Predictive values of serum phospholipase A2 receptor antibody and urinary IgG, α1- macroglobulin in patients with idiopathic membranous nephropathy and nephrotic syndrome
Authors: Liu Lili , Wang Haitao , Zhao Ban , Liu Xin , Sun Ying , Mao Yonghui 
Published: May 2020

Abstract
BackgroundThe biomarkers predicting long-term outcome of idiopathic membranous nephropathy (IMN) with nephrotic syndrome (NS) remains indeterminacy. We conducted this study to evaluate the different features between phospholipase A2 receptor (PLA2R)-associated and non-PLA2R-associated IMN, and to explore the association between serum PLA2R antibody (PLA2R-Ab), urinary immunoglobulin G (UIgG), urinary α1-macroglobulin (Uα1m) and renal outcomes in patients with idiopathic membranous nephropathy (IMN) and nephrotic syndrome (NS). MethodsIMN patients who were biopsy-proven and presenting NS were retrospectively recruited for the present study. Serum PLA2R-Ab levels were detected by enzyme-linked immunosorbent assay (ELISA) kits, and values over 20 RU/mL was considered positive. UIgG) and Uα1m were measured by immunonephelometry and corrected by urinary creatinine. The clinicopathologic features, remission and renal outcome were compared between the PLA2R-associated and non-PLA2R-associated IMN patients. Furthermore, the predictive values of biomarkers (PLA2R-Ab, UIgG/Cr and Uα1m/Cr) for remission and renal outcome were assessed by multivariate regression. The renal endpoint was defined as progression to end stage kidney disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥50% of baseline. ResultsA total of 111 IMN patients were enrolled this study, and 81 (73.0%) of them were PLA2R-associated. The mean age, 24-hour proteinuria and eGFR showed no difference between PLA2R-associated and non-PLA2R-associated groups (p>0.05). However, PLA2R-associated IMN patients had significantly higher UIgG/Cr (17.78 vs. 9.82 mg/g; median, p=0.001) and Uα1m (0.339 vs 0.202 mg/g; median, p<0.001) when compared to non-PLA2R-associated patients. Histologically, the PLA2R-associated group represented more proportion of patients with acute tubular necrosis (ATN) (27.16% vs. 3.33%, P=0.006) and glomerular C3 deposits (88.89% vs. 70.00%, P=0.016) than the non-PLA2R-associated group. During a median follow-up of 40 months (range 9 to 92), non-PLA2R-associated patients had significantly higher remission rate at the 6th and 12th month and end of follow-up, even after adjusting for the use of immunosuppressor. Furthermore, 11 (13.6%) patients reaching renal endpoint were all PLA2R-associated IMN. Multivariate regression analysis represented that baseline serum PLA2R-Ab titer was an independent predictor of remission (OR, 1.002; 95% confidence interval [CI] 1.001 to 1.004; p=0.002) and renal outcome (HR, 1.002; 95% CI 1.001-1.003, p= 0.004). Receiver operating characteristic (ROC) showed that serum PLA2R-Ab titer >216.93 RU/ml (AUC=0.778, p=0.003), UIgG/Cr >15.76mg/g (AUC=0.758, p=0.005) and Uα1m/Cr >0.3042mg/g (AUC=0.738, p=0.010) predicted renal failure in patients with IMN and NS. Kaplan-Meier curves indicated that subjects with combination of all three high biomarkers had significantly shorter renal survival (log rank p=0.007) than subjects with ≤2 high biomarkers. ConclusionHigh PLA2R-Ab levels is poor prognosis predictor of IMN in addition to proteinuria. In addition, combination of multiple factors (PLA2R-Ab, UIgG and Uα1m) represents a stronger predictive power. These findings suggested the potential different pathogenesis and progression in IMN with NS. Keywords: idiopathic membranous nephropathy, phospholipase A2 receptor antibody, urinary IgG, urinary α1- macroglobulin, nephrotic syndrome.