Terminal Complement Complex (C5b-9) in Children with Recurrent Hemolytic Uremic Syndrome

ABSTRACT

Recurrent hemolytic uremic syndrome (recHUS) is a heterogeneous group of disorders. The pathogenesis of recHUS is not fully understood. recHUS has a high risk of development of terminal renal insufficiency and other sequelae. Abnormalities in complement factor H or in membrane-bound complement inhibitors with consecutive complement activation can be found in approximately 30 to 50% of the patients. Starting in 2001, we evaluated 42 patients with recHUS from five European countries (Germany, Austria, Hungary, Switzerland, and the Czech Republic). We measured the terminal complement complex (TCC) by an enzyme-linked immunosorbent assay using a neoepitope-specific anti-C9 antibody in 17 patients in plasma (native complement activation), serum (after coagulation), and zymosan-activated serum (Z-serum; after stimulation of coagulation). We compared the results to those of 16 healthy persons. In patients with recHUS (eight males, nine females) with a median age of 10.8 years, the TCC values were higher in plasma (0.57 versus 0.48 μg/mL; p = 0.04) and serum (3.1 versus 2.2 μg/mL) than in those of the control group, with a median age of 28.6 years (six males, 10 females) The TCC values in patients with low C3 compared with patients with normal C3 levels were even higher in plasma and serum, and the ratio was much lower. Children with recHUS have higher concentrations of TCC in plasma and serum. The ratio of Z-serum to serum showed significantly lower values in children with recHUS (96.01 versus 150.3; p = 0.01). These findings indicate a higher grade of complement activation and consumption in recHUS, suggesting that TCC may mediate cell toxicity. This may play an important role in the inferior outcome of these patients. The isolated substitution of factor H, or other complement inhibitors to block TCC formation, may represent useful therapies for these patients.

KEYWORDS

End-stage renal disease (ESRD) - arterial hypertension - complement C3 - factor H - ELISA - VWF-protease

REFERENCES

• 1 Gerber A, Karch H, Allerberger F, Verweyen H M, Zimmerhackl L B. Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study.  J Infect Dis. 2002;  186 493-500
• 2 Zimmerhackl L B. Epidemiology, pathogenesis and therapeutic modalities in hemolytic-uremic syndrome.  Kidney Blood Press Res. 1998;  21 290-292
• 3 Sautter S. Klinischer Verlauf und Veränderungen im Komplementsystem bei Kindern mit rekurrierendem Hämolytisch-urämischen Syndrom [doctoral thesis]. Innsbruck, Austria: Medical University.  2004; 
• 4 Warwicker P, Donne R L, Goodship J A et al.. Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.  Nephrol Dial Transplant. 1999;  14 1229-1233
• 5 Caprioli J, Bettinaglio P, Zipfel P F et al.. Italian Registry of Familial and Recurrent HUS/TTP. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20.  J Am Soc Nephrol. 2001;  12 297-307
• 6 Noris M, Brioschi S, Caprioli J et al.. International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation.  Lancet. 2003;  362 1542-1547
• 7 Gerber A, Kirchhoff-Moradpour A H, Obieglo S et al.. Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality.  Pediatr Nephrol. 2003;  18 952-955
• 8 Würzner R, Orren A, Potter P et al.. Functionally active complement proteins C6 and C7 detected in C6- and C7-deficient individuals.  Clin Exp Immunol. 1991;  83 430-437
• 9 Jozsi M, Manuelian T, Heinen S, Oppermann M, Zipfel P F. Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology.  Histol Histopathol. 2004;  19 251-258
• 10 Rangan G K, Pippin J W, Couser W G. C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis.  Kidney Int. 2004;  66 1838-1848
• 11 Würzner R, Xu H, Franzke A, Schulze M, Peters J H, Götze O. Blood dendritic cells carry terminal complement complexes on their cell surface as detected by newly developed neoepitope-specific monoclonal antibodies.  Immunology. 1991;  74 132-138
• 12 Würzner R, Schulze M, Happe L et al.. Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies.  Complement Inflamm. 1991;  8 328-340
• 13 Ault B H. Factor H and the pathogenesis of renal diseases.  Pediatr Nephrol. 2000;  14 1045-1053
• 14 Sutor A H, Thomas K B, Prüfer F H, Grohmann A, Brandis M, Zimmerhackl L B. Function of von Willebrand factor in children with diarrhea-associate hemolytic-uremic syndrome (D+ HUS).  Semin Thromb Hemost. 2001;  27 287-292
• 15 Hughes J, Nangaku M, Alpers C E, Shankland S J, Couser W G, Johnson R J. C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis.  Am J Physiol Renal Physiol. 2000;  278 F747-F757
• 16 Prüfer F et al.. Terminal complement complex (TCC) in children with recurrent HUS (recHUS).  Eur J Pediatr. 2005;  164 R12