Complement activation contributes to pathogenesis of IgA nephropathy, lupus nephritis; inhibitors under active investigation
Presenters: Nicholas R. Medjeral-Thomas, MBBS, PhD, Imperial College London; Brad H. Rovin, MD, The Ohio State University Wexner Medical Center, Columbus
Medjeral-Thomas NR, Rovin BH. Complement in IgA nephropathy and lupus nephritis: role in pathogenesis and implications for treatment. Educational Symposium presented at American Society of Nephrology Kidney Week 2022, November 4, 2022, 12:45 pm – 1:45 pm.
Summary: A growing body of research demonstrates that complement plays a pathogenic role in IgA nephropathy and lupus nephritis (LN). Multiple agents investigating the targeting multiple arms of the complement activation pathway are under study in each disease, and the early data are promising.
The complement system, a central part of the immune response that coordinates innate and acquired immune responses, is activated by the classical, lectin, and alternative complement pathways. Studies of the system promise enhanced understanding of IgA nephropathy and lupus nephritis, with implications for treatment.
IgA nephropathy
Complement activity contributes to IgA nephropathy pathogenicity in most patients, said Nicholas R. Medjeral-Thomas, MBBS, PhD, Imperial College London, suggesting that complement inhibitors may benefit patients with IgA nephropathy. For example, C3 has been identified in most patients with IgA nephropathy. Immunohistochemical studies have shown deposition of proteins that indicate alternative lectin and terminal complement pathway activity in patients with IgA nephropathy; these findings are supported by serologic studies that detected complement activation products in IgA nephropathy patient samples and correlate with more severe disease. Evidence from multiple cohorts demonstrates that both lower and higher levels of circulating lectin complement proteins are associated with more severe disease.
Several anticomplement therapies in glomerular diseases are in clinical trials or have been approved (eg, eculizumab). In general, these agents are monoclonal antibodies, small molecular peptides and peptidomimetics, aptamers, and recombinant proteins and conjugates.
“Therapeutic complement inhibitors may be a useful intervention and perhaps even revolutionize the treatment of IgA nephropathy by being novel therapeutic agents but also potentially by providing novel biomarkers for patient selection and stratification for treatment,” said Prof. Medjeral-Thomas.
To date, nondirected nonspecific immunosuppressive agents (corticosteroids) have been the mainstay of treatment for IgA nephropathy. Clinical trial results with corticosteroids are mixed, reflecting the heterogeneity of IgA nephropathy in terms of clinical features, disease severity, and probably pathogenic mechanisms.
“This means that the key to patient response is patient selection, and the key to positive results from clinical trials are the characteristics of the cohorts included,” he said. Unfortunately, “no reliable and specific biomarker exists to identify patients who will respond to treatment. We’re currently limited to eGFR [estimated glomerular filtration rate] and persistent proteinuria.”
Additional therapies are needed, either in series or parallel to those currently available. Novel therapies must have a good side effect profile and targeted components of IgA nephropathy pathogenesis. “Ideally, we need biomarkers with which we can identify patients who are likely to respond to these treatments. This is where I think complement could play a role,” said Prof. Medjeral-Thomas.
Complement inhibitors could potentially be treatment options targeted to individuals in whom biomarkers of complement activity can be detected. A recent “explosion” of clinical trials of therapeutic complement inhibitors is exploring this possibility and providing a rich resource of clinical and biomarker data.
The first evidence of the use of therapeutic complement inhibitors in IgA nephropathy comes from the use of eculizumab, an anti-C5 terminal pathway inhibitor, in case studies where use of eculizumab resulted in stabilized kidney function and improved proteinuria.1 The results with eculizumab were mixed in patients with recurrent crescentic IgA nephropathy in kidney transplants,2 perhaps owing to its introduction at different points in the natural history of these diseases, often when significant and established scarring had occurred, he said.
Multiple agents and multiple arms of the complement activation pathway as targets are under study, and early data are promising. Safety has been established outside the setting of IgA nephropathy. “We are gaining confidence that if we vaccinate individuals against encapsulated bacteria, particularly those that cause meningitis, the safety profile of these agents is acceptable and even favorable compared to currently available treatments,” he said. Avacopan, a C5 receptor antagonist, had a favorable safety profile compared with prednisolone in patients with ANCA-associated vasculitis, even in individuals receiving other immunosuppressant agents.3
Narsoplimab, a lectin pathway inhibitor, demonstrated a reduction in proteinuria after 6 months of treatment in patients with IgA nephropathy, many of whom did not respond to previous immunosuppression.4 The 12-month experience with iptacopan in patients with native IgA nephropathy shows an average 57% reduction in proteinuria.5 Ravulizumab, a long-acting anti-C5 terminal pathway inhibitor, has also been studied.
Treating lupus nephritis
Molecular analysis of human lupus nephritis (LN) demonstrates overexpression of components of all 3 complement pathways. Early complement components are important in the opsonization and clearance of immune complexes, apoptotic cells, and cellular debris, all of which are thought to be important in the pathogenesis of LN, said Brad H. Rovin, MD, The Ohio State University Wexner Medical Center, Columbus. Deficiency in these early components may predispose individuals and animals to LN.
Preclinical models suggest an important role for the alternative pathway. Disrupting the alternative and terminal pathways therapeutically ameliorates LN. Avacopan, which blocks the C5a receptor, reduces the level of proliferative crescents corresponding with improved renal function. Anti-C5 treatment with eculizumab also has been shown to ameliorate LN in mice.
While data show that the alternative complement pathway is activated in LN, it might also have a protective role, as deficiencies of the alternative pathway convertases and terminal complement components have been demonstrated to ameliorate experimental LN.
Urine complement proteins have been detected in proliferative and membranous LN, and a trend (though not significant) for higher levels in patients with proliferative disease has been observed. Complement levels in active LN have considerable heterogeneity; this may enhance patient selection for complement-directed therapies because the heterogeneity suggests that complement-directed therapies may be targeted to specific LN patients, said Dr. Rovin.
Urine C5a and C5b-9 appear to reflect intrarenal complement activation, a target for therapeutics.
In patients treated with mycophenolate, steroids, or cyclophosphamide and steroids, urine C5a levels fall in responders but not in nonresponders, with many nonresponders showing continued complement activation after therapy.6 “These patients may achieve remission by adding a targeted alternative complement pathway inhibitor,” he said.
“Taken together, targeting the intrarenal complement system appears to be a good option for treating LN,” concluded Dr. Rovin. “Urine complement levels, especially C5b-9, may be good biomarkers for following treatment success and may identify patients who are candidates for complement-targeted drugs.”
References
- Le Quintrec M, Lionet A, Kandel C, et al. Eculizumab for treatment of rapidly progressive C3 glomerulonephropathy. Am J Kid Dis 215;65:484-489. doi:10.1053/j.ajkd.2014.09.025
- Chehade H, Guzzo G, Cachat F, et al. Eculizumab as a new treatment for severe acute post-infectious glomerulonephritis: two case reports. Front Med 2021; doi:10.3389/fmed.2021.663258
- Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609. doi:10.1056/NEJMoa2023386
- Lafayette RA, Rovin BH, Reich HN, Tumlin JA, Floege J, Barratt J. Safety, tolerability, and efficacy of narsoplimab, a novel MASP-2 inhibitor for the treatment of IgA nephropathy. Kidney Int Rep 2020;5:2032-2041. doi:10.1016/j.ekir.2020.08.003
- Barratt J, Rovin B, Zhang H, et al. Efficacy and safety of iptacopan in IgA nephropathy: results of a randomized double-blind placebo-controlled phase 2 study at 6 months. Kidney Int Rep 2022;7:S1-S436. doi:10.1016/j.ekir.2022.01.577
- Parikh SV, Malvar A, Song H, et al. Molecular profiling of kidney compartments from serial biopsies differentiate treatment responders from non-responders in lupus nephritis. Kidney Int 2022;102:845-865. 10.1016/j.kint.2022.05.033
Disclosures
Dr. Medjeral-Thomas reports consultant fees from Noavartis and research funding from Omeros.
Dr. Rovin reports consultant fees and honoraria from Alexion, AstraZeneca, Aurinia, Biocryst, Biogen, BMS, Calliditas, Chemocentryx, Corrona, EMD-Serono/Merck, Exagen, Galapagos, Genentech, Horizon, Human Genome Sciences (GSK), Idorsia, Janssen, MedImmune, Morphosys, Novartis, Omeros, Otsuka, Resonance, Retrophin, RILITE Foundation, Roche, and Vistera; and research funding from Biogen.
Link to summary of session: https://www.asn-online.org/education/kidneyweek/2022/program-session-details.aspx?sessId=440375