YEAR IN REVIEW GLOMERULAR DISEASE IN 2014
Advances in basic science and translational medicine Fernando C. Fervenza and Sanjeev Sethi
Knowledge of the pathogenesis of glomerular disease and approaches to therapy continued to advance in 2014. Key studies identified thrombospondin type‑1 domain-containing protein 7A as an antigenic target in primary membranous nephropathy, and demonstrated efficacy of rituximab as maintenance therapy in relapsing or steroiddependent nephrotic syndrome and antineutrophil cytoplasmic antibody-associated vasculitis. Fervenza, F. C. & Sethi, S. Nat. Rev. Nephrol. advance online publication 13 January 2015; doi:10.1038/nrneph.2014.248
In 2014 several important studies garnered attention in the field of glomerular disease. Here we discuss three key studies: the first provided new insights into the pathogenesis of membranous nephropathy (MN);1 the others evaluated rituximab as maintenance therapy in children with relapsing or steroid-dependent minimal change disease (MCD)2 and in adults with antineutrophil cytoplasmic antibody ( ANCA)-associated vasculitis (AAV).3
‘‘
...repeated courses of rituximab are associated with a reduced risk of relapse in patients with AAV
’’
Up to 30% of patients with primary MN are negative for antibodies to M‑type phospholipase–A2-receptor (PLA2R),4 suggesting that antibodies to other podocyte antigens might be responsible. In 2014, Tomas et al. demonstrated that antibodies to thrombospondin type‑1 domain-containing protein 7A (THSD7A) explain up to 10% of cases of anti-PLA2R negative MN.1 In this landmark study, a 250 kD glomerular protein—identified by mass spectrometry as an antibody against THSD7A—was detected in serum samples from 15 of 154 patients with this disease. Furthermore, IgG eluted from kidney biopsy samples from these 15 patients was specific for THSD7A, whereas healthy individuals (n = 44) and patients with anti-PLA2R-positive MN (n = 74) or other
glomerular diseases (n = 76) tested negative for anti-THSD7A antibodies. Similar to PLA2R, THSD7A localized to the basal aspect of the podocyte.1 This protein, which was initially characterized in endothelial cells, is associated with the actin cytoskeleton and has a role in endothelial cell migration and tube formation during angio genesis. Both THSD7A and PLA2R have large extracellular regions, multiple repeated disulfide-bonded and N‑glycosylated domains and react with serum only under non-reducing conditions. No reactivity of anti-PLA2R positive serum against THSD7A was detected.1 In PLA2R-positive MN, low antibody titres are associated with a high likelihood of spontaneous remission and might indicate that specific treatment should be delayed. No such information is yet available for THSD7A autoantibody, but as testing becomes clinically available it will likely contribute to an individualized approach to therapy for patients with MN. Rituximab—a chimeric monoclonal antibody directed against CD20 expressed on B cells—has achieved great success in the treatment of a number of autoimmune conditions affecting the kidney, including AAV and MN. Several studies, including a small randomized clinical trial with a short follow-up,5 have shown that rituximab can induce sustained remission with a marked reduction or discontinuation of corticosteroids and/or immunosuppressant agents in patients with MCD who are steroid-dependent or frequently relapse.
NATURE REVIEWS | NEPHROLOGY
In 2014, Iijima et al. conducted a doubleblind, randomized, placebo-controlled trial of rituximab in 48 children aged ≥2 years with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), most of whom had MCD.2 All participants were diagnosed with nephrotic syndrome between the ages of 1 year and 18 years and were experien cing a relapse at the time of study enrolment. They received rituximab 375 mg/m2 (maximum 500 mg) or placebo once a week for 4 weeks as well as standard cortico steroid treatment for relapse at screening, which was targeted to be discontinued after 10 weeks. All immunosuppressive agents were discontinued ≤169 days after ran domization. The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223–374 days) than in the placebo group (101 days, 95% CI 70–155 days; P 50% of patients have an additional relapse within months of follow-up.8,9 Some retrospective
studies have suggested that repeated doses of rituximab could be effective in main tenance of remission.10 In 2014, Guillevin et al. tested this approach in a nonblinded, randomized controlled trial. 3 115 adults with newly diagnosed or relapsing AAV (of whom 87 patients had granulomatosis with polyangiitis [GPA], 23 had microscopic polyangiitis [MPA], and 5 had renal-limited AAV) that was in complete remission after a cyclophosphamide–corticosteroid based regimen, were randomly assigned to receive azathioprine (2 mg/kg per day for 12 months, followed by 1.5 mg/kg per day for 6 months and 1 mg/kg per day until month 22) or rituximab (500 mg on days 0 and 14 and at months 6, 12, and 18 after study entry) as maintenance therapy. The primary end point was the rate of major relapse at month 28. At 28-month follow-up, 29% of patients in the azathioprine group and 5% of those in the rituximab group had experienced a major relapse (P = 0.002). Eight patients in the azathioprine group and one patient in the rituximab group had a major relapse within the first 12 months. The majority of major relapses were in patients with GPA (17 of 20) and in those with newly diagnosed disease (15 of 20). The frequencies of severe adverse events, including severe infections, were similar in the groups. This study demonstrates that repeated courses of rituximab are associated with a reduced risk of relapse in patients with AAV. However, as the majority of the patients had GPA, were proteinase 3–ANCA positive and had newly diagnosed disease, the applicability of these results to patients with MPA and those who are myeloperoxidase–ANCA positive requires further study. It could also be argued that tapering of azathioprine may have contributed to further increase in relapses after 12 months. To summarize, important studies published in 2014 identified a new antigenic target for primary MN1 and demonstrated efficacy of rituximab in relapsing or steroiddependent MCD 2 and as a maintenance
2 | ADVANCE ONLINE PUBLICATION
therapy for AAV.3 In our opinion, advances in understanding of the pathogenesis and improvements in therapy have made glomerular disease the most exciting area of nephrology in the last decade. Division of Nephrology and Hypertension, Department of Internal Medicine (F.C.F.), Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology (S.S.), Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA. Correspondence to: F.C.F.
[email protected] Competing interests The authors declare no competing interests. 1.
Tomas, N. M. et al. Thrombospondin type‑1 domain-containing 7A in idiopathic membranous nephropathy. N. Engl. J. Med. 371, 2277–2287 (2014). 2. Iijima, K. et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384, 1273–1281 (2014). 3. Guillevin, L. et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N. Engl. J. Med. 371, 1771–1780 (2014). 4. Beck, L. H. Jr et al. M‑type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009). 5. Ravani, P. et al. Short-term effects of rituximab in children with steroid and calcineurindependent nephrotic syndrome: a randomized controlled trial. Clin. J. Am. Soc. Nephrol. 6, 1308–1315 (2011). 6. Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010). 7. Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010). 8. Specks, U. et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N. Engl. J. Med. 369, 417–427 (2013). 9. Smith, R. M. et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 3760–3769 (2012). 10. Cartin-Ceba, R. et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center. Arthritis Rheum. 64, 3770–3778 (2012).
www.nature.com/nrneph © 2015 Macmillan Publishers Limited. All rights reserved
