These recommendations are endorsed by the Italian Society of Pediatric Nephrology. They can also be a tool of comparison with other existing guidelines in issues in which much controversy still exists.
AimOur aim was to update the recommendations for the diagnosis, treatment and follow‐up of the first febrile urinary tract infection in young children, which were endorsed in 2012 by the Italian Society of Pediatric Nephrology.MethodsThe Italian recommendations were revised on the basis of a review of the literature published from 2012 to October 2018. We also carried out an ad hoc evaluation of the risk factors to identify children with high‐grade vesicoureteral reflux or renal scarring, which were published in the previous recommendations. When evidence was not available, the working group held extensive discussions, during various meetings and through email exchanges.ResultsFour major modifications have been introduced. The method for collecting urine for culture and its interpretation has been re‐evaluated. We have reformulated the algorithm that guides clinical decisions to proceed with voiding cystourethrography. The suggested antibiotics have been revised, and we have recommended further restrictions of the use of antibiotic prophylaxis.ConclusionThese updated recommendations have now been endorsed by the Italian Society of Pediatric Nephrology and the Italian Society for Pediatric Infectivology. They can also be used to compare other recommendations that are available, as a worldwide consensus in this area is still lacking.
The mode of inheritance of Alport syndrome (ATS) has long been controversial. In 1927, the disease was hypothesized as a dominant condition in which males were more severely affected than females. In 1990, it was considered an X-linked (XL) semidominant condition, due to COL4A5 mutations. Later on, a rare autosomal recessive (AR) form due to COL4A3/COL4A4 mutations was identified. An autosomal dominant (AD) form was testified more recently by the description of some large pedigrees but the real existence of this form is still questioned by many and its exact prevalence is unknown. The introduction of next generation sequencing (NGS) allowed us to perform an unbiased simultaneous COL4A3-COL4A4-COL4A5 analysis in 87 Italian families (273 individuals) with clinical suspicion of ATS. In 48 of them (55%), a mutation in one of the three genes was identified: the inheritance was XL semidominant in 65%, recessive in 4% and most interestingly AD in 31% (15 families). The AD form must therefore be seriously taken into account in all pedigrees with affected individuals in each generation. Furthermore, a high frequency of mutations (>50%) was shown in patients with only 1 or 2 clinical criteria, suggesting NGS as first-level analysis in cases with a clinical suspicion of ATS.
Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.
Idiopathic hypercalciuria (IHC) has been reported mainly in children with hematuria in the 1980s and early 1990s, when renal sonography was just becoming routine. The presence of microcalculi, i.e., of hyperechogenic spots < 3 mm in diameter in renal calyces, was not taken into account in those studies. We attempted to outline clinical presentation and natural course of IHC not only in children with hematuria, but also in those with dysuria and/or recurrent abdominal/flank pain and a family history of nephrolithiasis, taking into account the finding of microcalculi. We analyzed retrospectively the data at diagnosis from 74 consecutive children aged 2.4-18 years (mean 8.6) with IHC (calciuria 4.1-15.1 mg kg-1 24 h-1, mean 6.1) and the outcome of 30 of them who were followed > or = 1 years (mean 3.2) with no specific therapy. At diagnosis, 38 patients (51%) had no hematuria, 42 (57%) had microcalculi and four (5%) had calculi. Of the patients with normal urinalysis, 71% had microcalculi or stones. The subjects with microcalculi and those with stones were significantly older than those without microcalculi and stones (P = 0.004 and 0.007). A normal urinalysis at our evaluation and a history of abdominal/flank pain were significantly more frequent in patients with microcalculi than in those without (P = 0.02 and 0.0001, respectively). During the follow-up, four of 30 patients formed stones 1-3 years after first diagnosis of IHC. More than half of children with IHC have microcalculi. The risk of formation of microcalculi or stones increases with age. The lack of hematuria does not exclude the presence of microcalculi or calculi. Hypercalciuria has to be suspected in children with dysuria and/or recurrent abdominal flank pain and a family history of nephrolithiasis, even when they have no hematuria.
The SLIT2 receptor ROBO2 plays a key role in the formation of the ureteric bud, and its inactivation in mice leads to supernumerary ureteric bud development, lack of ureter remodeling, and improper insertion of the ureters into the bladder. Recently, two heterozygous ROBO2 missense mutations were identified in two families with primary vesicoureteral reflux occurring in combination with congenital anomalies of the kidney and urinary tract (VUR/CAKUT). This study investigated a possible causal role of ROBO2 gene variants in 95 unrelated patients with primary VUR (n ϭ 78) or VUR/CAKUT. Eighty-two percent of all patients had a family history of genitourinary anomalies. Twenty-four ROBO2 gene variants were identified by direct sequencing of all 26 exons and the exon-intron boundaries. Of these, four led to amino acid substitutions: Gly328Ser, Asn515Ile, Asp766Gly, and Arg797Gln. When the families were examined, the missense variants co-segregated with VUR (three families) or VUR/CAKUT (one family). These variants were not found in 190 control subjects, and the affected amino acids have been conserved through evolution. In conclusion, a relatively high frequency of ROBO2 variants (5.1%) was found in familial cases; however, functional studies and validation in other cohorts are warranted.
Summary Background PNPLA3 I148M polymorphism has an effect on modulation of estimated glomerular filtration rate (eGFR) in nonobese nondiabetic adults and in children with histologically confirmed nonalcoholic fatty liver disease (NAFLD). Objectives The objective of the study is to explore the impact of PNPLA3 I148M polymorphism on eGFR in children with obesity with and without NAFLD. Methods We genotyped 591 patients with obesity for PNPLA3 I148M polymorphism. Anthropometrical, biochemical, and instrumental data were collected. NAFLD was defined by the presence of ultrasound‐detected liver steatosis and/or ALT levels greater than 40 IU/L. Results Patients with NAFLD showed significantly lower eGFR levels compared with subjects without NAFLD. Children with PNPLA3 MM genotype showed lower eGFR levels compared with those with either PNPLA3 IM or II genotypes both in the presence and absence of NAFLD. A general linear model for eGFR variance, including gender, duration of obesity, PNPLA3 genotypes, HOMA, BMI‐SDS, LDL‐C, and triglycerides as covariates, confirmed an inverse association between eGFR and PNPLA3 genotype only in the presence of NAFLD. Conclusions Children with obesity and PNPLA3 MM genotype show lower eGFR levels compared with other genotypes, with a major effect of this polymorphism in the presence of NAFLD.
Innovative approaches are needed for patients with systemic lupus erythematosus (SLE) who develop autoimmune haemolytic anaemia (AIHA) that does not respond to conventional treatment. Rituximab, a chimaeric anti-CD20 monoclonal antibody, has been demonstrated to be highly effective for in vivo B-cell depletion. We report an 18-year-old-girl with SLE and life-threatening AIHA that did not respond to steroids, intravenous immunoglobulin and cyclosporin A. Rituximab was given weekly at 375 mg/m2 for two doses. The drug was well tolerated and the patient had no adverse effects. Her haemolytic disorder markedly ameliorated, with a progressive increase of haemoglobin levels, starting a few days after therapy. The patient remains disease-free 7 months later.
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