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Progress in mechanism and targeted therapy of immune kidney disease mediated by complement
Received date: 2025-08-13
Online published: 2026-03-09
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are well-recognized complement-mediated kidney diseases. In recent years, an increasing body of evidence has demonstrated that the complement system plays a pivotal role in the pathogenesis of various immune-mediated kidney diseases, such as IgA nephropathy, membranous nephropathy (MN), lupus nephritis (LN), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and anti-glomerular basement membrane disease (anti-GBM disease). Although current immunosuppressive therapies and corticosteroids can partly control disease progression, these agents are frequently associated with severe adverse effects, and a portion of patients show suboptimal therapeutic responses. Therefore, the development of novel therapeutic strategies is an urgent necessity. Complement-targeted therapies have emerged as a research focus, providing new avenues for the treatment of immune-mediated kidney diseases. This review summarizes recent advancements in this field.
Jianmei YU , Weichun HE . Progress in mechanism and targeted therapy of immune kidney disease mediated by complement[J]. The Journal of Practical Medicine, 2026 , 42(5) : 899 -908 . DOI: 10.3969/j.issn.1006-5725.2026.05.023
| [1] | BARRATT J, LAFAYETTE R A, ZHANG H, et al. IgA nephropathy: The lectin pathway and implications for targeted therapy[J]. Kidney Int, 2023, 104(2): 254-264. doi:10.1016/j.kint.2023.04.029 . |
| [2] | NESTER C M, BARBOUR T, DE CORDOBA S R, et al. Atypical aHUS: State of the art[J]. Mol Immunol, 2015, 67(1): 31-42. doi:10.1016/j.molimm.2015.03.246 . |
| [3] | FAKHOURI F, ZUBER J, FRéMEAUX-BACCHI V, et al. Haemolytic uraemic syndrome[J]. Lancet, 2017, 390(10095): 681-696. doi:10.1016/S0140-6736(17)30062-4 . |
| [4] | BROCKLEBANK V, KUMAR G, HOWIE A J, et al. Long-term outcomes and response to treatment in diacylglycerol kinase Epsilon nephropathy[J]. Kidney Int, 2020, 97(6): 1260-1274. doi:10.1016/j.kint.2020.01.045 . |
| [5] | CORDERO L, CAVERO T, GUTIéRREZ E, et al. Rational use of eculizumab in secondary atypical hemolytic uremic syndrome[J]. Front Immunol, 2024, 14: 1310469. doi:10.3389/fimmu. 2023.1310469 . |
| [6] | NORIS M, REMUZZI G. C3G and ig-MPGN-treatment standard[J]. Nephrol Dial Transplant, 2024, 39(2): 202-214. doi:10.1093/ndt/gfad182 . |
| [7] | NORIS M, DAINA E, REMUZZI G. Membranoproliferative glomerulonephritis: No longer the same disease and may need very different treatment[J]. Nephrol Dial Transplant, 2023, 38(2): 283-290. doi:10.1093/ndt/gfab281 . |
| [8] | ZHANG Y, MEYER N C, FERVENZA F C, et al. C4 nephritic factors in C3 glomerulopathy: A case series[J]. Am J Kidney Dis, 2017, 70(6): 834-843. doi:10.1053/j.ajkd.2017.07.004 . |
| [9] | ROVIN B H, ADLER S G, BARRATT J, et al. Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases[J]. Kidney Int, 2021, 100(4): 753-779. doi:10.1016/j.kint.2021.05.015 . |
| [10] | NESTER C M, BOMBACK A S, ARICETA G, et al. VALIANT: Randomized, multicenter, double-blind, placebo-controlled, phase 3 trial of pegcetacoplan for patients with native or post-transplant recurrent C3G or primary (idiopathic) IC-MPGN[J]. Immunobiology, 2025, 230(4): 153039. doi:10.1016/j.imbio.2025.153039 . |
| [11] | SUZUKI H, KIRYLUK K, NOVAK J, et al. The pathophysiology of IgA nephropathy[J]. J Am Soc Nephrol, 2011, 22(10): 1795-1803. doi:10.1681/ASN.2011050464 . |
| [12] | 郑笑, 张艳君, 杨淑芬, 等. 补体因子H和补体因子H相关蛋白1、2、3和5与IgA肾病的关联性[J]. 实用医学杂志, 2018, 34(22): 3727-3730. doi:10.3969/j.issn.1006-5725.2018.22.015 . |
| [13] | CHEN P, YU G, ZHANG X, et al. Plasma galactose-deficient IgA1 and C3 and CKD progression in IgA nephropathy[J]. Clin J Am Soc Nephrol, 2019, 14(10): 1458-1465. doi:10.2215/CJN.13711118 . |
| [14] | TORTAJADA A, GUTIéRREZ E, GOICOECHEA DE J, et al. Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy[J]. Kidney Int, 2017, 92(4): 953-963. doi:10.1016/j.kint.2017.03.041 . |
| [15] | ZHU L, GUO W Y, SHI S F, et al. Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy[J]. Kidney Int, 2018, 94(1): 150-158. doi:10.1016/j.kint.2018.02.023 . |
| [16] | CHIU Y L, LIN W C, SHU K H, et al. Alternative complement pathway is activated and associated with galactose-deficient IgA(1) antibody in IgA nephropathy patients[J]. Front Immunol, 2021, 12: 638309. doi:10.3389/fimmu.2021.638309 . |
| [17] | MEDJERAL-THOMAS N R, TROLDBORG A, CONSTANTINOU N, et al. Progressive IgA nephropathy is associated with low circulating mannan-binding lectin-associated serine protease-3 (MASP-3) and increased glomerular factor H-related protein-5 (FHR5) deposition[J]. Kidney Int Rep, 2017, 3(2): 426-438. doi:10.1016/j.ekir.2017.11.015 . |
| [18] | YANG X, YUAN Y, SHAO X, et al. C4d as a screening tool and an independent predictor of clinical outcomes in lupus nephritis and IgA nephropathy[J]. Front Med, 2022, 9: 832998. doi:10.3389/fmed.2022.832998 . |
| [19] | ITAMI H, HARA S, SAMEJIMA K, et al. Complement activation is associated with crescent formation in IgA nephropathy[J]. Virchows Arch, 2020, 477(4): 565-572. doi:10.1007/s00428-020-02800-0 . |
| [20] | MEDJERAL-THOMAS N R, COOK H T, PICKERING M C. Complement activation in IgA nephropathy[J]. Semin Immunopathol, 2021, 43(5): 679-690. doi:10.1007/s00281-021-00882-9 . |
| [21] | PERKOVIC V, BARRATT J, ROVIN B, et al. Alternative complement pathway inhibition with iptacopan in IgA nephropathy[J]. N Engl J Med, 2025, 392(6): 531-543. doi:10.1056/NEJMoa2410316 . |
| [22] | BRUCHFELD A, MAGIN H, NACHMAN P, et al. C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study[J]. Clin Kidney J, 2022, 15(5): 922-928. doi:10.1093/ckj/sfab294 . |
| [23] | TOMAS N M, BECK L H Jr, MEYER-SCHWESINGER C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy[J]. N Engl J Med, 2014, 371(24): 2277-2287. doi:10.1056/NEJMoa1409354 . |
| [24] | CHINELLO C, DE HAAN N, CAPITOLI G, et al. Definition of IgG subclass-specific glycopatterns in idiopathic membranous nephropathy: Aberrant IgG glycoforms in blood[J]. Int J Mol Sci, 2022, 23(9): 4664. doi:10.3390/ijms23094664 . |
| [25] | DE VRIESE A S, GLASSOCK R J, NATH K A, et al. A proposal for a serology-based approach to membranous nephropathy[J]. J Am Soc Nephrol, 2017, 28(2): 421-430. doi:10.1681/ASN.2016070776 . |
| [26] | ZHANG M F, CUI Z, ZHANG Y M, et al. Clinical and prognostic significance of glomerular C1q deposits in primary MN[J]. Clin Chim Acta, 2018, 485: 152-157. doi:10.1016/j.cca. 2018. 06.050 . |
| [27] | RAVINDRAN A, MADDEN B, CHARLESWORTH M C, et al. Proteomic analysis of complement proteins in membranous nephropathy[J]. Kidney Int Rep, 2020, 5(5): 618-626. doi:10.1016/j.ekir.2020.01.018 . |
| [28] | DRACHENBERG C B, PAPADIMITRIOU J C, CHANDRA P, et al. Epidemiology and pathophysiology of glomerular C4d staining in native kidney biopsies[J]. Kidney Int Rep, 2019, 4(11): 1555-1567. doi:10.1016/j.ekir.2019.07.015 . |
| [29] | HADDAD G, LORENZEN J M, MA H, et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy[J]. J Clin Invest, 2021, 131(5): e140453. doi:10.1172/JCI140453 . |
| [30] | SEIFERT L, ZAHNER G, MEYER-SCHWESINGER C, et al. The classical pathway triggers pathogenic complement activation in membranous nephropathy[J]. Nat Commun, 2023, 14(1): 473. doi:10.1038/s41467-023-36068-0 . |
| [31] | KISTLER A D, SALANT D J. Complement activation and effector pathways in membranous nephropathy[J]. Kidney Int, 2024, 105(3): 473-483. doi:10.1016/j.kint.2023.10.035 . |
| [32] | REKVIG O P. The dsDNA, anti-dsDNA antibody, and lupus nephritis: What we agree on, what must be done, and what the best strategy forward could be[J]. Front Immunol, 2019, 10: 1104. doi:10.3389/fimmu.2019.01104 . |
| [33] | AYANO M, HORIUCHI T. Complement as a biomarker for systemic lupus erythematosus[J]. Biomolecules, 2023, 13(2): 367. doi:10.3390/biom13020367 . |
| [34] | GRUMACH A S, KIRSCHFINK M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach[J]. Mol Immunol, 2014, 61(2): 110-117. doi:10.1016/j.molimm.2014.06.030 . |
| [35] | TANHA N, TROELSEN L, FROM HERMANSEN M L, et al. MBL2 gene variants coding for mannose-binding lectin deficiency are associated with increased risk of nephritis in Danish patients with systemic lupus erythematosus[J]. Lupus, 2014, 23(11): 1105-1111. doi:10.1177/0961203314536478 . |
| [36] | MAHTO H, PATI A, SAHU S K, et al. Association of MBL-2 gene polymorphisms with systemic lupus erythematosus: An updated meta-analysis and trial sequential analysis[J]. Lupus, 2020, 29(10): 1227-1237. doi:10.1177/0961203320939156 . |
| [37] | PERAZZIO S F, SILVA N P DA, CARNEIRO-SAMPAIO M, et al. Mild and moderate Mannose Binding Lectin deficiency are associated with systemic lupus erythematosus and lupus nephritis in Brazilian patients[J]. Rev Bras Reumatol Engl Ed, 2016, 56(3): 220-227. doi:10.1016/j.rbre.2016.01.002 . |
| [38] | MACEDO A C L, ISAAC L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway[J]. Front Immunol, 2016, 7: 55. doi:10.3389/fimmu. 2016. 00055 . |
| [39] | WU E Y, MCINNIS E A, BOYER-SUAVET S, et al. Measuring circulating complement activation products in myeloperoxidase- and proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis[J]. Arthritis Rheumatol, 2019, 71(11): 1894-1903. doi:10.1002/art.41011 . |
| [40] | XIAO H, SCHREIBER A, HEERINGA P, et al. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies[J]. Am J Pathol, 2007, 170(1): 52-64. doi:10.2353/ajpath.2007.060573 . |
| [41] | XIAO H, DAIRAGHI D J, POWERS J P, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN[J]. J Am Soc Nephrol, 2014, 25(2): 225-231. doi:10.1681/ASN. 2013020143 . |
| [42] | MAZZARIOL M, MANENTI L, VAGLIO A. The complement system in antineutrophil cytoplasmic antibody-associated vasculitis: Pathogenic player and therapeutic target[J]. Curr Opin Rheumatol, 2023, 35(1): 31-36. doi:10.1097/BOR. 0000000000000914 . |
| [43] | KAMBAS K, CHRYSANTHOPOULOU A, VASSILOPOULOS D, et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease[J]. Ann Rheum Dis, 2014, 73(10): 1854-1863. doi:10.1136/annrheumdis-2013-203430 . |
| [44] | EKDAHL K N, TERAMURA Y, HAMAD O A, et al. Dangerous liaisons: Complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation[J]. Immunol Rev, 2016, 274(1): 245-269. doi:10.1111/imr.12471 . |
| [45] | MERKEL P A, NILES J, JIMENEZ R, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis[J]. ACR Open Rheumatol, 2020, 2(11): 662-671. doi:10.1002/acr2.11185 . |
| [46] | KUANG H, LIU J, JIA X Y, et al. Autoimmunity in anti-glomerular basement membrane disease: A review of mechanisms and prospects for immunotherapy[J]. Am J Kidney Dis, 2023, 81(1): 90-99. doi:10.1053/j.ajkd.2022.07.006 . |
| [47] | MA R, CUI Z, LIAO Y H, et al. Complement activation contributes to the injury and outcome of kidney in human anti-glomerular basement membrane disease[J]. J Clin Immunol, 2013, 33(1): 172-178. doi:10.1007/s10875-012-9772-2 . |
| [48] | OHLSSON S, HERLITZ H, LUNDBERG S, et al. Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease[J]. Am J Kidney Dis, 2014, 63(2): 289-293. doi:10.1053/j.ajkd. 2013. 08.032 . |
| [49] | ZHU M, WANG J, LE W, et al. Relationship between serum complement C3 levels and outcomes among patients with anti-GBM disease[J]. Front Immunol, 2022, 13: 929155. doi:10.3389/fimmu.2022.929155 . |
| [50] | MA R, CUI Z, HU S Y, et al. The alternative pathway of complement activation may be involved in the renal damage of human anti-glomerular basement membrane disease[J]. PLoS One, 2014, 9(3): e91250. doi:10.1371/journal.pone.0091250 . |
| [51] | EKDAHL K N, SOVERI I, HILBORN J, et al. Cardiovascular disease in haemodialysis: Role of the intravascular innate immune system[J]. Nat Rev Nephrol, 2017, 13(5): 285-296. doi:10.1038/nrneph.2017.17 . |
| [52] | NITHAGON P, CORTAZAR F, SHAH S I, et al. Eculizumab and complement activation in anti-glomerular basement membrane disease[J]. Kidney Int Rep, 2021, 6(10): 2713-2717. doi:10.1016/j.ekir.2021.07.001 . |
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