Sheffield Kidney Institute

To the Editor:

Membranoproliferative glomerulonephritis (MPGN) type II (MPGN II), also called dense-deposit disease, is a rare glomerular disease that often progresses to end-stage renal disease.1 MPGN II is associated with complement because of systemic C3 activation and deposition of C3 cleavage products along the glomerular basement membrane.2 Genetic causes include mutations in the genes encoding for complement factor H and C3, which result in deregulation of the C3 convertase.3 In addition, autoantibodies, such as C3 nephritic factor, which stabilize C3 convertase and induce a permanent activation of complement, have been identified in 50 to 80% of patients with MPGN II.4 Single cases of patients with autoantibodies to factor B and factor H have also been described. There is currently no effective treatment for patients with MPGN II, and the prognosis for survival after kidney transplantation is poor.

We now report combined factor B and C3 autoantibodies in two unrelated patients. Patient 1 was an 8-year-old girl with MPGN II and end-stage renal disease (see Panels A and B in the Supplementary Appendix, available with the full text of this letter at NEJM.org), and Patient 2 was a 20-year-old man with MPGN. Both patients lacked C3 nephritic factor but had autoantibodies to the two individual components of the C3 convertase (i.e., C3b and factor B) (Figure 1AFigure 1 Pathological Findings, Characterization of Factor B and C3b Autoantibodies, and Treatment in Autoimmune Membranoproliferative Glomerulonephritis Type II.). These autoantibodies enhance C3 convertase activity, as shown by higher levels of cleavage products Ba and C3a with the addition of isolated IgGs from both patients to normal human serum (Panel C in the Supplementary Appendix) or to the in vitro assembled C3 convertase (Panel D in the Supplementary Appendix). Patient 1 had heterozygous deficiency of genes encoding complement factor H–related proteins 1 (CFHR1) and 3 (CFHR3), indicating a genetic makeup that was different than that of patients with deficiency of complement factor H–related proteins and positive autoantibodies to factor H.5 Patients with autoimmune MPGN II have autoantibody development independent of homozygous deletion of the CFHR1 and CFHR3 genes.

On the basis of the diagnosis of autoimmune MPGN II, Patient 1 received weekly plasma exchanges and was administered daily immunosuppressive therapy (rituximab at a dose of 375 mg per square meter of body-surface area, tacrolimus at a dose of 0.25 mg per kilogram of body weight, mycophenolate mofetil at a dose of 1 g per square meter, and glucocorticoids at a dose of 1 mg per kilogram). Her C3b autoantibody levels decreased (from 0.8 to 0.4 arbitrary units [AU]), and her factor B autoantibody levels decreased (Figure 1B). Her Ba activation fragment decreased to background levels, and the C3 plasma levels increased to normal values (Figure 1C). She underwent transplantation, and plasma exchange was performed every other day before and for 3 weeks after transplantation. It then was continued weekly for 8 weeks after transplantation (from week 4 through week 12) and then every other week for 4 more weeks (from week 13 through week 16). Her serum creatinine level was 0.7 mg per deciliter (61.8 μmol per liter), and proteinuria was absent 1 week after transplantation. Eighteen months after transplantation, her condition was stable, with no disease recurrence. This autoimmune form of MPGN shows that in addition to C3 nephritic factor, additional autoantibodies develop in MPGN II that lead to complement deregulation that requires targeted treatment.

Drs. Chen and Müller and Drs. Skerka and Zipfel contributed equally to this letter.

Supported by the International Leibniz Research School, Jena School for Microbial Communication, Deutsche Forschungsgemeinschaft, and the National Institutes of Health.

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