The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the normal development of the fetal kidney. Late pregnancy blockage of the RAAS, through in-utero exposure to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers, is associated with poor fetal outcomes, including oligohydramnios, renal tubular dysplasia, postnatal anuric renal failure, and hypotension. The present case describes a 39 -year -old primigravida that was referred to the emergency department, at 37 weeks, for the evaluation of intrauterine growth restriction and suspected coarctation of the aorta (CoA). She was medicated with enalapril since the 35th week of gestation. She delivered a male infant, weighing 2,110 g, with no apparent malformations. CoA was excluded. During his first day of life, the patient developed anuria, acute renal failure, and hypotension, requiring ionotropic support. Renal ultrasound appeared normal. Diuresis was reinitiated at 48 hours of life after continued supportive measures. Kidney function tests progressively normalized. Additional investigations revealed a low concentration of angiotensin-converting enzyme. The patient is currently 12 months old and has had a favorable evolution. This case highlights the fact that even brief exposure to enalapril in the third trimester may cause RAAS blocker fetopathy. As long-term sequelae of ACEI-exposed infants are poorly described, close followup of renal complications is essential. Physicians should be aware of the deleterious effects of RAAS blockers in pregnancy.

Tubulointerstitial nephritis and uveitis syndrome is an underdiagnosed condition, characterized by the involvement of the kidney and the eye that affects mostly young people. Its pathophysiology remains poorly understood; however, pediatric morbidity is mostly associated with recurrences of uveitis. This article aimed to describe two clinical cases of tubulointerstitial nephritis and uveitis syndrome, with distinct presentations and clinical courses, illustrative of the diversity of this entity. Case1: An 11-year-old male was admitted to the hospital due to a non-oliguric acute kidney injury. A 24-hour urine examination revealed a tubular lesion, and two months later, he was diagnosed with bilateral anterior uveitis. He was started on steroids, with a favorable response. After six weeks, renal function and urine parameters returned to normal. Case 2: A 12-year-old male was admitted to the hospital with complaints of bilateral red eyes. He was diagnosed with bilateral anterior uveitis and treated with topical steroids with transient improvement. At the same time, the clinical investigation detected a tubular lesion. Four months later, due to a uveitis hypertensive flare with macular edema, methotrexate was added to his treatment, which had a favorable response. Six months later, the urinary abnormalities disappeared. The tubulointerstitial nephritis and uveitis syndrome should be actively searched in the presence of tubular renal abnormalities or uveitis in pediatric patients.

Proteinuria is a frequent finding in pediatric patients and in most cases, it is intermittent or transient. When proteinuria is moderate/severe and persistent, it may require an extensive complementary study, histopathological examination and genetic test, in order to clarify its etiology. Cubilin (CUBN) is a large glycosylated extracellular protein, initially detected in proximal tubular cells, and later in podocytes. Isolated persistent proteinuria caused by cubilin gene mutations is rare, only a few cases have been reported in the literature and even fewer patients underwent renal biopsy and electron microscopy that could help to elucidate the pathogenesis of the disease. The authors describe two pediatric clinical cases referred to pediatric nephrology consultation due to persistent proteinuria. Neither of them had any other complaints, and renal function and immunological and serological studies were normal. Renal histopathology showed podocytes changes and glomerular basal membrane alterations suggestive of Alport Syndrome. The genetic study identified two heterozygous variants in the cubilin gene in both, also later identified in their parents. They were started on ramipril, with improvement in proteinuria, and both patients remain asymptomatic and without changes in renal function. At present, due to the uncertainty of prognosis, it is suggested to keep CUBN gene mutation patients under close surveillance of proteinuria and renal function. The variable ultrastructural patterns of podocytopathy and glomerular basal membrane alterations in kidney biopsies of pediatric patients with proteinuria should lead to the diagnostic possibility of CUBN gene mutation in the differential diagnosis.

Xanthogranulomatous pyelonephritis (XPN) is an uncommon variant of chronic pyelonephritis with a poorly understood pathogenesis and a challenging diagnosis. It is rare in pediatric patients, particularly in the neonatal period. We report the case of an 18-day-old female neonate admitted to the emergency room due to macroscopic hematuria and poor feeding. Urinalysis revealed leukocyturia and she was initially admitted under the clinical suspicion of acute pyelonephritis. Renal ultrasound and magnetic resonance imaging (MRI) revealed a progressive nodular lesion in the middle third of the left kidney. Given the suspicion of renal abscess or neoplasm, the patient was transferred to our tertiary hospital. Urinary catecholamines and tumor markers had normal values. Percutaneous kidney biopsy confirmed XPN. Posterior computed tomography scan excluded extension to neighboring structures. A conservative management with systemic antibiotic therapy was decided. She completed 7 weeks of systemic antibiotic therapy (ampicillin and cefotaxime) with progressive reduction of lesion size and posterior calcification. Follow-up at 3 years was uneventful. The lipid profile and study of neutrophil function were normal. Voiding cystourethrography excluded vesicoureteral reflux. The authors intend to highlight the importance of a high index of suspicion of XPN to allow preoperative diagnosis. Histopathological assessment is mandatory to confirm XPN and exclude other entities mimicked by focal and unilateral progressive disease. There are only a few published cases of optimal clinical evolution solely with broad-spectrum antibiotics; however, this may allow a beneficial nephron-sparing approach in selected patients.

BACKGROUND:Acute kidney injury (AKI) is associated with worse outcomes and increased morbidity and mortality in pediatric intensive care unit (PICU) patients. The renal angina index (RAI) has been proposed as an early prediction tool for AKI development.OBJECTIVES:The objective was to evaluate outcomes of RAI-positive patients and to compare RAI performance with traditional AKI markers across different patient groups (medical/post-surgical). This was an observational retrospective study. All children admitted to a tertiary hospital PICU over a 3-year period were included. Electronic medical records were reviewed. Day 1 RAI was calculated, as was the presence and staging of day 3 AKI.RESULTS:A total of 593 patients were included; 56% were male, the mean age was 55 months, and 17% had a positive RAI. This was associated with day 3 AKI development and worse outcomes, such as greater need for kidney replacement therapy, longer duration of mechanical ventilation, vasoactive support and PICU stay, and higher mortality. For all-stage kidney injury, RAI presented a sensitivity of 87.5% and a specificity of 88.1%. Prediction of day 3 all-stage AKI by RAI had an AUC=0.878; its performance increased for severe AKI (AUC = 0.93). RAI was superior to serum creatinine increase and KDIGO AKI staging on day 1 in predicting severe AKI development. The performance remained high irrespective of the type of admission.CONCLUSIONS:The RAI is a simple and inexpensive tool that can be used with medical and post-surgical PICU patients to predict AKI development and anticipate complications, allowing for the adoption of preventive measures.

Acute kidney injury (AKI) is classified based on prerenal, intrinsic, and postrenal causes. In the newborn, AKI can occur after an insult during the prenatal, perinatal, or postnatal period. AKI is usually an underrecognized condition and its true incidence is unknown. AKI may result from the administration of a number of different nephrotoxic medications, which are often used concurrently in critically ill neonates, exponentially increasing the risk of renal injury. Drug toxicity may also compromise the formation and development of nephrons, and this is particularly important in preterm infants, who have incomplete nephrogenesis. Little is known about the pharmacokinetics and pharmacodynamics of different medications used in neonates, especially for the most immature infant, and the use of most medications in this population is off label. Strategies to prevent AKI include the avoidance of hypotension, hypovolemia, fluid imbalances, hypoxia, and sepsis as well as judicious use of nephrotoxic medications. Treatment strategies aim to maintain fluids and electrolytic and acid-base homeostasis, along with an adequate nutritional status. Neonates are especially prone to long-term sequelae of AKI and benefit from long-term follow-up. This review summarizes the most relevant aspects of nephrotoxicity in neonates and describes the prevention, treatment, and follow-up of AKI in neonates.

Objective Burosumab is an orphan medicinal product (OMP) approved in Europe for the treatment of X-linked hypophosphatemia (XLH). The aim of this study was to assess the value of burosumab versus conventional therapy for the treatment of paediatric XLH, through a multi-criteria decision analysis (MCDA) framework for health technology assessment (HTA) of OMPs in Portugal. Methods The MCDA framework considered 14 criteria related to disease burden, therapeutic value and economic burden. A multidisciplinary panel of national stakeholders participated in a two-phase exercise. In the first phase, relative weights and part-worth utilities for the criteria and their levels were elicited and a reimbursement likelihood function was calibrated through adaptive conjoint analysis. In the second phase, burosumab and conventional therapy were assessed against the criteria, providing a global value score (0-100) and reimbursement likelihood (0-100%) for both. Results Of the 14 criteria, disease burden, therapeutic value and economic burden criteria represented 27.29%, 57.17% and 15.53% of the total weight in the decision, respectively. All disease burden and some therapeutic value criteria, typically not included in traditional HTA, represented 47.88% of the total weight. Burosumab was unanimously considered superior to conventional therapy, with an average (range) global value score of 84.96 (82.48-86.54) against 48.06 (43.37-57.68), and reimbursement likelihood of 97.50% (96.78%-98.32%) against 43.66% (31.48%-68.73%), respectively. Conclusions MCDA represents a powerful tool in HTA decision-making for OMPs. The results of this MCDA acknowledge burosumab as a disease-modifying drug, deemed superior to conventional therapy for the treatment of paediatric XLH.

The atypical hemolytic uremic syndrome (aHUS) in the newborn is a rare disease, with high morbidity. Eculizumab, considered a first-line drug in older children, is not approved in neonates and in children weighing less than 5kg. We present a 5-day-old female newborn, born at 36 weeks' twin gestation, by emergency cesarean section due to cord prolapse, with birth weight of 2,035g and Apgar score of 7/7/7, who develops microangiopathic hemolytic anemia, thrombocytopenia, and progressive acute renal failure. In day 5, after diagnosis of aHUS, a daily infusion of fresh frozen plasma begins, with improvement of thrombocytopenia and very slight improvement in renal function. The etiologic study (congenital infection, Shiga toxin, ADAMTS13 activity, directed metabolic study) was normal. C3c was slightly decreased. On day 16 for maintenance of anemia and severe renal failure, she started 300mg/dose eculizumab. Anemia resolves in 10 weeks and creatinine has normal values after 13 weeks of treatment. The genetic study was normal. In this case, eculizumab is effective in controlling microangiopathy and in the recovery of renal function. Diagnosis of neonatal aHUS can be challenging because of phenotypic heterogeneity and potential overlap with other manifestations that may confound it, such as perinatal asphyxia or sepsis/disseminated intravascular coagulation.

The deletion of the long arm of chromosome 4 is rare, presenting with a variable phenotype depending on the chromosomic area affected. A term newborn with prenatal diagnosis of anhydramnios, dysplastic cystic kidneys, and cardiomegaly was born with generalized subcutaneous edema, several dysmorphic features, and progressive renal failure requiring dialysis. The infant continued to deteriorate and died at 52 days of age. Autopsy confirmed bilateral renal dysplasia with cysts. Array-comparative genomic hybridization (CGH) identified a large deletion on 4q25-q28.3, which is not yet described in association with renal disease. The clinical progression could be expected due to the severity of the perinatal clinical presentation.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Hyponatremic hypertensive syndrome (HHS) is characterized by hypertensive crisis, and hyponatremia secondary to unilateral renal damage with glomerular and tubular dysfunction. Elevated plasma levels of renin in most cases suggest that the stimulation of renin release from the ischemic kidney plays an important pathophysiologic role. Activation of the renin-angiotensin system results in hypertension and causes secondary hyperfiltration, pressure diuresis and sodium loss from contralateral non-damaged kidney. An elevated renin level is a pathognomonic finding in HHS. Potassium deficiency from hyperaldosteronism may further stimulate renin secretion and intensify this vicious circle. We report a female term newborn, who presented with hypertensive crisis on the seventh day after traumatic birth. The first three days of life were uneventful. Initial treatment with captopril resulted in severe hypotension and hemodynamic instability. Lab work revealed hyponatremia, hypokalemia, and elevated peripheral renin activity and aldosterone levels. Complementary sonography and magnetic resonance confirmed right adrenal gland hematoma and several ischemic areas in the upper pole of the right kidney. The diagnosis of HHS secondary to renal ischemia was evoked. HHS is a rare condition in the neonatal period, though still under-recognized. In the neonatal and early infancy period, renovascular disease is the most common cause of secondary hypertension. In this case, there was no sign of vascular disease, the renin-angiotensin system was activated secondary to direct renal ischemia and infarction. The intense renin stimulation and pressure through the contralateral normal kidney results in high pressure natriuresis facilitating a severe volume-depleted state. Although the use of renin-angiotensin system inhibitors is the treatment of choice, it is imperative to re-establish hydration and renal perfusion before starting this antihypertensive medication. We aimed to improve awareness of HHS diagnosis and prompt treatment, to prevent continuous renal damage and other life-threatening complications.

Dilated cardiomyopathy is the most common form of cardiomyopathy and the main cause of cardiac transplantation in children and in adults. Infants and children have a wider spectrum of etiologies, hampering their identification. The most frequent initial manifestation of dilated cardiomyopathy is symptomatic heart failure during exercise or at rest (although many patients are asymptomatic). Some causes are potentially reversible, therefore the investigation should be carefully planned and immediately performed after diagnosis. In most children no cause is identified, which limits the targeted therapeutic approach and therefore the effectiveness of the treatment. The authors present a case of dilated cardiomyopathy secondary to renovascular hypertension diagnosed in an infant with 3.5 month-old, highlighting the etiological investigation, treatment and evolution. The authors present this case emphasising the fact that the arterial hypertension diagnose in infants is not always easy, questioning the current recommendations relating to an initial evaluation on blood pressure. We postulate that the assessment of blood pressure in newborns can detect early renovascular hypertension (and even other cardiovascular diseases) and help prevent the development of deleterious effects, including fatal episodes (C) 2018 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

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.