PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system

Abstract

Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39-9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.

Figure 1. Flow chart of patients included in the study and their follow-up.

Of the 33 patients included in the study 16 were PLA₂R-Ab positive and 17 were PLA₂R-Ab negative at the start of the study. Nephrotic proteinuria developed in 13 PLA₂R-Ab positive and five PLA₂R-Ab negative patients. Immunosuppressive treatment was used in 13 PLA₂R-Ab positive patients and two PLA₂R-Ab negative patients. At the end of the follow-up eight patients were still PLA₂R-Ab positive, two of them had a remission of proteinuria (both partial remission) and five of them had a significant increase in serum creatinine. PLA₂R-Ab were negative in 25 patients at the end of the follow-up, 24 of them had a remission of proteinuria (16 complete remission, eight partial remission) and one of them had a significant increase in serum creatinine. CR = complete remission; PR = partial remission; NR = no remission. ^a = Significantly more PLA₂R-Ab positive patients developed nephrotic-range proteinuria compared to PLA₂R-Ab negative patients (Fisher’s exact test: p<0.005). ^b = Significantly more PLA₂R-Ab positive patients received immunosuppressive therapy compared to PLA₂R-Ab negative patients (Fisher’s exact test: p<0.001). ^c = Significantly less patients who were still positive for PLA₂R-Ab at the end of the study follow-up reached remission of proteinuria compared to patients who were negative for PLA₂R-Ab at the end of the follow-up (Fisher’s exact test: p<0.001). ^d = Significantly more patients who were still positive for PLA₂R-Ab at the end of the study follow-up had a significant increase of serum creatinine compared to patients who were negative for PLA₂R-Ab at the end of the follow-up (Fisher’s exact test: p = 0.001).

Figure 2. Proteinuria during the study follow-up.

Proteinuria significantly increased in PLA₂R-Ab positive patients (solid line) but remained low in PLA₂R-Ab negative patients (dashed line). The bars show the SD-values of proteinuria for PLA₂R-Ab positive patients (up) and PLA₂R-Ab negative patients (down). “N” gives the number of patients for whom data were available at these specific times of follow-up. “*” shows a statistically significant difference (p<0.05) between the single time point and the start of the study. “§” shows a statistically significant difference (p<0.05) between PLA₂R-Ab positive patients and PLA₂R-Ab negative patients.

Figure 3. Hazard ratios with 95% confidence intervals and p values as estimated by univariate (A) and multivariate (B) Cox regression analysis.

The explanatory variable PLA₂R-Ab levels was ln-transformed prior to analysis. Effects of age and PLA₂R-Ab levels are significant at α = 0.05. The corresponding hazard ratios indicate increasing risks for development of nephrotic range proteinuria with increasing age and PLA₂R-Ab levels (high PLA₂R-Ab levels).

Figure 4. Survival analysis by PLA₂R-Ab positivity.

4A) Time when PLA₂R-Ab positive or negative patients developed nephrotic range proteinuria. 4B) Kaplan-Meier curves. P values are from log rank tests. N = number of patients at risk at the different time points.