INTRODUCTION — IgA nephropathy (IgAN) is the most common cause of primary (idiopathic) glomerulonephritis throughout most resource-abundant settings [1].
The pathogenesis and etiology of IgAN will be reviewed here. The clinical presentation, diagnosis, treatment, and prognosis of this disorder are discussed separately:
●(See "IgA nephropathy: Clinical features and diagnosis".)
●(See "IgA nephropathy: Treatment and prognosis".)
MECHANISMS OF INJURY — The initiating event in the pathogenesis of IgA nephropathy (IgAN) is the mesangial deposition of IgA, which is predominantly polymeric IgA of the IgA1 subclass (polymeric IgA1-containing J chain). Codeposits of immunoglobulin G (IgG) and complement (C3 but usually not C1q) are also commonly seen and may contribute to disease severity. Mesangial deposition of secretory IgA has also been reported, but the pathogenic significance of this is unclear [2].
There are four key elements that contribute to IgAN, and the extent to which each is operational determines the severity, course, and eventual outcome of IgAN in any individual [3]:
●Generation of circulating IgA immune complexes with chemical and biological characteristics that favor mesangial deposition
●The ability of the reticuloendothelial system to effectively remove potentially pathogenic IgA immune complexes or under-glycosylated IgA1 aggregates from the circulation
●The mesangial cell affinity for and reaction to mesangial under-glycosylated IgA1 accumulation
●An inherent tendency to respond to tissue injury by mounting a response favoring inflammation and tissue scarring (eg, activation of the complement system), which in the kidney leads to progressive kidney injury with glomerulosclerosis and interstitial fibrosis, rather than resolution of inflammation without these sequelae
The mechanisms of secondary kidney injury are probably similar to those underlying other forms of chronic kidney disease and are discussed separately:
●(See "Secondary factors and progression of chronic kidney disease".)
●(See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)
Production of pathogenic IgA — An increased plasma IgA level alone is not sufficient to produce mesangial IgA deposits. Thus, patients with IgAN must produce a pool of circulating IgA molecules with special characteristics that promote mesangial deposition.
The heterogeneity in reported abnormalities suggests that there is more than one mechanism leading to the production of pathogenic circulating IgA immune complexes [4]. The following are some of the described abnormalities in circulating IgA and its production in IgAN [4-7]:
●The serum IgA is anionic, and lambda light chains are overrepresented.
●There is an increase in the amount of polymeric IgA in the serum.
●There is a high proportion of poorly O-galactosylated IgA1. (See 'Poor O-galactosylation of IgA1' below.)
●There are alterations in IgA1 sialylation. (See 'Alterations of IgA1 sialylation' below.)
Poor O-galactosylation of IgA1 — Compared with healthy subjects without IgAN, there is an increase in the proportion of poorly galactosylated IgA1 O-glycoforms in the serum (the IgA1 hinge region is variably glycosylated in health resulting in an array of different IgA1 glycoforms appearing in the serum) (figure 1). This increase in poorly galactosylated IgA1 O-glycoforms is found in serum IgA, as well as in IgA1 eluted from isolated kidney tissue [5,6,8]. Similar findings have been reported in children with either IgAN or IgA vasculitis (Henoch-Schönlein purpura) nephritis [9]. However, patients with IgAN can produce immunoglobulin D (IgD) that is highly galactosylated, and, therefore, it is unlikely that there is an overarching "defect" in immunoglobulin O-glycosylation in IgAN [7]. In addition, only a small fraction of serum IgA1 is poorly galactosylated, and only a small proportion of IgA1-committed plasma cells are synthesizing these poorly O-galactosylated glycoforms of IgA1.
Of note, these poorly galactosylated IgA1 O-glycoforms are referred to in the literature variably as:
●"Galactose-deficient IgA1"
●"Poorly galactosylated IgA1"
●"Under-glycosylated IgA1"
●"Aberrantly glycosylated IgA1"
Existing data would suggest that these IgA1 molecules are produced by mucosally primed plasma cells and that this IgA1 is, in fact, appropriately O-glycosylated for mucosal-derived IgA; it is therefore not structurally "abnormal," "aberrant," or "deficient." Thus, we will use the term poorly galactosylated IgA1 to describe what is believed to be the pathogenic form of IgA1 in IgAN. This poorly galactosylated IgA1 is the normal 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. (See 'Source and regulation of pathogenic IgA synthesis' below.)
IgA1 molecules lacking terminal galactose units have increased in vitro affinity for the extracellular matrix components fibronectin and type IV collagen [10], which will promote mesangial deposition.
Genetic control of IgA1 O-galactosylation — There is evidence to suggest that genetic factors play an important role in determining an individual's serum IgA1 O-glycoform profile [11]. As an example, high serum levels of poorly galactosylated IgA1 have been identified in 47 and 25 percent of first-degree relatives of patients with familial and sporadic IgAN, respectively [11]. The heritability of poorly O-galactosylated 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 poorly galactosylated IgA1 was found to be as high as 80 percent [12]. However, in this same study, the heritability of serum IgA levels was only 46 percent, suggesting that O-glycosylation of IgA1 is independent of serum IgA level. (See 'Genetic predisposition' below.)
Higher serum levels of poorly galactosylated IgA1 have been associated with a polymorphism in the gene-encoding core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1), one of the enzymes responsible for O-galactosylation of IgA1 [13,14]. 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 [13]. 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 poorly galactosylated IgA1 among Chinese patients with IgAN compared with White European patients. These findings suggest that factors other than IgA1 O-galactosylation are likely to play an important role in the pathogenesis of IgAN among different ethnic populations.
In addition to genetic factors, the expression of C1GALT1, and therefore the O-galactosylation of IgA1, is also regulated by microRNA (miRNA). MiRNAs are endogenous, small (18 to 24 nucleotides long), noncoding, single-stranded RNAs that regulate gene expression at the posttranscriptional level. Specifically, miRNAs bind to the messenger RNAs of various genes and lead to their degradation.
In a study that examined the miRNA profile of 75 patients with IgAN and 75 healthy controls [15], the following findings were observed:
●Leukocytes from patients with IgAN overexpressed a specific miRNA (miR-148b), and overexpression of miR-148b correlated with decreased expression of C1GAL-T1.
●The upregulation of miR-0148b was also associated with poor O-galactosylation of IgA1.
●The binding site for miR-0148b on the messenger RNA of C1GAL-T1 corresponded to the C1GAL-T1 polymorphism that was associated with IgAN in previous studies.
Alterations of IgA1 sialylation — Changes in sialylation of IgA1 in IgAN are more contentious with increased and decreased O-sialylation being reported. Increased alpha2,3-linked and alpha2,6-linked sialylation of serum IgA1 have been reported, and it has been suggested that this increase inhibits interaction with the asialoglycoprotein receptor (ASGP-R) on liver cells resulting in a reduced rate of systemic clearance of IgA-immune complexes and persistence of these IgA-immune complexes in the circulation [16-20].
IgA-immune complexes with a high sialic acid content bind mesangial cells more strongly, differentially upregulate mesangial cell integrins and nitric oxide synthesis, and induce apoptosis and suppress mesangial cell proliferation [21-25]. In addition, it has been postulated that sialylated IgA1 is more likely to bind extracellular matrix components because of its net negative charge. By contrast, a number of studies have reported reduced sialylation of serum IgA1 and tonsillar IgA1 in IgAN [26]. The significance of reduced IgA1 sialylation is equally contentious, with studies reporting that reduced sialylation plays a variable role in IgA1 self-aggregation and IgA-immune complex formation, mesangial cell proliferation and activation, and histopathological phenotype in IgAN [10].
Crucial to the interpretation of all these studies is the reliability and specificity of the lectins used to analyze the alpha2,3-linked and alpha2,6-linked sialic acid content of IgA1. Existing mass spectrometry data support IgA1 being undersialylated in IgAN; whether this relates to the alpha2,3- or alpha2,6-linked sialic acid or both is unknown [5,27].
Source and regulation of pathogenic IgA synthesis — The association of episodic visible hematuria with mucosal infections originally led to the hypothesis that IgAN was linked with abnormal mucosal antigen handling. This was supported by the observation that mesangial IgA and the increased IgA fraction in the serum are polymeric, which is normally produced at mucosal surfaces rather than in systemic immune sites. However, mucosal polymeric IgA plasma cell numbers are normal or even reduced in IgAN, and polymeric IgA antibody levels are not elevated in mucosal secretions [28,29].
Mucosal IgA responses to mucosal antigen challenge are also reduced, compared with healthy controls. This mucosal hyporesponsiveness, while perhaps not clinically relevant, argues against the mucosal IgA system being the source of the pathogenic fraction of serum IgA.
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 [29,30]. 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 [31-34]. Thus, the overproduction of polymeric "mucosal-type" IgA1 in the serum is likely 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 [4].
In addition to the bone marrow, the tonsils may be a source of abnormal IgA that forms immune complexes and deposits in the glomeruli [35,36]. As examples, a number of in vitro studies have demonstrated synthesis of poorly galactosylated polymeric IgA1 by tonsillar B cells, and there have been reports of a fall in serum levels of poorly galactosylated IgA following tonsillectomy [36]. However, there is a range of opinions as to the importance of the tonsils in IgAN. The data evaluating the possible efficacy of tonsillectomy as a therapy for IgAN are presented elsewhere. (See "IgA nephropathy: Treatment and prognosis", section on 'Adjunctive therapies'.)
There has been increasing interest in gut-associated lymphoid tissue (GALT) as being an important source of IgA production in IgAN, as well as the interplay among GALT, the gut microbiome, and intestinal barrier permeability [37]. 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 [38]. This area has become especially relevant with the development of GALT-directed therapies. As an example, an enteric capsule formulation of budesonide designed to release active compound in the distal ileum was shown to reduce proteinuria in patients with IgAN. (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 T cell control mechanisms to IgG production [39]. As with other immunoglobulin isotypes, type 2 T cell cytokines (interleukin [IL]-4, -5, and -6) 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, although T helper type 2 (Th2) T cells are undoubtedly involved. 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 [40].
Mediators that promote B cell maturation and proliferation are likely to play an important role in driving IgAN. Serum B cell-activating factor (BAFF) levels are increased in IgAN and correlate with disease severity [41]. Transgenic mice that overexpress BAFF demonstrated an IgAN-like disease, with mesangial IgA deposition [42]. Importantly, this was dependent upon the presence of gut commensal bacteria. Levels of a proliferation-inducing ligand (APRIL), another member of the TNF ligand superfamily (TNFSF) that shares common receptors with BAFF, are also increased in IgAN and correlate with worse prognosis [43]. Both BAFF and APRIL promote B cell class switching to IgA-producing plasma cells via the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) receptor.
A specific subpopulation of B lymphocytes (CD5+ CD19+ B cells) that do not require T cell regulation for immunoglobulin production have been implicated in many immune-mediated diseases. These lymphocytes are known to produce low-affinity IgA with many of the features characteristic of pathogenic IgA and are increased in the peripheral blood of patients with IgAN [44]. Changes in CD5+ CD19+ B cell populations may underlie, in part, the dysregulated IgA secretion seen in IgAN.
Production of autoantibodies and formation of IgA1-containing immune complexes — Poorly galactosylated IgA1 O-glycoforms have an increased tendency to both self-aggregate (perhaps due to the different physiological environment of plasma compared with mucosal secretions) and form antigen-antibody complexes with IgA and IgG antibodies directed against N-acetylgalactosamine residues in the IgA1 hinge region [45-48]. Both mechanisms favor the generation of macromolecular aggregates of polymeric IgA1 and IgA-immune complexes, which are more likely to deposit in the mesangium [10,49]. Serum levels of antibodies directed against poorly O-galactosylated IgA1 are variably reported to be associated with disease activity and progressive kidney disease in IgAN [8,50,51].
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 [47,52].
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 [16]. Reduced galactosylation of the IgA1 hinge region may affect its uptake by the asialoglycoprotein receptor on hepatocytes [53]. However, one study suggests that IgA1 is cleared minimally by the liver and that this process is not affected by the absence of the hinge region; thus, the importance of hepatic clearance of IgA1 in IgAN is uncertain [54]. A second route of IgA clearance is through CD89, a fragment, crystallizable (Fc) receptor for IgA expressed by myeloid and Kupffer cells [55]. IgAN is associated with downregulated CD89 expression on circulating myeloid cells, resulting in reduced clearance [56]. It has been proposed that this downregulation is a direct consequence of binding of poorly galactosylated IgA1-containing immune complexes with CD89 [56-58].
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 [59].
●Mesangial IgA deposits disappear when kidneys with IgAN are inadvertently transplanted into recipients who originally did not have IgAN [60].
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 [61-67], including the transferrin receptor (CD71), which binds IgA and aberrantly glycosylated polymeric IgA1 [66-68].
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.
Development of glomerular injury — IgAN is generally not associated with a marked cellular glomerular infiltration, suggesting that glomerular injury is mediated by resident glomerular cells. While IgG and complement components are often codeposited, IgA alone appears sufficient to provoke glomerular injury in the susceptible individual. This occurs predominantly through IgA-induced activation of mesangial cells and local complement activation.
IgA-induced activation of mesangial cells — Polymeric IgA elicits a phenotypic transformation in mesangial cells in vitro, with mesangial cell proliferation and secretion of extracellular matrix components [4]. 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 [69]. 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 [70-73]. In addition, polymeric IgA appears to stimulate the production of a variety of proinflammatory and profibrotic molecules, such as IL-6 [4,74,75]. 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 [76,77].
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 [78-82]. (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 and TGF-beta) on podocyte phenotype (including expression of nephrin, ezrin, and podocin and TNF-alpha secretion) in IgAN [83-86]. A progressive loss of podocyte markers has been shown to occur early at sites of capsular adhesions and in capillary loops [87]. 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 [87] and the early development of glomerular capsular adhesions [88] suggest the possibility that podocyte injury occurs in IgAN and there may be a podocytopathic variant of IgAN in which podocyte injury is the principle feature, possibly due to a direct interaction between IgA immune complexes and podocytes [89,90].
Local 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 [91-94]. (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 [93]. 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 [95]. MBL is able to bind to polymeric IgA, but not monomeric IgA, and its binding results in activation of C3 and C4 [96].
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 genome-wide association studies (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 [97,98]. 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 [99,100].
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 [101].
C3 and MBL are synthesized locally by mesangial cells and podocytes [102]; 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 [103].
Generic pathways of downstream scarring — There is clear evidence of early activation of the renin-angiotensin system in IgAN [71,104]. 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 also been increasing interest in the role of endothelin-1 (ET-1) in IgAN. ET-1 is a growth factor that acts via its two receptors, endothelin-A (ETA) and endothelin-B (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 [105]. Increased ET-1 and ETB receptor staining was observed in patients with IgAN and significant proteinuria [106]. A specific ETA receptor antagonist had a protective effect against the development of histopathological lesions and proteinuria in the ddY mouse model of IgAN [107]. Endothelin receptor blockade is being evaluated in several clinical trials for the treatment of IgAN. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)
ETIOLOGY — The etiology of IgA nephropathy (IgAN) is unknown in the great majority of cases. The possibility that infections contribute to the underlying pathogenesis of this disorder has been explored, as have genetic associations.
It has also been suggested that IgAN results from hypersensitivity to food antigens, in view of its association with celiac disease. There is, however, no evidence for widespread hypersensitivity to food antigens in IgAN [108].
In our opinion, IgAN is, at least in part, an autoimmune disease resulting from dysregulation of mucosal-type IgA immune responses. The autoantigens are a specific set of IgA1 O-glycoforms displaying poor O-linked galactosylation of the IgA1 hinge region. These O-glycoforms result in the generation of hinge glycan-specific IgA and immunoglobulin G (IgG) autoantibodies in susceptible individuals. As a result, any mucosal infection or food antigen may drive the production and release of pathogenic IgA into the circulation where it has the propensity to deposit within the mesangium and trigger glomerular injury. Why patients with IgAN are predisposed to high levels of these IgA1 O-glycoform autoantigens remains unknown.
Infections — The provocation of visible hematuria by mucosal infection in patients with IgAN and the presumption that the mesangial IgA represented deposited immune complexes led to the view that IgAN was a complication of infection. Cytomegalovirus, Haemophilus parainfluenzae, Staphylococcus aureus, and toxoplasmosis have been implicated [109-115].
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 [110]. 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 [112].
With respect to a possible viral etiology, Mx-proteins in white blood cells, which are induced by type 1 interferon responses to viral infections, are not increased in IgAN, nor are Mx-protein deposits found in the glomeruli, as might have been expected if ongoing viral infection contributed to the pathogenesis of IgAN [116].
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 aberrant IgA immune response rather than the antigen (infecting organism) itself. Support for this view comes from genetic studies that identified susceptibility loci in genes that influence the immune response to intestinal pathogens [38].
Genetic predisposition — Although IgAN is considered a sporadic disease, its presence among certain families suggests there may be a genetic predisposition, at least in some individuals [117].
A familial incidence has been described in the United States (in eastern Kentucky) and elsewhere [118-123]. This relationship may be independent of environmental factors and 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 [119]. 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 [38,97,123-137].
The frequency of subclinical IgAN in supposedly "normal" control populations means that most of the genetic studies thus far reported are examining clinical expression and not susceptibility to disease. In addition, most of these studies suffer from not having taken into account the phenomenon of "population stratification" and thus may represent "false positives" due to ancestry.
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
●Pathogenesis – The initiating event in the pathogenesis of IgA nephropathy (IgAN) is the mesangial deposition of IgA, which is predominantly polymeric IgA of the IgA1 subclass (polymeric IgA1). The factors that lead to development of disease are poorly understood but are thought to include dysregulated synthesis and metabolism of IgA (resulting in IgA immune complexes with characteristics that favor mesangial deposition) and the mesangial cell reaction to mesangial IgA accumulation. (See 'Mechanisms of injury' above.)
●Etiology – The etiology of primary IgAN is generally unknown. Environmental factors including dietary antigens and mucosal infections may drive the generation of pathogenic IgA immune complexes due to a dysregulated mucosal immune system. IgAN is a complex polygenic disease that involves both major histocompatibility complex (MHC) and non-MHC susceptibility alleles. (See 'Infections' above and 'Genetic predisposition' 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.
