Publications by authors named "Alberto Caldas Afonso"

24 Publications

  • Page 1 of 1

Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center.

J Bras Nefrol 2021 May 12. Epub 2021 May 12.

Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do Norte, Unidade de Nefrologia Pediátrica, Porto, Portugal.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, which primarily affects preschool-aged children. This study's aim was to describe the clinical profile, management, and long-term outcome of the genetic aHUS patients admitted to a tertiary care pediatric nephrology center during 20 years.

Methods: We performed a retrospective analysis of the clinical records of all aHUS patients younger than 18 years with identified genetic mutations. Data on clinical features, genetic study, therapeutic interventions, and long-term outcomes were reviewed.

Results: Five cases of aHUS with an identified genetic mutation were included; all were inaugural cases with the youngest being 4 months old. Complement factor H gene mutation was identified in four patients. Therapeutic plasma exchange was performed for acute management in 4 patients, one of whom also needed acute renal replacement therapy (peritoneal dialysis). All patients went on complete remission, 2 had more than one relapse but only 1 of these progressed to chronic kidney disease during the follow-up period (median (25th-75th percentile), 136 (43.5-200.5) months).

Conclusion: In children, the prognosis of renal function seems to be strongly dependent on the genetic background, thus being crucial to perform genetic study in all aHUS cases. In our cohort, 2 patients presented genetic mutations not previously described. Recent innovations on the genetic field leading to the identification of new mutations has lead to a better understanding of aHUS pathogenesis, but further studies, focusing on the genotype-phenotype correlation, with longer follow-up periods, are needed.
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http://dx.doi.org/10.1590/2175-8239-JBN-2020-0199DOI Listing
May 2021

Renal Transplant in Pediatric Patients With Congenital Abnormalities of the Lower Urinary Tract.

Exp Clin Transplant 2021 Apr 19;19(4):310-315. Epub 2021 Feb 19.

From the Unit of Pediatric Nephrology of the Pediatric Department - Centro Materno-Infantil do Norte - Centro Hospitalar Universitário do Porto, Portugal.

Objectives: Congenital abnormalities of the lower urinary tract can result in end-stage renal disease and are responsible for a significant number of renal transplants. Management of these patients is not always consensual, and more evidence is required about the frequency of associated complications. Our aim was to report the experience of a Pediatric Renal Transplant Unit with renal transplant in pediatric patients with congenital abnormalities of the lower urinary tract.

Materials And Methods: Data on renal transplants performed in pediatric patients with congenital abnormalities of the lower urinary tract between January 1, 2009, and December 31, 2019, in this center were retrospectively reviewed.

Results: Fifty-three pediatric renal transplants were performed in the institution during the considered time period. Of these, 26 transplants were performed in 24 patients with congenital abnormalities of the lower urinary tract, and 14 were male. The median age at the time of renal transplant was 10.5 years (interquartile range, 5.25-15 years), and the most frequent diagnoses were neurogenic bladder (n = 7; 29%) and posterior urethral valve (n = 7; 29%). Three patients (13%) underwent preemptive renal transplant, 15 were on peritoneal dialysis (63%), and 6 were on hemodialysis (25%). A total of 81 pyelonephritides were diagnosed in the 24 patients, mostly attributed to Escherichia coli, followed by Klebsiella pneumonia. The median follow-up was 92.5 months (interquartile range, 52.3-114 months). For patients with congenital abnormalities of the lower urinary tract, graft survival was 92.3% at 1, 5, and 10 years, with no deaths reported.

Conclusions: Renal transplant is the treatment of choice for pediatric patients with end-stage renal disease. The procedure does not seem to be associated with worse patient outcomes. Additionally, despite the significant number of pyelonephritides cases, it does not seem to result in decreased graft or patient survival.
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http://dx.doi.org/10.6002/ect.2020.0325DOI Listing
April 2021

Impact of physical activity on redox status and nitric oxide bioavailability in nonoverweight and overweight/obese prepubertal children.

Free Radic Biol Med 2021 02 11;163:116-124. Epub 2020 Dec 11.

Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal; EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Portugal; Department of Pediatric Nephrology, Centro Materno-Infantil Do Norte, Centro Hospitalar Universitário Do Porto, Porto, Portugal. Electronic address:

Nutritional status might contribute to variations induced by physical activity (PA) in redox status biomarkers. We investigated the influence of PA on redox status and nitric oxide (NO) production/metabolism biomarkers in nonoverweight and overweight/obese prepubertal children. We performed a cross-sectional evaluation of 313 children aged 8-9 years (163 nonoverweight, 150 overweight/obese) followed since birth in a cohort study (Generation XXI, Porto, Portugal). Plasma total antioxidant status (P-TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-HO), myeloperoxidase (MPO) and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were assessed, as well as their association with variables of reported PA quantification (categories of PA frequency (>1x/week and ≤1x/week)and continuous PA index (obtained by the sum of points)) in a questionnaire with increasing ranks from sedentary to vigorous activity levels. U-NOx was significantly higher in children who presented higher PA index scores and higher PA frequency. Separately by BMI classes, U-NOx was significantly higher only in nonoverweight children who practiced PA more frequently (p = 0.037). In overweight/obese children, but not in nonoverweight, P-TAS was higher among children with higher PA frequency (p = 0.007). Homeostasis model assessment index (HOMA-IR) was significantly lower in more active overweight/obese children, but no differences were observed in nonoverweight children. In the fully adjusted multivariate linear regression models for P-TAS, in the overweight/obese group, children with higher PA frequency presented higher P-TAS. In the U-NOx models, U-NOx significantly increased with PA index, only in nonoverweight children. Our results provide additional evidence in support of a protective effect of physical activity, in nonoverweight by increasing NO bioavailability and in overweight/obese children by enhancing systemic antioxidant capacity and insulin sensitivity. These results highlight the importance of engaging in regular physical exercise, particularly among overweight/obese children, in which a positive association between oxidant status and cardiometabolic risk markers has been described.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.005DOI Listing
February 2021

Prenatal alcohol exposure affects renal function in overweight schoolchildren: birth cohort analysis.

Pediatr Nephrol 2020 04 9;35(4):695-702. Epub 2019 Dec 9.

EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.

Background: Prenatal ethanol exposure has been shown to reduce nephron endowment in animal models, but the effect of alcohol during human pregnancy on postnatal kidney function has not been explored. We aim to investigate the potential association of maternal alcohol consumption during pregnancy with the offspring renal function, considering potential confounding by intrauterine growth and children's current nutritional status.

Methods: Prospective longitudinal study in a random sample of 1093 children from a population-based birth cohort. Anthropometrics and estimated glomerular filtration rate (eGFR) were assessed at 7 years of age. Multiple linear regression models were fitted, adjusting for child's gender, age, birthweight, and maternal age, education, prepregnancy nutritional status, and smoking.

Results: Thirteen percent of mothers consumed alcohol during pregnancy. At 7 years of age, eGFR was significantly lower in children with prenatal alcohol exposure (134 ± 17 vs.138 ± 16 mL/min/1.73m, p = 0.014). The effect was dose dependent and only present in overweight and obese children, among whom adjusted eGFR was -6.6(-12.0 to -1.1)mL/min/1.73m and -11.1(-21.3 to -1.2)mL/min/1.73m in those exposed to ≤ 40 g and to > 40 g of alcohol per week, respectively, compared to no consumption (p = 0.002).

Conclusions: Prenatal alcohol exposure has a dose-dependent adverse effect on renal function at school age in overweight and obese children.
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http://dx.doi.org/10.1007/s00467-019-04429-xDOI Listing
April 2020

Acute dialysis in children: results of a European survey.

J Nephrol 2019 Jun 4;32(3):445-451. Epub 2019 Apr 4.

Nephrology and Dialysis Unit, Pediatric Subspecialties Department, Institute for Scientific Research, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.
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http://dx.doi.org/10.1007/s40620-019-00606-1DOI Listing
June 2019

Childhood Obesity and Impact on the Kidney.

Nephron 2019 25;143(1):8-11. Epub 2018 Oct 25.

EPIUnit, Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.

Obesity is known to be associated with a myriad of cardiovascular and metabolic comorbidities. In children, several longitudinal studies have shown that obesity consequences start early in life and accompany the obese child into adulthood, implying a higher risk of adverse cardiovascular events. More recently, data related to the possible role of obesity in the risk of kidney disease in adults, independently of diabetes, has started to become more available. In children, the evidence is scarcer, but it has also been acknowledged that obesity acts as a risk factor for disease progression when kidney impairment already exists, thereby increasing the risk of death among children with end-stage renal disease (ESRD). Besides this, there is also evidence that otherwise healthy overweight and obese children have a significant increase in the risk of all-cause ESRD later in life. The potential mechanisms underlying this association need to be further discussed in order to allow the setting in motion of preventive strategies to halt chronic kidney disease development and progression.
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http://dx.doi.org/10.1159/000492826DOI Listing
July 2020

Prevalence of Hypertension in Children with Early-Stage ADPKD.

Clin J Am Soc Nephrol 2018 06 19;13(6):874-883. Epub 2018 Apr 19.

Pediatric Nephrology Division, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.

Background And Objectives: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited.

Design, Setting, Participants, & Measurements: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected.

Results: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; =0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; =0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; =0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; =0.10).

Conclusions: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.
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http://dx.doi.org/10.2215/CJN.11401017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989684PMC
June 2018

Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children.

JAMA Pediatr 2017 11 6;171(11):e172914. Epub 2017 Nov 6.

Department of Medicine, Rush University Medical Center, Chicago, Illinois.

Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults.

Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD.

Design, Setting, And Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016.

Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy.

Main Outcomes And Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2.

Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007).

Conclusions And Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.
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http://dx.doi.org/10.1001/jamapediatrics.2017.2914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121753PMC
November 2017

Longer duration of obesity is associated with a reduction in urinary angiotensinogen in prepubertal children.

Pediatr Nephrol 2017 Aug 23;32(8):1411-1422. Epub 2017 Mar 23.

Department of Pharmacology and Therapeutics, Faculty of Medicine of University of Porto, Porto, Portugal.

Background: We aimed to study the impact of obesity on urinary excretion of angiotensinogen (U-AGT) in prepubertal children, focusing on the duration of obesity and gender. Also, we aimed to evaluate whether plasma angiotensinogen (P-AGT) and hydrogen peroxide (HO) play a role in the putative association.

Methods: Cross-sectional evaluation of 305 children aged 8-9 years (160 normal weight, 86 overweight, and 59 obese). Anthropometric measurements and 24-h ambulatory blood pressure monitoring were performed. Angiotensinogen (AGT) was determined by a commercial enzyme-linked immunosorbent assay (ELISA) kit and HO by a microplate fluorometric assay.

Results: U-AGT and P-AGT levels were similar across body mass index (BMI) groups and between sexes. However, boys who were overweight/obese since the age of 4 years presented lower levels of U-AGT compared with those of normal weight at the same age. In children who were overweight/obese since the age of 4, urinary HO decreased with P-AGT.

Conclusions: A higher duration of obesity was associated with decreased U-AGT in boys, thus reflecting decreased intrarenal activity of the renin-angiotensin system. Also, children with a longer duration of obesity showed an inverse association between urinary HO and P-AGT. Future studies should address whether these results reflect an early compensatory mechanism to limit obesity-triggered renal dysfunction.
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http://dx.doi.org/10.1007/s00467-017-3639-yDOI Listing
August 2017

Dedicated Pediatricians in Emergency Department: Shorter Waiting Times and Lower Costs.

PLoS One 2016 26;11(8):e0161149. Epub 2016 Aug 26.

Centro Hospitalar de S. João, Porto, Portugal.

Background: Dedicated pediatricians in emergency departments (EDs) may be beneficial, though no previous studies have assessed the related costs and benefits/harms. We aimed to evaluate the net benefits and costs of dedicated emergency pediatricians in a pediatric ED.

Methods: Cost-consequences analysis of visits to a pediatric ED of a tertiary hospital. Two pediatric ED Medical Teams (MT) were compared: MT-A (May-September 2012), with general pediatrics physicians only; and MT-B (May-September 2013), with emergency dedicated pediatricians. The main outcomes analyzed were relevant clinical outcomes, patient throughput time and costs.

Results: We included 8,694 children in MT-A and 9,417 in MT-B. Medication use in the ED increased from 42.3% of the children in MT-A to 49.6% in MT-B; diagnostic tests decreased from 24.2% in MT-A to 14.3% in MT-B. Hospitalization increased from 1.3% in MT-A to 3.0% in MT-B; however, there was no significant difference in diagnosis-related group relative weight of hospitalized children in MT-A and MT-B (MT-A, 0.979; MT-B, 1.075). No differences were observed in ED readmissions or in patients leaving without being seen by a physician. The patient throughput time was significantly shorter in MT-B, with faster times to first medical observation. Within the cost domains analyzed, the total expenditures per children observed in the ED were 16% lower in MT-B: 37.87 euros in MT-A; 31.97 euros in MT-B.

Conclusion: The presence of dedicated emergency pediatricians in a pediatric ED was associated with significantly lower waiting times in the ED, reduced costs, and similar clinical outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161149PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001635PMC
August 2017

Determinants of carotid-femoral pulse wave velocity in prepubertal children.

Int J Cardiol 2016 Sep 14;218:37-42. Epub 2016 May 14.

EPIUnit - Institute of Public Health, University of Porto, Portugal; Department of Clinical Epidemiology, Predictive Medicine and Public Health, Faculty of Medicine of University of Porto, Portugal.

Background: Pulse wave velocity (PWV) is a noninvasive technique to evaluate arterial stiffness, a dynamic property of the vessels, reflecting their structure and function. Childhood obesity is associated with several cardiovascular comorbidities and to the progression of atherosclerosis. We aimed to compare carotid-femoral PWV between normal weight and overweight/obese prepubertal children and to quantify its association with other cardiovascular risk factors.

Methods: Cross-sectional study of 315 children aged 8-9years. Anthropometrics, 24-h ambulatory blood pressure (BP) and carotid-femoral PWV were measured. Classification of obesity was according to World Health Organization (WHO) body mass index (BMI)-for-age reference values.

Results: Compared to normal weight children, overweight and obese children presented significantly higher levels of PWV (4.95 (P25-P75: 4.61-5.23), 5.00 (4.71-5.33), 5.10 (4.82-5.50) m/s, respectively; ptrend<0.001). Significant positive correlations were found between PWV and total cholesterol, LDL cholesterol, triglycerides, fasting insulin and insulin resistance levels (HOMA-IR) and with high-sensitivity C-reactive protein (hs-CRP). In a multivariate linear regression model adjusted for sex, age, height and 24-h systolic blood pressure z-score, the independent determinants of PWV were BMI, HOMA-IR and the absence of dipping.

Conclusions: The association between PWV and the loss of dipping and insulin resistance levels, independently of the BMI, reinforces the contribution of these comorbidities to vascular injury in early life.
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http://dx.doi.org/10.1016/j.ijcard.2016.05.060DOI Listing
September 2016

Normalization of glomerular filtration rate in obese children.

Pediatr Nephrol 2016 08 23;31(8):1321-8. Epub 2016 Mar 23.

Epidemiology Research Unit (EPIUnit), Institute of Public Health, University of Porto (ISPUP), Rua das Taipas nr. 135, 4050-600, Porto, Portugal.

Background: Glomerular filtration rate (GFR) is conventionally indexed to body surface area (BSA), but this may lead to biased results when applied to subjects of abnormal body size. The aim of our study was to examine the impact of normalization to the BSA and alternative body size descriptors on measured and estimated GFR in overweight and obese children.

Methods: This was a cross-sectional study of 313 children aged 8-9 years old. GFR was measured by 24-h creatinine clearance (CrCl) and additionally estimated from serum creatinine and cystatin C (CysC) using the combined Zappitelli formula, both as absolute values and adjusted to various body size descriptors. The results were compared between 163 normal-weight, 89 overweight and 61 obese children.

Results: Compared to the normal-weight children, mean absolute GFR (both measured and estimated) was higher in the overweight and obese children, whereas BSA-adjusted GFR was lower. Linear regression models fitted in normal-weight children revealed equally close associations between absolute GFR and squared height, ideal body weight (IBW) and BSA derived from IBW. Normalization of GFR to the IBW-derived BSA completely eliminated the discrepancy between absolute and BSA-indexed GFR in overweight and obese children.

Conclusions: Indexing of GFR to BSA calculated from the ideal-rather than actual-body weight is a promising approach to avoid overcorrection when studying obese children. Further studies should assess the accuracy of this approach across the full range of age and BMI distribution.
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http://dx.doi.org/10.1007/s00467-016-3367-8DOI Listing
August 2016

Accelerated growth during childhood is associated with increased arterial stiffness in prepubertal children.

Int J Cardiol 2016 Feb 23;204:83-5. Epub 2015 Nov 23.

EPIUnit-Institute of Public Health, University of Porto, Porto, Portugal; Department of Clinical Epidemiology, Predictive Medicine and Public Health, Faculty of Medicine of University of Porto, Portugal.

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http://dx.doi.org/10.1016/j.ijcard.2015.11.149DOI Listing
February 2016

Association of myeloperoxidase levels with cardiometabolic factors and renal function in prepubertal children.

Eur J Clin Invest 2016 Jan 1;46(1):50-9. Epub 2015 Dec 1.

EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal.

Introduction: Myeloperoxidase (MPO), an enzyme linking obesity and cardiovascular (CV) risk in adults, has rarely been studied in young children and no studies assessed its association with renal function. We sought to explore a possible association between serum MPO levels, obesity, CV risk factors and renal function in prepubertal children.

Materials/methods: Cross-sectional evaluation of 309 children aged 8-9 years (161 normal weight, 148 overweight/obese), members of the birth cohort Generation I (Portugal). Anthropometrics (body mass index (BMI), waist-to-height ratio (WHtR) and % body fat mass (%BFM) by bioelectrical impedance analysis), 24-h ambulatory blood pressure monitoring and pulse wave velocity (PWV) were measured. Insulin resistance was estimated by the HOMA index (considering serum fasting glucose and insulin determinations). Serum MPO levels were assessed by immunoenzymatic assay.

Results: MPO levels were positively associated with obesity indices (BMI z-score, WHtR and %BFM). Higher MPO levels were associated with higher 24-h and night-time mean arterial pressure, with nondipping and with higher values of insulin resistance. In normal weight children, the endothelial function, as evaluated indirectly by PWV, was an independent predictor of MPO levels. In overweight/obese children, estimated glomerular filtration rate increased significantly across tertiles of MPO (Ptrend = 0·031) and this association held after adjustment for age, sex, neutrophil and monocyte counts and CV risk factors.

Conclusions: Our results reinforce the role of MPO as a risk marker in obesity and related CV morbidities in young children. MPO levels associate with the dipping pattern and PWV and, among overweight/obese children, an association exists between MPO and renal function.
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http://dx.doi.org/10.1111/eci.12564DOI Listing
January 2016

Urinary fibrogenic cytokines ET-1 and TGF-β1 are associated with urinary angiotensinogen levels in obese children.

Pediatr Nephrol 2016 Mar 19;31(3):455-64. Epub 2015 Oct 19.

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.

Background: Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor β1 (U-TGF-β1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin-angiotensin-aldosterone system (RAAS).

Methods: The was a cross-sectional evaluation of 302 children aged 8-9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-β1 and U-AGT levels were determined by immunoenzymatic methods.

Results: Obese children presented with the lowest levels of U-ET-1 and U-TGF-β1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-β1 tended to increase across tertiles (T1-T3) of U-AGT (U-ET-1: T1, 19.9 (14.2-26.3); T2, 32.5 (23.3-141.6); T3, 24.8 (18.7-51.5) ng/g creatinine, p = 0.007; U-TGF-β1: T1, 2.2 (1.8-4.0); T2, 4.3 (2.7-11.7); T3, 4.9 (3.8-10.1) ng/g creatinine, p = 0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-β1 was associated with U-AGT levels and 24 h-systolic BP.

Conclusions: Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-β1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury.
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http://dx.doi.org/10.1007/s00467-015-3232-1DOI Listing
March 2016

Gender and obesity modify the impact of salt intake on blood pressure in children.

Pediatr Nephrol 2016 Feb 29;31(2):279-88. Epub 2015 Sep 29.

Epidemiology Research Unit (EPIUnit), Institute of Public Health, University of Porto, Porto, Portugal.

Background: Most modifiable risk factors for high blood pressure (BP), such as obesity and salt intake, are imprinted in childhood and persist into adulthood. The aim of our study was to evaluate the intake of salt in children and to assess its impact on BP taking into account gender and nutritional status.

Methods: A total of 298 children aged 8-9 years were evaluated in a cross-sectional study. Anthropometric measurements and 24-h ambulatory monitoring were performed, and salt intake was determined by 24-h urinary sodium excretion.

Results: The average estimated salt intake among the entire cohort of children enrolled in the study was 6.5 ± 2.2 g/day, and it was significantly higher in boys than in girls (6.8 ± 2.4 vs. 6.1 ± 1.9 g/day, respectively; p = 0.018) and in overweight/obese children than in normal weight children (6.8 ± 2.4 vs. 6.1 ± 2.0 g/day, respectively; p = 0.006). Salt intake exceeded the upper limit of the US Dietary Reference Intake in 72% of children. Daytime systolic BP increased by 1.00 mmHg (95% confidence interval 0.40-1.59) per gram of daily salt intake in overweight/obese boys, but not in normal weight boys or in girls.

Conclusions: Our results demonstrate an extremely high salt intake among 8- to 9-year-old Portuguese children. Higher salt intake was associated with higher systolic BP in boys, specifically in those who were overweight/obese. Longitudinal studies are needed to further evaluate the causal relationship between obesity and high BP and the mechanism by which salt intake modulates this relationship. Nonetheless, based on our results, we urge that dietary salt reduction interventions, along with measures to fight the global epidemic of obesity, be implemented as early in life as possible.
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http://dx.doi.org/10.1007/s00467-015-3210-7DOI Listing
February 2016

Decreased renal function in overweight and obese prepubertal children.

Pediatr Res 2015 Oct 7;78(4):436-44. Epub 2015 Jul 7.

EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal.

Background: Obesity is a potentially modifiable risk factor for the development and progression of kidney disease, both in adults and children. We aim to study the association of obesity and renal function in children, by comparing estimated glomerular filtration rate (eGFR) in nonoverweight and overweight/obese children. Secondarily, we aim to evaluate the accuracy of equations on eGFR estimation when compared to 24-h urinary creatinine clearance (CrCl).

Methods: Cross-sectional study of 313 children aged 8-9 y, followed in the birth cohort Generation XXI (Portugal). Creatinine and cystatin C, GFR estimated by several formulas and CrCl were compared in 163 nonoverweight and 150 overweight/obese, according to World Health Organization growth reference.

Results: Overweight/obese children had significantly lower eGFR, estimated by all methods, except for CrCl and revised Schwartz formula. Despite all children having renal function in the normal range, eGFR decreased significantly with BMI z-score (differences ranging from -4.3 to -1.1 ml/min/1.73 m(2) per standard deviation of BMI). The Zappitelli combined formula presented the closest performance to CrCl, with higher correlation coefficients and higher accuracy values.

Conclusion: Young prepubertal children with overweight/obesity already present significantly lower GFR estimations that likely represent some degree of renal impairment associated with the complex deleterious effects of adiposity.
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http://dx.doi.org/10.1038/pr.2015.130DOI Listing
October 2015

Sex-Specific Mediating Role of Insulin Resistance and Inflammation in the Effect of Adiposity on Blood Pressure of Prepubertal Children.

PLoS One 2015 30;10(6):e0132097. Epub 2015 Jun 30.

EPIUnit-Institute of Public Health, University of Porto, Porto, Portugal; Department of Clinical Epidemiology, Predictive Medicine and Public Health, University of Porto Medical School, Porto, Portugal.

Objective: To evaluate the association between obesity indices and blood pressure (BP) at 4 years of age, in each sex, and to quantify to which extent this association is mediated by inflammation and insulin resistance (IR).

Materials And Methods: We studied 1250 4-year-old children selected from the population-based birth cohort Generation XXI. Associations between body mass index (BMI) z-score and waist-to-height ratio (WHtR), office BP, inflammation (high sensitivity C-reactive protein) and IR (HOMA-IR index) were assessed. Path Analysis, a modified multivariate regression approach, was applied to test causal models and quantify direct and indirect effects of predictors of systolic (SBP) and diastolic BP (DBP).

Results: SBP and DBP increased significantly with BMI and WHtR in both sexes. There was a strong direct association (explaining 74.1-93.2% of the total association) of both measures of adiposity with SBP, in both sexes. This association was additionally indirectly mediated by IR, particularly regarding WHtR (20.5% in girls and 9.4% in boys). Mediation by inflammation did not reach statistical significance in either sex. Regarding DBP, the direct effect of adiposity was strong (>95% for BMI and WHtR in boys) and the mediation by IR was much smaller in boys than in girls.

Discussion: The direct association between adiposity and BP in healthy 4-year-old children is strong and IR plays an important mediating role. The strength of effects of IR and inflammation suggests sex differences in the complex interplay between BP, adiposity and inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132097PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488421PMC
April 2016

Etiological agents and antimicrobial susceptibility in hospitalized children with acute pyelonephritis.

Acta Med Port 2015 Jan-Feb;28(1):15-20. Epub 2015 Feb 27.

Unit of Pediatric Nephrology. Hospital Pediátrico Integrado. Centro Hospitalar de São João. Porto. Portugal. Faculty of Medicine. University of Porto. Porto. Portugal.

Introduction: Antibiotic resistance driven by antibiotic use remains a major public health and professional concern. Our aim was to know the local prevalence of uropathogens and their antimicrobial susceptibility profile in acute pyelonephritis.

Material And Methods: A prospective study of patients admitted in a level III Pediatric Department ward with acute pyelonephritis from 1994 to 2012 was performed in Northern Portugal. Etiological agents and their antimicrobial sensitivity profile were evaluated in four timed periods (G1: 1994-97; G2: 2002; G3: 2007; G4: 2012).

Results: We evaluated 581 patients, 66% female with median age 22 months. Escherichia coli was the leading uropathogen and its prevalence remained stable during the last 18 years. It showed an increased sensitivity to amoxicillin-clavulanate from 71% in G1 to 81.5% in G4 (p = 0.001) and a decreased resistance rate from 8.7% in G1 to 2.8% in G4 (p = 0.008). Its sensitivity to 2nd and 3rd generation cephalosporin was more than 90% (p = ns) and more than 95% to nitrofurantoin (p = ns). Resistance rate of cotrimoxazole increased from 22% to 26% (p = 0.008).

Discussion: Escherichia coli remains the main uropathogen responsible for acute pyelonephritis, reason why its antimicrobial sensitivity profile will determine the empirical therapeutic choice.

Conclusions: Amoxicillin-clavulanate remains a good first-line choice for empirical treatment of acute pyelonephritis in our inpatient health care.
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http://dx.doi.org/10.20344/amp.5033DOI Listing
January 2017

Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

Clin J Am Soc Nephrol 2015 Apr 29;10(4):592-600. Epub 2015 Jan 29.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.

Design, Setting, Participants, & Measurements: Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal.

Results: Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis.

Conclusions: The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
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http://dx.doi.org/10.2215/CJN.06260614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386250PMC
April 2015

Growth cartilage expression of growth hormone/insulin-like growth factor I axis in spontaneous and growth hormone induced catch-up growth.

Growth Horm IGF Res 2012 Jun-Aug;22(3-4):129-33. Epub 2012 May 14.

Pediatric Rheumatology Unit, Pediatric Department, Hospital São João, Porto, Portugal.

Introduction: Catch-up growth following the cessation of a growth inhibiting cause occurs in humans and animals. Although its underlying regulatory mechanisms are not well understood, current hypothesis confer an increasing importance to local factors intrinsic to the long bones' growth plate (GP).

Aim: The present study was designed to analyze the growth-hormone (GH)-insulin-like growth factor I (IGF-I) axis in the epiphyseal cartilage of young rats exhibiting catch-up growth as well as to evaluate the effect of GH treatment on this process.

Material And Methods: Female Sprague-Dawley rats were randomly grouped: controls (group C), 50% diet restriction for 3 days+refeeding (group CR); 50% diet restriction for 3 days+refeeding & GH treatment (group CRGH). Analysis of GH receptor (GHR), IGF-I, IGF-I receptor (IGF-IR) and IGF binding protein 5 (IGFBP5) expressions by real-time PCR was performed in tibial growth plates extracted at the time of catch-up growth, identified by osseous front advance greater than that of C animals.

Results: In the absence of GH treatment, catch-up growth was associated with increased IGF-I and IGFBP5 mRNA levels, without changes in GHR or IGF-IR. GH treatment maintained the overexpression of IGF-I mRNA and induced an important increase in IGF-IR expression.

Conclusions: Catch-up growth that happens after diet restriction might be related with a dual stimulating local effect of IGF-I in growth plate resulting from overexpression and increased bioavailability of IGF-I. GH treatment further enhanced expression of IGF-IR which likely resulted in a potentiation of local IGF-I actions. These findings point out to an important role of growth cartilage GH/IGF-I axis regulation in a rat model of catch-up growth.
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http://dx.doi.org/10.1016/j.ghir.2012.04.004DOI Listing
June 2013

Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial.

Clin J Am Soc Nephrol 2010 Jul 3;5(7):1190-7. Epub 2010 Jun 3.

Department of Pediatric Nephrology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Celestino Villamil, s/n, E33006 Oviedo, Spain.

Background And Objectives: Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management.

Design, Setting, Participants, & Measurements: The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR
Results: Length gain in infants who were treated with GH was statistically greater (P<0.05) than that of nontreated children (14.5 versus 9.5 cm/yr; SD score 1.43 versus -0.11). The GH-induced stimulation of growth was associated with no undesirable effects on bone maturation, renal failure progression, or metabolic control. In addition, GH treatment improved forearm bone mass and increased serum concentrations of total and free IGF-I and IGF-binding protein 3 (IGFBP-3), whereas IGF-II, IGFBP-1, IGFBP-2, GH-binding protein, ghrelin, and leptin were not modified.

Conclusions: Infants with CRF and growth retardation despite good metabolic and nutritional control benefit from GH treatment without adverse effects during 12 months of therapy.
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http://dx.doi.org/10.2215/CJN.07791109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893059PMC
July 2010

Strict blood-pressure control and progression of renal failure in children.

N Engl J Med 2009 Oct;361(17):1639-50

Background: Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor.

Methods: After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion.

Results: A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease.

Conclusions: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)
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http://dx.doi.org/10.1056/NEJMoa0902066DOI Listing
October 2009

Urinary excretion of endothelin-1 (ET-1), transforming growth factor- beta1 (TGF- beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial.

Nephrol Dial Transplant 2007 Dec 26;22(12):3487-94. Epub 2007 Sep 26.

Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland.

Unlabelled: The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGF-beta1 and VEGF(165) was evaluated in 303 children with CKD stage II-IV (GFR 48 +/- 22 ml/min/1.73 m(2)) and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N = 183), obstructive uropathies (N = 47), glomerulopathies (N = 34), nephronophthisis (N = 19) and polycystic kidney disease (N = 20).

Results: The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls: 965 +/- 2042 vs 216 +/- 335 fmol/g creatinine for ET-1; 252 +/- 338 vs 155 +/- 158 ng/g for VEGF; 31.6 +/- 37.0 vs 10.9 +/- 9.8 ng/g for TGF-beta1 (each P < 0.0001). The excretion of ET-1 and TGF-beta1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGF-beta1 and VEGF excretion rates were inversely correlated with age (r = -0.22, -0.32 and -0.17, all P < 0.005) and renal function (r = -0.21, -0.13 and -0.15; P < 0.001; < 0.05; < 0.01; respectively) VEGF and TGF-beta1 excretion rates were positively correlated both in patients and controls.

Conclusions: Children with CKD exhibit significantly elevated urinary excretion of ET-1, TGF-beta1 and VEGF(165) in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGF-beta1 and VEGF(165) excretion, shown both in patients and healthy controls, indicates an interdependent nature of their generation.
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http://dx.doi.org/10.1093/ndt/gfm300DOI Listing
December 2007
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