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Alternative Pathway of Complement in Children with Diarrhea-Associated Hemolytic Uremic Syndrome

Joshua M. Thurman^*, Russell Marians, Woodruff Emlen, Susan Wood, Christopher Smith, Hillary Akana, V. Michael Holers, Martin Lesser, Myriam Kline, Cathy Hoffman^||, Erica Christen^||, and Howard Trachtman^||

^* Department of Medicine, Division of Nephrology, University of Colorado, Denver School of Medicine, Aurora, Colorado; Taligen Therapeutics, Aurora, Colorado; Department of Medicine, Division of Rheumatology, University of Colorado, Denver School of Medicine, Aurora, Colorado; Biostatistics Unit, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and ^|| Department of Pediatrics, Division of Nephrology, Schneider Children’s Hospital of North Shore-LIJ Health System, New Hyde Park, New York

Correspondence: Dr. Howard Trachtman, Schneider Children’s Hospital, Division of Nephrology, 269-01 76th Avenue, New Hyde Park, NY 11040. Phone: 718-470-3423; Fax: 718-470-0887; E-mail: trachtma{at}lij.edu

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.