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Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

ABSTRACT: 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.Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, ?FH) 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.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.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.

SUBMITTER: Westra D

PROVIDER: S-EPMC5203860 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

Westra Dineke D Volokhina Elena B EB van der Molen Renate G RG van der Velden Thea J A M TJ Jeronimus-Klaasen Annelies A Goertz Joop J Gracchi Valentina V Dorresteijn Eiske M EM Bouts Antonia H M AH Keijzer-Veen Mandy G MG van Wijk Joanna A E JA Bakker Jaap A JA Roos Anja A van den Heuvel Lambert P LP van de Kar Nicole C A J NC

Pediatric nephrology (Berlin, Germany) 20161007 2

<h4>Background</h4>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.<h4>Methods</h4>Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alte ...[more]

PMID: 27718086

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Project description:BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-?, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-? gene in a cohort with atypical hemolytic uremic syndrome was analyzed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Eighty-three patients with early-onset atypical hemolytic uremic syndrome (<2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-?. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. RESULTS: Four patients carried mutations in diacylglycerol kinase-?, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-? and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-? and C3 mutations. CONCLUSIONS: Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-? mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-? and complement mutations. A comprehensive understanding of the genetic component predisposing to atypical hemolytic uremic syndrome is, therefore, critical to guide an effective treatment.

Dataset Information

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

Publications

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

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