IgA nephropathy is a common kidney disease affecting the glomeruli, the tiny filtering units within the kidneys. This condition is characterized by the accumulation of an immune protein called immunoglobulin A (IgA) within these filters. Understanding how this protein buildup occurs and subsequently damages the kidneys is key to grasping the disease’s progression.
Understanding IgA and Its Initial Abnormality
IgA is a normal part of the body’s immune system, functioning as an antibody that primarily defends against infections at mucosal surfaces, such as those lining the gut and respiratory tract. It serves as a first line of defense, binding to pathogens and triggering an immune response to eliminate them.
In IgA nephropathy, a specific abnormality occurs in the IgA1 molecule, a subclass of IgA. This defect involves a lack of certain sugar molecules, specifically galactose, in a part of the IgA1 molecule known as its hinge region. This altered form is referred to as “galactose-deficient IgA1” (Gd-IgA1). Patients with IgA nephropathy often have elevated levels of this galactose-deficient IgA1 in their bloodstream.
The Immune System’s Misdirected Attack
The body’s immune system mistakenly identifies this galactose-deficient IgA1 (Gd-IgA1) as abnormal or foreign. This misidentification leads to the production of other antibodies, specifically IgG or IgA autoantibodies, that target and bind to the abnormal Gd-IgA1. When these antibodies bind to Gd-IgA1, they form larger structures called “immune complexes.”
These immune complexes then circulate through the bloodstream and become trapped and deposited within the mesangium, the central area of the glomeruli in the kidneys. This deposition of immune complexes within the kidney filters is a defining feature of IgA nephropathy.
The presence of these immune complexes in the mesangium triggers an inflammatory response. This activation recruits various immune cells to the site, leading to swelling and further immune system activation within the kidney. The complement system, another part of the immune defense, is also activated, contributing to the inflammatory cascade.
Kidney Damage and Its Long-Term Effects
The deposition of immune complexes and inflammation damage the kidney’s filtering units. The ongoing inflammatory process and immune cell activity cause mesangial cells within the glomeruli to proliferate, meaning they multiply excessively. These cells also increase their production of extracellular matrix components, which are proteins and carbohydrates that normally provide structural support.
This excessive cell proliferation and matrix production gradually lead to scarring within the glomeruli, a process known as fibrosis or glomerulosclerosis. As the glomeruli become scarred, their ability to filter waste products and excess water from the blood is impaired. This progressive damage also compromises the kidney’s ability to retain essential proteins, causing them to leak into the urine.
The impaired filtering and protein leakage manifest as common signs of IgA nephropathy, such as blood in the urine (hematuria) and protein in the urine (proteinuria). Hematuria can be microscopic, visible only under a microscope, or macroscopic, appearing as reddish or cola-colored urine. Proteinuria can range from mild to severe, sometimes causing foamy urine or swelling in the hands and feet. Over time, the continuous damage can lead to a decline in overall kidney function, potentially progressing to chronic kidney disease and, in some cases, kidney failure, which may require dialysis or a kidney transplant.
Factors Influencing Disease Development
Genetic and environmental factors contribute to IgA nephropathy development. There is evidence of a genetic predisposition, as a family history of IgA nephropathy can increase an individual’s risk. Studies have identified certain genes, often related to immune system regulation, that may play a role in susceptibility.
Environmental triggers also influence the disease, particularly mucosal infections. Respiratory or gastrointestinal infections are frequently observed to precede flare-ups of IgA nephropathy. These infections may stimulate the production of the abnormal galactose-deficient IgA1 or influence the immune system’s response to it, thereby contributing to the disease process.