Supplementary Material for: Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and −0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = −0.83 and −0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = −0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = −0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

引言：C3 肾小球肾炎（C3G）是一种罕见且渐进性的肾脏疾病，其发生源于补体替代途径（AP）的失调。在两项针对因子D（FD）抑制剂丹尼考潘的2期临床试验中（NCT03369236和NCT03459443），研究人员对参与研究的C3G患者的基线生物标志物进行了研究。方法：纳入了两项研究（NCT03369236和NCT03459443）的患者，其经活检确诊为C3G，每日蛋白尿量≥500毫克，估算的肾小球滤过率（eGFR）≥30毫升/分钟/1.73平方米。对中央病理实验室复评确认的C3G患者进行了生物标志物分析。在基线时，对补体和临床生物标志物、活检综合评分以及活动性和慢性指数进行了评估，并通过成对Spearman相关分析方法进行了分析。结果：纳入分析的患者共29人（中位数[四分位数范围]年龄：24.0[10.0]岁）。系统性补体AP激活的表现为C3和C5的介值浓度降低，sC5b-9升高，C4相对参考范围正常。C3与C5和sC5b-9表现出强烈的成对相关性（r = 0.80和−0.73，分别；p < 0.0001）。基线Ba和FD浓度与eGFR呈负相关（r = −0.83和−0.87，分别；p < 0.0001）。尿液中sC5b-9的浓度与血浆sC5b-9和蛋白尿量均呈相关性（r = 0.69和r = 0.83，分别；p < 0.0001）。活检活动性指数与系统性AP激活的生物标志物（包括C3）呈强相关性（r = −0.76，p < 0.0001），而慢性指数则与eGFR更为密切地对应（r = −0.57，p = 0.0021）。结论：补体生物标志物、肾脏功能与肾脏组织学之间的关联可能有助于深化对C3G的理解，并有助于对这种异质性疾病患者的特征描述。