Primary and secondary IgA nephropathy (IgAN) are associated with a number of complications affecting the kidneys and other sites of the body, including end-stage kidney disease (ESKD) and hypertension. Our featured experts review the extrarenal impacts, comorbidities, and complications associated with IgAN in this Expert Roundtables discussion.

The pathogenesis of IgAN begins with the production of an abnormal IgA molecule, which leads to the production of an autoantibody targeting the abnormal IgA molecule. When this autoantibody binds to the abnormal IgA molecule, the resulting immune complex can deposit into the mesangium of the kidney, inciting inflammation, complement activation, and the production of inflammatory cytokines that can cause fibrosis. In the absence of any other systemic disease, this process is considered to be primary IgAN.

A variety of other autoimmune diseases can coexist with IgAN, including inflammatory bowel disease and celiac disease. From a treatment standpoint, it is important to realize that we should not view secondary and primary IgAN with the same lens because managing many secondary processes associated with IgAN may lead to a diminution of the nephropathy component.

The traditional treatment for IgAN has been systemic corticosteroids, but clinical trials have shown that the side effects can be quite significant. For example, the TESTING trial was terminated early and was modified to use a lower dose of corticosteroids before continuing because the rate of serious adverse events was so much higher in the steroid-treated group than in the placebo-treated group and, in fact, led to death in some cases. The trend now is to use steroids less and less often for IgAN and move over to using more modern therapies, such as the gastrointestinal-targeted steroid budesonide, complement inhibitors, and DEARAs, on top of supportive care.

There are many secondary forms of IgAN for which we can see the same biopsy findings and risk for progressive kidney failure as we do for primary IgAN. In some patients, IgAN can be secondary to liver disease, especially very advanced liver disease. These patients typically have many systemic liver disease–related symptoms, including more fatigue, possible abdominal and/or leg swelling, and laboratory evidence of liver dysfunction. This form is usually clinically obvious, but other secondary forms can be a little more hidden. IgAN can be secondary to autoimmune diseases, particularly ankylosing spondylitis, and a number of gastrointestinal diseases, including sprue and enteritis. Another secondary form of IgAN that is more common in children than adults is IgA vasculitis. Although it classically presents as a rash sometimes with abdominal pain, it is frequently associated with nephritis. So, we have to rule out these potential causes of secondary IgAN before we can call a patient’s disease primary IgAN.

Both secondary and primary IgAN can lead to extrarenal manifestations. In primary IgAN, these manifestations can include fatigue, flank pain, and hematuria. In addition, IgAN and its treatment can lead to the development of comorbidities such as hypertension, hypercholesterolemia, and obesity, which are very serious risk factors for heart disease, vascular disease, heart attacks, and strokes. We suspect that if we can diagnose and treat IgAN early on, we can prevent a lot of extrarenal manifestations as patients get older, particularly those manifestations that are directly associated with disease progression.

Cardiovascular disease is one of the more significant extrarenal manifestations of IgAN and may end up being more significant to some patients over their lifetime than even their IgAN. There are other extrarenal effects such as fatigue and exercise intolerance, and patients who are particularly young may have a hard time with school because of difficulties thinking clearly.

A number of patients with IgAN develop ESKD. Unfortunately, this means that patients begin dealing with a number of symptoms that are not so much IgAN related, but rather are chronic kidney disease related, and that increases the amount of medications these patients need. Those with ESKD may need treatment for metabolic acidosis, hyperphosphatemia, or hyperkalemia, which can limit the use of important medications. So, as the disease progresses further down the road toward ESKD, patients begin accruing more medications that not only have potential side effects but also can impact the patient’s psyche because their disease is progressing regardless of what we are doing. I believe that part of the promise and hope of newer medications is that we can potentially alter the slope of the change in a patient’s glomerular filtration rate to slow the progression toward ESKD.