Correspondence

PLA2R Autoantibodies and Recurrent Membranous Nephropathy after Transplantation

N Engl J Med 2010; 363:496-498July 29, 2010

Article

To the Editor:

Membranous nephropathy is a leading cause of the nephrotic syndrome in adults. One third of patients have a progressive loss of renal function and reach end-stage renal disease.1 Membranous nephropathy recurs in up to 40% of patients after renal transplantation.2 Recently, Beck et al.3 found that patients with membranous nephropathy had circulating autoantibodies against M-type phospholipase A₂ receptor (PLA2R), which in the kidney is exclusively expressed on glomerular podocytes. Binding of PLA2R autoantibodies to this receptor is responsible for the induction of idiopathic membranous nephropathy.4

We report findings regarding a 56-year-old female patient with biopsy-proven membranous nephropathy, which was diagnosed in September 1999 and progressed to end-stage renal disease. In February 2004, the patient was started on hemodialysis and in July 2009 received a renal allograft from a deceased donor. The immunosuppressive therapy consisted of cyclosporine (125 mg twice daily), mycophenolate mofetil (720 mg twice daily), and glucocorticoids (5 mg once daily). The patient also received amlodipine (5 mg twice daily), ramipril (1.25 mg once daily), and pantoprazole (40 mg once daily). On day 3 after renal transplantation, proteinuria developed, which increased to 9000 mg of protein during a 24-hour period. Renal biopsy showed recurrent membranous nephropathy. After this condition was diagnosed, the patient was treated with rituximab (at a dose of 375 mg per square meter of body-surface area) twice within 2 weeks, in addition to standard immunosuppressive therapy (Figure 1Figure 1Anti–PLA2R Autoantibody Detected before and after Renal Transplantation.).

Anti–PLA2R-specific autoantibody titers were measured in serum that had been obtained from the patient before and after renal transplantation, as well as after rituximab therapy, by means of indirect immunofluorescence with the use of HEK 293 cells, which were transiently transfected with full-length complementary DNA encoding a PLA2R isoform. HEK 293 cells were used as substrates for indirect immunofluorescence after fixation in formaldehyde. Serum samples from patients with IgA nephropathy served as negative controls.

Anti–PLA2R autoantibody was detected in the patient's serum before and 3 months after transplantation (Figure 1). After rituximab therapy, anti–PLA2R autoantibody levels fell from 1:100 to 1:10 at 3 months and remained at 1:10 after 5 months. Proteinuria decreased from 9 g of urinary protein excretion per 24 hours to 3.14 g per 24 hours after 5 months.

These findings show the presence of anti–PLA2R autoantibody in a patient with end-stage renal disease caused by membranous nephropathy before and after renal transplantation. On the basis of the findings of Beck et al.,3 anti–PLA2R autoantibody in this patient could be responsible for the recurrence of membranous nephropathy in the renal transplant. Measurement of anti–PLA2R autoantibody titers in patients with membranous nephropathy who are undergoing dialysis before renal transplantation may identify a potential risk of recurrence of disease in the transplant and may lead to modification of immunosuppressive therapy for these patients.

Rolf Stahl, M.D.
Elion Hoxha, M.D.
University Medical Center Hamburg-Eppendorf, Hamburg, Germany
rstahl@uke.de

Kai Fechner, M.D.
Euroimmun, Lübeck, Germany

Supported by a grant from the Deutsche Forschungsgemeinschaft (KFO 228/STA193/9-1).

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

4 References

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   El-Zoghby ZM, Grande JP, Fraile MG, Norby SM, Fervenza FC, Cosio FG. Recurrent idiopathic membranous nephropathy: early diagnosis by protocol biopsies and treatment with anti-CD20 monoclonal antibodies. Am J Transplant 2009;9:2800-2807
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   Beck LH Jr. , Salant DJ. Membranous nephropathy: recent travels and new roads ahead. Kidney Int 2010;77:765-770
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Citing Articles (12)

Citing Articles

1. 1

   N. Kearney, J. Podolak, L. Matsumura, D. Houghton, M. Troxell. (2011) Patterns of IgG Subclass Deposits in Membranous Glomerulonephritis in Renal Allografts. Transplantation Proceedings 43:10, 3743-3746
   CrossRef

2. 2

   S. Khan. (2011) PLA2 receptor autoantibodies, complement activation and podocyte damage. Nephrology Dialysis Transplantation 26:12, 4151-4151
   CrossRef

3. 3

   H. Debiec, L. Martin, C. Jouanneau, G. Dautin, L. Mesnard, E. Rondeau, C. Mousson, P. Ronco. (2011) Autoantibodies Specific for the Phospholipase A2 Receptor in Recurrent and De Novo Membranous Nephropathy. American Journal of Transplantation 11:10, 2144-2152
   CrossRef

4. 4

   S. J. Cohney. (2011) Steroid Withdrawal in Patients Transplanted for IgA Nephropathy-A Disease-Specific Consideration?. American Journal of Transplantation 11:8, 1553-1555
   CrossRef

5. 5

   E. Hoxha, S. Harendza, G. Zahner, U. Panzer, O. Steinmetz, K. Fechner, U. Helmchen, R. A. K. Stahl. (2011) An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrology Dialysis Transplantation 26:8, 2526-2532
   CrossRef

6. 6

   Sudesh P. Makker, Alfonso Tramontano. (2011) Idiopathic Membranous Nephropathy: An Autoimmune Disease. Seminars in Nephrology 31:4, 333-340
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7. 7

   Pierre Ronco, Hanna Debiec. (2011) Advances in membranous nephropathy: Success stories of a long journey. Clinical and Experimental Pharmacology and Physiology 38:7, 460-466
   CrossRef

8. 8

   A. C. Chan. (2011) Rituximab's New Therapeutic Target: The Podocyte Actin Cytoskeleton. Science Translational Medicine 3:85, 85ps21-85ps21
   CrossRef

9. 9

   U. Kunzendorf. (2011) Phospholipase-A2-Rezeptor und membranöse Glomerulonephritis. Der Nephrologe 6:3, 268-269
   CrossRef

10. 10

    Debiec, Hanna, Ronco, Pierre, . (2011) PLA₂R Autoantibodies and PLA₂R Glomerular Deposits in Membranous Nephropathy. New England Journal of Medicine 364:7, 689-690
    Full Text

11. 11

    Chadwick E. Barnes, William A. Wilmer, Raul A. Hernandez, Jr., Christopher Valentine, Leena S. Hiremath, Tibor Nadasdy, Anjali A. Satoskar, Rose L. Shim, Brad H. Rovin, Lee A. Hebert. (2011) Relapse or Worsening of Nephrotic Syndrome in Idiopathic Membranous Nephropathy Can Occur even though the Glomerular Immune Deposits Have Been Eradicated. Nephron Clinical Practice 119:2, c145-c153
    CrossRef

12. 12

    Hyun Chul Chung, Jongha Park, Jong Soo Lee. (2011) Treatment of Posttransplantation Recurrent Glomerulonephritis: IgA Nephropathy, Membranous Nephropathy, Membranoproliferative Glomerulonephritis. The Journal of the Korean Society for Transplantation 25:2, 81
    CrossRef