Zee Jarcy, Hogan Jonathan J, Abdullah Ahmed, Liu Lili, Kiryluk Krzysztof, Beck Laurence H
Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Clin J Am Soc Nephrol. 2025 May 1;20(5):697-705. doi: 10.2215/CJN.0000000671. Epub 2025 Feb 28.
Antiphospholipase A2 receptor antibody seropositivity by ELISA ≥2 and positive indirect immunofluorescence was optimal. Noninvasive diagnosis of phospholipase A2 receptor–associated membranous nephropathy among patients with proteinuria is feasible using both assays.
Clinical practice guidelines recommend that a kidney biopsy is no longer required to confirm a diagnosis of membranous nephropathy (MN) in patients with nephrotic syndrome and a positive test for antiphospholipase A2 receptor antibodies (PLA2R-Ab). However, the optimal diagnostic strategy for using the PLA2R-Ab ELISA, PLA2R-Ab indirect immunofluorescence (IIF) test, and genetic risk score (GRS) for diagnosing MN, including the tests' optimal thresholds for positivity among incident patients with proteinuria, is still unknown.
We used serum samples at or before the first clinically indicated kidney biopsy from participants in the Nephrotic Syndrome Study Network to analyze test performance characteristics using different combinations and cutoffs of the PLA2R-Ab ELISA, IIF, and GRS for diagnosing MN. Secondary analyses included serum samples within 6 months after biopsy but before any immunosuppression use.
There were 325 study participants with serum samples available on or before the day of kidney biopsy and an additional 143 study participants with samples within 6 months after biopsy but before any immunosuppression use. Of these participants, 26% (=85) had biopsy-confirmed MN. The combination of ELISA ≥2 RU/ml and positive IIF was the optimal approach, with sensitivity of 0.60, specificity of 1.00, negative predictive value of 0.92, and positive predictive value of 1.00. Using IIF to confirm only borderline ELISA titers between 2 and 20 RU/ml resulted in similar sensitivity but specificity of >0.99. In our multiethnic study sample, we did not find improved diagnostic performance with the addition of GRSs.
In the Nephrotic Syndrome Study Network cohort, combined PLA2R-Ab testing with ELISA and IIF provided optimal test characteristics in making a noninvasive diagnosis of MN before or soon after kidney biopsy, including in patients with subnephrotic proteinuria. Further studies in multiethnic populations are needed to assess whether genetic data can augment this approach.
通过酶联免疫吸附测定（ELISA）抗磷脂酶A2受体抗体血清反应阳性≥2且间接免疫荧光呈阳性为最佳情况。对于蛋白尿患者，使用这两种检测方法对磷脂酶A2受体相关膜性肾病进行无创诊断是可行的。
临床实践指南建议，对于肾病综合征且抗磷脂酶A2受体抗体（PLA2R-Ab）检测呈阳性的患者，不再需要进行肾活检来确诊膜性肾病（MN）。然而，使用PLA2R-Ab ELISA、PLA2R-Ab间接免疫荧光（IIF）检测和遗传风险评分（GRS）诊断MN的最佳诊断策略，包括这些检测方法在初发蛋白尿患者中的最佳阳性阈值，仍然未知。
我们使用了肾病综合征研究网络参与者首次临床指示肾活检时或之前的血清样本，通过不同组合和截断值的PLA2R-Ab ELISA、IIF和GRS来分析诊断MN的检测性能特征。二次分析包括活检后6个月内但在使用任何免疫抑制治疗之前的血清样本。
有325名研究参与者在肾活检当天或之前有可用血清样本，另有143名研究参与者在活检后6个月内且在使用任何免疫抑制治疗之前有样本。在这些参与者中，26%（=85）经活检确诊为MN。ELISA≥2 RU/ml且IIF呈阳性的组合是最佳方法，敏感性为0.60，特异性为1.00，阴性预测值为0.92，阳性预测值为1.00。仅使用IIF来确认ELISA滴度在2至20 RU/ml之间的临界值，敏感性相似，但特异性>0.99。在我们的多民族研究样本中，添加GRS并未提高诊断性能。
在肾病综合征研究网络队列中，联合使用PLA2R-Ab ELISA和IIF检测在肾活检前或活检后不久对MN进行无创诊断时提供了最佳检测特征，包括对亚肾病性蛋白尿患者。需要在多民族人群中进行进一步研究，以评估遗传数据是否可以增强这种方法。
