IgA Nephropathy

Updated: Oct 11, 2017
  • Author: Mona Brake, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Background

Immunoglobulin A (IgA) nephropathy is characterized by predominant IgA deposition in the glomerular mesangium. [1] It is the most common cause of glomerulonephritis in the world. [2, 3] IgA nephropathy was first described by Berger and Hinglais in 1968, and is also known as Berger disease. [4]

IgA nephropathy is highly variable, both clinically and pathologically. Clinical features range from asymptomatic hematuria to rapidly progressive glomerulonephritis (RPGN). IgA nephropathy is most often associated with microscopic hematuria or recurrent macroscopic hematuria, and spontaneously resolving acute kidney injury can occur. Although it is a benign disease in most patients, as many as 40% of patients may eventually progress to chronic kidney disease and end-stage renal disease (ESRD). [5]

Pathologically, a spectrum of glomerular lesions can be seen, but mesangial proliferation with prominent IgA deposition is observed in almost all biopsies. See the images below.

Light microscopy of a glomerulus from a patient wi Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.
Immunofluorescence microscopy demonstrating large Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Although IgA nephropathy is a limited nonsystemic renal disease, many systemic diseases are sporadically associated with mesangial IgA deposition. Henoch-Schönlein purpura (HSP), a systemic illness, has been closely linked to IgA nephropathy. Other systemic diseases in which mesangial deposits of IgA are regularly observed include systemic lupus erythematosus, hepatitis, dermatitis herpetiformis, and ankylosing spondylitis.

For discussion of this disorder in children, see Pediatric IgA Nephropathy.

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Pathophysiology

IgA nephropathy appears to result from an ordered sequence of events, starting with galactose-deficient IgA1, which contains less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains. [6] .These may act as auto-antigens that trigger the production of glycan-specific autoantibodies and the formation of circulating immune complexes that are deposited in renal mesangium. These then induce glomerular injury through pro-inflammatory cytokine release, chemokine secretion, and the resultant migration of macrophages into the kidney. [7]

Deposited IgA is predominantly polymeric IgA1, which is mainly derived from the mucosal immune system. The association of some cases of IgA nephropathy with syndromes that affect the respiratory tract or gastrointestinal tract, such as celiac disease, led to the suggestion that IgA nephropathy is a disease of the mucosal immune system. This concept is also supported by the clinical observation that hematuria worsens during or after upper respiratory tract or gastrointestinal tract infections.

The role of the complement system in the pathogenesis of IgA nephropathy is controversial. While IgA antibodies cannot activate complement through the classic pathway, studies have shown that complement can be activated by the alternate pathway.

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Epidemiology

Frequency

United States

IgA nephropathy accounts for about 10% of biopsies performed for glomerular disease in the United States. Prevalence rates are lower in the United States than in Asian countries. These lower rates may be influenced by a conservative approach by nephrologists in the United States, who are reluctant to perform renal biopsies in asymptomatic patients with only mild abnormalities on urinalyses.

International

Distribution of IgA nephropathy varies in different geographic regions throughout the world. IgA nephropathy is observed in up to 40% of all biopsies performed for glomerular disease in Asia, compared with 20% in Europe and 10% in North America. High prevalence rates are observed in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, whereas low prevalence rates are the rule in the United Kingdom, Canada, and the United States.

A study from Scotland found a significant twofold increase in the diagnosis of IgA nephropathy in the patients residing in the most compared with the least deprived areas. The variation was not explained by the demographics of the underlying population. [8]

In Asia, routine urinalyses are performed for schoolchildren, and renal biopsies are performed for patients with asymptomatic hematuria, thus raising the reported prevalence of the disease. The estimated annual incidence in Japan is 3.9–4.5 per 100,000 population. [9]

The prevalence of IgA nephropathy is highest in geographic areas with large numbers of endemic helminthic species that infect humans, and most of the IgA nephropathy susceptibility loci identified by genome-wide association studies include genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens, which would confer protection against helminthic infestation. Thus, the increased risk of IgA nephropathy in these populations may be an untoward consequence of a protective adaptation to helminthic infections. It would also explain the association of mucosal infections as a frequent trigger for IgA nephropathy. [10]

Mortality/Morbidity

This disorder is thought to follow a benign course in most cases. However, many patients are at risk for slow progression to ESRD, which develops in approximately 15% of patients by 10 years and 20% by 20 years, though these percentages depend on how the disease is defined.

Race-, Sex-, and Age-related Demographics

IgA nephropathy is more common in whites and Asians and is rare in blacks, both in the United States and in Africa. The condition is frequently observed in Native Americans of the Zuni and Navajo tribes.

IgA nephropathy is more common in males than in females. Virtually all studies show a male predominance of at least 2:1, with reported ratios of up to 6:1. [11] The higher male predilection is observed in white patients in northern Europe and the United States.

IgA nephropathy can affect all ages but is most common in the second and third decades of life. Eighty percent of patients are aged 16-35 years at the time of diagnosis. The condition is uncommon in children younger than 10 years.

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