Iga Nephropathy, Susceptibility To, 1



End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide, affecting up to 1.3% of the population. Kidneys of patients with IgA nephropathy show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium. Typical clinical features include onset before age 40 with hematuria and proteinuria, and episodes of gross hematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence (Julian et al., 1985; D'Amico, 1987) and familial clustering (Scolari et al., 1999), along with subclinical renal abnormalities among relatives of cases, suggest a genetic component (Gharavi et al., 2000).

Genetic Heterogeneity of IgA Nephropathy

A locus for familial IgA nephropathy, called IGAN1, on chromosome 6q22-q23, was described by Gharavi et al. (2000). Another locus, IGAN2 (613944), was identified by Paterson et al. (2007) on chromosome 2q36. IGAN3 (616818) is caused by mutation in the SPRY2 gene (602466) on chromosome 13q31.

Polymorphisms in the ACE (106180) and AGT (106150) genes have been associated with progression to chronic renal failure in patients with IgA nephropathy.

Clinical Features

IgA nephritis was first described by Berger and Hinglais (1968).

Katz et al. (1980) reported 2 brothers with typical clinical and pathologic features of IgA nephritis. One presented with gross hematuria in association with an upper respiratory tract infection and both continued to show persistent microscopic hematuria with normal renal function and an absence of systemic complaints. Renal biopsies showed generalized, segmental mesangial matrix increase with a predominance of IgA in mesangial regions and dense deposits on electron microscopy in a similar location. Another brother and 3 other members of this family had signs of glomerulonephritis.

Bene et al. (1983) stated that the presence also of C3, C9, and occasionally factor B and properdin in the mesangial deposits in Berger disease indicates that the disease is an 'immune complex nephritis.' They noted that recurrent upper respiratory infections or intestinal disease such as celiac disease or inflammatory bowel disease frequently antedate nephritis.

Coppo et al. (1986) reported that a gluten-free diet resulted in a decrease in levels of IgA containing immune complexes in patients with primary IgA nephropathy. They proposed that, in these patients, gluten may act to enhance an abnormal absorption of various alimentary antigens, rather than as a direct immunogen. Thus, dietary factors may have a pathogenetic role in primary IgA nephropathy and may explain its uneven geographic distribution.

Levy (1989) commented on the familial association of Berger disease and anaphylactoid purpura. It was suggested that IgA nephropathy and anaphylactoid purpura may share the same immunologic mechanisms and may also be the consequence of an inherited susceptibility. The possible usefulness of linkage studies was suggested.

Julian et al. (1988) suggested that IgA nephropathy is the most common form of glomerular nephritis worldwide. Initially, the prognosis of IgA nephropathy was presumed to be benign; however, it was later recognized that more than 50% of patients develop insidious chronic renal failure. Pharmacologic blockade of angiotensin I converting enzyme (ACE; 106180) attenuates a progression of chronic glomerular disease in several experimental models and the use of ACE inhibitors slows the progressive decline of renal function in diabetic patients.


Bene et al. (1983) presented evidence for a mucosal origin for the mesangial IgA present in kidneys in IgA nephropathy.

Tomana et al. (1997) found that serum IgA1 protein isolated from patients with IgA nephropathy were galactosylated to a lesser degree compared to controls. The galactose deficiency was in the O-linked side chains located in the hinge region of the IgA1 molecule (see IGHA1; 146900). Incompletely galactosylated IgA1 was detected in complexes with IgG. The patients studied by Tomana et al. (1997) included a mother and 2 daughters who all showed deficient galactosylation of hinge region glycans, suggesting a genetic component. The findings supported the hypothesis that the formation of abnormal IgA1-IgG complexes impairs the rate of elimination and hepatic catabolism of IgA1 in patients with IgA nephropathy.

In renal glomeruli specimens isolated from 3 patients with IgAN, Allen et al. (2001) found that lectin binding to tissue IgA1 unglycosylated O-glycans was higher than that of serum IgA1 from the same individual and that of all serum samples from other IgAN patients except for 1 sample. The findings indicated that abnormally O-glycosylated IgA1 molecules show selective and preferential deposition in the mesangium.

Using mass spectrometry to evaluate 290 renal biopsy specimens and 4 serum samples from patients with IgAN, Hiki et al. (2001) found that the numbers of carbohydrates composing O-glycans in the hinge region of IgA1 were significantly fewer in both deposited and serum IgA1 molecules in patients compared to controls.

Suzuki et al. (2008) established EBV-immortalized cell lines from circulating IgA1-producing B cells derived from patients with IgAN. The degree of Gal deficiency in O-glycans on IgA1 in the cell supernatants was equivalent to that on serum IgA1. Further studies of these cell lines showed excess sialylation of GalNAc on the Gal-deficient O-linked glycans of IgA1 in IgAN cell lines. There was decreased expression and activity of C1GALT1 (610555), a galactosyltransferase, and its molecular chaperone C1GALT1C1 (300611) in IgAN cells compared to controls. In contrast, STGALNAC2 (610137), a sialyltransferase, showed increased expression and activity in IgAN cells. Suzuki et al. (2008) concluded that premature sialylation underlies the IgA1 Gal deficiency in IgA nephropathy.

Population Genetics

Katz et al. (1980) stated that the frequency of IgAN is said to be low in Britain and high in France, Australia, Hungary, and parts of North America.

McCoy et al. (1974) stated that the disorder is rare in blacks and Jennette et al. (1985) confirmed this.

Donadio and Grande (2002) stated that the prevalence of IgA nephropathy appears to be highest in Asia (Singapore, Japan, and Hong Kong), Australia, Finland, and southern Europe, with much lower prevalence rates in the United Kingdom, Canada, and the United States.

Donadio and Grande (2002) stated that the reported incidence in 3 regions in France and 1 each in the Netherlands, Germany, and Italy varied from 15 to 40 new cases per million population per year. In contrast, a study in the United States reported an increase from 5 cases (from 1975-1979) to 12 cases (from 1990-1994) per million population per year (in eastern and central Kentucky).

Donadio and Grande (2002) stated that IgA nephropathy may affect up to 1.3% of the worldwide population.

Wyatt and Julian (2013) noted that in the United States, the annual incidence of biopsy-documented IgA nephropathy is about 1 case per 100,000 persons, representing a lifetime risk of about 1 in 1,400. In New Mexico from 2000 to 2005, the incidence was highest among Native Americans, intermediate among Hispanics, and lowest among non-Hispanic whites. The annual incidence among children in the United States is about 0.5 cases per 100,000; however, in Japan, the incidence is 10 times as high. Furthermore, Wyatt and Julian (2013) noted that about 5% of individuals with IgA nephropathy have family members who are similarly affected, and that Henoch-Schonlein purpura nephritis and IgA nephropathy may occur in the same family.


Julian et al. (1985) described a remarkable familial aggregation of IgA nephropathy in patients from central and eastern Kentucky. 'Potentially related pedigrees containing 14 patients' were uncovered. An additional 17 members of the pedigree had clinical glomerulonephritis, and 6 had 'chronic nephritis' noted on their death certificates. A common ancestor was identified for 6 patients with IgA nephropathy. Particular HLA association could not be established. Although the experience suggested a genetic factor, the authors concluded that the mode of inheritance cannot be clearly defined. They stated that consanguinity was not increased in their population. Two of the largest series of cases were reported by Croker et al. (1983) and Jennette and Wall (1983) from North Carolina, the region from which the ancestors of many of the Kentucky families came.

Asamoah et al. (1987) studied plasma IgA concentration in 94 members of an eastern Kentucky family and 197 members of a Louisiana family. Some members of the Kentucky family had clinical and biopsy-proven IgA nephropathy. Segregation analysis suggested the existence of a recessive allele for high plasma IgA concentration. This allele was only slightly more prevalent in the Kentucky than in the Louisiana family, indicating that it is a minor, rather than a major, etiologic factor in IgA nephropathy. A lod score of 1.50 at 0% recombination was obtained for linkage of this locus with the ABO blood group locus (110300) on chromosome 9q34.

Hsu et al. (2000) reviewed evidence for genetic factors in the development and progression of IgAN, including the evidence for racial differences in its prevalence, a detailed summary of all reported occurrences of familial IgAN, and an exhaustive review of insights gained through the study of 2 mouse models of hereditary IgAN. They suggested that genetic analysis of clinically characterized large IgAN multiplex families and association studies complemented by family-based methods such as the transmission/disequilibrium test (TDT) could best identify disease/susceptibility genes.

Clinical Management

Donadio and Grande (2002) reviewed the clinical management of IgA nephropathy.

Wyatt and Julian (2013) reviewed IgA nephropathy, including its management.


By genomewide analysis of linkage in 30 multiplex IgA nephropathy kindreds, Gharavi et al. (2000) demonstrated linkage of an IgA nephropathy locus (IGAN1) to 6q22-q23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked.

Loci Pending Confirmation

Following up on the report of Gharavi et al. (2000), which mapped the IGAN1 locus on 6q22-q23, the partners of the European IgAN Consortium (Bisceglia et al., 2006) organized a second genomewide scan in 22 new informative Italian multiplex families. The new study involved a total of 186 subjects (59 affected and 127 unaffected) who were genotyped and included in a 2-stage genomewide linkage analysis. The regions 4q26-q31 and 17q12-q22 exhibited the strongest evidence of linkage by nonparametric analysis. These locations were also supported by multipoint parametric analysis, in which peak lod scores of 1.83 and 2.56 were obtained. The results provided further evidence of genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions was considered consistent with both an oligo/polygenic and a multiple susceptibility gene model for familial IGAN, with small or moderate effects in determining the pathologic phenotype.

Gharavi et al. (2011) carried out a genomewide association study of IgA nephropathy in 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow-up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. Gharavi et al. (2011) identified 3 independent loci in the major histocompatibility complex on chromosome 6p21, the strongest of which was represented by rs9275596, with a combined p value of 1.59 x 10(-26). The C allele of rs9275596 is a protective allele with an odds ratio of 0.62 in the heterozygous state and 0.43 in the homozygous state. Gharavi et al. (2011) also found a common deletion of CFHR1 (134371) and CFHR3 (605336) at chromosome 1q32 and a locus at chromosome 22q12 that both surpassed genomewide significance. The 5 loci they identified explained 4 to 7% of the disease variance and up to 10-fold variation in interindividual risk. Gharavi et al. (2011) observed that many of the alleles that protect against IgA nephropathy imparted increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely paralleled the variation in disease prevalence among Asian, European, and African populations, suggesting complex selective pressures.

Yu et al. (2012) performed a 2-stage genomewide association study of IgA nephropathy in Han Chinese with 1,434 affected individuals and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. Yu et al. (2012) identified associations at 17p13 (rs3803800, p = 9.40 x 10(-11), odds ratio = 1.21; rs4227, p = 4.31 x 10(-10), odds ratio = 1.23); and 8p23 (rs2738048, p = 3.18 x 10(-14), odds ratio = 0.79) that implicated the genes encoding TNFSF13 (604472) and alpha-defensin (DEFA1; 125220) as susceptibility genes. In addition, Yu et al. (2012) found multiple associations in the major histocompatibility complex (rs660895, p = 4.13 x 10(-20), odds ratio 1.34; rs1794275, p = 3.43 x 10(-13), odds ratio = 1.30; rs2523946, p = 1.74 x 10(-11), odds ratio = 1.21) and confirmed a previously reported association at 22q12 (rs12537, p = 1.17 x 10(-11), odds ratio = 0.78). Yu et al. (2012) found that rs660895 was associated with clinical subtypes of IgAN (p = 0.003), proteinuria (p = 0.025), and IgA levels (p = 0.047). Yu et al. (2012) concluded that IgAN is associated with variants near genes involved in innate immunity and inflammation.

Molecular Genetics

Associations Affecting Progression to End-Stage Renal Disease

Yoshida et al. (1995) studied 53 patients with biopsy-proven IgA nephropathy in whom creatinine clearance had been monitored over 5 years. Studying polymorphism of the ACE gene consisting of insertion (I) or deletion (D) (106180.0001) of a 287-bp DNA fragment, they found that 43% of patients who showed decline of renal function had the DD homozygous genotype, whereas it was present in only 7% of age-matched individuals without a history of the proteinuria and in only 16% of a group of patients with IgA nephropathy and stable renal function. After 48 weeks of ACE inhibitor administration, proteinuria significantly decreased in patients with the DD genotype but not in those with ID or II genotypes. The results indicated that the deletion polymorphism in the ACE gene, which maps to chromosome 17q23, is a risk factor for progression to chronic renal failure in IgA nephropathy, and that the deletion polymorphism predicts therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function.

Pei et al. (1997) could not demonstrate a relationship between either the insertion/deletion polymorphism of the ACE gene or the 1166A-C polymorphism of the angiotensin II type 1 receptor gene (AT2R1; 106165) and IgA nephropathy disease progression or proteinuria in univariate analysis. However, studying the met235-to-thr polymorphism of the angiotensinogen gene (AGT; 106150.0001), they found that patients with the AGT MT (79) and TT (29) genotypes had a faster rate of deterioration of creatinine clearance than those with the MM (60) genotype. Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype. Multivariant analysis detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype. Neither of these gene polymorphisms was associated with systemic hypertension. Thus, Pei et al. (1997) suggested that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy. AGT maps to chromosome 1q42-q43.

Associations Pending Confirmation

In a family in which 2 brothers had IgA nephropathy and 3 other members had urinary sediment abnormalities characteristic of glomerulonephritis, Katz et al. (1980) found that all 5 and only 1 unaffected member of the family were HLA-identical (HLA-Bw35; see 142830). Katz et al. (1980) noted 2 other reports of IgA nephritis in HLA-identical brothers, also with HLA-Bw35 (Sabatier et al., 1979; Tolkoff-Rubin et al., 1978).

Shimokawa et al. (2000) identified 2 polymorphisms (T-to-C transitions) in the functional promoter region of the FCAR gene on chromosome 19q13.4: at positions 114 bp upstream (-114) and 56 downstream (+56) relative to the major transcription start site. They also demonstrated that these polymorphisms affect reporter gene expression driven by the FCAR promoter in a monocytic cell line. Tsuge et al. (2001) examined these polymorphisms in 90 patients with IgA nephropathy (161950), in comparison with 50 patients with other primary glomerulonephritis, and 83 healthy adults. The frequency of the +56C allele in patients with IgA nephropathy (0.511) was significantly (P less than 0.01) higher than that in patients with other primary glomerulonephritis (0.350) and healthy adults (0.337). In addition, a significant increase in the frequency of the +56CC homozygous genotype was observed in patients with IgA nephropathy (27.8% vs approximately 10.0% in the other 2 groups). The frequency of the -114CC homozygous genotype in patients with IgA nephropathy was significantly increased compared with those in both control groups.

Accumulation of leukocytes within the glomerulus and interstitium of the kidney is considered to be a key pathogenetic mechanism in various types of glomerulonephritis. The selectins represent one group of adhesion molecules involved in these interactions. Evidence from various sources suggested an involvement of E-selectin (SELE; 131210), L-selectin (SELL; 153240), and perhaps P-selectin (SELP; 173610), as reviewed by Takei et al. (2002). The genes for these 3 forms of selectin are clustered on 1q24-q25. Takei et al. (2002) found that 2 single-nucleotide polymorphisms (SNPs) in the E-selectin gene and 6 SNPs in the L-selectin gene were significantly associated with IGAN in Japanese patients. All 8 SNPs were in almost complete linkage disequilibrium.

Obara et al. (2003) performed a case-control association study involving 389 Japanese patients with immunoglobulin A nephropathy (IgAN; 161950) and 465 controls. A significant association was found between IgAN and 6 SNPs in the PIGR gene on chromosome 1q31-q41. One of the SNPs, PIGR17, caused an amino acid substitution from alanine to valine at codon 580. Another SNP, PIGR2, may affect promoter activity. Pairwise analyses demonstrated that all 6 SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not.

In 271 patients with biopsy-proven IgA nephropathy, Song et al. (2003) analyzed the CYP11B2 -344C-T polymorphism (124080.0010) and investigated a possible association between the polymorphism and the prognosis of renal function using the Kaplan-Meier method and Cox proportional hazards regression model. They found that at the time of renal biopsy there was no difference among the genotypes in any clinical manifestations, including age, gender, urinary protein excretion, and blood pressure. Predictive risk factors for progressive renal dysfunction were identified as hypertension, urinary protein of more than 1.0 g/day, and no administration of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in both female and male patients. However, even after adjusting for these risk factors, the CC genotype of CYP11B2, which maps to chromosome 8q21, was a significant risk factor only in female patients with a hazard ratio of 4.284 (p = 0.0022). In contrast, no effect at all was observed in male patients.

Song et al. (2003) studied the association of the 161C-T polymorphism in the PPARG gene, which maps to chromosome 3p25, in IgA nephropathy. They analyzed the association of the polymorphism with renal prognosis in IgAN patients using the Kaplan-Meier method and Cox proportional hazard regression model. The PPARG polymorphism was not associated with renal survival rate. However, when patients were stratified into those either with or without hypertension at the time of diagnosis, the renal survival of the CT/TT genotypes was significantly better in those without hypertension than those with the CC genotype. Thus, Song et al. (2003) concluded that the PPARG 161C-T polymorphism is associated with the survival of IgAN patients without hypertension, and that the T allele of the polymorphism may have a protective effect on the progression of IgAN.

In a study of 216 Korean patients with IgA nephropathy who were followed for 86 months, Yoon et al. (2003) found that an excess of the -159C polymorphism of the CD14 gene (158120), which maps to chromosome 5q31, occurred in patients with progressive disease (p = 0.03) and the risk of disease progression increased as the number of C alleles increased (p for trend = 0.002). The hazard ratio for progression in patients with the CC genotype was 3.2 (p = 0.025) compared to patients with the TT genotype. After lipopolysaccharide stimulation, soluble CD14 was released more abundantly from the peripheral blood mononuclear cells of TT patients than from those of CC patients (p = 0.006), although there was no difference in membrane-bound CD14 expression. TT patients released less IL6 (147620) than CC patients after stimulation (p = 0.0003). Yoon et al. (2003) suggested that the CD14 -159 polymorphism is an important marker for the progression of IgA nephropathy and may modulate the level of the inflammatory response.

Animal Model

Zheng et al. (1999) generated transgenic mice expressing uteroglobin (UGB; 192020) antisense RNA and UGB knockout mice. These mice had abnormal glomerular deposition of fibronectin (FN1; 135600) and collagen. Deposition was greater in the mice lacking Ugb. Immunohistochemical analysis demonstrated IgA and C3 (120700) accumulation in the glomeruli of both mouse models, but not accumulation of IgM or IgG. Deposition was moderate in heterozygous mice and heavy in homozygous null mice. The histologic findings were accompanied by high levels of circulating IgA-FN complexes. The Ugb-deficient mice also developed microhematuria, as seen in human IgAN. In vitro, ELISA analysis showed that Ugb inhibits the formation of IgA-FN complexes. Fluorescence microscopy demonstrated that Ugb -/- mice coinjected with IgA and UGB failed to deposit IgA in the glomerulus. RT-PCR analysis of isolated glomeruli showed increased expression of Fn and collagen (type IV; see 120130) as well as platelet-derived growth factor (Pdgf; see 190040) in Ugb -/- mice compared with Ugb +/+ mice. Immunohistochemical analysis indicated increased expression of Pdgf mRNA but not transforming growth factor-beta (190180) mRNA in the knockout mice. Zheng et al. (1999) proposed that the lung-derived circulating factor that prevents IgAN may be UGB and that the Ugb knockout mouse represents a valid model of human IgAN that has almost all of its clinical features.

Wang et al. (2004) examined a murine model that spontaneously develops T cell-mediated intestinal inflammation accompanied by pathologic features similar to those of human IgA nephropathy. Intestinal inflammation mediated by member 14 of the tumor necrosis factor ligand superfamily (TNFSF14; 604520), which is a ligand for the lymphotoxin-beta receptor (LTBR; 600979), not only stimulated IgA overproduction in the gut but also resulted in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Engagement of Ltbr by Tnfsf14 was essential for both intestinal inflammation and hyperserum IgA syndrome in this model. Wang et al. (2004) found increased IgA-producing cells in the gut, elevated serum IgA levels, and severe hematuria in a majority of patients with inflammatory bowel disease (see IBD1; 266600). The authors concluded that dysregulated TNFSF14 expression and intestinal inflammation are critical to the pathogenesis of IgA nephropathy.