Serum Levels of BAFF and APRIL Predict Clinical Response in Anti-PLA2R-Positive Primary Membranous Nephropathy

Abstract

Primary membranous nephropathy (PMN) is a renal-specific autoimmune disease caused by circulating autoantibodies that target glomerular podocyte antigens (PLA2R/THSD7A). However, very little is known on the molecular mechanisms controlling B cell response in this nephropathy. The present study was aimed at correlating the serum levels of B cell activators BAFF/BLyS and APRIL with the presence of anti-PLA2R antibodies in PMN patients and with long-term clinical outcome. To this aim, 51 patients with anti-PLA2R-positive biopsy-proven PMN and nephrotic range proteinuria (>3.5 g/24 hours) were enrolled between January 2009 and December 2015 and treated with conventional 6-month immunosuppressive therapy. After 6 months, 29 patients (56.9%) cleared circulating anti-PLA2R, while in remaining 22 (43.1%), they persisted. Intriguingly, in the first group, baseline serum levels of BAFF/BLyS and APRIL were significantly lower than those in the second one. Moreover, after 6 months of immunosuppressive therapy, an overall reduction in both cytokine serum levels was observed. However, in PMN patients with anti-PLA2R clearance, this reduction was more prominent, as compared with those with anti-PLA2R persistence. When related to clinical outcome, lower baseline BAFF/BLyS (<6.05 ng/mL) and APRIL (<4.20 ng/mL) serum levels were associated with significantly higher probability to achieve complete or partial remission after 24-month follow-up. After dividing the entire study cohort into three groups depending on both cytokine baseline serum levels, patients with both BAFF/BLyS and APRIL below the cut-off showed a significantly higher rate of complete or partial remission as compared with patients with only one cytokine above the cut-off, while the composite endpoint was achieved in a very low rate of patients with both cytokines above the cut-off. Taken together, these results provide new insights into the role of BAFF/BLyS and APRIL in both the pathogenesis of anti-PLA2R-positive PMN and the response to immunosuppressive therapy.

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

“…Key B cell-related cytokines are upregulated in MN. Consistent with observations in other antibody-mediated autoimmune diseases, serum BAFF and APRIL levels were elevated in MN, although this was mostly observed in the group with detectable anti-PLA 2 R antibodies [114,115]. The different molecular profiles observed in different types of MN suggest that the mechanism of loss of immune tolerance may depend on the target antigen in question.…”

“…The different molecular profiles observed in different types of MN suggest that the mechanism of loss of immune tolerance may depend on the target antigen in question. Baseline serum baseline BAFF and APRIL levels were lower in patients who achieved a complete or partial response to standard immunosuppressive treatments as opposed to patients who had a limited or no response, and a marked reduction in the circulating levels of these cytokines was associated with favourable clinical outcomes [115]. In a separate study, high serum baseline APRIL was also associated with less complete response, while high serum baseline BAFF was associated with relapse [114].…”

PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma

“…Statistical analysis was performed as described elsewhere [69,70,71]. In detail, statistical calculations were performed with MedCalc 9.2.0.1 (MedCalc software, Mariakerke, Belgium) and PASW 18 software (PASW 18, SPSS, Chicago, Ill, USA).…”

Level of interleukin-35 in patients with idiopathic membranous nephropathy and its predictive value for remission time

“…The currently reported indicators used to evaluate the immune status and predict the remission time of IMN patients include the changes of aPLA2R titer ( 30 ) and BAFF levels ( 31 ). However, they are mainly used in IMN patients with positive aPLA2R, but for nearly 30% of IMN patients with negative aPLA2R, there is a lack of corresponding indicators.…”