IgA nephropathy (NORD)

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IgA is a class of immunoglobulin, or antibody, and nephropathy means kidney disease. IgA nephropathy, sometimes known as Berger disease, is the most common form of nephropathy worldwide, and it happens when an abnormal IgA forms and deposits in the kidneys, causing kidney damage.
IgA is the main antibody found in breast milk, tears, saliva, and the mucosal secretions of respiratory tract, gastrointestinal tract, and the genitourinary tract.
Unlike other antibodies, IgA can be secreted out in pairs or a dimeric form called secretory IgA, which is literally two IgA antibodies attached together.
By being bound together, it helps both antibodies avoid degradation by proteolytic enzymes in harsh environments like the gut.
Now, IgA comes in subclasses—IgA1 and IgA2, IgA1 is found mainly in the serum while IgA2 is more often found in the mucus secretions, typically in its dimeric form.
Now, the hinge region of the IgA1 heavy chain—the part that gives the antibody a bit of flexibility to bind multiple antigens without being torn apart—is made up of a string of amino acids.
Among these are serine and threonine residues which are O-linked glycosylated, meaning they have a sugar molecule, specifically galactose, attached to their oxygen.
Now these glycosylated IgA1 antibodies are identified by the body and degraded when too much of it accumulates. In IgA nephropathy, though, there is abnormal glycosylation of these serine and threonine residues, causing them to be galactose-deficient.
These galactose-deficient IgA1s are not identified by the body, and therefore not degraded, allowing them to simply accumulate in the body.
In addition, it’s thought that these galactose-deficient IgA1 antibodies are different enough from normal IgA1 antibodies that the body no longer recognizes them as self.
In response, the body generates IgG antibodies that target the abnormally glycosylated residues. And these are known as anti-glycan IgG antibodies.
When these anti-glycan IgG antibodies bind to abnormal IgA1, immune complexes are formed. These immune complexes can travel through the bloodstream where they get trapped at sites of filtration, like the kidney.
IgA nephropathy is therefore a type III hypersensitivity disorder, meaning that pathology and inflammation will happen at the site the immune complexes deposit, not where they are formed.
The immune complexes specifically deposit in the mesangium which is the tissue in the Bowman’s capsule that offers structural support to the glomerular capillaries.
In fact, the mesangium is continuous with the smooth muscles of the afferent and efferent arterioles, and fills in the space between the loops of blood vessels, hence the name.
When the abnormal IgA1-IgG immune complexes deposit in the mesangium, the alternative complement pathway is activated, leading to the release of proinflammatory cytokines and migration of macrophages into the kidney, all of which contributes to glomerular injury.
Usually the glomerulus and mesangium help filter the blood to remove wastes while keeping larger proteins and cells—including red blood cells—from entering the urine.
So when there is glomerular injury, red blood cells sneak into the urine—causing hematuria, which contributes to this being a type of nephritic syndrome.
Typically, IgA nephropathy presents in childhood as either microscopic or gross hematuria, meaning seen under a microscope or with the naked eye, and it typically develops during an infection involving the mucosal lining, like infections of the gastrointestinal or respiratory tract.
In these sorts of infections, IgA1 antibody production gets ramped up, leading to IgG anti-glycan formation, and immune complex deposition in the glomerular mesangium, causing inflammation.
With each mucosal infection, the glomeruli undergo inflammation and injury, so over time—on the scale of decades—individuals may slowly progress to renal failure.
The exact reason why the abnormal IgA1 forms in the first place is unclear, but genetic factors likely play an important role.
On light microscopy, there’ll often be mesangial proliferation, or expansion of the mesangium, and upon getting a closer look with electron microscopy, there’ll be immune complexes deposited within the mesangium.
Those immune complexes can also be visualized on immunofluorescence, although one important finding that can help differentiate from other immune-complex mediated nephropathies is that these complexes involve IgA.
These findings, though, can also be found in another IgA-mediated disease, called Henoch-Schonlein purpura or HSP, except that in IgA nephropathy only the kidney’s involved, whereas in HSP the kidneys can be affected, as well as the skin, connective tissue, scrotum, joints, and GI tract.
Once the kidneys have been scarred they can’t be repaired, so treatment is mainly focused on preventing further damage and avoiding end stage kidney disease.
Controlling the blood pressure can help, by eating well and reducing salt and cholesterol intake, as well as taking specific antihypertensive medications.
Preventing the formation of immune complexes can help In addition, corticosteroids, like prednisone, can prevent an individual’s immune system from making both the defective IgA1 as well as the anti-glycan IgG which bind together to form the immune complexes.
Alright, as a quick recap, IgA nephropathy is the most common cause of nephropathy worldwide, and it’s a type of nephritic syndrome in which abnormal IgA1 immunoglobulin is targeted by anti-gycan auto-antibodies, forming immune complexes that are then deposited in the glomerular mesangium, which then start up a type III hypersensitivity reaction which causes glomerular injury and hematuria.
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