INTRODUCTION — IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis throughout most resource-abundant settings [1].
The pathogenesis of IgAN will be reviewed here. Other aspects of IgAN are discussed separately:
●(See "IgA nephropathy: Clinical features and diagnosis".)
●(See "IgA nephropathy: Treatment and prognosis".)
●(See "IgA nephropathy: Recurrence after transplantation".)
●(See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
THE FOUR-HIT HYPOTHESIS — IgAN is an autoimmune disease resulting from dysregulation of mucosal-type IgA immune responses. The autoantigens are a specific set of IgA1 O-glycoforms displaying reduced O-linked galactosylation of the IgA1 hinge region. Excess levels of these O-glycoforms in the circulation result in the generation of hinge glycan-specific immunoglobulin G (IgG) and IgA autoantibodies in susceptible individuals.
The pathogenesis of IgAN is framed by the widely accepted "four-hit hypothesis," which postulates that a sequence of four events must occur for clinically significant disease to develop (figure 1):
●Increased presence in the circulation of IgA1 molecules with reduced O-galactosylation of the IgA1 hinge region (also referred to as galactose-deficient IgA1 [Gd-IgA1])
●Production of IgG and IgA autoantibodies that recognize Gd-IgA1
●Formation of circulating immune complexes containing IgG and IgA autoantibodies bound to Gd-IgA1
●Deposition of these circulating immune complexes in the glomerular mesangium, triggering kidney injury
Hit 1: Production of poorly glycosylated IgA1 (Gd-IgA1) — The "first hit" in the pathogenesis of IgAN is an increase in serum levels of a pool of circulating IgA molecules with special characteristics that promote mesangial deposition (figure 1).
IgA1 O-glycosylation — In humans and higher primates, IgA exists as two isoforms, IgA1 and IgA2. These isoforms can exist as monomers or polymers and are present in mucosal tissues and the circulation. IgA1 has an extended hinge region between the first and second constant domains that has between three and six O-glycans chains attached to serine or threonine residues at specific positions (figure 2). O-glycosylation of the IgA1 hinge region involves the addition of N-acetylgalactosamine (GalNAc) to a serine/threonine residue, followed by the addition of a galactose moiety to GalNAc. Additional modifications can occur via sialylation of the GalNAc or galactose moieties. These steps produce a combination of different IgA1 O-glycoforms with varying degrees of galactosylation and sialylation.
In patients with IgAN, there is an increase in circulating IgA1 that is polymeric and lacks terminal galactose moieties or GalNAc and galactose in its hinge region. This form of IgA1 is termed "poorly galactosylated IgA1" or "galactose-deficient IgA1" (Gd-IgA1). This increase in poorly galactosylated IgA1 O-glycoforms is found in serum IgA, as well as in IgA1 eluted from isolated kidney tissue [2-4]. Similar findings have been reported in children with either IgAN or IgA vasculitis (Henoch-Schönlein purpura) nephritis [5]. Gd-IgA1 is an O-glycosylated form of IgA1 produced at mucosal surfaces, and its increased presence in the serum and mesangium likely reflects a subtle dysregulation of the mucosal immune system in IgAN.
Gd-IgA1 has increased in vitro affinity for the extracellular matrix components fibronectin and type IV collagen [6], which may promote mesangial deposition.
Genetic control of IgA1 O-galactosylation — Genetic and epigenetic factors may play an important role in determining O-galactosylation of the IgA1 hinge region. As an example, high serum levels of Gd-IgA1 have been identified in 47 and 25 percent of first-degree relatives of patients with familial and sporadic IgAN, respectively [7]. The heritability of Gd-IgA1 among familial IgAN cohorts has been estimated between 54 and 76 percent. In a study of healthy monozygotic and dizygotic twin pairs, the heritability of serum levels of Gd-IgA1 was found to be as high as 80 percent [8]. Heritability of serum IgA levels was only 46 percent, suggesting that O-galactosylation of IgA1 is independent of serum IgA level.
Higher serum levels of Gd-IgA1 have been associated with a polymorphism in the gene encoding core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase (C1GALT1), one of the enzymes responsible for O-galactosylation of IgA1 [9,10]. In one study of White European and Chinese populations, this association was not confined to patients with IgAN but was also identified in healthy subjects and patients with membranous nephropathy [9]. Although IgAN is more common in Chinese compared with White populations, a lower frequency of the C1GALT1 risk haplotype was observed in the Chinese cohort, which corresponded with lower serum levels of Gd-IgA1 among Chinese patients with IgAN compared with levels among White European patients. These findings may suggest that factors other than IgA1 O-galactosylation are likely to play an important role in the pathogenesis of IgAN among different ethnic populations.
MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate gene expression at the posttranscriptional level. Expression of the miRNA, miR-148b, has been found to be increased in leukocytes from patients with IgAN, and overexpression of miR-148b correlated with decreased expression of C1GAL-T1 and increased secretion of Gd-IgA1 [11]. The binding site for miR-148b on the messenger RNA of C1GALT1 corresponded to the C1GALT1 polymorphism that was associated with IgAN in previous studies.
Source and regulation of Gd-IgA1 production in IgAN — The source of Gd-IgA1 production in patients with IgAN remains under investigation. A potential mucosal origin of Gd-IgA1 is suggested by the following observations:
●IgAN can present with gross (visible) hematuria that is concurrent with mucosal inflammation and infection (eg, an upper respiratory tract infection).
●Mesangial and circulating Gd-IgA1 in patients with IgAN is primarily polymeric, which is normally produced at mucosal surfaces rather than in systemic immune sites.
●The pattern of IgA1 hinge region O-galactosylation of Gd-IgA1 closely resembles that seen in IgA1 of mucosal origin and IgA1 directed against mucosally encountered antigens.
However, mucosal polymeric IgA plasma cell numbers are normal or even reduced and polymeric IgA antibody levels are not elevated in mucosal secretions in IgAN [12,13]. By contrast, there is an increase in polymeric IgA1 plasma cells in the bone marrow of patients with IgAN, and these are believed to be derived from mucosally primed B cells [13,14]. Systemic antigen challenge results in increased titers of circulating polymeric IgA1 antibodies (displaying a mucosal phenotype), which are thought, largely, to be derived from these dislocated, mucosally primed plasma cells [15-18]. In patients with IgAN, circulating GdIgA1-expressing B cells were identified to preferentially express lambda light chains, which are also found in increased quantities in mesangial deposits in IgAN, and also express mucosal (upper respiratory tract and gut) homing receptors [19]. Thus, the overproduction of polymeric "mucosal-type" IgA1 in the serum is likely, in part, to stem from an aberrant mucosal immune response resulting in mistrafficking of "mucosal" plasma cells to systemic sites due to defective homing during mucosal immune responses [20].
The two mucosal-associated lymphoid tissues (MALT) most studied in IgAN are the nasal-associated lymphoid tissue (NALT) and gut-associated lymphoid tissue (GALT). Which MALT sites contribute most significantly to Gd-IgA1 production remain unclear and are likely to vary between individuals.
●Nasal-associated lymphoid tissue – There is evidence that the tonsils may be a source of Gd-IgA1 [21,22]. A number of in vitro studies have demonstrated synthesis of polymeric Gd-IgA1 by tonsillar B cells, and there have been reports of a fall in serum levels of Gd-IgA1 following tonsillectomy [22]. Recognition of pathogen-associated molecular patterns (PAMPs) by toll-like receptors 7 and 9 (TLR7 and TLR9) has been shown to be important in promoting disease in a mouse model of IgAN and is present in the tonsillar tissue of patients with IgAN, supporting the involvement of NALT in the pathogenesis of IgAN [23,24]. However, there are differences in opinion as to the importance of the tonsils in IgAN, which could in part reflect variabilities in disease pathogenesis in different parts of the world. The data evaluating tonsillectomy as a therapy for IgAN are presented elsewhere. (See "IgA nephropathy: Treatment and prognosis", section on 'Adjunctive therapies'.)
●Gut-associated lymphoid tissue – There has been increasing interest in a gut-kidney axis as being an important source of pathogenic IgA in IgAN, with important interplays between the GALT, the gut microbiome, and integrity of the intestinal barrier [25]. The gut produces the most IgA out of all mucosal sites [26]. A genome-wide association study (GWAS) highlighted a number of risk alleles at loci that are implicated in the maintenance of the intestinal barrier and regulation of the mucosal immune response to pathogens [27]. Patients with IgAN were found to have higher circulating levels of gut-homing regulatory B cells, memory B cells, and IgA-expressing memory B cells [28]. This area has become especially relevant with the development of GALT-directed therapies, such as targeted-release formulation budesonide. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)
Although the specific mechanisms that control IgA synthesis in the various immune sites are not well defined, systemic production of IgA appears to be under similar control mechanisms to those of IgG production [29], with major roles for B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Both BAFF and APRIL are critical for mucosal B cell survival, maturation, proliferation, and IgA class switch recombination (and therefore in the production of Gd-IgA1). Serum BAFF and APRIL levels are increased in IgAN and correlate with disease severity [30,31]. Therapies that inhibit APRIL and/or BAFF are under investigation for the treatment of IgAN [32-34]. As with other immunoglobulin isotypes, type 2 T cell cytokines (interleukin [IL]-4, -5, and -6) also promote B cell class switching to IgA and subsequent proliferation and differentiation of IgA-producing cells. IgA production is also specifically and potently promoted by the cytokines IL-10 and transforming growth factor (TGF)–beta, which have suppressive effects on IgG production.
The control of mucosal IgA production is less well understood. BAFF and APRIL are highly expressed with the MALT. Furthermore, transgenic mice that overexpress BAFF demonstrated an IgAN-like disease with mesangial IgA deposition due to expansion of IgA-secreting plasma cells in the gut lamina propria [35]. Importantly, this was dependent upon the presence of gut commensal bacteria.
An imbalance of type 1 and type 2 T cell subsets has been proposed as an explanation for the dysregulated IgA responses seen in IgAN. In addition, there is provisional work suggesting that types 1 and 2 cytokines differentially affect IgA1 O-glycosylation [36].
Hit 2: Production of anti-Gd-IgA1 autoantibodies — The production of IgG and IgA autoantibodies that specifically recognize Gd-IgA1 represents the "second hit" of the four-hit hypothesis (figure 1).
Autoantibodies in IgAN recognize GalNac residues in the hinge region of Gd-IgA1 [37]. These Gd-IgA1-specific autoantibodies can be IgG or IgA, but IgG is the predominant isotype [38,39]. IgG autoantibodies against Gd-IgA1 contain a specific alanine to serine substitution in the heavy chain variable region that is critical for binding to Gd-IgA1 and appears to result from a somatic mutation that may be influenced by exposure to specific environmental antigens [37,40].
What triggers the production of anti-Gd-IgA1 autoantibodies in patients with IgAN is unclear, but genetic factors, in particular classical human leukocyte antigen (HLA) alleles within the major histocompatibility complex (MHC) locus, are likely to contribute. Healthy individuals can have equivalent levels of Gd-IgA1 to those with IgAN, without developing autoantibodies or kidney disease. (See 'Genetic susceptibility' below.)
Serum levels of Gd-IgA1-specific autoantibodies are variably reported to be associated with disease activity and progressive kidney disease in IgAN [4,38,41].
Hit 3: Formation of Gd-IgA1-containing circulating immune complexes — The formation of circulating immune complexes containing IgG or IgA autoantibodies bound to Gd-IgA1 represents the "third hit" of the four-hit hypothesis (figure 1).
The circulating immune complexes in patients with IgAN consist of IgG autoantibodies that are bound to polymeric Gd-IgA1 [42]. In addition to IgG, IgA, IgM, and complement pathway components can also be found in these circulating immune complexes [43]. Gd-IgA1 also has an increased tendency to self-aggregate, perhaps due to the different physiological environment of plasma compared with mucosal secretions.
Levels of circulating immune complexes in patients with IgAN have been shown to correlate with clinical and histologic activity, such as microscopic hematuria, episodes of macroscopic hematuria, and the percentage of glomeruli with crescents [44].
IgG antibodies against poorly O-galactosylated IgA1 contain a specific amino acid sequence, Y1CS3, in the heavy chain variable region that differs from a Y1CA3 sequence in similar isotype-matched healthy control patients. The S3 residue, which has been shown to be critical for binding to poorly galactosylated IgA1, is not observed in germline DNA and appears to be the result of a somatic mutation that may be influenced by exposure to specific environmental antigens [37,40].
Hit 4: Deposition of circulating immune complexes and kidney injury — Gd-IgA1-containing immune complexes are more likely to deposit in the mesangium [6,42]. Mesangial deposition of circulating immune complexes containing Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies and activation of mesangial cells to induce kidney injury represent the "fourth hit" of the four-hit hypothesis (figure 1).
While IgG and complement components are often codeposited, IgA may be detected alone. In these cases, IgG may be deposited in small amounts that are undetectable by standard immunofluorescence techniques but may be observed with confocal microscopy [45].
Impaired IgA clearance — Impaired systemic clearance of IgA promotes IgA deposition in the mesangium. Persistent mesangial IgA accumulation occurs by one or both of two mechanisms: The rate of IgA deposition exceeds the mesangial clearance capacity, or the deposited IgA is resistant to mesangial clearance.
●Systemic clearance – Alterations in systemic IgA and IgA–immune complex clearance mechanisms will facilitate their persistence in the serum. The liver plays an important role in IgA clearance from the circulation, and radiolabeled IgA clearance studies suggest reduced hepatic clearance in IgAN [46]. Reduced galactosylation of the IgA1 hinge region may affect its uptake by the asialoglycoprotein receptor on hepatocytes [47]. A second route of IgA clearance is through CD89, a fragment crystallizable (Fc) receptor for IgA expressed by myeloid and Kupffer cells [48]. IgAN is associated with downregulated CD89 expression on circulating myeloid cells, resulting in reduced clearance [49]. It has been proposed that this downregulation is a direct consequence of binding of Gd-IgA1-containing immune complexes with CD89 [49-51].
●Mesangial clearance – Mesangial IgA deposition is not always associated with the development of glomerular inflammation. Furthermore, mesangial IgA deposition may be reversible, as suggested by the following observations:
•Sequential biopsy studies of patients who underwent clinical remission were accompanied by disappearance of IgA deposits [52].
•Mesangial IgA deposits disappear when kidneys with IgAN are inadvertently transplanted into recipients who originally did not have IgAN [53].
A proposed pathway for mesangial clearance is through mesangial cell receptor–mediated endocytosis and catabolism of IgA deposits. A number of candidate receptors on the mesangial cell have been described [54-60], including the transferrin receptor (CD71), which binds IgA and polymeric Gd-IgA1 [59-61].
It is possible that impaired binding of IgA to mesangial cell receptor(s) could lead to defective mesangial IgA clearance and thereby contribute to IgA accumulation and the development of glomerular injury, in a positive feedback loop manner.
IgA1-induced activation of mesangial cells — Polymeric IgA1 elicits a phenotypic transformation in mesangial cells in vitro, with mesangial cell proliferation and secretion of extracellular matrix components [20]. Spleen tyrosine kinase (Syk) is expressed by mesangial cells, and, in vitro, Syk inhibition reduced the proliferative and proinflammatory effects of IgA immune complexes on mesangial cells [62]. Glomerular phospho-Syk expression was shown to be increased in IgAN.
There is increased expression of TGF-beta and components of the renin-angiotensin system in IgAN [63-66]. In addition, polymeric IgA appears to stimulate the production of a variety of proinflammatory and profibrotic molecules, such as IL-6 [20,67,68]. Expression of platelet-derived growth factor (PDGF) B and D chains, proteins known to be important in the pathogenesis of mesangioproliferative glomerulonephritis, are upregulated in glomeruli in IgAN and have been shown in mouse models to induce marked mesangial cell proliferation [69,70].
The production of inflammatory mediators by mesangial cells and podocytes in response to IgA-containing immune complex deposition results in the recruitment of inflammatory cells, predominantly macrophages. Endocapillary hypercellularity, observed as a marker of worse prognosis as part of the Oxford classification of IgAN, correlates with glomerular CD68 count, a marker of macrophages [71]. In addition, tubulointerstitial macrophage infiltration is a driver for tubulointerstitial inflammation and fibrosis in IgAN [72].
Codeposition of IgG may synergistically contribute to the development of a proinflammatory phenotype in mesangial cells, thereby influencing the degree of glomerular injury and clinical outcome [45,73-76]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Pathology'.)
Mesangial cell–podocyte crosstalk — Several studies support the influence of mesangial cell–derived soluble mediators (such as tumor necrosis factor [TNF]-alpha, TGF-beta, and platelet-activating factor) on podocyte phenotype (including expression of nephrin, ezrin, and podocin and TNF-alpha secretion) in IgAN [77-81]. A progressive loss of podocyte markers has been shown to occur early at sites of capsular adhesions and in capillary loops [82]. IgA-induced mesangial cell activation may influence not only local changes within the mesangium but also glomerulotubular communication and the development of interstitial damage in IgAN through alterations in podocyte function.
The loss of podocyte markers [82] and the early development of glomerular capsular adhesions [83] suggest the possibility that podocyte injury occurs in IgAN and there may be a podocytopathic variant of IgAN in which podocyte injury is the principal feature, possibly due to mesangial cell mediator release or even direct interaction between IgA immune complexes and podocytes [84,85].
Complement activation — Local complement activation appears to influence the extent of glomerular injury. C3 is codeposited with IgA in over 90 percent of patients with IgAN. Both the alternative and lectin pathways may be activated, leading to generation of the anaphylatoxins C3a and C5a and the membrane attack complex C5b-9, with subsequent promotion of inflammatory mediator and matrix protein production by mesangial cells [86-89]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Pathology'.)
Lectin pathway activation occurs in a subset of patients and is associated with worse kidney injury, highlighting the heterogeneous nature of this condition. In a biopsy series, one-fourth of patients displayed evidence of lectin pathway activation (as determined by glomerular deposition of mannose-binding lectin [MBL], L-ficolin, MBL-associated serine protease [MASP], and C4d), and these patients had increased proteinuria and kidney damage compared with those with no lectin pathway involvement [88]. In another study, approximately one-third of patients had evidence of lectin pathway activation (mesangial C4d deposition in the absence of the classical pathway component C1q), and these patients had a marked reduction in 10-year kidney survival [90]. MBL is able to bind to polymeric IgA, but not monomeric IgA, and its binding results in activation of C3 and C4 [91].
Other studies suggest that factor H, a regulator of the alternative pathway, and the complement factor H–related (CFHR) proteins play an important role in IgAN. Two GWAS identified that a single nucleotide polymorphism (SNP) in the complement factor H (CFH)/CFHR locus, resulting in deletion of CFHR-3 and CFHR-1, protects against the risk of developing IgAN [92,93]. CFHR-3 and CFHR-1 compete with the binding of factor H to C3, and their deletion results in uninhibited factor H-C3 binding and downregulation of the alternative pathway; conversely, an increase in their levels leads to increased alternative pathway activity. CFHR-1 levels have been shown to be increased in two cohorts of IgAN patients and associated with progressive disease [94,95].
There is also evidence for systemic activation of complement in a subpopulation of patients with IgAN, with elevated levels of split products of activated C3 reported [96].
C3 and MBL are synthesized locally by mesangial cells and podocytes [97]; it is possible that the binding of polymeric IgA to mesangial cells incites local complement activation independent of systemic complement activity. The contribution of this in situ complement synthesis and activation to progressive glomerular injury is unknown. (See "Mechanisms of immune injury of the glomerulus".)
The increasing ability to perform mass spectrometry–based proteomics in glomerular disease may be an interesting approach to further define components, including complement, within immune deposits and to delineate the intracellular signaling pathways involved in the pathogenesis of IgAN [98].
Downstream pathways of injury and fibrosis — There is clear evidence of early activation of the renin-angiotensin system in IgAN [64,99]. Use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is one of the cornerstones of management. (See "IgA nephropathy: Treatment and prognosis", section on 'Angiotensin inhibition'.)
There has been increased interest in the role of endothelin (ET)-1 in IgAN. ET-1 is a growth factor that acts via its two receptors, ETA and ETB receptor. It may have several deleterious effects in the kidney, including vasoconstriction, mesangial cell proliferation, podocyte disruption, production of extracellular matrix, inflammation, and fibrosis [100]. Increased ET-1 and ETB receptor staining was observed in patients with IgAN and significant proteinuria [101]. A specific ETA receptor antagonist had a protective effect against the development of histopathologic lesions and proteinuria in the ddY mouse model of IgAN [102]. Endothelin receptor antagonism is being evaluated in several clinical trials in IgAN. The dual endothelin angiotensin receptor antagonist sparsentan received conditional approval from the US Food and Drug Administration (FDA) for reduction of proteinuria in patients with IgAN at risk of rapid disease progression. (See "IgA nephropathy: Treatment and prognosis", section on 'Dual endothelin angiotensin receptor antagonists'.)
Pathways common to other forms of chronic kidney disease (CKD), such as those involving the mineralocorticoid receptor system, TGF-beta, and Wnt/beta-catenin signaling, are likely to play a role in promoting kidney fibrosis in progressive IgAN. Results are awaited from the Finerenone in Non-Diabetic CKD (FIND-CKD) trial, which will assess the efficacy and safety of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in addition to standard of care in delaying progression of nondiabetic CKD, and it is likely that a large cohort of patients with IgAN will be enrolled into this trial.
ENVIRONMENTAL FACTORS
Infections — The provocation of gross (visible) hematuria by mucosal infection in patients with IgAN has led to the view that mesangial IgA deposition may be triggered by infection (figure 1). Cytomegalovirus, Haemophilus parainfluenzae, Staphylococcus aureus, and toxoplasmosis have been implicated [103-109]. During the coronavirus 2019 (COVID-19) pandemic, flares of IgAN were reported with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination, further supporting a link between mucosal infection and inflammation and IgA deposition in susceptible individuals [110].
As an example, in a clinical study from Japan, kidney biopsy specimens from 116 patients with IgAN and 122 patients with other types of kidney disease were examined for the presence of S. aureus antigen in the glomeruli [104]. Although antigen was not detected in non-IgA disease, 68 percent of specimens from patients with IgAN had S. aureus cell envelope antigen localized with IgA antibody in the glomeruli. Another report from Japan suggested that, at least in that region, the inciting event may be pharyngeal colonization with H. parainfluenzae [106].
While a number of different exogenous antigens have been identified in glomerular deposits in IgAN, this observation is not consistently reported across all studies. As a result, it seems more probable that the development of IgAN is a consequence of a dysregulated mucosal IgA immune response rather than a specific IgA response to a specific antigen (infecting organism). Support for this view comes from genetic studies that identified susceptibility loci in genes that influence the immune response to intestinal pathogens [27].
Exogenous mucosal antigens — It has also been suggested that IgAN may result from a dysregulated mucosal IgA response to food antigens, in view of rare associations between IgAN and celiac and inflammatory bowel disease [25,111]. Mucosal IgA responses to several oral antigens, including food and vaccine antigens, are increased in patients with IgAN compared with responses in healthy individuals [112]. There is, however, no evidence for a relationship between any particular dietary antigen and risk of development of IgAN in humans. Furthermore, exclusion diets, outside of those for patients with proven celiac disease, do not improve outcomes in IgAN. Dietary restriction of gluten was studied in a clinical trial in patients with IgAN without celiac disease [113]. Although levels of proteinuria temporarily reduced (which could have been a nonspecific effect), there was no overall effect on clinical outcomes. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions'.)
Gut microbiome — There is great interest in the role of the mucosal microbiome in IgAN. The mucosal microbiome is in continuous communication with the mucosal-associated lymphoid tissues (MALT), modulating mucosal IgA responses to maintain a mucosal microenvironment that is amenable to the microbiota.
In vitro data have shown that pathogen-associated molecular patterns (PAMPs), by binding to pattern recognition receptors (PRRs) on mucosal lymphocytes, are capable of directly influencing not only IgA secretion by mucosal lymphocytes but also the expression of O-glycosyltransferases and the extent of IgA1 O-glycosylation. It is therefore possible that mucosal dysbiosis may be one of the factors responsible for dysregulated mucosal IgA synthesis and increases in circulating galactose-deficient IgA1 (Gd-IgA1) in IgAN. Indeed, the spontaneous development of IgA glomerular deposits in BAFF-overexpressing transgenic mice was dependent upon the presence of gut commensal bacteria [35]. In a separate rodent model of IgAN, mesangial IgA deposits were significantly reduced when mice were treated with broad spectrum antibiotics that rendered the gut sterile [114]. In a subsequent study using this model, fecal microbiota transplantation (FMT) was performed from healthy human subjects, those with nonprogressive IgAN, and those with progressive IgAN [115]. Microbiota from patients with progressive IgAN induced an increase in serum BAFF and Gd-IgA1 levels, while microbiota from healthy subjects led to a temporary reduction in albuminuria.
In a small cross-sectional study of the gut microbiome in IgAN, patients with progressive disease had a reduced gut microbial diversity compared with nonprogressors and healthy subjects [116]. Differences have also been reported in tonsillar crypt, salivary, and subgingival microbiomes in IgAN [117-119]. Case reports in which FMT has been performed in patients with IgAN have reported a clinical response, in terms of reductions in proteinuria [120,121].
GENETIC SUSCEPTIBILITY — Although IgAN is considered a sporadic disease, rare familial cases have been described in the United States (in eastern Kentucky) and elsewhere [122-128]. This may reflect an inherited susceptibility to develop mesangial glomerulonephritis. One study in Italy, for example, studied 269 asymptomatic, first-degree relatives of patients with IgAN [124]. Persistent microscopic hematuria was found in 42 patients (15.6 percent); biopsy confirmed the presence of IgAN in four of these patients.
Familial IgAN and susceptibility to sporadic IgAN are most likely due to variants in multiple loci involving both the major histocompatibility complex (MHC) and non-MHC susceptibility alleles [27,92,128-142]. As study sizes increase, more genetic risk alleles are being identified, and from available genome-wide association studies (GWAS), these risk alleles are most commonly associated with biological pathways and processes associated with mucosal immunity, maintenance of mucosal integrity, and pathways common to many other autoimmune diseases [27].
The frequency of subclinical IgAN in supposedly "normal" control populations means that all genetic studies thus far reported are examining clinical expression and not susceptibility to disease.
Genetic study of IgAN is further complicated by the uncertainty as to whether IgAN is truly a single entity and the presence of subclinical IgAN in apparently normal control populations. Taken together, available genetic studies suggest that IgAN is a genetically heterogeneous entity that does not have classic Mendelian inheritance attributable to a single gene locus but is a complex polygenic disease probably involving both MHC and non-MHC susceptibility alleles.
SUMMARY
●Overview – IgA nephropathy (IgAN) is an autoimmune disease resulting from dysregulation of mucosal-type IgA immune responses. The autoantigens are a specific set of IgA1 O-glycoforms displaying reduced O-linked galactosylation of the IgA1 hinge region, referred to as galactose-deficient IgA1 (Gd-IgA1). Excess levels of these O-glycoforms in the circulation produced by B cells (or plasma cells) in mucosal and/or systemic sites (eg, bone marrow) lead to the generation of hinge glycan-specific immunoglobulin G (IgG) and IgA autoantibodies by B cells in susceptible individuals, and formation of immune complexes that subsequently deposit within the glomerular mesangium. (See 'The four-hit hypothesis' above.)
●Four-Hit Hypothesis – The pathogenesis of IgAN is framed by the "four-hit hypothesis," which postulates that a sequence of four events must occur for clinically significant disease to develop (figure 1):
•Hit 1 – Increased presence in the circulation of IgA1 molecules with reduced O-galactosylation of the IgA1 hinge region (Gd-IgA1). (See 'Hit 1: Production of poorly glycosylated IgA1 (Gd-IgA1)' above.)
•Hit 2 – Production of IgG and IgA autoantibodies that recognize Gd-IgA1. (See 'Hit 2: Production of anti-Gd-IgA1 autoantibodies' above.)
•Hit 3 – Formation of circulating immune complexes containing IgG and IgA autoantibodies bound to Gd-IgA1. (See 'Hit 3: Formation of Gd-IgA1-containing circulating immune complexes' above.)
•Hit 4 – Deposition of these circulating immune complexes in the glomerular mesangium, triggering kidney injury. (See 'Hit 4: Deposition of circulating immune complexes and kidney injury' above.)
●Environmental factors – Certain environmental factors may also contribute to the pathogenesis of IgAN:
•Infections – The provocation of gross (visible) hematuria by mucosal infection in patients with IgAN has led to the view that mesangial IgA deposition may be triggered by infection. Cytomegalovirus, Haemophilus parainfluenzae, Staphylococcus aureus, and toxoplasmosis have been implicated. (See 'Infections' above.)
•Exogenous mucosal antigens – IgAN may result from a dysregulated mucosal IgA response to food antigens (and possibly respiratory tract antigens), in view of rare associations between IgAN and celiac and inflammatory bowel disease. Mucosal IgA responses to several oral antigens, including those contained within foods and vaccines, are increased in patients with IgAN compared with responses in healthy individuals; however, there is no evidence for a relationship between any particular dietary antigen and risk of development of IgAN. (See 'Exogenous mucosal antigens' above.)
•Gut microbiome – There is great interest in the role of the gut mucosal microbiome in IgAN. The gut microbiome is in continuous communication with the gut-associated lymphoid tissues (GALT), modulating mucosal IgA responses to maintain a mucosal microenvironment that is amenable to the microbiota. It is possible that gut mucosal dysbiosis may be one of the factors responsible for dysregulated mucosal IgA synthesis and increases in circulating Gd-IgA1 in IgAN. (See 'Gut microbiome' above.)
●Genetic susceptibility – Although IgAN is considered a sporadic disease, rare familial cases have been described in the United States (in eastern Kentucky) and elsewhere. Available genetic studies suggest that IgAN is a genetically heterogeneous entity that does not have classic Mendelian inheritance attributable to a single gene locus but is a complex polygenic disease probably involving both major histocompatibility complex (MHC) and non-MHC susceptibility alleles. (See 'Genetic susceptibility' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John Feehally, DM, FRCP, who contributed to an earlier version of this topic review.
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