Anti Phospholipase A2 Receptor 1 Antibodies and Membranous Nephropathy Recurrence After Kidney Transplantation

Abstract

Introduction: Membranous nephropathy can lead to end-stage kidney disease, for which kidney transplantation is the preferred therapy. However, the disease often relapses, which can impact allograft survival.

Methods: We conducted a prospective multicenter study in France involving 72 patients with membranous nephropathy who were awaiting and then underwent kidney transplantation. In addition, we established a retrospective validation cohort of 65 patients. The primary objective was to evaluate the prognostic significance of pretransplant anti phospholipase A2 receptor 1 (PLA2R1) antibodies on the recurrence of membranous nephropathy. The study also assessed the incidence rate, time to onset, and risk factors for recurrence, as well as allograft outcome.

Results: The prospective cohort showed a 26% cumulative incidence of membranous nephropathy recurrence after a median follow-up of 23.5 months. This was confirmed by a 28% cumulative incidence after a median follow-up of 67 months in the retrospective cohort. A strong association was found between the presence of anti-PLA2R1 antibodies prior to transplantation and the risk of disease recurrence (risk ratio = 5.9; 95% confidence interval [CI]: 2.3-15.7; P < 0.0001). These results were confirmed in the retrospective cohort. Monitoring of anti-PLA2R1 antibodies in the immediate posttransplant period is of limited value, because recurrence occurred early in the first 6 months (median delay of 5 [3-14] months) after transplantation despite decreasing antibody levels.

Conclusion: The presence of anti-PLA2R1 antibodies prior to transplantation was a strong predictor of recurrence of allograft membranous nephropathy. An individualized immunomonitoring and management strategy for kidney transplant candidates with anti-PLA2R1-associated membranous nephropathy should be considered.

Keywords: anti-PLA2R1 antibodies; kidney transplantation; membranous nephropathy; recurrence.

Graphical abstract

Figure 1

Flow chart showing patients enrollment. Patients with membranous nephropathy awaiting transplantation or transplanted for less than 3 months were included in the prospective cohort and followed for a maximum of 60 months. Patients with membranous nephropathy who had been transplanted for more than 3 months were included in the retrospective cohort. D0, day 0 of the transplantation; MN, membranous nephropathy.

Figure 2

Prognostic value of baseline anti-PLA2R1 antibodies on membranous nephropathy recurrence after transplantation in the prospective cohort. (a) Anti-PLA2R1 antibody levels at baseline. Patients who relapsed after transplantation had significantly higher anti-PLA2R1 antibody levels on the day of transplantation than patients who did not relapse (60 [IQR: 16–226] RU/ml vs. 2 [IQR: 2–12] RU/ml; P < 0.0001). Statistical significance was determined by a Mann-Whitney test. (b) Receiver operator characteristic curve comparing baseline anti-PLA2R1 antibody levels between patients who will relapse and those who will not relapse. The anti-PLA2R1 antibody level cut-off value with the best prognostic performance at D0 was 15.50 RU/ml (sensitivity 79%, 95% CI: 67%–88%; specificity 79%, 95% CI: 57%–91%; area under the curve: 0.78; P = 0.0003). (c) Relapse-free survival of kidney transplant patients with membranous nephropathy. The cut-off value of 15.50 RU/ml, as determined by ROC curve, was used to distinguish patients at risk from those not at risk for relapse after transplantation (P < 0.0001). Kaplan-Meier analysis was used to estimate the relapse-free survival of patients with membranous nephropathy based on their anti-PLA2R1 antibody level. Abs, antibodies; AUC, area under the curve; CI, confidence interval; D0, day 0; IQR, interquartile range; PLA2R1, phospholipase A2 receptor 1; ROC curve, receiver operator characteristic curve; Se, sensitivity; Sp, specificity.

Figure 3

Prognostic value of baseline anti-PLA2R1 antibodies on membranous nephropathy recurrence after transplantation in the retrospective cohort. (a) Anti-PLA2R1 antibody levels at baseline. Patients who relapsed after transplantation had significantly higher anti-PLA2R1 antibody levels on the day of transplantation than patients who did not relapse (11.5 [IQR: 2.0–50.50] RU/ml vs. 2.0 [IQR: 2.0–2.0] RU/ml; P = 0.0002). Statistical significance was determined by a Mann-Whitney test. (b) Receiver operator characteristic curve comparing baseline anti-PLA2R1 antibody levels between patients who will relapse and those who will not relapse. The anti-PLA2R1 antibody level cut-off value with the best prognostic performance at D0 was 3.50 RU/ml (sensitivity 83% [95% CI: 70%–91%], specificity 67% [95% CI: 44%–84%], AUC: 0.74, P = 0.003). (c) Relapse-free survival of kidney transplant patients with membranous nephropathy. The cut-off value of 3.50 RU/ml, as determined by ROC curve, was used to distinguish patients at risk from those not at risk for relapse after transplantation (P < 0.0001). Kaplan-Meier analysis was used to estimate the relapse-free survival of patients with membranous nephropathy based on their anti-PLA2R1 antibody level. Abs, antibodies; AUC, area under the curve; CI, confidence interval; D0, day 0; IQR, interquartile range; PLA2R1, phospholipase A2 receptor 1; ROC curve, receiver operator characteristic curve; Se, sensitivity; Sp, specificity.