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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic PKD1 variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including PKHD1, HNF1B and PKD1 allowed the identification of biallelic PKD1 variants. Furthermore, we review the medical literature in order to report likely PKD1 hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare PKD1 missense variants, especially if previously unreported, remain challenging.

Rationale & Objective: The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship. Study Design: Multicenter cross-sectional study. Setting & Participants: University hospital pediatrics departments. Subjects: Two hundred eighty-one patients with CSK. Predictors: Weight, height, BMI-SDS (standard deviation score), duration of overweight/obesity, pubertal stage, systolic (SBP) and diastolic (DBP) blood pressure, eGFR, and renal ultrasound were obtained at the last follow-up visit. The population was classified on the basis of nutritional status and divided in tertiles for duration of overweight/obesity. We compared eGFR levels among these categories. A simple regression was used to correlate eGFR with BMI-SDS. To evaluate if other factors could influence the relationship between eGFR and BMI-SDS, a general linear model was performed, including gender, birth weight

The case of a two-year-old girl finally diagnosed with haemolytic uremic syndrome is described.

Febrile urinary tract infection (UTI) is currently considered the most frequent cause of serious bacterial illness in children in the first 2 years of life. UTI in paediatrics can irreversibly damage the renal parenchyma and lead to chronic renal insufficiency and related problems. To avoid this risk, an early effective antibiotic treatment is essential. Moreover, prompt treatment is mandatory to improve the clinical condition of the patient, prevent bacteraemia, and avoid the risk of bacterial localization in other body sites. However, antibiotic resistance for UTI-related bacterial pathogens continuously increases, making recommendations rapidly outdated and the definition of the best empiric antibiotic therapy more difficult. Variation in pathogen susceptibility to antibiotics is essential for the choice of an effective therapy. Moreover, proper identification of cases at increased risk of difficult-to-treat UTIs can reduce the risk of ineffective therapy. In this review, the problem of emerging antibiotic resistance among pathogens associated with the development of paediatric febrile UTIs and the best potential solutions to ensure the most effective therapy are discussed. Literature analysis showed that the emergence of antibiotic resistance is an unavoidable phenomenon closely correlated with the use of antibiotics themselves. To limit the emergence of resistance, every effort to reduce and rationalise antibiotic consumption must be made. An increased use of antibiotic stewardship can be greatly effective in this regard.

Background In recent years, several studies have been published on the prognosis of children with congenital solitary kidney (CSK), with controversial results, and a worldwide consensus on management and follow-up is lacking. In this consensus statement, the Italian Society of Pediatric Nephrology summarizes the current knowledge on CSK and presents recommendations for its management, including diagnostic approach, nutritional and lifestyle habits, and follow-up. Summary of the recommendations We recommend that any antenatal suspicion/diagnosis of CSK be confirmed by neonatal ultrasound (US), avoiding the routine use of further imaging if no other anomalies of kidney/urinary tract are detected. A CSK without additional abnormalities is expected to undergo compensatory enlargement, which should be assessed by US. We recommend that urinalysis, but not blood tests or genetic analysis, be routinely performed at diagnosis in infants and children showing compensatory enlargement of the CSK. Extrarenal malformations should be searched for, particularly genital tract malformations in females. An excessive protein and salt intake should be avoided, while sport participation should not be restricted. We recommend a lifelong follow-up, which should be tailored on risk stratification, as follows: low risk: CSK with compensatory enlargement, medium risk: CSK without compensatory enlargement and/or additional CAKUT, and high risk: decreased GFR and/or proteinuria, and/or hypertension. We recommend that in children at low-risk periodic US, urinalysis and BP measurement be performed; in those at medium risk, we recommend that serum creatinine also be measured; in high-risk children, the schedule has to be tailored according to kidney function and clinical data.

In the field of medical care, successful transition from pediatric-centered to adult-oriented healthcare can provide a sense of continuity in the development of youth, and prepare them to accept responsibility for and manage their own chronic kidney condition in complete autonomy. The so-called transition process requires the presence of some basic aspects: a multidisciplinary team, which acts as a bridge between child and adult services; a comprehensive clinical, cognitive, psychological, and social change for the young people; the involvement of family and caregivers. Within the framework of transition and chronicity during the developmental age, we selected international papers explaining models which agreed on some important steps in the transition process, although many differences can be observed between different countries. In fact, in Europe, the situation appears to be heterogeneous as regards certain aspects: the written transition plan, the educational programmes, the timing of transfer to adult services, the presence of a transition coordinator, a dedicated off-site transition clinic. We then analyzed some studies focusing on patients with renal diseases, including the first to contain a standardized protocol for transition which was launched recently in the USA, and which seems to have already achieved important positive, although limited, results. In Italy, the issue of transition is still in its infancy, however important efforts in the management of chronic kidney disease have already been initiated in some regions, including Emila Romagna, which gives us hope for the future of many young people.

Purpose: Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients’ resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. Methods: The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. Results: Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2–25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10−3–6.7 × 10−1). Significant results were confirmed in the entire cohort. Conclusions: Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.

Background This study aimed to evaluate the effect of oral dexamethasone in reducing kidney scars in infants with a first febrile urinary tract infection (UTI). Methods Children aged between 2 and 24 months with their first presumed UTI, at high risk for kidney scarring based on procalcitonin levels (≥1 ng/mL), were randomly assigned to receive dexamethasone in addition to routine care or routine care only. Kidney scars were identified by kidney scan at 6 months after initial UTI. Projections of enrollment and follow-up completion showed that the intended sample size could not be reached before funding and time to complete the study ran out. An amendment to the protocol was approved to conduct a Bayesian analysis. Results We randomized 48 children, of whom 42 had a UTI and 18 had outcome kidney scans (instead of 128 planned). Kidney scars were found in 0/7 and 2/11 patients in the treatment and control groups respectively. The probability that dexamethasone could prevent kidney scarring was 99% in the setting of an informative prior probability distribution (which fully incorporated in the final inference the information on treatment effect provided by previous studies) and 98% in the low-informative scenario (which discounted the prior literature information by 50%). The probabilities that dexamethasone could reduce kidney scar formation by up to 20% were 61% and 53% in the informative and low-informative scenario, respectively. Conclusions Dexamethasone is highly likely to reduce kidney scarring, with a more than 50% probability to reduce kidney scars by up to 20%. Trial registration number EudraCT number: 2013-000388-10; registered in 2013 (prospectively registered) Graphical Abstract

Hypokalemia and metabolic alkalosis can be present in different rare diseases, and the differential diagnosis of these forms is challenging. Apparent mineralcorticoid (AME) excess syndrome is one of these conditions. Characterized by increased blood pressure due to excessive sodium retention and plasma volume, it is caused by a mutation in the HSD11B2 gene encoding the oxydoreductase enzyme 11β-hydroxysteroide dehydrogenase type 2. We report the case of a child presenting with failure to thrive associated with early detection of hypokalemia, metabolic alkalosis, nephrocalcinosis and hypertension in which AME syndrome was detected. A novel mutation in the HSD11B2 gene was identified in this patient. In clinical pictures characterized by metabolic alkalosis and hypokalemia, the evaluation of renin, aldosterone and blood pressure is crucial for accurate diagnosis. AME syndrome is a rare disorder that can be an insidious but lethal disease, if untreated. With clinical signs appearing during the first days of life. Early diagnosis is imperative in order to enable prompt and adequate treatment to improve the outcome of these patients.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype&ndash, genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G&gt, A, p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD&mdash, both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7R&alpha, expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

We assessed renal function outcome in children with congenital solitary kidney and evaluated prognostic risk factors.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.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%, p0.001). Occurrence of proteinuria and/or systemic hypertension was present in less than 5% of children.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.

Aim Our 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. Methods The 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. Results Four 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. Conclusion These 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 term osteopetrosis describes a group of rare hereditary diseases of the skeleton, characterized by an increase in bone density, caused by a defect in the development or function of osteoclasts. It comprises a clinically and genetically heterogeneous conditions ranging from infantile onset life-threatening forms to mildest adult onset forms. "Malignant" osteopetrosis is characterized by bone fragility, short stature, compressive neuropathies, hypocalcaemia, pancytopaenia. The deficiency of carbonic anhydrase II causes a moderate form, presenting classically as a triad of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification. This condition leads to specific craniofacial dysmorphisms associated with upper airway obstruction that may result in obstructive sleep apnea. Herein we report a case of osteopetrosis with RTA associated with severe OSAS successfully treated with continuous positive airway pressure (CPAP).

Background. Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods. Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results. Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions. CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Acute pyelonephritis is one of the most serious bacterial illnesses during childhood. Escherichia coli is responsible in most cases, however other organisms including Klebsiella, Enterococcus, Enterobacter, Proteus, and Pseudomonas species are being more frequently isolated. In infants, who are at major risk of complications such as sepsis and meningitis, symptoms are ambiguous and fever is not always useful in identifying those at high risk. A diagnosis of acute pyelonephritis is initially made on the basis of urinalysis; dipstick tests for nitrites and/or leukocyte esterase are the most accurate indicators of infection. Collecting a viable urine sample for urine culture using clean voided methods is feasible, even in young children. No gold standard antibiotic treatment exists. In children appearing well, oral therapy and outpatient care is possible. New guidelines suggest less aggressive imaging strategies after a first infection, reducing radiation exposure and costs. The efficacy of antibiotic prophylaxis in preventing recurrence is still a matter of debate and the risk of antibiotic resistance is a warning against its widespread use. Well-performed randomized controlled trials are required in order to better define both the imaging strategies and medical options aimed at preserving long-term renal function.

Dent disease is a rare X-linked tubulopathy with low molecular weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis and progressive renal failure. We describe the case of a 9-year-old boy who presented with nephrotic-range albuminuria at the age of 3 years. In the absence of a clear diagnosis, a renal biopsy was performed at 4 years, which revealed minimal change disease. Due to the presence of low molecular weight proteinuria, even in the absence of hypercalciuria, a diagnosis of Dent disease was considered. While there were no mutations in the CLCN5 gene, the diagnosis was confirmed by the presence of a missense mutation (p.Arg318Cys) in the OCRL gene. Conclusion: Given the large phenotypic variability of the disease and based on our experience, we believe that children with low molecular weight proteinuria, even without hypercalciuria, should be investigated for Dent disease.

The management of children with a febrile urinary tract infection has always been a matter of debate. While some recent trials have succeeded in leading to agreement on certain issues, other important points of contention remain, in particular urine collection methods, imaging strategies, and prevention of recurrence.

Urinary Tract Infections (UTIs) are common in every day pediatric practice. During the first 6 years of life, circa 6 to 7% of girls and 2.5% of boys will develop a UTI. UTI fall into two categories: non febrile lower UTI or cystitis and febrile upper UTI or pyelonephritis. The latter is considered by many to be the most common serious bacterial illness in children [1]. If UTI is suspected, urinalysis and urine culture should be performed. Collection methods used in clinical practice can be either invasive or non invasive, yet all carry a risk of contamination by bacteria not present in the bladder. Clean voided methods are preferable as they are quite easy to perform and reliable, while invasive methods should be limited to children in poor general health [2]. In the presence of clinical signs and positive urine analysis, while awaiting the results of antimicrobial sensitivity testing, antibiotic treatment should be started as soon as possible, considering local resistance patterns. The route of administration, either parenterally or orally, depends on the condition of the child and the severity of the infection and does not affect the duration of fever, recurrence of UTI or the incidence of post infectious scars. The need for imaging after a first febrile UTI has long been debated. New insights have led us to consider less aggressive imaging strategies, given the high rate of spontaneous resolution of vesico ureteral reflux with age and the good renal outcome for patients with acquired scarring. Therefore, voiding cystography and renal dimercaptosuccinic acid scintigraphy are not routinely recommended [2-4]. It is known that there are several risk factors for the recurrence of UTI. Some are not modifiable (age, gender, familiarity), while others (reflux, phimosis, bladder function, voiding habits, constipation and fluid intake) are modifiable thanks to behavioral changes and/or medical treatments. As regards preventive interventions, the most controversial is the use of antibiotic prophylaxis and currently none of the recently published guidelines recommend a routine use [2,4].

OBJECTIVE: To evaluate the yield, economic, and radiation costs of 5 diagnostic algorithms compared with a protocol where all tests are performed (ultrasonography scan, cystography, and late technetium99dimercaptosuccinic acid scan) in children after the first febrile urinary tract infections. METHODS: A total of 304 children, 2 to 36 months of age, who completed the diagnostic follow-up (ultrasonography, cystourethrography, and acute and late technetium99dimercaptosuccinic acid scans) of a randomized controlled trial (Italian Renal Infection Study 1) were eligible. The guidelines applied to this cohort in a retrospective simulation were: Melbourne Royal Children’s Hospital, National Institute of Clinical Excellence (NICE), top down approach, American Academy of Pediatrics (AAP), and Italian Society of Pediatric Nephrology. Primary outcomes were the yield of abnormal tests for each diagnostic protocol; secondary outcomes were the economic and radiation costs. RESULTS: Vesicoureteral reflux (VUR) was identified in 66 (22%) children and a parenchymal scarring was identified in 45 (15%). For detection of VUR (47/66) and scarring (45/45), the top down approach showed the highest sensitivity (76% and 100%, respectively) but also the highest economic and radiation costs (€52 268. 624 mSv). NICE (19/66) and AAP (18/66) had the highest specificities for VUR (90%) and the Italian Society of Pediatric Nephrology had the highest specificity (20/45) for scars (86%). NICE would have been the least costly (€26 838) and AAP would have resulted in the least radiation exposure (42 mSv). CONCLUSIONS: There is no ideal diagnostic protocol following a first febrile urinary tract infection. An aggressive protocol has a high sensitivity for detecting VUR and scarring but carries high financial and radiation costs with questionable benefit.

Renal hypodysplasia (RHD) is a congenital disorder, characterized by an abnormally developed kidney. Mutations in genes such as PAX2, HNF1-beta, TCF2, EYA1, that encode factors critical in early renal development, are being found. RHD is the leading cause of chronic renal failure in childhood, with or without associated urologic abnormalities such as vesicoureteric reflux and urinary tract obstruction. Antenatal detection has improved understanding of this disorder, resulting in enhanced outcomes through earlier intervention, including peritoneal dialysis. Management requires a multidisciplinary team approach that commences prior to the birth of the child.

Background Infant mortality rate (IMR) is a key public health indicator. Maternal age is a well-known determinant of pregnancy and delivery complications and of infant morbidity and mortality. In Italy the Infant Mortality Rate was 3.7/1000 during 2005, lower than the average IMR for the European Union (4.94/1000). Sicily is the Italian region with the highest IMR, 5/1000, and neonatal mortality rate (NMR), 3.8/1000, with substantial variation among its nine districts. The present study compared a high IMR/NMR district (Messina) with a low IMR/NMR district (Palermo) during the period 2004-2006 to evaluate potential determinants of the IMRs' differences between the two districts and specifically the impact of maternal age. Methods The Death Causes Registers identified all deaths during the first year of life recorded among infants born to residents of the two districts in 2004-2006. For every case, available hospital charts records were abstracted using a standardized form designed to capture information on potential determinants of infant death. For each district and for each year, IMRs and NMRs were computed. Chi-squared statistics tested the significance of differences between district-specific IMRs. A Poisson regression model was used to analyze the relationship between maternal age, district of residence and IMR. Results The 246 death registry-confirmed cases included 143 (58.1%) males and 103 (41.2%) females, with mean age at death of 33.3 days (SD: 64.5, median: 5.5). The average IMR for 2004-2006 was significantly higher for the Messina district than for the Palermo district (p = 0.0001). The IMR ratio was 1.6 (95%CI: 1.2 - 2.1). The IMRs declined from 2004 to 2006. A significant interaction (p = 0.04) between maternal age and district of residence was documented. Conclusion The association between advanced maternal age and infant deaths in the Messina district was due in part to the excess of newborns from advanced age mothers, but also to increased risk of death among such newborns. The significant interaction between district of residence and maternal age indicated that the IMR excess in the Messina district cannot be explained by disproportionately high live birth rates among older mothers and suggested the hypothesis that health care facilities in the Messina district could be less well prepared to provide assistance to the excess of high risk pregnancies and deliveries, as compared to Palermo district.

Per una diagnosi rapida, e quindi per la prevenzione delle complicanze, e per una corretta terapia della acidosi tubulare renale è utile la stretta colaborazione con lo specialista nefrologo.