UPSTREAM VS. DOWNSTREAM: COMPLEMENT INHIBITION STRATEGIES FOR PEDIATRIC C3G AND AHUS—EFFICACY, SAFETY, AND LONG-TERM KIDNEY OUTCOMES
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Keywords
pediatric; C3 glomerulopathy; atypical hemolytic uremic syndrome; complement inhibition; C5 blockade; alternative pathway
Abstract
Complement dysregulation drives C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS), two rare pediatric kidney diseases with substantial risks for chronic kidney disease, dialysis, and transplant complications. Therapeutic strategies target either upstream complement nodes or the downstream terminal pathway at C5.
For pediatric aHUS, C5 blockade with eculizumab and ravulizumab demonstrates consistent clinical benefit with acceptable safety in trials and registries, though meningococcal disease prevention is mandatory. For pediatric C3G, upstream approaches—especially factor B inhibition with iptacopan—show early signals of proteinuria reduction and kidney function stabilization, but pediatric-specific data remain limited within broader mixed-age cohorts. Across both conditions, longer-term renal trajectories, relapse rates after stopping therapy, and transplant outcomes in children are incompletely documented. Until robust pediatric trials arrive, C5 blockade anchors aHUS care, while upstream strategies in C3G require case-by-case consideration based on phenotype, access, and transparent discussion of evidence gaps.
References
2. Tanaka K, Adams B, Greenbaum LA, et al. The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients previously treated with eculizumab. Pediatr Nephrol. 2000. doi:10.1007/s00467-020-04774-2.
3. Kavanagh D, Greenbaum LA, Bagga A, et al. Phase 3 open-label study of factor B inhibitor iptacopan in atypical hemolytic uremic syndrome (APPELHUS): design and rationale. Kidney Int Rep. 2006.doi:10.1016/j.ekir.2023.04.029.
4. Nester CM, Eisenberger U, Karras A, Le Quintrec M, Lightstone L, et al. Iptacopan reduces proteinuria and stabilizes kidney function in C3 glomerulopathy cohorts. Kidney Int Rep. 2005. doi:10.1016/j.ekir.2024.10.023.
5. Bomback AS, Nester CM, et al. Oral iptacopan therapy in patients with C3 glomerulopathy (APPEAR-C3G): phase 3 randomized, placebo-controlled trial. Lancet. 2005. doi:10.1016/S0140-6736(25)01148-1.
6. Nester C, Appel GB, Bomback AS, Bouman KP, et al. [Title visible in PDF; patient-oriented translational research in C3G]. Am J Nephrol. 2002;53:687–700. doi:10.1159/000527167.
7. Nester C, Appel GB, Bomback AS, Bouman KP, et al. [Companion article title visible in PDF]. Am J Nephrol. 2002;53:687–700.
8. Centers for Disease Control and Prevention (CDC). Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000;69(9).
9. The Turkish Journal of Pediatrics editorial group. Pediatric aHUS review. Turk J Pediatr. 2002;66:1–16. doi:10.24953/turkjped.2023.596.
10. Caby-Tosi JL, Marantz JL, et al. Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome: 10-year experience. Br J Haematol. 2001 doi:10.1111/bjh.15790.
11. Thomas S et al. Current concepts in C3 glomerulopathy. Indian Journal of Nephrology. 2004, 26 (6). Doi:10.4103/0971-4065.134089.
12. Nester et al. Developing Therapies for C3 Glomerulopathy: Report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group. Clinical Journal of the American Society of Nephrology 19(9):p 1201-1208, September 2004. | DOI: 10.2215/CJN.0000000000000505Raina R, Krishnappa V, Blaha T, et al. Atypical Hemolytic-Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment. Ther Apher Dial. 2000;(1):4-21. doi:10.1111/1744-9987.12763
13. Yerigeri K, Kadatane S, Mongan K, et al. Atypical Hemolytic-Uremic Syndrome: Genetic Basis, Clinical Manifestations, and a Multidisciplinary Approach to Management. J Multidiscip Healthc. 2023;16:2233-2249. Published 2003 Aug 4. doi:10.2147/JMDH.S245620
14. Noris M, Bresin E, Mele C, et al. Hemolytic-Uremic Syndrome. 2002 Nov 16. 2007.
15. Dixon BP, Kavanagh D, Dominquez-Gutierrez A, et al. Ravulizumab in atypical hemolytic uremic syndrome. Blood”. 2001.
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Dr Agraharam Patel Bharath
Department of pediatrics, Prathima Institute of Medical Sciences Karimnagar
Dr D Ramesh
Department of pediatrics, Apollo Institute of Medical Sciences and Research, Hyderabad