was based on a single negative VCUG or direct isotope cystogram. A survival analysis identified variables significantly associated with VUR resolution. Cox's regression model was applied to identify variables independently associated with the dependent variable. RESULTS: After adjustment, four variables remained as independent predictors of VUR resolution: nonwhite race, relative risk (95% confidence interval) of 1.5 (1.1-1.9; P = 0.009); mild grade of VUR, 3.3 (2.1-5.3; P < 0.001); absence of renal damage, 3.3 (2.4-4.5; P < 0.001); and absence of dysfunctional voiding, 2.0 (1.4-3.1; P < 0.001). For mild VUR, three variables were significantly associated: male gender, 1.7 (1.1-2.6; P = 0.012); absence of renal damage, 3.4 (1.8-6.4; P < 0.001); and unilateral VUR, 1.6 (1.1-2.3; P = 0.004). For moderate/severe VUR, three variables were significantly associated: nonwhite race, 1.7 (1.1-2.6; P = 0.01); absence of renal damage, 3.0 (2.0-4.4; P < 0.001); and absence of dysfunctional voiding, 2.8 (1.4-5.5; P = 0.004). CONCLUSION: Few factors are amenable to intervention to modify the natural history of VUR. According to our findings, there are only two possible interventions: avoiding renal scars and managing voiding dysfunction.

A visita domiciliar como estratégia assistencial no cuidado de doentes crônicos / Home visits as an assistance strategy in chronic disease care / La visita domiciliar como estrategia asistencial en el cuidado de enfermos crónicos

O estudo trata da importância da utilização da visita domiciliar na identificação de características e informações relacionadas às conseqüências da doença renal crônica na vida de pacientes e familiares atendidos pelos profissionais do Programa Interdisciplinar de Prevenção e Assistência na IRC em Crianças e Adolescentes do Hospital das Clínicas da UFMG. Foram visitados 21 doentes, sendo entrevistado um familiar. Entre as modificações ocorridas com a família, foram citadas as dificuldades de o familiar responsável pelos cuidados ter atividades fora do lar e as mudanças dos padrões alimentares de toda a família. A visita domiciliar se mostrou uma estratégia assistencial eficiente, contribuindo para a relação entre pacientes, familiares e profissionais.

This study emphasizes the importance of home visits in identifying the characteristics and information on the consequences of chronic renal disease in the life of patients and their families cared for by health workers in the Interdisciplinary Program for Prevention and Care in the Chronic Renal Failure for Children and Adolescents at the University Hospital of the Federal University of Minas Gerais. Twenty-one patients were visited and a family memeber of each one was interviewed. Modifications in the family included difficulties when the person caring for the patient had outdoor activities and the changes in eating patterns for the whole family. Home visits showed themselves to be an efficient strategy for care, contributing to the relation between patients, family members and health workers.

El estudio trata sobre la importancia de utilizar la visita domiciliaria para identificar características e informaciones relacionadas con las consecuencias de la enfermedad renal crónica en la vida de pacientes y familiares atendidos por los profesionales del Programa Interdisciplinario de Prevención y Asistencia a la IRC (insuficiencia renal crónica) en Niños y Adolescentes del Hospital de Clínicas de la UFMG (Universidad Federal de Minas Gerais). Se efectuaron visitas a 21 enfermos y entrevista a un familiar. Entre las modificaciones ocurridas en la familia se citaron las dificultades del familiar responsable de los cuidados para conciliar sus tareas fuera del hogar y los cambios en la alimentación de toda la familia. La visita domiciliaria demostró ser una estrategia asistencial eficiente que contribuye a la relación entre pacientes, familiares y profesionales.

[Baseline clinical features of 483 children and adolescents with primary vesicoureteral reflux: a retrospective study]. / Características clínicas e laboratoriais à admissão de 483 crianças e adolescentes com refluxo vésico-ureteral primário: estudo retrospectivo.

OBJECTIVES: To evaluate the clinical/radiological features of patients with primary vesicoureteral reflux (VUR) admitted to a single institution from 1969 to 1999. METHODS: At admission, after the institution of chemoprophylaxis, patients were investigated by CUM, DMSA, and US. The children were managed with periodical clinical and laboratory evaluations. Analyses were performed with the data obtained at admission. RESULTS: A total of 483 patients were enrolled in the protocol. There was a predominance of females (70%) and caucasian race (70%). Mean age at VUR diagnosis was 26 months and 92.5% of the patients had urinary infection before admission. A total of 710 refluxing units were analyzed. The distribution of reflux grade was: grade I (49; 7%); II (254; 36%); III (190; 26%); IV (161; 23%) e V (56; 8%). Approximately one half of the units analyzed were from patients presenting renal damage at admission. The distribution of the severity of renal damage was as follows: mild (36%), moderate (34%), and severe (30%). There was a significant risk of severe renal damage for the males (OR = 1.74, 95% CI = 1.2 - 2.5, p = 0.002). CONCLUSION: There was a predominance of VUR among females and most presented a mild or moderate degree. However, there was a high percentage of renal damage at admission and a tendency to greater morbidity for the males.