Complement diagnostics and therapeutics for the pediatric population: early successes and opportunities for further...

Complement-mediated diseases are individually rare, often rapidly progressive, and historically associated with high rates of permanent organ injury or death but are now among the most therapeutically actionable conditions in pediatric nephrology, hematology, and rheumatology. As demonstrated by thrombotic microangiopathy, and hemolytic uremic syndrome in particular, diagnostic delay can contribute directly to irreversible kidney injury. Complement inhibition has substantially improved outcomes in these conditions that previously carried a substantial risk of end-stage kidney disease. This review addresses the complement system as a clinical and therapeutic framework for the practicing pediatric clinician. The pathophysiology of the major complement-mediated diseases affecting children is examined, with atypical hemolytic uremic syndrome and transplant-associated thrombotic microangiopathy as central disease models alongside paroxysmal nocturnal hemoglobinuria, C3 glomerulopathy, IgA nephropathy, and ANCA-associated vasculitis. Approved complement inhibitors are reviewed by mechanistic position in the cascade, with attention to the clinical implications of terminal versus proximal pathway inhibition. Laboratory diagnosis, monitoring, and assessment of complement blockade adequacy are addressed, including practical limitations of complement testing in clinical practice. Critical gaps are examined, including diagnostic delays, absent validated biomarkers, inadequate pediatric trial infrastructure, and conditions without targeted therapies. Emerging therapeutics, point-of-care diagnostics, and pediatric-specific considerations including transition of care and reproductive counseling complete the review. Complement therapeutics have meaningfully altered the trajectory of some of the most severe and inadequately treated pediatric diseases. This field continues to evolve rapidly, with expanding indications and novel agents, though drug development challenges, diagnostic and monitoring gaps, and equitable consideration of pediatric application of these novel agents remain essential priorities.