IgA nephropathy: the lectin pathway and implications for targeted therapy

Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system—particularly the lectin and alternative pathways of complement—has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients. Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system—particularly the lectin and alternative pathways of complement—has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients. Immunoglobulin A nephropathy (IgAN) is the most commonly occurring glomerular disease, and many patients progress to kidney failure even with optimal supportive care and currently available therapy.1Moriyama T. Tanaka K. Iwasaki C. et al.Prognosis in IgA nephropathy: 30-year analysis of 1,012 patients at a single center in Japan.PLoS One. 2014; 9e91756Crossref Scopus (158) Google Scholar,2Kwon C.S. Daniele P. Forsythe A. Ngai C. A systematic literature review of the epidemiology, health-related quality of life impact, and economic burden of immunoglobulin a nephropathy.J Health Econ Outcomes Res. 2021; 8: 36-45Crossref PubMed Scopus (17) Google Scholar Patients with IgAN and persistent proteinuria (>0.75 g/d) have a high risk of progressive loss of kidney function.3Rovin B.H. Adler S.G. Barratt J. et al.Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases.Kidney Int. 2021; 100: 753-779Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar Systemic corticosteroids may temporarily slow the progression of kidney disease in these patients, but the data are not consistent and toxicity remains an issue.3Rovin B.H. Adler S.G. Barratt J. et al.Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases.Kidney Int. 2021; 100: 753-779Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar When possible, patients with persistent proteinuria should be considered for participation in a clinical trial, in the hopes of discovering safer, effective therapy.3Rovin B.H. Adler S.G. Barratt J. et al.Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases.Kidney Int. 2021; 100: 753-779Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar There is clearly an unmet medical need for additional treatment options to slow or even reverse the loss of kidney function. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the downstream pathogenesis of kidney injury. Activation of the complement system—particularly through the lectin and alternative pathways—has emerged as a key mediator of kidney injury in IgAN, including potential contributions to tubulointerstitial fibrosis, and is an attractive target for investigational therapy. The role of the alternative pathway in the pathophysiology of IgAN has been reviewed extensively elsewhere.4Poppelaars F. Faria B. Schwaeble W. Daha M.R. The contribution of complement to the pathogenesis of IgA nephropathy: are complement-targeted therapies moving from rare disorders to more common diseases?.J Clin Med. 2021; 10: 4715Crossref PubMed Scopus (19) Google Scholar Thus, this review focuses on the growing scientific and clinical evidence supporting the pathophysiologic role of the lectin pathway and the possible therapeutic role of lectin pathway inhibition in IgAN. Recent research has elucidated many aspects of how IgAN develops and how it results in kidney injury, but there is still much that remains to be determined. A "four-hit" process has been postulated for IgAN pathophysiology.5Suzuki H. Kiryluk K. Novak J. et al.The pathophysiology of IgA nephropathy.J Am Soc Nephrol. 2011; 22: 1795-1803Crossref PubMed Scopus (535) Google Scholar,6Tumlin J.A. Madaio M.P. Hennigar R. Idiopathic IgA nephropathy: pathogenesis, histopathology, and therapeutic options.Clin J Am Soc Nephrol. 2007; 2: 1054-1061Crossref PubMed Scopus (68) Google Scholar The first hit is the generation (and increased systemic presence) of "mucosal type" poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1).7Rehnberg J. Symreng A. Ludvigsson J.F. Emilsson L. Inflammatory bowel disease is more common in patients with IgA nephropathy and predicts progression of ESKD: a Swedish population-based cohort study.J Am Soc Nephrol. 2021; 32: 411-423Crossref PubMed Scopus (25) Google Scholar, 8Liu X.Z. Zhang Y.M. Jia N.Y. Zhang H. Helicobacter pylori infection is associated with elevated galactose-deficient IgA1 in IgA nephropathy.Ren Fail. 2020; 42: 539-546Crossref PubMed Scopus (12) Google Scholar, 9Floege J. Feehally J. The mucosa-kidney axis in IgA nephropathy.Nat Rev Nephrol. 2016; 12: 147-156Crossref PubMed Scopus (92) Google Scholar This Gd-IgA1 is believed to be predominantly generated by the intestinal mucosal-associated lymphoid tissue, which has been identified as a novel therapeutic target in IgAN.10Barratt J. Rovin B.H. Cattran D. et al.Why target the gut to treat IgA nephropathy?.Kidney Int Rep. 2020; 5: 1620-1624Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The second hit is the formation of antiglycan IgA and IgG autoantibodies recognizing Gd-IgA1.11Tomana M. Matousovic K. Julian B.A. et al.Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG.Kidney Int. 1997; 52: 509-516Abstract Full Text PDF PubMed Scopus (288) Google Scholar,12Tomana M. Novak J. Julian B.A. et al.Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies.J Clin Invest. 1999; 104: 73-81Crossref PubMed Scopus (409) Google Scholar In the third hit, Gd-IgA1 forms polymeric IgA1 immune complexes, with or without antiglycan autoantibodies.13Suzuki H. Novak J. IgA glycosylation and immune complex formation in IgAN.Semin Immunopathol. 2021; 43: 669-678Crossref PubMed Scopus (24) Google Scholar,14Knoppova B. Reily C. Maillard N. et al.The origin and activities of IgA1-containing immune complexes in IgA nephropathy.Front Immunol. 2016; 7: 117Crossref PubMed Scopus (115) Google Scholar The fourth hit involves the deposition of these complexes in the glomerular mesangium, activating (among other injury pathways) the complement system, which contributes to kidney inflammation and scarring.4Poppelaars F. Faria B. Schwaeble W. Daha M.R. The contribution of complement to the pathogenesis of IgA nephropathy: are complement-targeted therapies moving from rare disorders to more common diseases?.J Clin Med. 2021; 10: 4715Crossref PubMed Scopus (19) Google Scholar,15Medjeral-Thomas N.R. O'Shaughnessy M.M. Complement in IgA nephropathy: the role of complement in the pathogenesis, diagnosis, and future management of IgA nephropathy.Adv Chronic Kidney Dis. 2020; 27: 111-119Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The complement system is a key component of innate and adaptive immunity that mediates inflammation and fibrosis, both systemically and locally in organs.16Mosolits S. Magyarlaki T. Nagy J. Membrane attack complex and membrane cofactor protein are related to tubulointerstitial inflammation in various human glomerulopathies.Nephron. 1997; 75: 179-187Crossref PubMed Scopus (23) Google Scholar, 17Khalili M. Bonnefoy A. Genest D.S. et al.Clinical use of complement, inflammation, and fibrosis biomarkers in autoimmune glomerulonephritis.Kidney Int Rep. 2020; 5: 1690-1699Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Caliskan Y. Demir E. Karatay E. et al.Oxidative stress and macrophage infiltration in IgA nephropathy.J Nephrol. 2022; 35: 1101-1111Crossref PubMed Scopus (5) Google Scholar, 19Taylor S. Whitfield M. Barratt J. Didangelos A. The metalloproteinase ADAMTS5 is expressed by interstitial inflammatory cells in IgA nephropathy and is proteolytically active on the kidney matrix.J Immunol. 2020; 205: 2243-2254Crossref PubMed Scopus (5) Google Scholar, 20Takahata A. Arai S. Hiramoto E. et al.Crucial role of AIM/CD5L in the development of glomerular inflammation in IgA nephropathy.J Am Soc Nephrol. 2020; 31: 2013-2024Crossref PubMed Scopus (19) Google Scholar, 21Rauen T. Floege J. Inflammation in IgA nephropathy.Pediatr Nephrol. 2017; 32: 2215-2224Crossref PubMed Scopus (37) Google Scholar, 22Boor P. Konieczny A. Villa L. et al.Complement C5 mediates experimental tubulointerstitial fibrosis.J Am Soc Nephrol. 2007; 18: 1508-1515Crossref PubMed Scopus (92) Google Scholar In the classical pathway, binding of the pattern-recognition molecule, C1q, to IgG or IgM antibodies or to immune complexes initiates a cascade of events starting with the activation of C2 and C4. In the lectin pathway, carbohydrates expressed on the surface of injured cells or pathogens bind to 1 of 6 pattern-recognition molecules: mannan-binding lectin (MBL), collectin-10, collectin-11, ficolin-1, ficolin-2, or ficolin-3.23Garred P. Genster N. Pilely K. et al.A journey through the lectin pathway of complement-MBL and beyond.Immunol Rev. 2016; 274: 74-97Crossref PubMed Scopus (272) Google Scholar These pattern-recognition molecules form complexes with MBL-associated serine proteases 1 (MASP-1) and 2 (MASP-2), which activate C2 and C4.24Matsushita M. Thiel S. Jensenius J.C. et al.Proteolytic activities of two types of mannose-binding lectin-associated serine protease.J Immunol. 2000; 165: 2637-2642Crossref PubMed Scopus (272) Google Scholar,25Gavriilaki E. Ho V.T. Schwaeble W. et al.Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy.Exp Hematol Oncol. 2021; 10: 57Crossref PubMed Scopus (8) Google Scholar In both the classical and lectin pathways, activated C2 and C4 combine generating a C3 convertase (C4b2b), which cleaves C3 to its active components. The activation of C3 can also occur in a C4-independent "bypass" manner26Boudhabhay I. Poillerat V. Grunenwald A. et al.Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.Kidney Int. 2021; 99: 581-597Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar; MASP-2, when bound to a lectin pathway activation complex, has been shown to activate C3 directly in the absence of C4 or C2.27Yaseen S. Demopulos G. Dudler T. et al.Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.FASEB J. 2017; 31: 2210-2219Crossref PubMed Scopus (41) Google Scholar In addition to activating complement components, MASP-2 (when complexed with the pattern-recognition molecule MBL of the lectin pathway) also cleaves prothrombin to promote clot formation.28Krarup A. Wallis R. Presanis J.S. et al.Simultaneous activation of complement and coagulation by MBL-associated serine protease 2.PLoS One. 2007; 2: e623Crossref PubMed Scopus (206) Google Scholar Key evidence supporting the contribution of the alternative pathway to IgAN includes the presence of Factor B, Factor H, and Factor H–related proteins in kidney biopsies.4Poppelaars F. Faria B. Schwaeble W. Daha M.R. The contribution of complement to the pathogenesis of IgA nephropathy: are complement-targeted therapies moving from rare disorders to more common diseases?.J Clin Med. 2021; 10: 4715Crossref PubMed Scopus (19) Google Scholar Factor H–related proteins appear to compete with Factor H, preventing it from deactivating C3b. The initial rate-limiting step of the alternative pathway is cleavage of Factor B by Factor D.29Barratt J. Weitz I. Complement Factor D as a strategic target for regulating the alternative complement pathway.Front Immunol. 2021; 12712572Crossref PubMed Scopus (38) Google Scholar Mature Factor D is the result of proteolytic activation of its zymogen form, pro-Factor D, by MASP-3, initiating a cascade of proteolytic cleavages that lead to the alternative pathway C3 convertase (C3bBb).29Barratt J. Weitz I. Complement Factor D as a strategic target for regulating the alternative complement pathway.Front Immunol. 2021; 12712572Crossref PubMed Scopus (38) Google Scholar This results in the activation of additional C3. MASP-3 may link the alternative and lectin pathways of complement; it is responsible for activating Factor D in the alternative pathway and also complexes with pattern-recognition molecules of the lectin pathway.30Kusakari K. Machida T. Ishida Y. et al.The complex formation of MASP-3 with pattern recognition molecules of the lectin complement pathway retains MASP-3 in the circulation.Front Immunol. 2022; 13907023Crossref PubMed Scopus (2) Google Scholar,31Dobó J. Szakács D. Oroszlán G. et al.MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked.Sci Rep. 2016; 631877Crossref PubMed Scopus (93) Google Scholar Patients with IgAN and progressive kidney disease, as compared with patients with stable kidney disease, have reduced plasma MASP-3, reduced glomerular deposition of Factor H, and increased glomerular deposition of Factor H–related proteins 1 and 5, consistent with plasma MASP-3 being consumed as a result of activation of the alternative pathway in patients with disease progression.32Medjeral-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 (51) Google Scholar In addition to amplifying responses to the classical and lectin pathways, the alternative pathway might be activated directly in IgAN. IgA1 deposits in the mesangium contain properdin, a key component of the alternative pathway.33Ghosh S. Das S. Mukherjee J. et al.Enumerating the role of properdin in the pathogenesis of IgA nephropathy and its possible therapies.Int Immunopharmacol. 2021; 93107429Crossref PubMed Scopus (7) Google Scholar In vitro and in vivo research has shown that properdin can act as a pattern-recognition molecule for injured tissues.34O'Flynn J. Kotimaa J. Faber-Krol R. et al.Properdin binds independent of complement activation in an in vivo model of anti-glomerular basement membrane disease.Kidney Int. 2018; 94: 1141-1150Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,35Daha M.R. van Kooten C. Role of complement in IgA nephropathy.J Nephrol. 2016; 29: 1-4Crossref PubMed Scopus (61) Google Scholar Other research has shown that properdin does not act as a pattern-recognition molecule to generate C3b but stabilizes existing C3b previously generated by the classical pathway, the lectin pathway, or by spontaneous tick-over of the alternative pathway.36Harboe M. Johnson C. Nymo S. et al.Properdin binding to complement activating surfaces depends on initial C3b deposition.Proc Natl Acad Sci U S A. 2017; 114: E534-E539Crossref PubMed Scopus (51) Google Scholar Once C3 is activated, all 3 pathways lead to the activation of C5 and then binding of C5b, 6, 7, 8, and 9, resulting in assembly of the "membrane attack complex" C5b–9. Intermediate products of the complement system (activated C3, C4, and C5) also contribute to the immune response through inflammation and stimulation of chemotaxis and phagocytosis. Compared with healthy individuals, patients with IgAN have increased mesangial deposition of C5b–9 and have been variably described to also have peripheral capillary loop, tubule basement membrane, and vascular C5b–9 deposition.37Koopman J.J.E. van Essen M.F. Rennke H.G. et al.Deposition of the membrane attack complex in healthy and diseased human kidneys.Front Immunol. 2021; 11599974Crossref PubMed Scopus (26) Google Scholar The intensity of glomerular staining for C5b–9 correlates with glomerular hypercellularity, glomerulosclerosis, interstitial inflammation, interstitial fibrosis, tubular atrophy, and disease progression in patients with IgAN.37Koopman J.J.E. van Essen M.F. Rennke H.G. et al.Deposition of the membrane attack complex in healthy and diseased human kidneys.Front Immunol. 2021; 11599974Crossref PubMed Scopus (26) Google Scholar Several studies have examined urinary C5b–9 as a possible noninvasive biomarker for IgAN severity, with mixed results. Urinary C5b–9 is higher in patients with IgAN than in healthy subjects, and urinary C5b–9 is positively correlated with the extent of kidney damage in some studies38Onda K. Ohsawa I. Ohi H. et al.Excretion of complement proteins and its activation marker C5b-9 in IgA nephropathy in relation to renal function.BMC Nephrol. 2011; 12: 64Crossref PubMed Scopus (75) Google Scholar, 39Segarra-Medrano A. Carnicer-Caceres C. Valtierra-Carmeno N. et al.Study of the variables associated with local complement activation in IgA nephropathy.Nefrologia. 2017; 37: 320-329Crossref PubMed Google Scholar, 40Yu B.C. Park J.H. Lee K.H. et al.Urinary C5b-9 as a prognostic marker in IgA nephropathy.J Clin Med. 2022; 11: 820Crossref PubMed Scopus (5) Google Scholar but not in others.17Khalili M. Bonnefoy A. Genest D.S. et al.Clinical use of complement, inflammation, and fibrosis biomarkers in autoimmune glomerulonephritis.Kidney Int Rep. 2020; 5: 1690-1699Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,41Brenchley P.E. Coupes B. Short C.D. et al.Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy.Kidney Int. 1992; 41: 933-937Abstract Full Text PDF PubMed Scopus (79) Google Scholar,42Morita Y. Ikeguchi H. Nakamura J. et al.Complement activation products in the urine from proteinuric patients.J Am Soc Nephrol. 2000; 11: 700-707Crossref PubMed Google Scholar A fall in urinary C5b–9 has been reported to precede disease remission,17Khalili M. Bonnefoy A. Genest D.S. et al.Clinical use of complement, inflammation, and fibrosis biomarkers in autoimmune glomerulonephritis.Kidney Int Rep. 2020; 5: 1690-1699Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar but baseline urinary C5b–9 does not independently predict estimated glomerular filtration rate decline or clinical response during treatment.40Yu B.C. Park J.H. Lee K.H. et al.Urinary C5b-9 as a prognostic marker in IgA nephropathy.J Clin Med. 2022; 11: 820Crossref PubMed Scopus (5) Google Scholar Additional research is needed to confirm the relative contributions of each pathway to the activation of complement in patients with IgAN, whether particular subgroups of patients can be identified with more dominant activation of one pathway, and how this relates to outcomes (Figure 1, Table 1).4Poppelaars F. Faria B. Schwaeble W. Daha M.R. The contribution of complement to the pathogenesis of IgA nephropathy: are complement-targeted therapies moving from rare disorders to more common diseases?.J Clin Med. 2021; 10: 4715Crossref PubMed Scopus (19) Google Scholar,25Gavriilaki E. Ho V.T. Schwaeble W. et al.Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy.Exp Hematol Oncol. 2021; 10: 57Crossref PubMed Scopus (8) Google Scholar,33Ghosh S. Das S. Mukherjee J. et al.Enumerating the role of properdin in the pathogenesis of IgA nephropathy and its possible therapies.Int Immunopharmacol. 2021; 93107429Crossref PubMed Scopus (7) Google Scholar,35Daha M.R. van Kooten C. Role of complement in IgA nephropathy.J Nephrol. 2016; 29: 1-4Crossref PubMed Scopus (61) Google Scholar,43Lee H.J. Choi S.Y. Jeong K.H. et al.Association of C1q deposition with renal outcomes in IgA nephropathy.Clin Nephrol. 2013; 80: 98-104Crossref PubMed Scopus (39) Google Scholar, 44Nishiwaki H. Hasegawa T. Nagayama Y. et al.Absence of mesangial C1q deposition is associated with resolution of proteinuria and hematuria after tonsillectomy plus steroid pulse therapy for immunoglobulin a nephropathy.Nephron. 2015; 130: 1-7Crossref PubMed Scopus (7) Google Scholar, 45Hisano S. Matsushita M. Fujita T. et al.Mesangial IgA2 deposits and lectin pathway-mediated complement activation in IgA glomerulonephritis.Am J Kidney Dis. 2001; 38: 1082-1088Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 46Roos 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 (344) Google Scholar, 47Endo M. Ohi H. Ohsawa I. et al.Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.Nephrol Dial Transplant. 1998; 13: 1984-1990Crossref PubMed Scopus (170) Google Scholar, 48Lhotta K. Wurzner R. Konig P. Glomerular deposition of mannose-binding lectin in human glomerulonephritis.Nephrol Dial Transplant. 1999; 14: 881-886Crossref PubMed Scopus (113) Google Scholar, 49Liu L.L. Liu N. Chen Y. et al.Glomerular mannose-binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy.Clin Exp Immunol. 2013; 174: 152-160Crossref PubMed Scopus (23) Google Scholar, 50Matsuda M. Shikata K. Wada J. et al.Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy.Nephron. 1998; 80: 408-413Crossref PubMed Scopus (71) Google Scholar, 51Wei M. Guo W.Y. Xu B.Y. et al.Collectin11 and complement activation in IgA nephropathy.Clin J Am Soc Nephrol. 2021; 16: 1840-1850Crossref PubMed Scopus (7) Google Scholar, 52Farrar C.A. Tran D. Li K. et al.Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury.J Clin Invest. 2016; 126: 1911-1925Crossref PubMed Scopus (103) Google Scholar, 53Nauser C.L. Howard M.C. Fanelli G. et al.Collectin-11 (CL-11) is a major sentinel at epithelial surfaces and key pattern recognition molecule in complement-mediated ischaemic injury.Front Immunol. 2018; 9: 2023Crossref PubMed Scopus (15) Google Scholar, 54Wu W. Liu C. Farrar C.A. et al.Collectin-11 promotes the development of renal tubulointerstitial fibrosis.J Am Soc Nephrol. 2018; 29: 168-181Crossref PubMed Scopus (33) Google Scholar Additional key questions for future research include whether patterns of lectin pathway and alternative pathway activation change during the natural history of IgAN in an individual patient, or if the contributions of each pathway vary by patient-specific factors such as race, ethnicity, or age.Table 1Key evidence for the role of the complement pathway in IgANPathwayKey evidenceClassical•Binding of IgG/IgM antibodies or immune complexes to C1q forms C1s, which activates C2 and C4, but mesangial deposition of C1q occurs in only 0% to 20% of patients with IgAN,43Lee H.J. Choi S.Y. Jeong K.H. et al.Association of C1q deposition with renal outcomes in IgA nephropathy.Clin Nephrol. 2013; 80: 98-104Crossref PubMed Scopus (39) Google Scholar, 44Nishiwaki H. Hasegawa T. Nagayama Y. et al.Absence of mesangial C1q deposition is associated with resolution of proteinuria and hematuria after tonsillectomy plus steroid pulse therapy for immunoglobulin a nephropathy.Nephron. 2015; 130: 1-7Crossref PubMed Scopus (7) Google Scholar, 45Hisano S. Matsushita M. Fujita T. et al.Mesangial IgA2 deposits and lectin pathway-mediated complement activation in IgA glomerulonephritis.Am J Kidney Dis. 2001; 38: 1082-1088Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar suggesting that the classical pathway is rarely involved in glomerular changes.Lectin•Carbohydrates on injured cells or pathogens bind to 1 of 6 pattern-recognition molecules: MBL, collectin-10, collectin-11, ficolin-1, ficolin-2, or ficolin-3. Up to 50% of patients with IgAN show glomerular deposition of MBL with IgA1.45Hisano S. Matsushita M. Fujita T. et al.Mesangial IgA2 deposits and lectin pathway-mediated complement activation in IgA glomerulonephritis.Am J Kidney Dis. 2001; 38: 1082-1088Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 46Roos 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 (344) Google Scholar, 47Endo M. Ohi H. Ohsawa I. et al.Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.Nephrol Dial Transplant. 1998; 13: 1984-1990Crossref PubMed Scopus (170) Google Scholar, 48Lhotta K. Wurzner R. Konig P. Glomerular deposition of mannose-binding lectin in human glomerulonephritis.Nephrol Dial Transplant. 1999; 14: 881-886Crossref PubMed Scopus (113) Google Scholar, 49Liu L.L. Liu N. Chen Y. et al.Glomerular mannose-binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy.Clin Exp Immunol. 2013; 174: 152-160Crossref PubMed Scopus (23) Google Scholar, 50Matsuda M. Shikata K. Wada J. et al.Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy.Nephron. 1998; 80: 408-413Crossref PubMed Scopus (71) Google Scholar•IgA1 immune complexes from patients with IgAN increase mesangial secretion of collectin-11, which deposits with IgA1 complexes on cell surfaces and initiates the activation of complement and deposition of C3.51Wei M. Guo W.Y. Xu B.Y. et al.Collectin11 and complement activation in IgA nephropathy.Clin J Am Soc Nephrol. 2021; 16: 1840-1850Crossref PubMed Scopus (7) Google Scholar•Deposition of collectin-11 activates MASP-2 and leads to inflammation, fibrosis, and tubular damage.52Farrar C.A. Tran D. Li K. et al.Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury.J Clin Invest. 2016; 126: 1911-1925Crossref PubMed Scopus (103) Google Scholar, 53Nauser C.L. Howard M.C. Fanelli G. et al.Collectin-11 (CL-11) is a major sentinel at epithelial surfaces and key pattern recognition molecule in complement-mediated ischaemic injury.Front Immunol. 2018; 9: 2023Crossref PubMed Scopus (15) Google Scholar, 54Wu W. Liu C. Farrar C.A. et al.Collectin-11 promotes the development of renal tubulointerstitial fibrosis.J Am Soc Nephrol. 2018; 29: 168-181Crossref PubMed Scopus (33) Google ScholarAlternative•Increased levels of Factor B, Factor H, or Factor H–related proteins are present in most kidney biopsies from patients with IgAN.4Poppelaars F. Faria B. Schwaeble W. Daha M.R. The contribution of complement to the pathogenesis of IgA nephropathy: are complement-targeted therapies moving from rare disorders to more common diseases?.J Clin Med. 2021; 10: 4715Crossref PubMed Scopus (19) Google Scholar In addition to spontaneous tick-over of the alternative pathway and amplification of the lectin pathway,35Daha M.R. van Kooten C. Role of complement in IgA nephropathy.J Nephrol. 2016; 29: 1-4Crossref PubMed Scopus (61) Google Scholar mesangial deposition of properdin (a pattern-recognition molecule for the alternative pathway)33Ghosh S. Das S. Mukherjee J. et al.Enumerating the role of properdin in the pathogenesis of IgA nephropathy and its possible therapies.Int Immunopharmacol. 2021; 93107429Crossref PubMed Scopus (7) Google Scholar suggests that direct activation of the alternative pathway may occur in patients with IgAN.IgAN, immunoglobulin A nephropathy; MAC, membrane attack complex; MASP, mannan-binding lectin-associated serine protease; MBL, mannan-binding lectin.