LAUSR

Primary membranous nephropathy (MN) is a glomerulus-specific autoimmune disorder caused by anti-phospholipase A2 receptor (anti-PLA2R) antibodies in 70-80% of cases. We sought to investigate the utility of anti-PLA2R antibody as a non-invasive screening method for the diagnosis of primary MN in patients with nephrotic syndrome (NS). A total of 203 consecutive patients with NS admitted in the Nephrology Department of Fundeni Clinical Institute, Bucharest, Romania, between January 2015 and December 2019 were screened for anti-PLA2R antibodies by an ELISA assay (Euroimmun, Lubeck, DE). A positive anti-PLA2R serology was defined as an ELISA value over 2 RU/ml. Subsequently, all patients underwent kidney biopsy to confirm the histological diagnosis. Of the 203 patients with NS, 113 (55.7%) patients tested negative for anti-PLA2R antibodies, while 23 (11.3%) and 67 (33%) patients had an anti-PLA2R antibody titer of 2-20 RU/ml and >20 RU/ml, respectively. Mean age and serum creatinine of the entire cohort were 53 ± 13 years and 1.84 ± 1.63 mg/dl, respectively, while median 24-h proteinuria was 6.8 g/day (IQR: 4.8 – 10.6). Thirty patients (14.7%) were identified to have a potential secondary cause of NS. Ninety-five patients (46.8%) had a histological diagnosis of MN, while 108 patients were diagnosed with other glomerular disorders. In patients with anti-PLA2R antibody titer > 20 RU/ml, the most frequent histological diagnosis was MN (n=61, 91%) with 6 patients having other glomerular patterns of injury (two FSGS, one minimal-change disease, one membrano-proliferative glomerulonephritis, one diabetic nephropathy and one postinfectious glomerulonephritis) (Figure 1). Of patients with intermediate anti-PLA2R antibody titer (2-20 RU/ml), 39% had MN and 61% had other glomerular disorders (Figure 1). Eighteen patients with MN had a positive work-up for secondary causes, eight patients (44%) having an anti-PLA2R antibody titer > 20 RU/ml. Additionally, patients with anti-PLA2R antibody titer > 20 RU/ml had a lower serum creatinine (1.5 ± 0.89 mg/dl) than patients with intermediate titer (1.89 ± 1.21 mg/dl) and those with negative titer (2.03 ± 1.98 mg/dl) (Figure 2). When analyzing the diagnostic performance of anti-PLA2R antibodies in the entire cohort we identified an AUC of 0.83 (95%CI, 0.78-0.89; p<0.001), the cut-off titer of 20 RU/ml having a sensibility, specificity, positive predictive value (PPV) and negative predictive value of 65%, 94%, 91% and 75%, respectively. The accuracy of anti-PLA2R antibodies for non-invasive diagnosis of primary MN was improved in the subgroup of patients that were younger than 60 years (AUC=0.88; 95%CI, 0.82-0.95; p<0.001, with a PPV and NPV of 91% and 80%), had an estimated glomerular filtration rate over 60 ml/min (AUC=0.85; 95%CI, 0.77-0.93; p<0.001, with a PPV and NPV of 95% and 69%) or had a negative work-up for secondary causes of NS (AUC=0.88; 95%CI, 0.82-0.93; p<0.001, with a PPV and NPV of 93% and 80%). Serum anti-PLA2R antibody screening in patients with NS is a useful method for the diagnosis of primary MN. In younger patients (less than 60 years-old) that have a preserved renal function and a negative work-up for secondary causes a positive anti-PLA2R antibody test highly predicts a diagnosis of primary MN.