IgA nephropathy causes
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IgA nephropathy (IgAN; sometimes called Berger disease) is a kidney condition marked by the buildup of immunoglobulin A (IgA) in the glomeruli, the kidneys’ filtering units. Over time, these IgA deposits and the body’s immune response to them can lead to chronic (long-term) kidney disease or kidney (renal) failure.
Doctors and researchers are still studying IgA nephropathy causes, but they currently think the condition involves an autoimmune process influenced by multiple environmental and genetic factors.
What causes IgA nephropathy?
There are two types of IgA nephropathy, called primary IgAN and secondary IgAN.
Primary IgAN
Experts commonly describe primary IgAN pathogenesis (how IgAN starts) using a proposed four-hit model:
- The body starts to make an abnormal form of the immune protein IgA called galactose-deficient IgA1 (gd-IgA1). Normal IgA has several sugar molecules attached to it, and gd-IgA1 is missing an important sugar called galactose. This abnormal form can be recognized by the immune system as a target.
- The immune system reacts to gd-IgA1 by making antibodies against it. These are called autoantibodies because they react against a substance produced within the body.
- Immune complexes made up of gd-IgA1 and these antibodies form in the blood and become deposited in the glomeruli.
- These deposited immune complexes activate cells in the glomeruli and parts of the immune system, leading to inflammation, cell growth, and other changes that can damage the kidneys.
Secondary IgAN
Secondary IgAN develops as a result of another condition. Conditions associated with secondary IgAN include liver disease, inflammatory bowel disease, celiac disease, psoriasis, some lung diseases and cancers, and exposure to certain medications.
IgA vasculitis
IgA vasculitis (also known as Henoch–Schönlein purpura) is very similar to primary IgAN. Like IgAN, it is thought to involve abnormal IgA and immune-complex formation. However, IgA vasculitis can affect several parts of the body, including the skin, joints, gastrointestinal tract, and kidneys. It mostly affects children and tends to be more acute (shorter-lasting) than IgAN. IgA vasculitis in children often resolves on its own, even without treatment, although it can sometimes recur.
How IgA normally helps protect the body
IgA is the second-most common immunoglobulin (antibody) in the body and is found in mucous membranes, including those of the respiratory, digestive, and genitourinary tracts. Immune protection at these surfaces is called mucosal immunity. The body makes two types of IgA with slightly different structures, called IgA1 and IgA2. IgA helps neutralize harmful bacteria, viruses, and other irritants. It also helps regulate immune responses to foreign but nonharmful substances, including substances found in food.
How immune complexes can become trapped in the kidneys
Because gd-IgA1 differs from normal IgA1, the immune system may react to it by making autoantibodies against it. These autoantibodies bind to gd-IgA1, forming immune complexes. As blood circulates through the kidneys for filtration, these immune complexes can become deposited in the glomerular mesangium, where they bind to receptors on mesangial cells.
Why kidney inflammation and scarring develop
Kidney inflammation and scarring in IgAN happen because the IgA deposits in the kidneys activate mesangial cells, causing them to multiply and produce molecules that promote inflammation and fibrosis (scarring). The activated mesangial cells also trigger other immune responses and release molecules that can affect nearby kidney cells, increasing the permeability of the glomeruli and affecting how the kidneys filter blood. Over time, these processes combine to damage the kidneys and impair their filtration ability.
Is IgA nephropathy genetic?
Elevated gd-IgA1 can be found in people who do not develop IgAN, including some relatives of people with the disease. Experts think that genetics may play a role in a person’s risk of developing IgAN. However, there isn’t one single gene that causes the condition. So far, scientists have identified at least 18 different gene segments associated with IgAN, including genes that influence the immune response, gd-IgA1 levels in the blood, and enzymes involved in attaching sugars to proteins.
Mucosal immunity, the gut, and the respiratory tract
Experts now think that autoimmune IgA nephropathy might begin because of impaired regulation of mucosal immunity. The immune cells that produce gd-IgA1 are thought to originate largely in mucosa-associated lymphoid tissue (MALT), which includes the tonsils and lymphoid tissue in the gut and respiratory tract. In fact, in Japan, where IgAN is relatively common, tonsil removal (tonsillectomy) is sometimes used as part of treatment for IgAN. However, a large European study did not find that tonsillectomy was associated with slower IgAN progression.
The relationship between infections and IgA nephropathy is complicated. Episodes of hematuria (bloody urine) in IgAN frequently coincide with upper respiratory and other mucosal infections. In some people who are genetically susceptible, infections may trigger the production of gd-IgA1, although gd-IgA1 alone is not enough to cause IgAN. Changes in the gut microbiome — the community of microorganisms that live in the gut — and immune reactions to certain foods may also contribute to IgAN development. However, these factors are not thought to be sufficient on their own to cause the disease.
What does not cause IgA nephropathy?
Although there are associations between mucosal immunity, infections, gut biology, and IgAN, no specific infection, food antigen, or other single factor is known to cause the condition. Instead, IgA nephropathy appears to develop through a complex mix of genetic and environmental factors, and most cases occur sporadically rather than as part of a known family pattern. As doctors and researchers continue to study IgAN, scientific understanding of its causes is likely to continue to improve.
IgA Nephropathy News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
