Department of Medicine and Surgery, Pathology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.
Nephrology Unit, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
J Nephrol. 2018 Aug;31(4):543-550. doi: 10.1007/s40620-018-0489-z. Epub 2018 Apr 6.
Membranous nephropathy (MN) can be idiopathic (iMN) or manifest as a result of systemic underlying conditions as a secondary epiphenomenon. For the prognostic and predictive consequences of this discrimination, the routine use of reliable markers is crucial. This large MN series aimed to evaluate the routine and standardized immunohistochemical (IHC) employment of a panel of 3 biomarkers-phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), and immunoglobulin (Ig)G4-in the differential diagnosis of MN forms, contributing to the validation of the technique and the correct interpretation of reproducible patterns of reactivity.
We classified 95 patients with a biopsy proven diagnosis of MN as primary (n = 72) or secondary (n = 23) cases based on clinical data. After performing an IHC assay directed against PLA2R, THSD7A and IgG4 antigens, samples were interpreted by three different nephropathologists to assess the positivity/negativity of the staining according to new interpretation criteria.
Useful interpretation criteria were introduced to exclude false positive patterns of reactivity and to identify only true granular membranous or mesangial deposits in MN. The IHC directed against PLA2R resulted positive in 51 iMN cases and negative in 21, while 4/23 secondary forms were considered positive. Based on these data the technique showed a sensitivity of 71% and specificity of 83%. On the other hand, the IHC analysis for IgG4 resulted positive in 44 cases of iMN and negative in 28 cases, while only 4/23 secondary forms were positive (same cases positive to PLA2R). Finally, THSD7A was found to be positive only in 1 case, which was negative to PLA2R and IgG4. The combination of the results allowed a classification of the series into two major groups: "double-positive" (PLA2R+/IgG4+/THSD7A-) and "triple-negative" (PLA2R-/IgG4-/THSD7A-) cases.
Based on these data, the diagnostic performance of the three biomarkers used in a "tandem fashion" can reach 79% sensitivity and 83% specificity, significantly reducing the risk of a false-positive or false-negative result and improving the routine characterization of this frequent glomerulonephritis.
膜性肾病（MN）可以是特发性的（iMN），也可以作为系统性潜在疾病的继发表现。为了区分这种情况的预后和预测后果，常规使用可靠的标志物至关重要。本项大规模 MN 研究旨在评估常规和标准化免疫组化（IHC）应用 3 种生物标志物（磷脂酶 A2 受体（PLA2R）、血小板反应蛋白 1 型结构域包含 7A 型（THSD7A）和免疫球蛋白（Ig）G4）在 MN 形式的鉴别诊断中的作用，有助于验证该技术并正确解释可重复的反应模式。
我们根据临床数据将 95 例经活检证实的 MN 患者分为原发性（n=72）或继发性（n=23）病例。在对 PLA2R、THSD7A 和 IgG4 抗原进行 IHC 检测后，由 3 位不同的肾病学家根据新的解读标准评估染色的阳性/阴性结果。
引入了有用的解读标准来排除假阳性反应模式，并仅识别 MN 中的真正颗粒状膜性或系膜沉积物。针对 PLA2R 的 IHC 在 51 例 iMN 中呈阳性，在 21 例中呈阴性，而 23 例继发性中 4 例被认为呈阳性。根据这些数据，该技术的灵敏度为 71%，特异性为 83%。另一方面，针对 IgG4 的 IHC 分析在 44 例 iMN 中呈阳性，在 28 例中呈阴性，而只有 23 例继发性中有 4 例呈阳性（与 PLA2R 相同）。最后，THSD7A 仅在 1 例中呈阳性，该例对 PLA2R 和 IgG4 均呈阴性。将结果组合起来，可将该系列分为两大主要组：“双阳性”（PLA2R+/IgG4+/THSD7A-）和“三阴性”（PLA2R-/IgG4-/THSD7A-）。
基于这些数据，三种生物标志物以“串联方式”使用的诊断性能可达到 79%的灵敏度和 83%的特异性，显著降低假阳性或假阴性结果的风险，并改善这种常见肾小球肾炎的常规特征。
