Complement mutations in diacylglycerol kinase-ε-associated atypical hemolytic uremic syndrome

Abstract

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-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, & 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-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.

Results: Four 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.

Conclusions: Data 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.

Keywords: complement; genetic renal disease; hemolytic uremic syndrome.

Figure 1.

Pedigrees of patients with atypical hemolytic uremic syndrome carrying diacylglycerol kinase-ε (DGKE) mutations. For each pedigree, the index patients are indicated with arrows, and the chromatograms for the corresponding mutations are shown. Segregation of the mutations is indicated with colored symbols. HUS, hemolytic uremic syndrome; ND, genetic analyses have not yet been performed.

Figure 2.

Location of the diacylglycerol kinase-ε mutations found in Spanish patients with atypical hemolytic uremic syndrome (aHUS). A diagram of the diacylglycerol kinase-ε protein depicting the different protein domains is shown. Arrows identify the positions of the five mutations found in the screening of the early-onset Spanish patients with aHUS. C1 domain, kinase catalytic domain and kinase accessory domain; HD, hydrophobic domain.

Figure 3.

Evolution of blood parameters in hemolytic uremic syndrome 272 (HUS272). The evolution of the (A) C3, (B) platelets, and (C) lactate dehydrogenase (LDH) serum levels in patient HUS272 from the disease onset are shown. Arrows indicate the start of the plasma therapy (fresh frozen plasma [FFP]) and the Eculizumab (Ecu) treatment. C3 levels in the mother (Mo) and father (Fa) are also indicated.