Introduction and Aims: Atypical haemolytic uraemic syndrome (aHUS) leads to thrombotic microangiopathy (TMA) and organ damage due to chronic complement activation. In patients (pts) with aHUS, eculizumab (Ecu) inhibits complement-mediated TMA and significantly improves clinical outcomes. This exploratory analysis of biomarkers investigates mechanisms of aHUS pathophysiology, determines impact of terminal complement blockade and correlates biomarker levels with renal function.
Methods: Biomarker levels in healthy volunteers (HV; n=9-20) were compared with those in adult pts with aHUS treated with Ecu in a prospective trial (n=26-38). Biomarkers were assessed in plasma, serum and urine using standard methods.
Results: A profile of significantly elevated biomarkers reflecting complement alternative pathway activation (Ba), inflammation (sTNFR1), coagulation (D-Dimer), endothelial activation (sVCAM-1) and injury (thrombomodulin, TM) was present at baseline (BL) in >94% of aHUS pts compared with HV (all p<0.0001). Levels of urinary soluble C5b-9 (sC5b-9) were significantly elevated in 23/27 (85%) of pts (p<0.0001 vs HV). Regardless of degree of renal function, sustained eculizumab treatment rapidly normalized sC5b-9 levels (not shown) and reduced levels of sTNFR1 and D-dimer by up to 94% and 99%, respectively; TM levels decreased more slowly to near normal levels by 1 year of treatment (Figure). sVCAM-1 and Ba levels were also significantly reduced compared to BL but regardless of degree of renal function, remained elevated compared to HV levels, reflecting the underlying genetic dysregulation of complement in aHUS (Figure). At 1 year, improvement in renal function with eculizumab treatment was highly negatively correlated with Ba, sTNFR1, sVCAM-1 and TM levels indicating the clinical relevance of these markers.
Conclusions: These data demonstrate a relationship between terminal complement activation and endothelial damage leading to tissue injury. Persistent proximal complement and endothelial activation does not translate into endothelial damage with sustained Ecu treatment.
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