Anita Ammenti

Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up

We report the recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged 2 months to 3 years. They were prepared by a working group of the Italian Society of Pediatric Nephrology after careful review of the available literature and a consensus decision, when clear evidence was not available.

Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Long-term clinical consequences of urinary tract infections during childhood: a review

Kidney scarring related to urinary tract infection in childhood has been considered the cause of serious long‐term clinical consequences. This assumption is now debated, as the advent of routine antenatal ultrasound in the 1980s has shown that a consistent part of the changes previously attributed to postinfectious scarring is mainly due to congenital malformations. With the aim of determining what is presently known on the long‐term clinical consequences of urinary tract infections (UTIs) in childhood, we performed a review of the literature on the relation between UTIs and blood pressure, renal function, growth and pregnancy‐related complications. By searching Medline/PubMed and Embase from 1980 to 2011, we identified 20 cohorts of children from 23 papers.

Nephrocalcinosis in children: a retrospective multi-centre study

Aim:  To review the data of children with NC and to analyse aetiology, clinical manifestations, growth and renal function at presentation; to relate growth and renal function to changes in NC in patients with a follow‐up of at least 12 months.

Neonatal variant of Bartter syndrome presenting with acidosis.

An infant is reported with the “neonatal variant” of Bartter syndrome, presenting at 5 weeks of age with metabolic acidosis associated with a life-threatening water and electrolyte depletion. Alkalosis was first shown after 2 weeks of vigorous fluid, sodium, and potassium substitution. We suggest that the extreme fluid and electrolyte losses associated with the “neonatal form” of Bartter syndrome could lead to acidosis more often than previously suspected, and may cause underdiagnosis of a possibly fatal condition.

Idiopathic hypercalciuria in infants with renal stones

In children older than 2 years, hypercalciuria is the most common metabolic cause of renal stones. In infants, its prevalence is not well established. Since 1990, we observed five infants in whom renal stones or microcalculi were diagnosed between the age of 5 and 19 months. One of them was lost to follow up. In the present report, we describe the four patients who underwent metabolic evaluation and in whom idiopathic hypercalciuria (IH) was diagnosed. We conclude that IH is a frequent cause of microcalculi and renal stones in infants, and a screen for this condition is warranted in this age group.

Prescription of drugs blocking the renin-angiotensin system in Italian children

Little is known about the prescription pattern of antihypertensive drugs for children with impaired kidney function. We have therefore documented the use of antihypertensive drugs in this patient group by evaluating the Italian pediatric population-based registry of patients with chronic kidney disease on conservative treatment (ItalKid) from 1995 to 2003. In 1995, prescriptions written for antihypertensive drugs for use by children were approximately equally divided among drugs blocking the renin-angiotensin system and calcium channel blockers (38 vs. 43% of all prescriptions), followed by β-blockers and diuretics (15 and 4%, respectively). During subsequent years the proportion of prescriptions for drugs blocking the renin-angiotensin system increased (2003: 61%; p<0.001) and that of calcium channel blockers decreased (2003: 18%, p<0.001). In 1995, blockers of the renin-angiotensin system were prescribed, either as monotherapy or in combination, in 53% of the patients, but the relative frequency of the patients prescribed these drugs increased up to 83% in 2003 (p<0.0005). In conclusion, physicians caring for Italian children with impaired kidney function are increasingly prescribing drugs blocking the renin-angiotensin system.

Novel mutations of the CLCN5 gene including a complex allele and A 5′ UTR mutation in Dent disease 1

To the Editor : Dent disease (DD) 1 (OMIM 300009) is an X-linked disorder of renal tubular function, characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and progressive renal failure, and associated with mutations in the ClC-5 Cl−/H+ endosomal exchanger all located in the coding region of the CLCN5 gene (1, 2). We report here the identification of 15 novel mutations including a complex allele and a nucleotide substitution in the 5′UTR region of the CLCN5 gene. Thirty patients with clinical suspicion of DD were screened by single-strand conformation polymorphism (SSCP) analysis and direct sequencing for the presence of mutations in the coding sequence and the exon-intron boundaries as well as in the 5′untranslated exons of the CLCN5 gene. All the patients were of Italian origin, except 1 from the United Kingdom. Sixteen of the 30 patients presented CLCN5 mutations of which 15 were novel and 1 recurrent (S244L). The phenotypic characteristics of patients with and without CLCN5 mutations are reported in Table 1. The table shows that LMWP, hypercalciuria and nephrocalcinosis, represent the triad of manifestations most relevant for the diagnosis of DD 1. Table 2 reports the 15 novel CLCN5 mutations identified in DD patients. Each of the missense and deletion–insertion mutations predicts a structurally significant alteration to the ClC-5 Cl−/H+ exchanger, and is thus likely to be of importance in the aetiology of the disease. The three frameshift mutations, leading to premature termination codons (PTC), can induce either a truncated ClC-5 product or mRNA degradation through nonsense-mediated decay which are likely to result in a loss of antiporter function and chloride conductance. The two in-frame codon deletion and the insertion are thought to alter the ClC-5 α-helices H and I, which are two of the four major helices involved in the formation of dimer interface (3). All the missense mutations, except one located in the C-terminal domain, are at or near the ClC-5 dimer interface. Moreover they involved amino acids conserved among different species or present in all known ClCs and were predicted with a high confidence to affect protein function by both the web program SIFT (4) and PolyPhen (5). For four out of six missense mutations (W58L, G512D, V519D, P621L) and for T277_L278 ins S mutation it was possible to establish that they segregated with DD trait in family members. Three intronic mutations affecting the canonical consensus splicing donor site of intron 4, 8 and 11 were detected in three patients. In two of them, the presence of an aberrantly spliced ClC-5 mRNA in leukocytes, leading to a truncated or absent protein, confirmed the functional significance of the mutations (Fig. 1). The presence of an aberrantly spliced mRNA due to the IVS4 +4 A>G could not be proved by transcription polymerase chain reaction (RT-PCR) analysis because the patient’s RNA was not available. The Automated Splice-Site Analysis program (ASSA; (6)), however, predicts that this variant would lower the strength of the donor splice-site leading probably to exon 4 skipping. We identified a complex allele (S386F and S388fsX434) in one patient from North Italy, inherited from his mother and grandmother. Since both the web program SIFT and PolyPhen predicted that the missense mutation S386F did not affect protein function, and the search for potential exonic splicing enhancer (ESE) motifs using ESE finder (7), RESCUE-ESE (8) and ASSA did not evidence any modification, we wondered if the mutation was indeed a polymorphism. The substitution was not found in our series of 69 patients affected by DD and in 311 X chromosomes from umbilical cord DNA samples thus

Congenital Solitary Kidney in Children: Size Matters

PURPOSE We assessed renal function outcome in children with congenital solitary kidney and evaluated prognostic risk factors. MATERIALS AND METHODS We retrospectively studied the clinical charts of 210 children presenting with congenital solitary kidney at 2 pediatric nephrology and 5 pediatric units between January 2009 and October 2012. Children 0 to 18 years old with a congenital solitary kidney confirmed by scintigraphy were enrolled. Of the patients 146 were suitable for analysis. Median followup was 4.6 years. Primary outcome was decreased estimated glomerular filtration rate, and secondary outcome was occurrence of proteinuria and/or systemic hypertension. Primary outcome-free survival analysis was performed, including multiple regression analysis of significant risk factors. RESULTS Decreased estimated glomerular filtration rate was present in 12% of children at a median age of 2.2 years. Primary outcome-free survival analysis revealed an estimated event-free survival of 82% (95% CI 74% to 91%) at 10 years. Estimated survival rate was significantly decreased in children with additional congenital anomalies of the kidney/urinary tract (54% vs 88% overall) or insufficient renal length vs expected for normal congenital solitary kidney. The latter was the strongest predictor of decreased estimated outcome-free survival (49% vs 89%, p <0.001). Occurrence of proteinuria and/or systemic hypertension was present in less than 5% of children. CONCLUSIONS Some children with congenital solitary kidney show decreased glomerular filtration rate. Associated anomalies of the kidney/urinary tract and insufficient renal length appear to be significant risk factors. Adequate length of the congenital solitary kidney is a key parameter for maintenance of renal function and should be examined routinely during followup.