Alternative and Terminal Complement Pathway Biomarkers At Presentation More Precisely Define The Clinical Diagnosis Of aHUS

Recent studies demonstrating the effectiveness of eculizumab in the treatment of atypical hemolytic uremic syndrome (aHUS) have increased the need for more rapid and objective diagnostic tests to help confirm the diagnosis of aHUS over other thrombotic microangiopathies (TMA).

We performed a retrospective study of all patients enrolled in the Ohio State University TTP/aHUS Registry since 2003. From this cohort of patients diagnosed with an acute TMA (platelets<100 x 10⁹/ with schistocytes present, and without an alternative explanation), patients with a pretreatment serum creatinine >2.25 mg/dL and measureable ADAMTS13 activity (>10%) were analyzed. The clinical and demographic data for these 19 patients are shown in Table 1. Banked plasma samples from these study subjects were used to measure complement activation factors Bb (alternative pathway (AP)), C4d (classical pathway), C3a, (generalized complement activation), C5a, and C5b-9 complex (terminal complement pathway (TCP)). These complement biomarker data were analyzed in the context of a documented mutation in complement regulatory proteins and response to therapy with PEX and/or eculizumab. Response was defined as a normal platelet count and improved serum creatinine (at 6 months) independent of PEX therapy or with continued eculizumab therapy.

The median complement biomarker data at presentation are shown in Table 2. Complement activation products are generally sensitive biomarkers for aHUS patients. Notably, elevation of the AP (Bb) and the TCP (C5b-9) biomarkers were more prominent and were seen in 16/19 and 19/19 patients respectively. This is in contrast to previously published data from acquired TTP patients from our group that demonstrated less pronounced activation of the AP and TCP at presentation (accepted for publication, JTH). Similar levels of alternative, classical and terminal complement activation were seen among patients regardless of mutation status or response to PEX. In a preliminary analysis using a one sample T-test model, (Bb) activation was shown to be significantly lower in the non-responder to eculizumab compared to the 8 responding patients. TCP activation was also lower in the non-responder but did not show statistical significance.

Complement biomarkers of the alternative and terminal complement pathway may more precisely define the diagnosis of aHUS. These hypothesis generating data suggest that pre-treatment complement biomarkers provide valuable information in the diagnosis of aHUS and could be useful in the prediction of response to eculizumab

No relevant conflicts of interest to declare.