Alexion, AstraZeneca Rare Disease, Boston, MA, USA.
Mol Diagn Ther. 2023 Jan;27(1):61-74. doi: 10.1007/s40291-022-00620-3. Epub 2022 Nov 4.
Clinically validated biomarkers for monitoring of patients with complement-mediated thrombotic microangiopathy (CM-TMA) including atypical hemolytic uremic syndrome (aHUS) are unavailable. Improved characterization of biomarkers in patients with aHUS may inform treatment and monitoring for patients with CM-TMA.
This analysis used data collected from 55/56 (98.2 %) adult patients with aHUS enrolled in the global Phase III study of ravulizumab (NCT02949128). Baseline (pre-treatment) patient serum, plasma and urine biomarker levels were compared with the maximum observed levels in normal donors and evaluated for associations with pre-treatment plasma exchange/infusion and dialysis status. Biomarkers were also assessed for associations with key clinical measures at baseline and with changes at 26 and 52 weeks from treatment initiation via linear regression analyses.
Complement-specific urine levels (factor Ba and sC5b-9) were elevated in >85 % of patients and are significantly associated with pre-treatment kidney dysfunction. Baseline levels of other evaluated biomarkers were elevated in >70 % of patients with aHUS, except for plasma sC5b-9 and serum sVCAM-1. Lower levels of urine complement markers at baseline are significantly associated with improvements in total urine protein and estimated glomerular filtration rate at 26 and 52 weeks of treatment. Clinical assessment of complement activation by a receiver operating characteristic analysis of Ba and sC5b-9 was more sensitive and specific in urine matrix than plasma.
This analysis identified a set of biomarkers that may show utility in the prognosis of CM-TMA, including their potential for measuring and predicting response to anti-C5 therapy. Further studies are required to enhance patient risk stratification and improve management of these vulnerable patients.
NCT02949128, ClinicalTrials.gov.
目前尚无用于监测补体介导的血栓性微血管病（CM-TMA）患者的临床验证生物标志物，包括非典型溶血尿毒综合征（aHUS）。更好地描述 aHUS 患者的生物标志物特征，可能有助于为 CM-TMA 患者提供治疗和监测。
本分析使用了在全球 III 期 ravulizumab 研究中入组的 55/56 例（98.2%）成年 aHUS 患者的数据（NCT02949128）。比较了患者基线（治疗前）血清、血浆和尿液生物标志物水平与正常供者的最高观察值，并评估了其与治疗前血浆置换/输注和透析状态的关系。还评估了生物标志物与基线关键临床指标的关系，并通过线性回归分析评估了其与治疗起始后 26 周和 52 周的变化关系。
补体特异性尿液水平（因子 Ba 和 sC5b-9）在>85%的患者中升高，与治疗前肾功能不全显著相关。除了血浆 sC5b-9 和血清 sVCAM-1 外，其他评估生物标志物的基线水平在>70%的 aHUS 患者中升高。基线时尿液补体标志物水平较低，与治疗 26 周和 52 周时总尿蛋白和估算肾小球滤过率的改善显著相关。通过对 Ba 和 sC5b-9 的尿液基质进行受试者工作特征分析评估补体激活的临床评估，其敏感性和特异性均高于血浆。
本分析确定了一组可能对 CM-TMA 预后有用的生物标志物，包括其测量和预测抗 C5 治疗反应的潜力。需要进一步的研究来增强患者风险分层，并改善对这些脆弱患者的管理。
NCT02949128，ClinicalTrials.gov。
