PLA2R autoantibodies, a multifaceted biomarker in nephrotic syndrome and membranous nephropathy

Abstract Background and hypothesis The PLA2R antibody test is a valuable first-line diagnostic tool for primary membranous nephropathy (MN), helping to identify PLA2R-related MN and potentially eliminating the need for a kidney biopsy in some individuals. By reducing the reliance on biopsies, the test streamlines diagnosis and improves patient care. However, determining the optimal PLA2R measurement method and cut-off is critical to maximising the benefits of the test and minimising any harms. Methods A systematic review and meta-analysis were performed to evaluate serum- and urine-based biomarkers for distinguishing between PLA2R-related MN and non-PLA2R MN. Searches were conducted in databases including Medline, Embase, Cochrane Library, Scopus, Web of Science, INAHTA, and ClinicalTrials.gov. The methodology followed Cochrane-recommended guidelines for systematic reviews and meta-analyses, and the QUADAS-2 tool was utilised to assess the overall risk of bias. Results Ninety one studies met the eligibility criteria for inclusion in the review. Of these, 38 studies reporting the accuracy of the PLA2R-Ab test using the EUROIMMUN ELISA method and 27 using the EUROIMMUN IF method were suitable for meta-analysis.. The pooled sensitivity and specificity of EUROIMMUN ELISA at a cut-off value of 20 RU/ml were 0.64 (95% CI: 0.56, 0.72) and 94.7% (95% CI: 90.5 - 97.1%), respectively. The pooled sensitivity and specificity of EUROIMMUN IF at a threshold of 1:10 was 0.69 (95% CI: 0.637 – 0.739) and 0.98 (95% CI: 0.931 – 0.994), respectively. Risk of bias was higher for studies evaluating the IF compared to ELISA test. We also explored whether the timing of the index test had an impact on the pooled diagnostic accuracy results; no significant differences were found. Conclusions By evaluating the specificity and sensitivity of EUROIMMUN ELISA PLA2R-Ab and immunofluorescence (IF), we demonstrate that at ELISA levels ≥20 RU/mL, alongside thorough secondary screening, a kidney biopsy may be unnecessary. However, lower or negative levels still warrant a biopsy.