Serological and Genetic Complement Alterations in Infection-induced and Complement-mediated Hemolytic Uremic Syndrome

Overview

Journal Pediatr Nephrol

Specialties Nephrology
Pediatrics

Date 2016 Oct 9

PMID 27718086

Citations 27

Authors

Dineke Westra

Elena B Volokhina

Renate G van der Molen

Thea J A M van der Velden

Annelies Jeronimus-Klaasen

Joop Goertz

Valentina Gracchi

Eiske M Dorresteijn

Antonia H M Bouts

Mandy G Keijzer-Veen

Joanna A E van Wijk

Jaap A Bakker

Anja Roos

Lambert P van den Heuvel

Nicole C A J van de Kar

Affiliations

Soon will be listed here.

Abstract

Background: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.

Methods: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.

Results: Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.

Conclusions: In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

Citing Articles

The role of the complement system in Shiga toxin-associated hemolytic uremic syndrome.

Bocanegra V, Luna M, Costantino V, Lorenzo A, Marino R, Miatello R Pediatr Nephrol. 2025; .

PMID: 39792253 DOI: 10.1007/s00467-024-06629-6.

Shiga toxin-producing Escherichia coli infection as a precipitating factor for atypical hemolytic-uremic syndrome.

Mortari G, Bigatti C, Gaffi G, Lionetti B, Angeletti A, Matarese S Pediatr Nephrol. 2024; 40(2):449-461.

PMID: 39347991 PMC: 11666682. DOI: 10.1007/s00467-024-06480-9.

Distinct protein patterns related to postnatal development in small for gestational age preterm infants.

Smit E, Romijn M, Langerhorst P, van der Zwaan C, van der Staaij H, Rotteveel J Pediatr Res. 2024; .

PMID: 39152333 DOI: 10.1038/s41390-024-03481-0.

Recruitment of Vitronectin by Bacterial Pathogens: A Comprehensive Overview.

Pellegrini A, Pietrocola G Microorganisms. 2024; 12(7).

PMID: 39065153 PMC: 11278874. DOI: 10.3390/microorganisms12071385.

Eculizumab in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: a systematic review.

de Zwart P, Mueller T, Sparta G, Luyckx V Pediatr Nephrol. 2023; 39(5):1369-1385.

PMID: 38057431 PMC: 10943142. DOI: 10.1007/s00467-023-06216-1.

References

Komhoff M, Roofthooft M, Westra D, Teertstra T, Losito A, van de Kar N . Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics. 2013; 132(2):e540-4. DOI: 10.1542/peds.2012-2581. View

Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G . A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int. 2006; 70(3):423-31. DOI: 10.1038/sj.ki.5001581. View

Branten A, Kock-Jansen M, Klasen I, Wetzels J . Urinary excretion of complement C3d in patients with renal diseases. Eur J Clin Invest. 2003; 33(6):449-56. DOI: 10.1046/j.1365-2362.2003.01153.x. View

Zegers I, Keller T, Schreiber W, Sheldon J, Albertini R, Blirup-Jensen S . Characterization of the new serum protein reference material ERM-DA470k/IFCC: value assignment by immunoassay. Clin Chem. 2010; 56(12):1880-8. DOI: 10.1373/clinchem.2010.148809. View

Geerdink L, Westra D, van Wijk J, Dorresteijn E, Lilien M, Davin J . Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatr Nephrol. 2012; 27(8):1283-91. PMC: 3382652. DOI: 10.1007/s00467-012-2131-y. View

Robson W, Leung A, Fick G, McKenna A . Hypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron. 1992; 62(3):296-9. DOI: 10.1159/000187063. View

Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui H, Lacraz A . Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2013; 29(3):565-72. PMC: 3938298. DOI: 10.1093/ndt/gft470. View

Wurzner R, Riedl M, Rosales A, Orth-Holler D . Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS). Semin Thromb Hemost. 2014; 40(4):508-16. DOI: 10.1055/s-0034-1375298. View

Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J . Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ. 2012; 345:e4565. PMC: 3400392. DOI: 10.1136/bmj.e4565. View

10.

Legendre C, Licht C, Muus P, Greenbaum L, Babu S, Bedrosian C . Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013; 368(23):2169-81. DOI: 10.1056/NEJMoa1208981. View

11.

Bu F, Maga T, Meyer N, Wang K, Thomas C, Nester C . Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2013; 25(1):55-64. PMC: 3871781. DOI: 10.1681/ASN.2013050453. View

12.

Monnens L, Molenaar J, Lambert P, Proesmans W, van MUNSTER P . The complement system in hemolytic-uremic syndrome in childhood. Clin Nephrol. 1980; 13(4):168-71. View

13.

Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S . Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010; 5(10):1844-59. PMC: 2974386. DOI: 10.2215/CJN.02210310. View

14.

Fang C, Fremeaux-Bacchi V, Liszewski M, Pianetti G, Noris M, Goodship T . Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood. 2007; 111(2):624-32. PMC: 2200836. DOI: 10.1182/blood-2007-04-084533. View

15.

Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E . Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood. 2014; 124(11):1715-26. PMC: 4162105. DOI: 10.1182/blood-2014-02-558296. View

16.

Jozsi M, Licht C, Strobel S, Zipfel S, Richter H, Heinen S . Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 2007; 111(3):1512-4. DOI: 10.1182/blood-2007-09-109876. View

17.

Orth D, Ehrlenbach S, Brockmeyer J, Khan A, Huber G, Karch H . EspP, a serine protease of enterohemorrhagic Escherichia coli, impairs complement activation by cleaving complement factors C3/C3b and C5. Infect Immun. 2010; 78(10):4294-301. PMC: 2950363. DOI: 10.1128/IAI.00488-10. View

18.

Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang W, le Quintrec M . Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013; 45(5):531-6. PMC: 3719402. DOI: 10.1038/ng.2590. View

19.

Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C . Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2008; 24(4):687-96. DOI: 10.1007/s00467-008-0964-1. View

20.

Ahlenstiel-Grunow T, Hachmeister S, Bange F, Wehling C, Kirschfink M, Bergmann C . Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome. Nephrol Dial Transplant. 2016; 31(7):1114-21. DOI: 10.1093/ndt/gfw078. View