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 ... 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 6q22-q23, was described by Gharavi et al. (2000). Another locus, IGAN2 (613944), was identified by Paterson et al. (2007) on chromosome 2q36. Polymorphisms in the ACE (106180) and AGT (106150) genes have been associated with progression to chronic renal failure in patients with IgA nephropathy.
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 ... 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 retards the progressive decline of renal function in diabetic patients.
- 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 ... - 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.
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 ... 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.