IgA nephropathy is one of the most common causes of recurrent microscopic or gross hematuria and is the most common glomerular disease revealed by renal biopsy worldwide. This condition usually affects children and young adults and begins as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper-respiratory tract infection. Typically, the hematuria lasts several days and then subsides, but it recurs periodically, usually in the setting of a viral infection. It may be associated with local pain.
The hallmark of the disease is the deposition of IgA in the mesangium. Some experts have considered IgA nephropathy to be a localized variant of Henoch-Schönlein purpura, also characterized by IgA deposition in the mesangium. In contrast with IgA nephropathy, which is confined to the kidney, Henoch-Schönlein purpura is a systemic syndrome also involving the skin (purpuric rash), gastrointestinal tract (abdominal pain), and joints (arthritis).
An abnormally glycosylated IgA1 (i.e., galactose-deficient IgA1 [Gd-IgA1]) immunoglobulin is thought to play a central role in the pathogenesis. This abnormal IgA may elicit an autoimmune response, and autoantibodies may form large immune complexes with circulating IgA. These complexes deposit in the glomerular mesangium; this unusual location may be related to physicochemical features of the IgA and may be facilitated by an IgA1 receptor (CD71) on mesangial cells. The presence of C3 in the mesangium and the absence of C1q and C4 points to activation of the alternative complement pathway in the pathogenesis. A genetic influence is suggested by the occurrence of IgA nephropathy in families and in HLA-identical siblings, and increased frequency of certain HLA and complement genotypes in some populations. Taken together, these data suggest that in genetically susceptible individuals, respiratory or gastrointestinal exposure to microbial or other antigens (e.g., viruses, bacteria, food proteins) may lead to increased IgA synthesis, some of which is abnormally glycosylated, and deposition of IgA and IgA-containing immune complexes in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. In support of this scenario, IgA nephropathy occurs with increased frequency in individuals with celiac disease, in whom intestinal mucosal defects are seen, and in liver disease, in which there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy).
Histologically,thelesionsinIgAnephropathyvaryconsiderably.
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Fig. 14.10 IgAnephropathy.CharacteristicimmunofluorescencedepositionofIgA,principallyinmesangialregions,isevident.IgA, ImmunoglobulinA.
proliferativeGN);diffusemesangialproliferation(mesangioproliferativeGN);or(rarely)overtcrescenticGN.Thecharacteristicimmunofluorescencepictureisofmesangial deposition of IgA, oftenwithC3andproperdinandsmalleramountsofIgGorIgM(
Fig.14.10 ).Earlycomponentsoftheclassicalcomplementpathwayusuallyareabsent.Electronmicroscopyconfirmsthepresenceofelectron-densedepositsinthemesangium.