Complement in IgA Nephropathy: The Role of Complement in the Pathogenesis, Diagnosis, and Future Management of IgA Nephropathy

Immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of chronic and end-stage kidney disease. IgAN pathogenesis is incompletely understood. In particular, we cannot adequately explain the heterogeneity in clinical and histologic features and severities that characterizes IgAN. This limits patient stratification to appropriate and effective treatments and the development of disease-targeted therapies. Studies of the role of the alternative, lectin, and terminal complement pathways in IgAN have enhanced our understanding of disease pathogenesis and inform the development of novel diagnostic and therapeutic strategies. For example, recent genetic, serologic, and immunohistologic evidence suggests that imbalances between the main alternative complement pathway regulator protein (factor H) and competitor proteins that deregulate complement activity (factor H–related proteins 1 and 5, FHR1, and FHR5) associate with IgAN severity: a relative abundance of FHR1 and FHR5 amplifies complement-dependent inflammation and exacerbates kidney injury. Ongoing characterization of the mechanisms by which complement activity contributes to IgAN pathogenesis will facilitate the development of complement-based diagnostic techniques, biomarkers of disease activity and severity, and novel targeted therapies. Immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of chronic and end-stage kidney disease. IgAN pathogenesis is incompletely understood. In particular, we cannot adequately explain the heterogeneity in clinical and histologic features and severities that characterizes IgAN. This limits patient stratification to appropriate and effective treatments and the development of disease-targeted therapies. Studies of the role of the alternative, lectin, and terminal complement pathways in IgAN have enhanced our understanding of disease pathogenesis and inform the development of novel diagnostic and therapeutic strategies. For example, recent genetic, serologic, and immunohistologic evidence suggests that imbalances between the main alternative complement pathway regulator protein (factor H) and competitor proteins that deregulate complement activity (factor H–related proteins 1 and 5, FHR1, and FHR5) associate with IgAN severity: a relative abundance of FHR1 and FHR5 amplifies complement-dependent inflammation and exacerbates kidney injury. Ongoing characterization of the mechanisms by which complement activity contributes to IgAN pathogenesis will facilitate the development of complement-based diagnostic techniques, biomarkers of disease activity and severity, and novel targeted therapies. Clinical Summary•Recent evidence identifies the alternative, lectin, and terminal pathways of complement as key drivers of kidney injury in immunoglobulin A (IgA) nephropathy.•Genetic, serologic, and histologic evidence associates imbalances of complement regulation and activation with markers of IgA nephropathy severity.•Complement pathway proteins could be important diagnostic biomarkers and novel therapeutic targets for IgA nephropathy in the future. •Recent evidence identifies the alternative, lectin, and terminal pathways of complement as key drivers of kidney injury in immunoglobulin A (IgA) nephropathy.•Genetic, serologic, and histologic evidence associates imbalances of complement regulation and activation with markers of IgA nephropathy severity.•Complement pathway proteins could be important diagnostic biomarkers and novel therapeutic targets for IgA nephropathy in the future. Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerular disease defined by dominant or codominant glomerular IgA deposition.1Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (763) Google Scholar The pathogenesis of IgAN is incompletely understood. Glomerular IgA deposition can be incidentally detected by kidney biopsy in up to 16% of kidney transplant donors or deceased persons lacking clinical or histologic evidence of disease.2Waldherr R. Rambausek M. Duncker W.D. Ritz E. Frequency of mesangial IgA deposits in a non-selected autopsy series.Nephrol Dial Transpl. 1989; 4: 943-946Crossref PubMed Scopus (105) Google Scholar,3Suzuki K. Honda K. Tanabe K. Toma H. Nihei H. Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan.Kidney Int. 2003; 63: 2286-2294Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Even among patients with clinically evident disease, IgAN encompasses a wide spectrum of clinical manifestation that includes isolated microscopic hematuria, synpharyngitic macroscopic hematuria, nephrotic syndrome, acute kidney injury, and established CKD.4D'Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome.Semin Nephrol. 2004; 24: 179-196Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar IgAN prognosis is also highly variable: up to 10% of patients will present with rapidly progressive glomerulonephritis, 30-40% will progress slowly through CKD, 5-15% will spontaneously remit, and the remaining 40% will show persistent benign features such as isolated microscopic hematuria.5Jarrick S. Lundberg S. Welander A. et al.Mortality in IgA nephropathy: a nationwide population-based cohort study.J Am Soc Nephrol. 2019; 30: 866-876Crossref PubMed Scopus (38) Google Scholar Substantial demographic variability also exists: IgAN is most common in East Asia, where men and women are affected with equal frequency, occurs with intermediate frequency in Caucasians, where men are more frequently affected than women, and occurs rarely in Africa or in African-Americans living in the United States. Disease severity also differs by race/ethnicity, for example, in Canada, disease is more severe in patients of Asian ancestry compared with non-Asian patients residing in similar localities.6Barbour S.J. Cattran D.C. Kim S.J. et al.Individuals of Pacific Asian origin with IgA nephropathy have an increased risk of progression to end-stage renal disease.Kidney Int. 2013; 84: 1017-1024Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Consistent with this clinical heterogeneity, IgAN encompasses a spectrum of histology findings, ranging from isolated ultrastructural glomerular deposits to crescentic glomerulonephritis. The Oxford Classification of IgAN describes histology features that are reliably identifiable and independently predictive of clinical outcomes.7Working Group of the International IgA Nephropathy Network and the Renal Pathology Society Cattran D.C. Coppo R. et al.The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar Markers of both active glomerular inflammation and chronic kidney injury8Haas M. Verhave J.C. Liu Z.H. et al.A multicenter study of the predictive value of crescents in IgA nephropathy.J Am Soc Nephrol. 2017; 28: 691-701Crossref PubMed Scopus (167) Google Scholar are included, and the original classification system has been validated in large replication cohorts.9Coppo R. Troyanov S. Bellur S. et al.Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments.Kidney Int. 2014; 86: 828-836Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar However, individual components of the Oxford classification are not specific to IgAN, and, accordingly, do not reveal IgAN pathogenesis or trigger kidney injury. Our incomplete understanding of underlying reasons for the histologic and clinical heterogeneity that characterizes IgAN limits the development of pathogenesis-targeted therapies and the stratification of patients to treatments that are most likely to be effective. However, an emerging appreciation for the role of the complement system in the development and progression of IgAN might help fill this knowledge and treatment gap and is the subject of this review. The recurrence of IgAN in healthy kidney transplants given to recipients with IgAN, and the spontaneous clearance of IgA deposits from kidneys with IgAN inadvertently given to recipients without IgAN, indicate that disease pathogenesis is dependent on circulating factors.10Berger J. Yaneva H. Nabarra B. Barbanel C. Recurrence of mesangial deposition of IgA after renal transplantation.Kidney Int. 1975; 7: 232-241Abstract Full Text PDF PubMed Scopus (211) Google Scholar,11Silva F.G. Chander P. Pirani C.L. Hardy M.A. Disappearance of glomerular mesangial IgA deposits after renal allograft transplantation.Transplantation. 1982; 33: 241-246PubMed Google Scholar Prevailing theories of IgAN pathogenesis focus on the nature and quantity of circulating IgA and IgA-containing immune complexes (ICs). The leading disease model involves a four-step process.12Yeo S.C. Cheung C.K. Barratt J. New insights into the pathogenesis of IgA nephropathy.Pediatr Nephrol. 2018; 33: 763-777Crossref PubMed Scopus (69) Google Scholar The first 'hit' is increased levels of circulating galactose-deficient IgA subclass 1 (gd-IgA1). Humans synthesize two IgA subclasses, with distinct hinge regions: the IgA1 hinge region contains an amino acid motif with numerous O-linked glycans. IgA1 with O-linked glycans deficient in galactose (gd-IgA1) are found at higher circulating levels in IgAN patients compared with ethnically matched healthy controls. IgA1 eluted from IgAN glomeruli shows abnormal O-glycosylation, demonstrating gd-IgA1 in glomerular deposits.13Allen A.C. Bailey E.M. Brenchley P.E. Buck K.S. Barratt J. Feehally J. Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients.Kidney Int. 2001; 60: 969-973Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar Also, higher gd-IgA1 levels correlate with markers of disease progression,14Gale D.P. Molyneux K. Wimbury D. et al.Galactosylation of IgA1 is associated with common variation in C1GALT1.J Am Soc Nephrol. 2017; 28: 2158-2166Crossref PubMed Scopus (67) Google Scholar supporting their pathogenicity. IgA1 can be found in monomeric and polymeric forms.15Robert T. Berthelot L. Cambier A. Rondeau E. Monteiro R.C. Molecular insights into the pathogenesis of IgA nephropathy.Trends Mol Med. 2015; 21: 762-775Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Whereas monomeric IgA is the dominant circulating form, polymeric IgA is normally predominantly found in external secretions. However, patients with IgAN demonstrate higher proportions of polymeric IgA in circulation compared with healthy controls.16Hiki Y. Odani H. Takahashi M. et al.Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy.Kidney Int. 2001; 59: 1077-1085Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 17Coppo R. Amore A. Aberrant glycosylation in IgA nephropathy (IgAN).Kidney Int. 2004; 65: 1544-1547Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 18Moldoveanu Z. Wyatt R.J. Lee J.Y. et al.Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels.Kidney Int. 2007; 71: 1148-1154Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar Abnormal innate immune responses to mucosal infections or antigens might contribute to these findings. The second hit involves the production of autoantibodies to gd-IgA1. These autoantibodies are often characterized by an amino acid substitution that increases antibody affinity for O-linked glycans, particularly exposed N-acetylgalactosamine (GalNac).19Suzuki H. Fan R. Zhang Z. et al.Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity.J Clin Invest. 2009; 119: 1668-1677PubMed Google Scholar Autoantibody generation might result from prior immune responses to viruses or bacteria also expressing GalNac.1Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (763) Google Scholar Serum anti–gd-IgA1 IgG levels correlate with proteinuria severity, supporting pathogenicity.20Berthoux F. Suzuki H. Thibaudin L. et al.Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy.J Am Soc Nephrol. 2012; 23: 1579-1587Crossref PubMed Scopus (180) Google Scholar The third hit is the development of circulating ICs containing gd-IgA1 and IgG or IgA autoantibodies against gd-IgA1 (gd-IgA1-ICs). The identification of glomerular IgG in IgAN correlates with mesangial and endocapillary proliferation21Bellur S.S. Troyanov S. Cook H.T. Roberts I.S. Working Group of International IgA Nephropathy Network and Renal Pathology Society Immunostaining findings in IgA nephropathy: correlation with histology and clinical outcome in the Oxford classification patient cohort.Nephrol Dial Transpl. 2011; 26: 2533-2536Crossref PubMed Scopus (87) Google Scholar and IgG colocalizes with IgA by confocal microscopy.22Rizk D.V. Saha M.K. Hall S. et al.Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1.J Am Soc Nephrol. 2019; 30: 2017-2026Crossref PubMed Scopus (48) Google Scholar Furthermore, even when not identified by routine immunofluorescence, IgG that is immune reactive with gd-IgA1 can be extracted from frozen IgAN kidney biopsy tissue, confirming the universality and presumed importance of glomerular anti–gd-IgA1 IgG in IgAN.22Rizk D.V. Saha M.K. Hall S. et al.Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1.J Am Soc Nephrol. 2019; 30: 2017-2026Crossref PubMed Scopus (48) Google Scholar These data suggest that gd-IgA1-ICs deposit in glomeruli and trigger inflammation.12Yeo S.C. Cheung C.K. Barratt J. New insights into the pathogenesis of IgA nephropathy.Pediatr Nephrol. 2018; 33: 763-777Crossref PubMed Scopus (69) Google Scholar Finally, the fourth hit involves mesangial cell proliferation, glomerular inflammation, and injury. This step likely encompasses a number of pathogenic processes including, but not limited to, interactions between gd-IgA1-ICs and mesangial cells, mesangial cell activation, extracellular matrix expansion, cytokine release, podocyte cross-talk, inflammatory cell infiltration, glomerular inflammation, and glomerulosclerosis: the complement system has recently been shown to play a key role in activating or modifying many of these responses.23Rizk D.V. Maillard N. Julian B.A. et al.The emerging role of complement proteins as a target for Therapy of IgA nephropathy.Front Immunol. 2019; 10: 504Crossref PubMed Scopus (65) Google Scholar The four-hit IgAN pathogenesis model addresses a number of important disease associations and observations. However, it incompletely explains key elements of IgAN natural history. In particular, why do patients with similar quantities of glomerular IgA deposition exhibit such wide variability in histologic and clinical features? What determines gd-IgA1-IC immunogenicity and pathogenicity? How can we better identify patients at highest risk for severe disease manifestations and more rapid progression? Emerging understanding of the role of the complement system in IgAN pathogenesis might help answer some of these questions. Evidence of complement system activity was noted in patients with IgAN many decades ago.24Berger J. IgA glomerular deposits in renal disease.Transpl Proc. 1969; 1: 939-944PubMed Google Scholar,25Tortajada A. Gutierrez E. Pickering M.C. Praga Terente M. Medjeral-Thomas N. The role of complement in IgA nephropathy.Mol Immunol. 2019; 114: 123-132Crossref PubMed Scopus (46) Google Scholar However, its contribution to IgAN pathogenesis was poorly understood. More recent studies of the role of the alternative, lectin, and terminal complement pathways in IgAN have enhanced our understanding of IgAN pathogenesis and inform the development of novel diagnostic and therapeutic strategies.23Rizk D.V. Maillard N. Julian B.A. et al.The emerging role of complement proteins as a target for Therapy of IgA nephropathy.Front Immunol. 2019; 10: 504Crossref PubMed Scopus (65) Google Scholar,25Tortajada A. Gutierrez E. Pickering M.C. Praga Terente M. Medjeral-Thomas N. The role of complement in IgA nephropathy.Mol Immunol. 2019; 114: 123-132Crossref PubMed Scopus (46) Google Scholar The complement system is an important component of innate and adaptive immunity. It comprises a potent network of activating and regulating proteins that discriminate healthy, damaged, and nonself surfaces.26Ricklin D. Hajishengallis G. Yang K. Lambris J.D. Complement: a key system for immune surveillance and homeostasis.Nat Immunol. 2010; 11: 785-797Crossref PubMed Scopus (2480) Google Scholar Traditionally, the complement system is considered to have three activating arms: the classical, lectin, and alternative pathways. Once activated, each pathway culminates in C3 cleavage to the anaphylatoxin C3a and activated fragment C3b and, in the absence of regulation, C3 amplification. The mechanisms of C3 amplification are common to all three pathways but are critically dependent on the alternative pathway. Unregulated C3 amplification cascades to terminal pathway activation, including release of the anaphylatoxin C5a and formation of the membrane attack complex (C5b9).27Walport M.J. Complement. First of two parts.N Engl J Med. 2001; 344: 1058-1066Crossref PubMed Scopus (2400) Google Scholar Inappropriate complement activation and/or inadequate complement regulation leads to inflammation and injury. The classical pathway is activated by the binding of the C1 complex to ICs of IgM and IgG.28Merle N.S. Church S.E. Fremeaux-Bacchi V. Roumenina L.T. Complement system Part I - Molecular mechanisms of activation and regulation.Front Immunol. 2015; 6: 262Crossref PubMed Scopus (848) Google Scholar C1q is rarely detectable in IgAN, indicating classical pathway activation does not contribute significantly to IgAN pathogenesis.29Rauterberg E.W. Lieberknecht H.M. Wingen A.M. Ritz E. Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis.Kidney Int. 1987; 31: 820-829Abstract Full Text PDF PubMed Scopus (126) Google Scholar The lectin pathway is triggered by an interaction between lectin pathway pattern recognition molecules and carbohydrate arrays on surfaces such as bacterial cell walls. Lectin pattern recognition molecules include mannan-binding lectin (MBL), ficolins, and collectins, which circulate in complexes with MBL-associated serine proteases (MASPs), MASP-1, MASP-2 and MASP-3.30Axelgaard E. Jensen L. Dyrlund T.F. et al.Investigations on collectin liver 1.J Biol Chem. 2013; 288: 23407-23420Crossref PubMed Scopus (58) Google Scholar, 31Ma Y.J. Skjoedt M.O. Garred P. Collectin-11/MASP complex formation triggers activation of the lectin complement pathway--the fifth lectin pathway initiation complex.J Innate Immun. 2013; 5: 242-250Crossref PubMed Scopus (94) Google Scholar, 32Matsushita M. Endo Y. Fujita T. Cutting edge: complement-activating complex of ficolin and mannose-binding lectin-associated serine protease.J Immunol. 2000; 164: 2281-2284Crossref PubMed Scopus (272) Google Scholar, 33Matsushita M. Kuraya M. Hamasaki N. Tsujimura M. Shiraki H. Fujita T. Activation of the lectin complement pathway by H-ficolin (Hakata antigen).J Immunol. 2002; 168: 3502-3506Crossref PubMed Scopus (170) Google Scholar, 34Liu Y. Endo Y. Iwaki D. et al.Human M-ficolin is a secretory protein that activates the lectin complement pathway.J Immunol. 2005; 175: 3150-3156Crossref PubMed Scopus (208) Google Scholar Lectin pathway activation leads to the formation of a C4-containing C3 convertase (which is the same as the classical pathway C3 convertase). However, because C1q is not a component of this pathway, lectin pathway activation is distinguished from classic pathway activation by the presence of C4d in the absence of C1q. The alternative complement pathway has two important roles. First, through continuous tick-over activation, it can rapidly trigger complement activity in the absence of ICs and nonself carbohydrate residues. Alternative pathway activation leads to the formation of a C3-containing C3 convertase. This alternative pathway C3 convertase also amplifies C3 activity regardless of the initiating pathway, which is the second role of the alternative pathway. Consequently, the alternative pathway is responsible for 80% of complement activation.27Walport M.J. Complement. First of two parts.N Engl J Med. 2001; 344: 1058-1066Crossref PubMed Scopus (2400) Google Scholar Alternative pathway activity is evidenced by low circulating C3 and immunohistologic C3 deposition. If C3 deposition is identified without significant C1q, C4d, or immunoglobulin, as seen in C3 glomerulopathy, disease pathogenesis is thought to involve dysregulated alternative pathway activity.35Barbour T.D. Pickering M.C. Cook H.T. Recent insights into C3 glomerulopathy.Nephrol Dial Transpl. 2013; 28: 1685-1693Crossref PubMed Scopus (68) Google Scholar Other alternative pathway proteins including properdin and C3 fragments such as C3dg can be detected as further evidence of alternative pathway activity. C3 amplification leads to the formation of C5 convertase, which cleave C5 to the anaphylatoxin C5a and the active fragment C5b. Through the terminal pathway, C5b forms C5b9. Accordingly, although complement effector mechanisms of C5b9 deposition, anaphylatoxin release, and inflammatory cell infiltration can initially be triggered by either the classical, lectin, or alternative pathway, the process must also involve alternative pathway–dependent C3 amplification. Tight regulation of the alternative complement pathway is paramount to homeostasis and health. Complement factor H (FH) is an essential regulator of alternative pathway activation and amplification. The FH-related (FHR) proteins are structurally similar to FH but lack the complement regulatory FH region.36Jozsi M. Tortajada A. Uzonyi B. Goicoechea de Jorge E. Rodriguez de Cordoba S. Factor H-related proteins determine complement-activating surfaces.Trends Immunol. 2015; 36: 374-384Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar By interacting with similar ligands, such as C3b and glycosaminoglycans, members of the FHR family can competitively attenuate FH-dependent complement regulation, shifting the balance between complement activation and regulation.37Medjeral-Thomas N. Pickering M.C. The complement factor H-related proteins.Immunol Rev. 2016; 274: 191-201Crossref PubMed Scopus (50) Google Scholar Accordingly, FHR protein variants can alter susceptibility to complement-mediated injury. The earliest descriptions of IgAN identified C3 with mesangial IgA in more than 90% of cases.24Berger J. IgA glomerular deposits in renal disease.Transpl Proc. 1969; 1: 939-944PubMed Google Scholar The extent of mesangial codeposition of C3 correlates with IgAN severity and progression, suggesting that alternative pathway activity contributes to glomerular injury.38Maillard N. Wyatt R.J. Julian B.A. et al.Current understanding of the role of complement in IgA nephropathy.J Am Soc Nephrol. 2015; 26: 1503-1512Crossref PubMed Scopus (186) Google Scholar,39Kim S.J. Koo H.M. Lim B.J. et al.Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy.PLoS One. 2012; 7: e40495Crossref PubMed Scopus (98) Google Scholar Other alternative pathway proteins have also been identified in biopsy specimens of patients with IgAN, including properdin (75-100% of biopsies), FH (30-90%) and two FHR proteins, FHR protein (FHR)1 and FHR5.38Maillard N. Wyatt R.J. 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Liu G. et al.Levels of urinary complement factor H in patients with IgA nephropathy are closely associated with disease activity.Scand J Immunol. 2009; 69: 457-464Crossref PubMed Scopus (39) Google Scholar Glomerular FHR5 deposition was present in all IgAN cases from a series of glomerular diseases and was found in mesangial locations similar to IgA and C3.40Murphy B. Georgiou T. Machet D. Hill P. McRae J. Factor H-related protein-5: a novel component of human glomerular immune deposits.Am J Kidney Dis. 2002; 39: 24-27Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Recently, glomerular FHR5 deposition has been associated with IgAN progression and correlated with deposition of the C3 fragments C3b/iC3b/C3c (the antibody cannot differentiate these fragments) and C3dg as well as C5b9 and negative glomerular FH staining.44Medjeral-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.Kidney Int Rep. 2018; 3: 426-438Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar These findings suggest FH competition occurs at the site of kidney injury, with resulting augmented complement activation. Unlike FHR5, no correlation was found between FHR1 glomerular staining intensity and IgAN severity.44Medjeral-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.Kidney Int Rep. 2018; 3: 426-438Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar These data identify FHR5 as an important and independent contributor to alternative pathway dysregulation in IgAN. Glomerular C4d and absent C1q, indicative of lectin pathway activation,29Rauterberg E.W. Lieberknecht H.M. Wingen A.M. Ritz E. Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis.Kidney Int. 1987; 31: 820-829Abstract Full Text PDF PubMed Scopus (126) Google Scholar was identified in 39% of 283 IgAN patients from Spain and was a significant predictor of end-stage kidney disease (ESKD) after multivariate analysis.45Espinosa M. Ortega R. Sanchez M. et al.Association of C4d deposition with clinical outcomes in IgA nephropathy.Clin J Am Soc Nephrol. 2014; 9: 897-904Crossref PubMed Scopus (133) Google Scholar Glomerular deposition of specific lectin pathway proteins also associates with IgAN severity. Endo and colleagues detected MBL and MASP-1 in 24% of kidney biopsies in patients with IgAN compared with just 3% in patients with other glomerulopathies.46Endo M. Ohi H. Ohsawa I. Fujita T. Matsushita M. Fujita T. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.Nephrol Dial Transpl. 1998; 13: 1984-1990Crossref PubMed Scopus (166) Google Scholar Deposition of MBL/MASP-1 was associated with deposition of other glomerular alternative and terminal pathway markers, suggesting lectin pathway activation triggers alternative pathway–dependent amplification and cascades to terminal pathway activity. Roos and colleagues similarly demonstrated glomerular MBL, L-ficolin, MASP1/3, and C4d deposition in 25% of a cohort of 60 patients with IgAN, which associated with proteinuria, serum creatinine, and kidney failure.47Roos A. Rastaldi M.P. Calvaresi N. et al.Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease.J Am Soc Nephrol. 2006; 17: 1724-1734Crossref PubMed Scopus (312) Google Scholar Terminal complement pathway activation, as evidenced by glomerular C5b9 deposition, was first identified in IgAN over 3 decades ago.29Rauterberg E.W. Lieberknecht H.M. Wingen A.M. Ritz E. Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis.Kidney Int. 1987; 31: 820-829Abstract Full Text PDF PubMed Scopus (126) Google Scholar More recently, terminal pathway proteins have also been confirmed by proteomic analysis of microdissected IgAN biopsies.41Paunas T.I.F. Finne K. Leh S. et al.Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy.Clin Proteomics. 2017; 14: 30Crossref PubMed Scopus (24) Google Scholar C5b9 deposition in IgAN is associated with glomerular inflammation and progression to glomerulosclerosis.48Stangou M. Alexopoulos E. Pantzaki A. Leonstini M. Memmos D. C5b-9 glomerular deposition and tubular alpha3beta1-integrin expression are implicated in the development of chronic lesions and predict renal function outcome in immunoglobulin A nephropathy.Scand J Urol Nephrol. 2008; 42: 373-380Crossref PubMed Scopus (29) Google Scholar Serologic evidence of complement activation in IgAN further supports a contribution from alternative pathway activation to glomerular injury. Decreased plasma C3 levels with increased C3 activation products (iC3b and C3d), indicative of fluid phase alternative pathway activation, correlate with poor histopathologic features and outcomes.39Kim S.J. Koo H.M. Lim B.J.