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Management of IgAN

CE / CME

Improving Outcomes in IgAN: Expert Guidance on Evolving Management and Treatment

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: July 01, 2024

Expiration: June 30, 2025

CME/CE Information

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Genetics Hits: Intestinal Immune Network for IgA Production

Watch this brief video to gain a better understanding about the pathogenesis of IgAN.

We have learned a lot about the pathogenesis of nephropathy over the past 40 years. A great deal of our knowledge has been derived from studies of the genetics of IgAN, which have highlighted the importance of the mucosal immune system in the pathogenesis of the disease. Although this is a complicated slide, it highlights many of the genes that have been identified as being important to the development of IgAN. Many of these genes are involved in the mucosal immune system, and involve both innate immunity and acquired immunity—the generation of antibodies—which is unsurprising for a disease named after its key antibody.3

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The Multihit Model

Information from studies and identification of these important factors has led to us to develop a multi-hit model of the pathogenesis of IgAN, which is demonstrated here.

It starts with an increase in circulating form of IgA1, called galactose-deficient IgA1. This is a particular type of IgA1 that is produced mostly in the mucosal immune system. In patients with IgAN, they have been found to have high amounts of this galactose-deficient IgA1 in their circulation as well. This galactose-deficient IgA1 acts as an antigen against which other antibodies form, which is Hit 2, the production of antiglycan antibodies. When these antibodies stick together, they form immune complexes, seen in Hit 3.

These immune complexes can form in the circulation and then deposit in the kidney, or they may form locally if the galactose-deficient IgA1 is in the mesangium. But we know that the IgA that is seen in the mesangium of the kidney is almost exclusively galactose-deficient IgA1, and so when immune complexes form and when antibodies target that galactose-deficient IgA1, immune complexes activate the immune system, as seen in Hit 4. This leads to activation of mesangial cells, fibrosis, recruitment of inflammatory cells, activation of complement, and the final common pathway of glomerular injury and glomerular sclerosis that leads to proteinuria and GFR loss.14,15

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Biomarkers of Progression

Various biomarkers have been studied in IgAN, some of which are highlighted in this slide. Among the most important is GFR. GFR is interesting as a biomarker of progression because it is also the outcome that we are interested in. Low GFR may lead to a kidney transplant or dialysis, so it is both the outcome and indicative of the outcome due to the progressive nature of GFR decline.

Proteinuria is a particularly useful biomarker because in studies of IgAN, changes in proteinuria have been correlated to changes in outcome. This has led to the development of drugs based on proteinuria outcomes, recognizing that that response in proteinuria is predictive of long-term benefits in kidney protection.

Hematuria is challenging to use as a biomarker in a quantitative way. Gross hematuria in many studies seems to be correlated with improved outcomes, but this may be because patients with gross hematuria typically are diagnosed earlier due to earlier warning signs. The disappearance of microscopic hematuria or the presence of microscopic hematuria has been shown to be associated with disease severity in some studies and with immunological activity as well.

The kidney biopsy gives us beneficial prognostic information and is crucial not just for diagnosis, but due to a well-validated system that gives us prognostic information about the form of IgAN that a patient has. It also helps us identify some of the rarer forms of IgAN mentioned earlier. Many other biomarkers have been explored in in research studies, but are not yet widely available or validated for use in clinical practice.16

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Risk Assessment: Kidney Biopsy

Regarding biopsy, the official classification is referred to as the Oxford classification or the MEST-C classification, named after the variables involved. This system was developed by groups of pathologists looking at hundreds of kidney biopsies identifying these 5 variables that are fairly reliably detected on a kidney biopsy, are reproducible among pathologists, and are indicative and impactful in longitudinal studies of prognosis. It is important to note this classification was developed as a diagnostic classification and as a prognostic classification, but it does not necessarily tell us how a person should be treated. Although work has been done to try to help understand which of these variables might indicate, for example, sensitivity to certain types of immunosuppression like corticosteroids, we cannot make strong claims based on this, and the KDIGO guidelines do not currently provide specific biopsy-directed treatment recommendations.10,17

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IgAN Disease Progression and Risk Assessment

A group of nephrologists and pathologists developed the International IgAN Prediction Tool, published in 2019 and available as a smartphone app and a calculator that anyone can use freely. Essentially, this tool allows the input of variables from the time of biopsy and helps produce a risk of progression to end-stage kidney disease over a series of years based on those variables. This can be very helpful in guiding discussions with patients because once patients receive their diagnosis, they will often ask, “What does the diagnosis mean? And how much time do I have before this might cause kidney failure?” This tool can help you provide an estimate of the amount of time that they might typically expect to experience before progressing to kidney failure.18,19

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