Clinical significance of serum and mesangial galactose-deficient IgA1 in patients with IgA nephropathy

Introduction
Galactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN.
Methods
We retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55.
Results
Although levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02–1.89; p = 0.038).
Conclusions
Although IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.

引言
半乳糖缺陷型IgA1（Galactose-deficient IgA1，Gd-IgA1）是IgA肾病（IgA nephropathy，IgAN）的关键致病因子，但其作为疾病特异性生物标志物的价值仍存在争议。本研究旨在明确Gd-IgA1在IgAN患者中的临床意义。

方法
本研究回顾性分析了2007年以来昭和大学医院经肾活检（renal biopsy，RB）确诊为IgAN的111例患者。采用抗人Gd-IgA1特异性单克隆抗体（KM55）进行酶联免疫吸附试验（enzyme-linked immunosorbent assay，ELISA），比较111例IgAN患者、18例过敏性紫癜肾炎（Henoch-Schönlein purpura nephritis，HSPN）患者、29例狼疮性肾炎（lupus nephritis，LN）患者、28例抗中性粒细胞胞浆抗体相关性血管炎（ANCA-associated vasculitis，AAV）患者及13例微小病变型肾病（minimal change disease，MCD）患者在肾活检时的血清Gd-IgA1（serum Gd-IgA1，s-Gd-IgA1）水平。同时，采用KM55对石蜡包埋组织切片进行免疫组化染色，检测系膜区Gd-IgA1（mesangial Gd-IgA1，m-Gd-IgA1）沉积情况。

结果
尽管IgAN与HSPN患者的血清Gd-IgA1（s-Gd-IgA1）水平相当，但IgAN患者的s-Gd-IgA1水平显著高于LN、AAV及MCD患者（IgAN vs. HSPN、LN、AAV、MCD：16.2±9.1 vs. 14.2±10.8，p=0.263；12.7±9.4，p=0.008；13.1±7.3，p=0.059；8.2±4.8 μg/mL，p<0.001）。系膜区Gd-IgA1沉积仅在IgAN或HSPN患者中检出。IgAN患者的s-Gd-IgA1升高与m-Gd-IgA1阳性显著相关，且组织病理学分期较晚的IgAN患者可见s-Gd-IgA1升高及m-Gd-IgA1沉积。此外，伴肾小球硬化及肾小管间质病变的IgAN患者s-Gd-IgA1水平显著升高。IgAN患者的系膜区Gd-IgA1沉积强度与估算肾小球滤过率（estimated glomerular filtration rate，eGFR）呈负相关。多因素分析显示，s-Gd-IgA1升高是IgAN患者估算肾小球滤过率下降30%的显著危险因素（风险比HR=1.37，95%置信区间CI：1.02~1.89，p=0.038）。

结论
尽管IgAN与HSPN仍难以鉴别，但s-Gd-IgA1升高及m-Gd-IgA1沉积是反映IgAN严重程度的可靠诊断指标。血清Gd-IgA1可作为IgAN患者肾脏预后的预测因子。因此，Gd-IgA1可作为IgAN患者的重要生物标志物。