Elsevier

Seminars in Nephrology

Volume 28, Issue 1, January 2008, Pages 27-37
Seminars in Nephrology

Secondary IgA Nephropathy

https://doi.org/10.1016/j.semnephrol.2007.10.004Get rights and content

Summary

IgA nephropathy (IgAN) is the most common pattern of primary glomerulonephritis seen in the Western world. In the majority of cases the cause remains unknown. Cases of familial IgAN and secondary IgAN have been reported and these have provided insights into underlying genetic and environmental triggers for this common glomerular disease. Secondary IgAN is seen most commonly in patients with liver disease or mucosal inflammation, in particular affecting the gastrointestinal tract. A number of dietary and microbial antigens have been identified in circulating IgA immune complexes and mesangial IgA deposits, suggesting that environmental factors may play a role in the pathogenesis of IgAN. There is an increasing literature reporting associations between IgAN and other diseases. Whether these reports represent chance associations or genuine shared pathophysiology is discussed.

Section snippets

Epidemiology of Secondary IgA Nephropathy

Compared with primary IgAN very little is known about the incidence of secondary IgAN. In the series from France reported by Berthoux, pp. 4-9, in this issue IgAN secondary to cirrhosis accounted for 9% of all biopsy-proven cases of IgAN over a 12-year period. Similar to primary IgAN, the apparent prevalence of secondary IgAN will be influenced by renal biopsy practice, for example, in high-risk patients with coagulopathy secondary to hepatic dysfunction. IgAN typically is considered to be a

Pathophysiologic Relationship of Primary and Secondary IgA Nephropathy

The initiating event in the pathogenesis of primary and secondary IgAN is the mesangial deposition of IgA. The recurrence of glomerular IgA deposits in up to 60% of patients with primary IgAN who receive renal allografts indicates that mesangial IgA probably is derived from a circulating pool of pathogenic IgA.18 Not all IgA that deposits in the mesangium triggers a mesangial response characterized by glomerular injury, arguing that mesangial IgA deposition and the development of

Environmental Antigens

Many studies have found increased circulating IgA-IC containing food antigens in IgAN12, 13, 14, 21, 22 and a number of studies have reported changes in various clinical and laboratory parameters on exposure to specific foods.15, 22 Circulating IgA antibodies to a variety of milk and egg proteins including casein and bovine serum albumin have been reported in IgAN15, 23 and indirect immunofluorescence has identified mesangial IgA-IC deposits containing casein, soybean protein, and rice protein.

IgA Synthesis

IgA synthesis requires close cooperation between B and T lymphocytes and precise regulation of the lymphocytic microenvironment. It is therefore not surprising that clonal disorders of predominantly B-lineage cells (lymphoma and IgA myeloma) have been linked on occasion with excessive IgA production and IgAN.6, 32 Interestingly, in the majority of cases high circulating levels of IgA alone are insufficient to cause IgAN, it is only when the monoclonal IgA has specific physicochemical

Clearance of Circulating IgA Containing Immune Complexes

IgA normally is cleared from the circulation by the liver and by leukocytes through receptor-mediated endocytosis. A study in primary IgAN using radiolabelled complexes of IgA and IgG from normal individuals has shown reduced hepatic clearance in IgAN.33 Hepatocytes express an asialoglycoprotein receptor (ASGP-R) that recognizes asialyl N- and O-linked carbohydrate chains on a wide variety of glycoproteins including IgA.34 Hepatic ASGP-R–mediated endocytosis therefore is likely to be an

Hepatic IgAN

Hepatic IgAN occurs most frequently but not exclusively as a complication of alcoholic liver disease. Hepatic IgAN is associated with alterations in the IgA immune system characterized by high levels of circulating IgA-IC.40, 41 It has been proposed that hepatic IgAN is a chance association of 2 common conditions,42 however, most evidence suggests hepatic IgAN is a distinct clinicopathologic entity.43 Information on hepatic IgAN is based largely on autopsy and biopsy studies.42, 44, 45, 46, 47,

Celiac Disease

CD is characterized by malabsorption, chronic mucosal inflammation affecting the small intestine, and villous atrophy. These occur as a direct result of exposure to wheat gluten or related rye and barley proteins. It is associated strongly with HLA-DQ2 and/or DQ8, but there also may be a contributory effect from non-HLA genes.66 CD has been associated with a wide range of diseases and immune disorders including IgAN.67 The presence of high levels of IgA against food antigens including gliadin

IgAN Secondary to Mucocutaneous Infection

As previously discussed, acute and chronic infection with a range of pathogens can be associated with both acute exacerbation and slow progression of primary IgAN. This is seen most commonly with mucosal infection including tonsillitis, pharyngitis, infections of the upper and lower gastrointestinal tract, urinary tract, and respiratory tract. There are also case reports documenting associations with periodontal disease and tooth abscesses. There is currently no evidence in human beings that

Conclusions

Without a clearer understanding of the pathogenesis of primary IgAN it remains difficult to dissect out those diseases in which there is only a chance association with primary IgAN and those diseases in which there might be shared pathophysiology. In our opinion many of the associations in the literature describe environmental and microbial triggers in primary IgAN, which undoubtedly drive the generation of pathogenic IgA and mesangial IgA deposition, but do not induce fundamental changes in

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