Challenges in Understanding Acute Postinfectious Glomerulonephritis: Are Anti-Factor B Autoantibodies the Answer?

Acute postinfectious GN (APIGN) is a common cause of acute nephritic syndrome in children that develops following an infection, mainly by Streptococcus bacteria.1 Histologically, it is characterized by a proliferative GN, bright glomerular C3 immunofluorescence staining with or without Igs, and subepithelial hump-like deposits on electron microscopy. It has been proposed that the kidney lesion is driven by glomerular deposition of bacterial antigens followed by the formation of in situ immune complexes and/or glomerular deposition of preformed circulating immune complexes.2,3 Clinically, the disease presents with hematuria, proteinuria, and low serum C3 levels. A large majority of patients recover within days to weeks, and the overall prognosis is good. Indeed, after resolution of the infection, immune complexes are cleared, complement activity shuts down, and GN resolves. However, in a subgroup of patients, the disease follows an atypical course, with chronic C3 consumption, persistent proteinuria, and even progression to ESKD.4 The latter course closely resembles that observed in patients with C3 glomerulopathy (C3G), which encompasses a spectrum of glomerular diseases associated with chronic hypocomplementemia and poor renal outcome.5 Similar to APIGN, C3G often presents after a preceding infection, and at onset, patients exhibit clinical, biochemical, and histopathologic features that overlap with APIGN, making a differential diagnosis very difficult.5 In fact, it has been proposed that APIGN and C3G could represent opposite ends of a disease spectrum. C3G is mediated by hyperactivation of the alternative pathway of complement, associated in about half of all cases with autoantibodies—the C3 nephritic factors (C3NeFs)—that stabilize the alternative pathway C3 or C5 convertases or more rarely, with genetic abnormalities that affect complement proteins and regulators.5,6 The mechanisms that lead to complement activation in APIGN, however, remain unclear. Immune complexes against Streptococcus bacteria antigens in the circulation and in the kidney are expected to activate the classic complement pathway. However, the observation that a large majority of patients with APIGN have decreased serum C3 levels and normal C4 levels during the acute phase suggests that there is a selective activation of the alternative complement pathway.4,7 Streptococcal proteins, such as the nephritis-associated plasmin receptor, have been shown in vitro to induce C3 activation via the alternative pathway,8 but these studies require in vivo confirmation. In this issue of JASN, Chauvet et al.7 provide relevant insights into the mechanisms through which the alternative complement pathway is activated in APIGN. In a cohort of 34 children, they identified autoantibodies against factor B (FB)—one of the two components of the C3 convertase, the key enzyme in the activation of the alternative complement pathway—in 31 of them. The autoantibodies were mainly of the IgG1 subclass, and they were transient to the extent that, during follow-up, their titer decreased or became negative in 29 patients. This study provides convincing evidence that the antibodies play a pathogenetic role in APIGN. (1) At disease onset, the anti-FB autoantibody titer correlated inversely with plasma C3 levels and directly correlated with levels of the terminal complement complex sC5b-9. (2) The disappearance of the antibodies was associated with the normalization of markers of complement activation. (3) In functional studies, the anti-FB antibodies isolated from the patients enhanced the activity of the alternative pathway C3 convertase in the fluid phase and/or on the cell surface. Chauvet et al.7 did not address the mechanisms underlying the formation of anti-FB autoantibodies during the acute phase of APIGN. They hypothesize that bacterial antigens may have molecular mimicry with FB and favor the occurrence of anti-FB antibodies, but the failure to identify any sequence homology between the FB peptides most frequently recognized by these autoantibodies and the sequence of Streptococcal proteins raises doubts about this interpretation. The authors' alternative hypothesis—that antibody generation was favored by the formation of FB neoepitopes following alternative pathway activation by the Streptococcal surface—also seems unlikely because Chauvet et al.7 show that these antibodies react against intact FB but cannot recognize the neopepitopes of the C3bBb C3 convertase complex. It is important to note that the anti-FB antibodies were not able to prolong the t1/2 of preformed C3 convertase formed on red blood cells, a finding that is consistent with their inability to react with the C3 convertase complex.7 Thus, these antibodies should be distinguished from the C3NeFs that are commonly found in patients with C3G or immune complex–associated membranoproliferative GN and stabilize the C3 or C5 convertase complexes.9 One could speculate that anti-FB antibodies may favor the interaction of FB with C3b and the formation of the alternative pathway C3 convertase. What are the clinical implications of these findings? In children with nephritic syndrome and hypocomplementemia, one can envision that using the tests for anti-FB antibodies and C3NeFs might help clinicians to distinguish between APIGN and C3G, in particular when C3G is triggered by infection. The presence of anti-FB antibodies would suggest APIGN and a good prognosis, whereas C3G would be a more likely diagnosis in the absence of anti-FB antibodies, especially in children who are also positive for C3NeFs. An early differential diagnosis during the acute phase is crucial to avoid the administration of intensified immunosuppression in children with APIGN who will likely have a favorable outcome with only supportive care or with a short course of steroids and to identify patients at risk of C3G who may benefit from emerging complement-inhibitory drugs. Nevertheless, the implications of the results obtained by Chauvet et al.7 should be considered with caution, and further studies are needed to establish the actual specificity and sensitivity of anti-FB antibodies for a differential diagnosis. First of all, the data should be replicated in other independent, well characterized cohorts of patients. The number of children studied by Chauvet et al.7 is rather small, and the distinction between APIGN was not absolute: anti-FB antibodies were not identified in 9% of patients with APIGN, whereas 14% of children with C3G had anti-FB autoantibodies, and the latter finding is consistent with previous data in the literature.10 The test for anti-FB antibodies should be validated and developed for clinical use. Moreover, the retrospective nature of the study did not make it possible to assess whether anti-FB autoantibodies are the drivers of alternative pathway activation and of renal disease in APIGN or whether complement activation was already present before the emergence of anti-FB antibodies. To answer this question, a prospective study is needed in which C3 and sC5b-9 levels and anti-FB autoantibodies are analyzed in children with Streptococcal infection, starting before the occurrence of renal symptoms. In such a study, results from children who go on to develop APIGN should be compared with results from controls with infection only to evaluate whether the positivity of anti-FB antibodies is specific for APIGN. In summary, this study is an important step toward understanding the mechanisms underlying complement activation that are associated with APIGN, and it also paves the way for improving differential diagnosis with C3G. There is a long list of important work that needs to be conducted in the future, but the harvest should be rich. Disclosures Dr. Noris has received honoraria from Alexion Pharmaceuticals for giving lectures and participating in advisory boards. Dr. Remuzzi has consultancy agreements with AbbVie, Alexion Pharmaceuticals, AstraZeneca, Bayer Healthcare, Concert Pharmaceuticals, Novartis Pharma, Otsuka Pharmaceutical Europe, and Reata Pharmaceuticals. Dr. Remuzzi did not accept personal remuneration; compensation is paid to his institution for research and educational activities. Funding Dr. Noris was supported by grants from Bando Ricerca Finalizzata, Progetto DDD Onlus–Associazione per la lotta alla DDD (Milan, Italy), and Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia (Rome, Italy) and by Ministero della Salute grant RF-2016-02361720.