Efficacy and safety of dapagliflozin in children with kidney disease: real-world data.

BACKGROUND: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown results in slowing estimated glomerular filtration rate (eGFR) decline and reducing proteinuria in adult patients with chronic kidney disease. This retrospective study examines dapagliflozin's effects in 22 children with kidney disease and proteinuria. METHODS: Children with a median age of 15.6 years were treated with dapagliflozin for > 3 months between July 2022 and December 2023. All children had been treated with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 1 month before starting dapagliflozin. RESULTS: The most common kidney disease diagnoses in this study included Alport syndrome (n = 7) and medication-resistant nephrotic syndrome or focal segmental glomerulosclerosis (n = 7). After 6.1 months of treatment, dapagliflozin treatment did not result in significant changes in eGFR or proteinuria. However, at the latest follow-up, a statistically significant decrease in eGFR was noted (65.5 compared to the baseline 71.1 mL/min/1.73 m2, P = 0.003). Proteinuria remained stable between baseline and the last follow-up (final spot urine protein/creatinine ratio (uPCR) 0.7 vs. baseline uPCR 0.6 mg/mg, P = 0.489). In the subgroup analysis of children treated for > 8 months, the eGFR decline post-treatment changed from - 0.5 to - 0.2 ml/min/1.73 m2 per month (P = 0.634). Only two children discontinued dapagliflozin due to suspected adverse events. CONCLUSIONS: Dapagliflozin has not been associated with serious side effects. Further prospective clinical trials are needed to confirm the efficacy and safety of dapagliflozin in children with kidney disease.

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up. RESULTS: The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Long-term outcomes and associated prognostic risk factors of childhood-onset lupus nephritis.

Background: This study investigated the clinical characteristics and kidney outcomes of childhood-onset lupus nephritis (LN), and risk factors associated with prognosis. Methods: We enrolled 216 patients with histologically diagnosed LN during childhood. The Korean Society of Pediatric Nephrology organized a retrospective cohort study of childhood-onset LN in 13 major pediatric nephrology centers in South Korea. Results: The mean age at kidney biopsy was 13.2 ± 3.22 years. The main forms of presentation were nephrotic syndrome and/or hematuria in 152 patients (70.4%), and the most common histological finding was World Health Organization (WHO) class IV in 138 patients (63.9%), followed by WHO class III in 34 patients (15.7%). In the outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At last follow-up, 32 patients (14.8%) developed advanced chronic kidney disease (CKD). Male sex and failure to achieve remission at 12 months of treatment were significant risk factors for developing advanced CKD (hazard ratio of 2.57 and 2.29, respectively). Conclusion: Our study demonstrated the clinical characteristics and long-term outcomes of patients with childhood-onset LN. Male sex and failure to achieve remission in the first year of treatment were predictive of advanced CKD. Therefore, prompt awareness and close monitoring of these high-risk patients are needed, which may further improve the prognosis of children with LN.

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome.

Single gene pathogenic mutations have been implicated in up to 30% of pediatric steroid-resistant nephrotic syndrome (SRNS) cases, mostly in infantile patients. Among them is LAMA5, which has been recently discovered and encodes the laminin α5 chain. The laminin α5ß2γ1 heterotrimer is an essential component of the glomerular basement membrane and is necessary for embryogenesis and immune modulation. Biallelic LAMA5 variants have been identified in one adult and ten pediatric nephrotic syndromes (NS) patients with variable phenotypes. Biallelic truncating mutations in this gene have recently been proven to cause SRNS. Here, we present another case of infantile SRNS related to novel compound heterozygous variations of LAMA5 (c.3434G > A, p.Cys1145Tyr and c.6883C > T, p.Gln2295*), the first reported case with one missense and one nonsense allele. A 10-month-old female patient presented with eyelid edema and massive proteinuria without any extrarenal symptoms or family history. The patient was diagnosed with SRNS. Renal biopsy revealed focal segmental glomerulosclerosis with widely effaced epithelial foot processes and a "moth-eaten" appearance. She progressed to end stage kidney disease (ESKD), requiring dialysis at 31 months of age, and underwent a deceased-donor kidney transplant at 6 years of age. Four months after transplantation, she developed Ebstein-Barr Virus (EBV) infection related to post-transplantation lymphoproliferative disorder (PTLD). After chemotherapy, the patient remained healthy with adequate renal function without disease recurrence for the past 7 years. We also identified previous cases of biallelic LAMA5 variants associated with the nephrotic phenotype and analyzed the available clinical and genetic information. All reported patients had an onset of NS ranging from 3 months to 8 years, with no other syndromic features. Response to therapy and renal outcomes varied greatly; most patients exhibited steroid resistance, five progressed to ESKD, and two received kidney transplantation (KT). There was one report of PTLD. Our patient's phenotype was markedly more severe than those with biallelic missense variants and somewhat less severe than those with two truncating variants. LAMA5 defects may also play a role in PTLD, though no conclusions can be made with such limited cases. LAMA5 should be considered a candidate gene for SRNS and should be actively tested in cases with no other genetic diagnosis.