Supplementary Material for: Immune Deposits, Complement Activation and APOL1 Risk variants in Focal Segmental Glomerulosclerosis

Background: The role of immune deposits and complement activation in APOL1 mediated focal segmental glomerulosclerosis (FSGS) remains unclear. Using the CureGN cohort, we examined the associations between APOL1 renal risk variants (RRVs), glomerular immune deposits, and urinary complement activation.
Methods: We analyzed glomerular IgG, IgM and C3 deposition, kidney biopsy findings, urinary membrane attack complex (sC5b9) levels and clinical data in FSGS patients, regardless of race. Study participants patients were categorized as high-risk (two RRVs) or low risk (zero to one RRV).
Results: Of 175 participants, 148 (84%) had genetic testing, among whom 31 were high-risk and 117 were low-risk participants. High-risk participants had a higher prevalence of collapsing FSGS (45% vs 11%, p<0.001) and mesangial IgG deposition (intensity>0) (32% vs 3%, p<0.001). Incident participants enrolled within 6 months of biopsy showed a trend toward higher urinary sC5b9 to protein ratio in high-risk participants [0.15 (0.08-0.31) vs 0.03 (0-0.20) μg/g, p=0.09]. IgG staining correlated with urinary sC5b9 levels (r=0.34, p=0.008), suggesting a link between IgG deposition and urinary membrane attack complex excretion.
Conclusions: APOL1 high-risk FSGS is associated with mesangial IgG deposition and increased urinary membrane attack complex levels, implicating immune-mediated mechanisms in FSGS pathogenesis.

背景：载脂蛋白L1（APOL1）介导的局灶节段性肾小球硬化症（focal segmental glomerulosclerosis, FSGS）中，免疫沉积物与补体激活的具体作用仍未明确。本研究依托CureGN队列，探讨了APOL1肾脏风险变异体（renal risk variants, RRVs）、肾小球免疫沉积物与尿液补体激活之间的关联。方法：本研究纳入不限种族的FSGS患者，对其肾小球免疫球蛋白G（IgG）、免疫球蛋白M（IgM）及补体C3沉积情况、肾活检结果、尿液可溶性膜攻击复合物（sC5b9）水平及临床资料进行分析。研究对象按携带RRVs的数量分为高风险组（携带2个RRVs）与低风险组（携带0或1个RRVs）。结果：175名研究参与者中，148例（84%）完成了基因检测，其中31例归属高风险组，117例归属低风险组。高风险组的塌陷型FSGS患病率显著更高（45% vs 11%，p<0.001），系膜区IgG沉积（强度>0）的比例也显著升高（32% vs 3%，p<0.001）。在肾活检后6个月内入组的新发患者中，高风险组的尿液sC5b9/蛋白比值呈现升高趋势[0.15(0.08~0.31) vs 0.03(0~0.20) μg/g，p=0.09]。IgG染色强度与尿液sC5b9水平呈正相关（r=0.34，p=0.008），提示IgG沉积与尿液膜攻击复合物排泄存在关联。结论：APOL1高风险型FSGS与系膜区IgG沉积及尿液膜攻击复合物水平升高相关，提示免疫介导机制参与了FSGS的发病过程。