Kalliopi Vardaki

Background Bardet–Biedl syndrome (BBS) is a rare multisystem ciliopathy with significant kidney involvement. Reliance on serum creatinine for estimating glomerular filtration rate (GFR) may underestimate impairment for children with reduced muscle mass or obesity. Cystatin-C is an alternative marker less affected by muscle mass, but its role in BBS surveillance remains under-explored. Methods This retrospective cross-sectional study included 87 paediatric patients with genetically confirmed BBS diagnosis from the UK National BBS Service in London. Paired creatinine(sCr-eGFR) and cystatin-C-based eGFR (cys-C-eGFR) were calculated using the CKiD-U25 calculator. CKD staging differences were compared using Wilcoxon signed-rank and Spearman correlation tests. Results Participants had a median age of 12.87 years and a median BMI of 27.22 kg/m ² . The median sCr-eGFR was 100.7 ml/min/1.73 m² versus 79.7 ml/min/1.73 m² for cys-C-eGFR, with a modest correlation between methods (r = 0.45). Using cystatin C-based equations, 43.7% of patients were classified into a higher CKD stage compared to creatinine-based estimates (p < 0.001). Female sex was significantly associated with greater reclassification to a higher stage (56.6% of females vs. 29.3% of males, p < 0.05). No significant difference in classification was observed across BMI percentiles or genotype subgroups. Conclusion Reliance on serum creatinine alone may underestimate kidney impairment in BBS, especially in females. Cystatin-C appears to identify more patients with reduced eGFR. Routine use could improve early detection, guide timely intervention and inform surveillance. Further prospective studies with measured GFR are needed to validate these findings.

Background: Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal resistance to arginine vasopressin, most commonly caused by pathogenic variants in the AVPR2 gene. While X-linked NDI classically affects males, heterozygous females may exhibit variable clinical expression. Certain AVPR2 variants are associated with partial NDI and milder phenotypes. Methods: We conducted a retrospective family study of a multigenerational Greek pedigree with suspected hereditary NDI. Clinical, biochemical, and pedigree data were collected through chart review and family interviews. Genetic analysis was performed using whole-exome sequencing, and variant interpretation followed ACMG/AMP guidelines. Results: Fourteen individuals across four generations were evaluated. Molecular analysis identified a familial AVPR2 (NM_000054.7):c.964C>T (p.Pro322Ser) missense variant in three males and three females, with obligate carrier status inferred in two deceased females, segregating in an X-linked pattern. Hemizygous males exhibited a broad phenotypic spectrum, ranging from partial NDI with later onset to severe early-onset disease with urinary tract complications. Heterozygous females showed variable expression, from asymptomatic carriers to mildly symptomatic individuals. The variant co-segregated with disease and, based on ACMG criteria, it was classified as pathogenic. Conclusions: In our family, the AVPR2 c.964C>T (p.Pro322Ser) variant was associated with a remarkably broad clinical spectrum, ranging from asymptomatic heterozygous females to severe early-onset disease with urinary tract complications in affected males. These observations emphasize the need for early molecular diagnosis, systematic evaluation of female carriers, and long-term surveillance to prevent disease-related complications and optimize genetic counselling.

Background: Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal resistance to arginine vasopressin, most commonly caused by pathogenic variants in the AVPR2 gene. While X-linked NDI classically affects males, heterozygous females may exhibit variable clinical expression. Certain AVPR2 variants are associated with partial NDI and milder phenotypes. Methods: We conducted a retrospective family study of a multigenerational Greek pedigree with suspected hereditary NDI. Clinical, biochemical, and pedigree data were collected through chart review and family interviews. Genetic analysis was performed using whole exome sequencing and variant interpretation followed ACMG/AMP guidelines. Results: Fourteen individuals across four generations were evaluated. Molecular analysis identified a familial AVPR2 (NM_000054.7):c.964C>T (p.Pro322Ser) missense variant in three males and three females, with heterozygous status suspected in two deceased females, segregating in an X-linked pattern. Hemizygous males exhibited a broad phenotypic spectrum, ranging from partial NDI with later onset to severe early-onset disease with urinary tract complications. Heterozygous females showed variable expression, from asymptomatic carriers to mildly symptomatic individuals. The variant co-segregated with disease and, based on ACMG criteria, it was classified as pathogenic. Conclusions: This study expands the phenotypic spectrum associated with the AVPR2 p.Pro322Ser variant and highlights marked intrafamilial variability in both hemizygous males and heterozygous females. These findings underscore the role of modifying factors in disease expression and emphasize the importance of genetic diagnosis for early management and family counseling in NDI.

Background: Idiopathic nephrotic syndrome (NS) is the most common glomerular disease in children. While corticosteroids remain the first-line treatment for inducing remission, their prolonged or frequent use can suppress the hypothalamic–pituitary–adrenal (HPA) axis, potentially leading to adrenal insufficiency (AI). However, the true burden of this complication remains poorly understood and inconsistently reported. This study aimed to systematically evaluate the prevalence, diagnostic methods, risk factors, and clinical implications of steroid-induced AI in children with NS. Methods: A systematic search of Medline was conducted up to October 3, 2025, and the references of relevant publications were also hand-searched for eligible studies. We looked for studies that assessed adrenal function or AI in pediatric patients with NS treated with corticosteroids. Only English-language studies were included; case reports, abstracts, and reviews were excluded. In total, 13 studies involving 516 pediatric patients met the inclusion criteria. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines and was registered in the PROSPERO database (CRD420251082353, June 27, 2025). Due to methodological heterogeneity, a narrative synthesis was performed. Results: The reported prevalence of AI ranged from 5.9 to 92.9%, largely influenced by the diagnostic test used and the timing of assessment. Seven different testing methods were identified, with the 2-h ACTH stimulation test demonstrating the highest diagnostic yield. Definitions of AI and cortisol cutoff values varied considerably across studies. AI was more commonly observed in children with frequently relapsing or steroid-dependent NS, as well as in those with prolonged or repeated exposure to corticosteroids. Associations with age were inconsistent. AI was also linked to an increased risk of relapse, particularly during infections. Children with suppressed adrenal function may be at risk of adrenal crisis if not administered stress-dose corticosteroids during periods of physiological stress. Conclusion: Included studies were mostly small, single-center, and methodologically heterogeneous. There was a lack of consensus on diagnostic criteria and limited long-term follow-up data. Steroid-induced AI is a common and potentially under-recognized complication in children with idiopathic NS, especially in high-risk groups. Due to inconsistent diagnostic practices, the actual prevalence of AI is unclear. There is a critical need for further research, standardized testing protocols, and clinical guidelines. Clinicians may consider screening for AI in children with high cumulative steroid exposure and consider cortisol replacement accordingly. Graphical A higher resolution version of the Graphical abstract is available as Supplementary information.

Background: Complicated urinary tract infections (cUTI) present a challenge to the clinician because of the variety in clinical syndromes included and consequent difficulties in synthesizing evidence. A harmonized definition of cUTI does not exist. In national guidelines, management recommendations for cUTI are often neglected. We aimed to define the four most important controversies and formulate management recommendations for cUTI in children and adolescents. Methods: The European Society of Pediatric Infectious Diseases Guideline Committee convened a working group of experts from microbiology, pediatric nephrology and infectious diseases with expertise in managing children with UTI. A comprehensive literature review was done using PubMed, Embase and the Cochrane library to find studies in children under 18 years published until December 2024. Four controversies were defined from experience and available evidence. Children with cUTI were categorized into 5 subgroups: anatomical/functional urological abnormalities, multiple UTI recurrences, severe clinical presentation, nonurological underlying conditions and neonates. Respective management guidelines were formulated through the evidence and by consensus of working group members. Recommendations were made using GRADE criteria. Results: The term cUTI is generally used to define children with UTI with an increased likelihood of failing conventional management. The included 5 subgroups are the most likely to need additional investigations at diagnosis and during the course of infection, initial intravenous antibiotics, longer treatment duration, antibiotic prophylaxis, follow-up imaging and surgical referral. These are detailed for each subgroup. Conclusions: These comprehensive guidelines offer evidence-graded recommendations specifically for pediatric cUTI, addressing gaps that exist in current guidelines.