Qu Z, Zhang M, Cui Z, Wang J, Wang M, Zhang Y, Wang F, Wang X, Meng L, Cheng X, Liu G, Zhao M: Antibodies against M-Type Phospholipase A2 Receptor May Predict Treatment Response and Outcome in Membranous Nephropathy. Am J Nephrol 2018;48:438–446
The pathological “pattern-of-injury” designated as membranous nephropathy (MN) is pathogenetically heterogeneous. Among those subjects with this lesion of MN who have apparently primary rather than secondary MN, about 65 – 80 % (depending on the assay used and geographical location of the patient) have a pathogenesis linked to formation of auto-antibodies to the PLA2R antigen. This impact of the presence or absence of anti-PLA2R antibody (and the levels of antibody in the circulation) on outcomes of apparently primary MN have been the subject of intense study in recent years. In general, these studies have strongly suggested that measurement of these auto-antibodies contribute materially to management decisions and prediction of outcomes of PLA2R associated MN, but many uncertainties remain unresolved.
Zhang and co-workers retrospectively examined a large Chinese cohort of patients with apparent primary MN (n = 359), among whom 65 % has anti-PLA2R antibody by an IFA assay and 56 % had anti-PLA2R antibody by an ELISA assay (using a cut-off of 20 RU/ml as positive). Positive antibody levels by ELISA were positively correlated with the magnitude of proteinuria at diagnosis, and failure of antibody levels to become negative (with or without treatment) were highly correlated with no clinical remission (in a smaller cohort of 57 subjects followed serially). Fourteen of 125 patients with negative anti-PLA2R antibody by IFA had positive PLA2R antigen despotism in glomeruli b renal biopsy. None of the PLA2R negative patients in the cohort (n = 125) had anti-THSD7A antibodies or THSD7A antigen deposition. Patients with high levels of anti-PLA2R antibody or PLA2R antigen in glomeruli had higher levels of proteinuria than those with negative studies. A total of 254 patients in the entire cohort (n = 359) were treated with immunosuppressive agents (with or without steroids), and 208 (58 % of the total cohort) achieved a clinical remission (75 with a complete remission, and 133 with a partial remission). Spontaneous remissions occurred in patients with low or absent anti-PLA2R antibody. No remission was correlated with higher levels of anti-PLA2R antibody (by ELISA), higher levels of proteinuria and lower serum albumin levels.
Of the 359 patients in the entire cohort (248 positive for anti-PLA2R antibody, and 111 with negative PLA2R antibody) 12 reached end-stage renal disease (ESRD) and 67 developed a 50 % decline of estimated glomerular filtration rate (eGFR) from baseline during follow-up (total 22 %). Older age, higher levels of anti-PLA2R antibody were associated with a poor renal outcome. With therapy the anti-PLA2R antibody became negative in 80 % of patients, and a lack of a decline in antibody levels was highly correlated with a poor renal outcome. Relapses were infrequent (5/57 patients) and were associated with persistence of anti-PLA2R antibody following treatment.
In summary, this retrospective analysis of a large cohort of Chinese subjects with apparent primary MN adds important new information and specifically adds new knowledge about the impact of assessing anti-PLA2R antibody status for predicting outcomes. Nevertheless, prospectively acquired data form validation studies are still needed.
In an accompanying editorial, Jack FM Wetzels of Nijmegen, The Netherlands, adds a note of caution for the interpretation of this study. First, the ELISA anti-PLA2R antibody assay is not very sensitive. Only 81 % of patients with PLA2R antigen hyper-expression in glomeruli + IFA positive anti-PLA2R antibody (the gold standard for defining a PLA2R associated form of MN) were positive for anti-PLA2R by ELSA (using a cut-off of 20 RU/ml) – a 19 % “false negative” rate. 91 % of patients who were IFA positive also had PLA2R antigen hype-expression in glomeruli. Second, using a definition of < 20 RU/ml (ELISA) as PLA2R-negative introduces a bias since some patients with a true PLA2R associated pathogenesis can have very low antibody levels. Third, the study included patients previously treated with immunosuppressive agents, so the results may not apply to treatment- naïve subjects with MN. Fourth, patients with non-nephrotic proteinuria were included in the analysis which may have introduced a bias in the findings. The main interest is in nephrotic patients with MN as these are the patients requiring treatment, and who may have the poorest outcomes. Finally, the response to treatment of anti-PLA2R antibody positive MN may depend on the levels of antibody (by ELISA) present at diagnosis. The modality employed in treatment may have differential efficacy depending on the levels of anti-PLA2R antibody (see Van de Logt et al. Kidney Int 2018; 87:1263-1264) and the issue concerning responses to treatment of MN by different modalities in anti-PLA2R antibody positive and negative patients with apparent primary MN is still unsettled.
Despite these caveats the study by the Chinese group of investigators has revealed some new insights into the relationships between serology and outcome in MN, and has raised some interesting questions for future studies.