IgA Nephropathy (IgAN), a common form of kidney disease, has been a focus of recent medical inquiries. Recent studies, however, have illuminated a critical aspect: the important role of the gut-kidney axis in IgA nephropathy. This discovery not only deepens our understanding of IgAN but also paves the way for innovative treatment approaches.
By Majd Isreb, MD, FACP, FASN, IFMCP
A primer on the nephron
The nephron, the kidney’s fundamental filtering unit, comprises two main parts: the glomeruli and tubules. The glomerulus (pleural glomeruli), first, is a compact yet intricate structure formed by a network of small blood vessels. These vessels are lined with “endothelial cells,” which, along with cells called podocytes, create a selective barrier. This barrier filters blood, retaining larger molecules and cells. Mesangial cells provide structural support and regulate blood flow within the glomerulus.
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Understanding IgA nephropathy
IgA nephropathy is an autoimmune disorder predominantly affecting mesangial cells. The disease process begins when the immune system erroneously produces abnormal IgA proteins. These proteins, perceived as foreign, instigate an immune response. Immune complexes formed in this process accumulate in the kidneys, attaching to mesangial cells, leading to inflammation and kidney tissue damage.
The ‘four-hit’ hypothesis of IgAN
The pathogenesis of IgAN is encapsulated in the “four-hit hypothesis,” which posits:
- Elevated levels of abnormal IgA1 (galactose-deficient IgA1 or gd-IgA1)
- Autoantibody production against this abnormal IgA1
- Formation of immune complexes involving these autoantibodies and CD89
- Deposition of these complexes in the glomerular mesangium, culminating in kidney damage
Significant to IgAN is dimeric IgA1, predominantly originating from the gut’s mucosa-associated lymphoid tissue (MALT). In fact, the site of gd-IgA1 production is presumed to be the Peyer’s patches of the gut and mesenteric lymph nodes.
The exact reason for abnormal IgA1 production remains unknown, but genetic and environmental factors likely contribute. This review article offers detailed insights into IgAN’s innate and adaptive immune mechanisms. It is freely accessible.
Genetic predisposition in IgA nephropathy
Genome-wide association studies (GWAS) involving over 20,000 patients have identified specific genetic variants linked to IgAN. These variants relate to intestinal mucosal integrity (think leaky gut), inflammatory bowel disease and immune responses to intestinal pathogens.
Epidemiological studies have further underscored the connection between gut disorders and IgAN, suggesting a higher incidence of inflammatory bowel diseases in IgAN patients. Another study found that patients with celiac disease are at more risk for IgAN.
The gut-kidney axis in IgA nephropathy
Emerging research underscores the significant impact of gut health on the kidneys, particularly in the context of IgA Nephropathy. Gut microbiota and their derivatives are crucial in this regard. Gut dysbiosis in predisposed individuals may trigger IgAN.
Studies have identified specific microbiota imbalances in IgAN patients, including Escherichia-Shigella dysbiosis. Another study showed that gut of patients with IgAN have higher levels of Streptococcus and Enterococcus and lower levels of Bacteroidetes and Bacteroides. The study also showed multiple metabolites that are generated from the gut microbiota and are associated with IgAN.
The link between gut microbiota, dysbiosis, and IgAN is further supported by the remission of IgAN after fecal transplant and the improvement of IgAN in mice treated with broad-spectrum antibiotics.
However, the association between increased intestinal permeability and IgAN remains inconclusive. For example, this study showed that increased intestinal permeability is common in patients with various glomerular diseases and not unique to IgAN. While other studies found a significant link between increased IgAN and increased gut permeability.
Finally, healthy gut microbiota produces short-chain fatty acids (SCFAs) that are crucial for the health and integrity of the gut. A recent study looked at the changes in SCFAs in patients with IgAN and found that their levels are much lower in these patients. These levels were associated with clinical activity and gut microbiota.
Dietary triggers in IgAN
Dietary sensitivities are prevalent in IgAN patients, with gluten being a notable trigger due to its link with celiac disease. However, many other food triggers were associated with IgAN. Increased intestinal permeability was documented to precede the IgA immune response to food triggers.
The following foods have been found in different studies to be a possible trigger for IgAN:
- Soy.
- Egg whites.
- Milk protein.
- Gliadin/gluten.
- Oat.
Therefore, testing IgAN patients for celiac disease by testing for tissue transglutaminase-IgA antibodies and total IgA levels or even HLA typing (HLA-DQ2 and DQ8) may be indicated.
Unfortunately, common food sensitivity testsdo not test for IgA antibodies. Therefore, food sensitivity testing using IgE and IgG antibodies may not be sufficient to identify food triggers for a specific patient. Therefore, an elimination diet remains the gold standard for that purpose.
Mesangial cells: Intersection of the gut- kidney axis in IgA nephropathy
Mesangial cells, the primary site for IgAN in the kidneys, have receptors for IgA1 antibodies. Interestingly, the mere presence of abnormal Gd-IgA1 is not sufficient to cause IgAN. Mesangial cells in IgAN patients exhibit increased interleukin-6 production and higher matrix gene expression, indicating a specific predisposition.
Substances from the gut, like toll-like receptor 4 (TLR-4), which rises with gram-negative bacteria dysbiosis, are also found in mesangial cells of IgAN patients. Blocking TLR-mediated signaling could be a promising approach for reversing IgAN. This can be accomplished by berberine, N-acetyl-L-Cysteine, and resveratrol.
Recommended Testing for IgAN
In addition to conventional urine and blood tests, we recommend having the patient undergo an elimination diet for 3-4 weeks, as mentioned above. The following testing might also be helpful to assess for triggers and mediators:
- Food sensitivity profile for IgA and IgG such as the one offered by Vibrant Wellness.
- Comprehensive stool analysis that includes testing for SCFAs such as the one offered by Doctor’s Data.
- Celiac profile such as the one offered by Genova Diagnostics.
- Testing for mediators such as vitamin D, and zinc levels.
The bottom line
The exploration of the gut-kidney axis in IgAN exemplifies the dynamic nature of medical science. By understanding these complex interconnections, we can better approach diseases like IgAN with more integrated and precise treatments.
