Which are the causes of IgA nephropathy?

TL;DR: IgA nephropathy is an autoimmune condition caused by the abnormal deposition of galactose-deficient IgA1 immune complexes in the kidney's filtering units, leading to inflammation and damage. While the exact trigger remains unknown, the condition is likely caused by a complex interplay between genetic susceptibility, environmental factors, and an aberrant immune response.

What exactly causes IgA nephropathy?

The primary mechanism of IgA nephropathy involves the body's immune system. In a healthy person, the immune protein IgA (specifically the IgA1 subtype) circulates in the blood to help fight infections. In individuals with IgA nephropathy, these IgA1 molecules are "galactose-deficient," meaning they lack certain sugar molecules. The body mistakenly identifies these abnormal proteins as foreign and produces antibodies against them. These antibody-antigen clusters, known as immune complexes, travel through the bloodstream and become trapped in the glomeruli—the tiny filters of the kidneys. This entrapment triggers an inflammatory response, which leads to the scarring and kidney damage characteristic of the disease.

Is IgA nephropathy a hereditary condition?

IgA nephropathy is not considered a classic Mendelian genetic disorder (where a single gene mutation guarantees the disease). Instead, it has a strong genetic predisposition. Researchers have identified several susceptibility loci—specific regions on chromosomes—that increase a person's risk of developing the condition. Because 347 members of the DiseaseMaps.org community are living with this condition, we see that while it is not strictly "inherited" in a simple way, family history can play a role. It is better described as a polygenic condition, meaning multiple small genetic variations work together to make an individual more susceptible to the immune system's error.

Are there environmental triggers for IgA nephropathy?

While the underlying immune malfunction is internal, environmental factors are often the "spark" that causes the disease to flare or progress. Common factors associated with the clinical manifestation of IgA nephropathy include:

• Mucosal infections: Many patients notice symptoms shortly after a respiratory or gastrointestinal infection, as these areas are rich in IgA-producing cells.


• Dietary factors: Research suggests that gut microbiome health and certain dietary proteins may influence the production of abnormal IgA1.


• Environmental toxins: Exposure to certain environmental pollutants is currently being investigated as a potential secondary trigger.

How is the cause different from a risk factor?

It is important to distinguish between the cause and risk factors for IgA nephropathy. The cause is the specific biological failure—the production of galactose-deficient IgA1 and its subsequent deposit in the kidneys. A risk factor is a characteristic that makes it more likely for that biological failure to occur or worsen. For example, being male, of East Asian descent, or having a family history are risk factors, but they do not "cause" the disease on their own. Understanding this distinction is vital for researchers at DiseaseMaps.org who are looking into how to prevent disease progression.

What does current research tell us about the etiology?

Scientists are currently focused on the "multi-hit hypothesis" to explain the etiology of IgA nephropathy. This theory suggests that the disease only develops if a series of four "hits" occurs: (1) production of abnormal IgA1, (2) production of antibodies against that IgA1, (3) formation of immune complexes, and (4) the deposition of these complexes in the kidney. Current research is heavily invested in identifying biomarkers that can predict which patients will progress to end-stage renal disease and finding therapies that can target the production of these abnormal proteins at the source.

Next steps

• Consult a nephrologist to monitor your eGFR (estimated glomerular filtration rate) and proteinuria levels regularly.


• Join the IgA nephropathy community on DiseaseMaps.org to share experiences and track symptom triggers with others.


• Discuss with your medical team whether participating in clinical trials for new B-cell targeting therapies is appropriate for your stage of the disease.


• Maintain a heart-healthy, low-sodium diet as recommended by your renal dietitian to reduce the workload on your kidneys.

Medical disclaimer: This content is for educational purposes only and does not constitute medical advice, diagnosis, or treatment; always seek the advice of your physician or other qualified health provider with any questions regarding a medical condition.

References

• NIH Genetic and Rare Diseases Information Center (GARD): IgA nephropathy overview.


• Orphanet: Rare kidney disease database.


• OMIM (Online Mendelian Inheritance in Man): Genetic susceptibility loci for IgA nephropathy.


• Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines.