Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases

Background: In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. Methods: Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. Results: The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. Conclusions: We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research

High throughput sequencing in sporadic forms of steroid-resistant nephrotic syndrome in children frequently identifies heterogeneous genetic alterations that predict resistance to immunosuppressive treatments

In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations

Identification and characterization of a new candidate gene for steroid resistant nephrotic syndrome

Nephrotic syndrome (NS) is characterized by consistent proteinuria, oedema, hypoalbuminemia, and it can be classified as steroid-sensitive (about 90%) or steroid-resistant (SRNS-about 10%). To date, mutations in at least 15 genes have been found to cause SRNS and although mutations in NPHS1 or NPHS2 are frequent causes of children SNSR, mutations in other genes are very rare. In addition, multiple allelism and heterogeneity together with a phenotypic clinical overlap require an extensive mutational analysis effort to identify the molecular aetiology. To identify SRNS by molecular diagnosis has important clinical implication, as this would prevent unnecessary administration of corticosteroids and immunosuppressants. We performed targeting and whole-exome (re)sequencing in 25 probands with a diagnosis of a paediatric SNSR (including 25 subjects steroid-sensitive). Because mutations in several genes have been demonstrated to lead to familial or sporadic SNSR, we focused our attention on these genes and on those candidates potentially implicated in the pathogenesis of the disorder. We identified a putative new candidate gene that may allow to define a novel clinical entity in the field of genetic disorders (hyperactivation of this gene was described to cause NS in podocyte-specific transgenic mice). Definition of the causative role of these mutations would represent the first case of an defect leading to a disorder where SRNS is part of a more complex clinical syndrome including also immunologic alterations. The results of our work may lead to the identification of a new causative gene for SRNS and provide definition of a previously unidentified clinical syndrom

Urine-derived human renal progenitor cultures for modeling of genetic kidney disorders in subject studied by Next Generation Sequencing

The advent of high-throughput sequencing has fostered the identification of novel causative genes of kidney disorders, and has allowed the continuous discovery of genetic variants of unknown significance often raising the problem of the functional testing of their pathogenic role. However, emerging evidence implicates that influence of the genomic background of the patient, as well as epigenetic modifications are critical in determining the clinical phenotype. Renal progenitor cell (RPC) cultures obtained from the affected patient may represent an ideal alternative for personalized disease modeling. Since loss of renal cells in urine naturally occurs in patients, urine may represent a potential RPC source. In this study, we selected and amplified RPC cultures from the urine of patients with renal disease, and we evaluated the possibility to use these cells for modeling of genetic kidney disorders. Urin-RPC were obtained from five children affected by Nephrotic Syndrome carrying mutations in genes encoding for podocyte cytoskeleton proteins, identified thought Next Generation Sequencing, as well as from children without genetic alterations (five). The first cells exhibited altered synthesis of mutated proteins, abnormal cytoskeleton structure and functional abnormalities; by contrast, the second ones showed normal phenotype, structure and function. The development of functional assays with Urin-RPC could serve as a fundamental step for rapid testing of putative pathogenic mutations. In particular, this tool can provide an essential support for the clinical diagnosis of nephrotic syndrome in patients carrying variants of uncertain significance and provide information to optimize an affected individual’s personalized medical care

Pretransplant serum FT3 levels in kidney graft recipients are useful for identifying patients with higher risk for graft failure.

OBJECTIVE: End-stage renal disease (ESRD) is a condition associated with thyroid disturbances both in function and morphology. Recent studies demonstrated that serum free triiodothyronine 3 (FT3) levels are negatively correlated with serum markers of inflammation and endothelial activation in patients with ESRD. However, no previous research evaluated serum thyroid function parameters in relation to kidney graft outcome, as we aim to do so in this study. DESIGN: Serum FT3, free thyroxine 4 (FT4) and TSH levels were measured before transplantation in 196 kidney graft recipients. RESULTS: The graft survival rate at 5 years for all patients was 92.3%. Kidney graft recipients with normally functioning grafts showed serum pretransplant thyroid parameters similar to patients who experienced graft failure. Life-time analysis was performed after stratification of patients according to pretransplant serum FT3 levels < 3.1 pmol/l or > 3.1 pmol/l. A significantly different 5-year death-censored graft survival rate (93.9%vs. 76.5% for patients with normal or low FT3 levels, respectively; P < 0.01) and similar survival rate (death of patients with functioning grafts) (21.1%vs. 5.9%; P = 0.288) were observed. No similar feature was found for FT4 or TSH, suggesting that the effect is not related to hypothyroidism but rather dependent upon inappropriately low FT3 levels. Pretransplant serum FT3 levels were similar in patients who experienced early acute rejections as compared with nonrejector patients. CONCLUSIONS: The results of this study demonstrate that among patients with ESRD undergoing kidney transplantation, those displaying lower pretransplant serum FT3 levels are at higher risk for subsequent graft failure. The demonstration of a predictive value of serum FT3 levels for graft survival suggests that measurement of pretransplant serum FT3 levels might represent a clinically useful parameter to identify patients with increased risk for graft failure

URINE-DERIVED HUMAN RENAL PROGENITOR CULTURES FOR MODELING OF GENETIC KIDNEY DISORDERS

The development of functional assays with u-RPC obtained from patients with genetic kidney disorders could serve as a fundamental step for rapid testing of putative pathogenic mutations. In particular, this tool can provide an essential support for the clinical diagnosis of nephrotic syndrome in patients carrying variants of uncertain significance in podocyte genes. The results of this study demonstrate that u-RPC cultures represent an innovative research tool which provide information to optimize an affected individual’s personalized medical care