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Purpose: Repeated gadolinium-based contrast agent (GBCA)-enhanced MRIs are crucial in the diagnosis and follow-up of oncologic and chronic disorders in pediatric patients. The aim of the study was to evaluate the frequency and severity of adverse reactions to GBCAs in children after a single vs. multiple GBCA-enhanced abdomen MRIs. Material and methods: All pediatric patients with at least one GBCA-enhanced abdominal MRI between 2009 and 2020 were retrospectively evaluated based on adverse reactions reports, according to the classification system of the American College of Radiology and guidelines on contrast agents of the European Society of Urogenital Radiology. A Student´s t-test analysis, a spearman ρ-correlation and a Chi-square test between the reported adverse reactions and the total number of GBCA applications, and the number of each applied GBCA was calculated. A p-value <0.05 was considered significant. Results: Of 623 patients with 964 GBCA-enhanced abdomen MRIs, there were 464 patients with only one and 159 patients with multiple GBCA administrations. Of 964 GBCA doses administrated, two cases with urticaria (mild allergy-like adverse reaction) and one case with vomiting (mild chemotoxic adverse reaction) were recorded (3/964 = 0.31%), but all the reports were in patients with multiple GBCA administration (3/159 = 1.89%). No adverse reactions in patients with a single GBCA administration were observed. The reported adverse reactions correlated significantly with the total number of GBCAs (p<0.001) and the number of each GBCA (p<0.001 or p = 0.002). The independent two-tailed t-tests, and the chi-square test were significant (p<0.001, p = 0.003). Conclusion: GBCA-associated adverse reactions are rare and mostly mild, but initially well-tolerated GBCA could cause adverse reactions due to the increase likelihood of drug hypersensitivity upon repeated GBCA exposure. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma‐glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12‐related disease from other entities with elevated GGT. [ABSTRACT FROM AUTHOR]

Background Chronic deterioration of kidney graft function is related to inadequate immunosuppression (IS). A novel tool to assess the individual net state of IS in transplanted patients might be the monitoring of Torque teno virus (TTV) viral load. TTV is a non-pathogen virus detectable in almost all individuals. TTV level in the peripheral blood has been linked to the immune-competence of its host and should thus reflect IS after solid organ transplantation. Methods TTV plasma load was quantified monthly by RT-PCR for a period of 1 year in 45 kidney-transplanted children. Post-transplant time was at least 3 months. The relation of the virus DNA levels to IS and transplant-specific clinical and laboratory parameters was analysed longitudinally. Results TTV DNA was detectable in 94.5% of the plasma samples. There was a significant association with the post-transplant follow-up time as well as with the type of IS regimen, with lower virus loads in patients after longer post-transplant time and mTOR inhibitor-based IS. Furthermore, a significant positive correlation with the dose of prednisolone and mycophenolate mofetil was found. Conclusions TTV levels show an association/correlation with the strength of IS. Further studies are needed in order to evaluate TTV measurement as a tool for IS monitoring for hard clinical outcomes such as presence of donor-specific antibodies, rejections or infections-common consequences of insufficient or too intense IS., Author(s): Phoebe Uhl [sup.1] , Andreas Heilos [sup.1] , Gregor Bond [sup.2] , Elias Meyer [sup.3] , Michael Böhm [sup.1] , Elisabeth Puchhammer-Stöckl [sup.4] , Klaus Arbeiter [sup.1] , Thomas [...]

Background A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. Methods A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. Results High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2—which is not reliable because of the small number of cases—strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3–4 had worse renal survival than patients in Clusters 1–2. Conclusions Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints., Methods: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7)., Results: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF., Conclusions: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)