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Clinical Trial
. 2015 May 21;125(21):3253-62.
doi: 10.1182/blood-2014-09-600411. Epub 2015 Apr 1.

Eculizumab Reduces Complement Activation, Inflammation, Endothelial Damage, Thrombosis, and Renal Injury Markers in aHUS

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Free PMC article
Clinical Trial

Eculizumab Reduces Complement Activation, Inflammation, Endothelial Damage, Thrombosis, and Renal Injury Markers in aHUS

Roxanne Cofiell et al. Blood. .
Free PMC article

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, β2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F1+2 and d-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973.

Figures

Figure 1
Figure 1
Biomarker levels in patients with normal platelet counts and normal LDH and haptoglobin levels at baseline. Median levels of markers of complement activation, vascular inflammation/damage and coagulation, and renal injury were elevated in patients with aHUS with and without (A) normal platelet count and (B) normal LDH and haptoglobin levels at baseline. Error bars represent 95% confidence intervals.
Figure 2
Figure 2
Biomarker levels in patients receiving PE/PI at baseline. PE/PI does not affect biomarkers of complement activation, vascular inflammation/damage and coagulation, and renal injury in patients with aHUS compared with HV at baseline. Median levels and 95% confidence intervals are represented.
Figure 3
Figure 3
Biomarker levels during terminal complement blockade with eculizumab. Longitudinal decreases in median levels of biomarkers of (A) complement activation, (B) vascular inflammation/damage and coagulation, and (C) renal injury were demonstrated with eculizumab therapy in patients with aHUS compared with HV. Changes in biomarker levels with ongoing eculizumab treatment are displayed using box-whisker graphs showing median, 25th and 75th percentiles, and range. *Levels were significantly reduced compared with baseline; the P value of reduction at the first significant time point is shown.
Figure 4
Figure 4
Biomarker levels in patients with or without an identified complement regulatory gene mutation or polymorphism. Biomarker profiles were elevated at baseline and were reduced during eculizumab treatment in patients with aHUS with or without an identified complement regulatory gene mutation/polymorphism compared with HV. Longitudinal median biomarker levels are shown with P values relative to HV levels indicated.

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