By Donna J. Lager, M.D.
IgA nephropathy was first reported in 1968 by Berger and Hinglais and is considered to be the most common glomerulonephritis worldwide with the highest incidences reported in Asian populations (1, 2). In Japan, up to 50% of new cases of glomerulonephritis and 40% of ESRD are due to IgA nephropathy. In the United States IgA nephropathy accounts for approximately 10% of cases of glomerulonephritis, and in Western Europe, 30%. This global variation may be due to the presence of screening programs to detect urinary abnormalities, particularly in Asia, biopsy practices of Nephrologists, and race (1-4).
In a recent multi-national study of 265 patients with IgA nephropathy, the mean age at presentation was 30 years (range 4-73 years), 72% were male and 22% were children less than 18 years of age. In this group, 66% were Caucasian, 27% Asian, and only 3% African (5). Patients with IgA nephropathy may present with incidental hematuria and proteinuria discovered on routine
urinalysis, with gross hematuria concurrent with a respiratory infection or gastroenteritis, or with gross hematuria and renal dysfunction (1, 2, 4-7).
Henoch Schönlein purpura (HSP), a form of systemic vasculitis with IgA dominant immune deposits in small vessels of the skin, gut, and kidney, occurs more commonly in children 3 to 10 years of age, although adult cases are also described. Approximately 50% of cases occur before the age of 5 years. Males are affected twice as often as females and in North America Caucasians have the highest incidence and African Americans the lowest. The overall incidence in children is estimated to be 13.5 to 22.1 cases per 100,000, however, this may be an underestimation (1). The classic clinical presentation of HSP includes skin rash, polyarthralgias, abdominal pain, and renal disease. The skin rash is described as “palpable purpura” and is common on the lower extremities and arms, however, it can occur elsewhere.
The arthralgias commonly involve the joints of the lower extremities with less common involvement of upper extremity joints. Gastrointestinal symptoms include colicky abdominal pain, vomiting, and/or bleeding and occur in 50-75% of patients. Any portion of the bowel may be involved, however, jejunum and ileum are most common and complications, although rare, include bowel infarction, perforation, and intussusception. The incidence of renal disease in HSP is approximately 32% (range 20-56%) in children and 59% (range 49-78%) in adults. Chronic renal disease secondary to HSP is associated with the greatest morbidity (1, 8).
The clinical presentation of HSP-associated glomerulonephritis is variable. Most adults and children with HSP nephritis present with hematuria, including macroscopic hematuria, which is more commonly noted in children. New-onset hypertension and elevated serum creatinine in addition to hematuria (acute nephritic syndrome) are present in 30-50% of children and
adults. Most patients also have proteinuria which in 20-45% is in the nephrotic range (1).
Renal biopsies from patients with both IgA nephropathy and HSP show similar features. The glomeruli may appear normal but usually show variable degrees of mesangial proliferation. Segmental and global endocapillary proliferation may be present as well as necrotizing and crescentic disease.
The latter is more commonly seen in HSP, particularly in children (Figure 1). Chronic changes including segmental and global glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be present in more advanced disease. IgA nephropathy is defined by the presence of dominant IgA deposition (IgA1 subclass) within glomeruli on immunofluorescent staining (Figure 2). There is also variable staining for IgG, IgM, C3, and light chains, often with more prominent staining for lambda light chain. The deposits are confirmed as predominantly mesangial by electron microscopy and have a typical “paramesangial” location, adjacent to the basement membrane along the mesangial waist region (Figure 3).
The pathogenesis of IgA nephropathy is related to the presence of circulating immune complexes containing aberrantly glycosylated IgA1. There are two structurally and functionally distinct subclasses of IgA; IgA1 and IgA2. The heavy chains of IgA1 molecules contain a unique insertion in the hinge-region segment between the first and second constant region domains that has a high content of proline, serine and threonine and is the site of attachment of up to five O-linked glycan chains. The O-linked glycan chains consist of N-acetylgalactosamine with a ß1,3-linked (or a2,6 linked) galactose that may be sialylated. Galactose deficient variants with terminal N-acetylgalactosamine or sialylated N-acetylgalactosamine are more common in patients with IgA nephropathy than in normal circulatory IgA1, and are found predominantly in the glomerular immune deposits and in circulating immune complexes (9, 10).
It has been suggested that some IgA1 molecules produced by immunoglobulin-secreting cells in patients with IgA nephropathy are galactose-deficient and are recognized by anti-glycan IgG (or IgA1) antibodies. The IgA1 containing immune complexes escape normal clearance mechanisms, reach the renal circulation, pass through the fenestrae in the glomerular capillaries overlying the mesangium, bind to mesangial cells and induce glomerular injury. IgA nephropathy would, therefore, be classified as an autoimmune disease with the aberrantly glycosylated IgA1 acting as the autoantigen (9).
The outcome of patients with IgA nephropathy and HSP is favorable with 10-year kidney survivals in pediatric IgA nephropathy of 87-95% world-wide, and 78-90% for pediatric HSP (11). More than half of pediatric cases will eventually have a normal urinalysis without hematuria or proteinuria (8). Treatment of those with persistent urinary abnormalities or renal dysfunction with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) is advocated as supportive therapy, with oral prednisone or pulse high-dose methylprednisolone reserved for patients with more active disease and over 25% glomerular crescents on biopsy (8, 12).
IgA nephropathy recurs in 50-60% of patients who undergo renal transplantation for ESRD, and mesangial IgA deposits are detectable within weeks to months post-transplant. Graft loss secondary to recurrent IgA nephropathy varies from 45-70% on long-term follow-up (13).
References:
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11. Cattran DC, Coppo R, Cook HT et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney International 76:534-545, 2009.
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13. Golgert WA, Appel GB, Hariharan S. Recurrent Glomerulonephritis after Renal Transplantation: An Unsolved Problem. Clin J Am Soc Nephrol 3:800-807, 2008.
Date of last revision: October 2009.