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Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.

ABSTRACT: In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

SUBMITTER: Fakhouri F

PROVIDER: S-EPMC2865741 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.

Fakhouri Fadi F Fakhouri Fadi F Roumenina Lubka L Provot François F Sallée Marion M Caillard Sophie S Couzi Lionel L Essig Marie M Ribes David D Dragon-Durey Marie-Agnès MA Bridoux Frank F Rondeau Eric E Frémeaux-Bacchi Veronique V

Journal of the American Society of Nephrology : JASN 20100304 5

In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abn ...[more]

PMID: 20203157

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Project description:Background and objectivesAtypical 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-ε, 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-ε gene in a cohort with atypical hemolytic uremic syndrome was analyzed.Design, setting, participants, & measurementsEighty-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-ε. 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.ResultsFour patients carried mutations in diacylglycerol kinase-ε, 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-ε and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-ε and C3 mutations.ConclusionsData suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-ε mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-ε 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

Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.

Publications

Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.

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