Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome

Abstract

Background and objectives: Diarrhea-associated hemolytic uremic syndrome (D+HUS) is a common cause of acute kidney injury in children. Mutations in alternative pathway (AP) complement regulatory proteins have been identified in severe cases of thrombotic microangiopathy, but the role of the AP in D+HUS has not been studied. Therefore, we determined whether plasma levels of markers of activation of the AP are increased in D+HUS and are biomarkers of the severity of renal injury that predict the need for dialysis.

Design, setting, participants, & measurements: Patients were randomly selected from among participants in the HUS-SYNSORB Pk trial. Plasma samples were collected on days 1, 4, 7, and 10 after enrollment and day 28 after discharge from the hospital. Levels of two complement pathway products, Bb and SC5b-9, were determined by ELISA.

Results: Seventeen children (6 boys and 11 girls; age, 5.4 +/- 3.5 yr) were studied. Eight (47%) required dialysis support, and two had serious extrarenal events. On the day of enrollment, plasma levels of Bb and SC5b-9 were significantly increased in all patients compared with healthy controls (P < 0.01). The elevated concentrations normalized by day 28 after discharge. Circulating levels of complement pathway fragments did not correlate with severity of renal injury or occurrence of complications.

Conclusions: Patients with acute-onset D+HUS manifest activation of the AP of complement that is temporally related to the onset of disease and that resolves within 1 mo. Therapies to inhibit the AP of complement may be useful in attenuating the severity of renal injury and extrarenal complications.

Figure 1.

The bar graphs show the mean plasma concentration of Bb (A) and SC5b-9 (B) in patients with D+HUS on day 1 of their illness and at day 28 after hospitalization. The mean value for each AP of complement fragment in normal controls (n = 4) is included in each panel.

Figure 2.

The graphs show the plasma concentration of Bb (A) and SC5b-9 (B) over the course of the D+HUS episode in a patient who required dialysis [(+)HD] and in a patient who was treated with conservative medical management for the acute kidney injury [(−)HD].

Figure 3.

The bar graph shows the mean peak concentration of Bb and SC5b-9 in patients with required renal replacement therapy and those who did not need this supportive treatment.