The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment. METHODS: Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4-8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period. RESULTS: No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m2 at baseline, 93.5 mL/min/1.73m2 at 26 weeks, and 104 mL/min/1.73m2 at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study. CONCLUSIONS: Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4-8 weeks. TRIAL REGISTRATION: Trial identifiers: Trial ID: ALXN1210-aHUS-312 Clinical trials.gov : NCT03131219 EudraCT number: 2016-002499-29 Graphical abstract.

Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy.

INTRODUCTION: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN. METHODS: We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined. RESULTS: Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls. CONCLUSIONS: Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.