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Edgar Lerma, MD, provides insights into the pathophysiology of IgA nephropathy (IgAN) and the therapeutic promise of targeting APRIL.

Recent advancements in the understanding of IgA nephropathy (IgAN)—the most prevalent primary glomerulonephritis worldwide—have elucidated novel therapeutic pathways targeting A proliferation-inducing ligand (APRIL), a pivotal cytokine in IgA production. These developments have the potential to transform the treatment landscape for this significant cause of chronic kidney disease.

Physician’s Weekly (PW) spoke with Edgar Lerma, MD, Clinical Professor of Medicine at the University of Illinois at Chicago Section of Nephrology, to provide further insights into the pathophysiology of IgAN and the therapeutic promise of APRIL inhibition.

PW: How prevalent is IgAN, and which populations are most at risk?

Dr. Lerma: IgAN has an annual global incidence of approximately 2.5 cases per 100,000 persons, making it the most common primary glomerulonephritis, and is more prevalent in males and individuals of Asian and Caucasian descent. IgAN can affect people of any age, but most patients are diagnosed when they’re between 20 and 40 years of age. So, instead of looking ahead to that time when they could be retiring or slowing down and really enjoying that part of their lives, the probable future they’re facing is one of kidney failure, or end-stage kidney disease, involving dialysis or possibly kidney transplantation. That knowledge places a substantial burden on both patients and their families.

What have been the traditional approaches to managing IgAN?

In the past, IgAN management was primarily about symptom management and blood pressure control. The focus was on antihypertensive agents called renin-angiotensin system blockers for blood pressure control, and then lifestyle modifications, such as sodium restriction, increased physical activity, weight loss, and smoking cessation, were also recommended. In cases where the patient didn’t respond to these measures, immunosuppressive therapies were considered; however, these carried significant risks, including long-term toxicity and adverse side effects.

Now that we have a better understanding of the pathophysiology of IgAN, of the mechanism, we have more options: novel therapeutic agents that directly target the key pathophysiologic steps leading to kidney failure, offering our patients new hope.

Why could targeting APRIL be a game-changer for IgAN management?

Because APRIL is a cytokine within the tumor necrosis factor superfamily that’s integral to the development and progression of IgAN. It plays a crucial role by promoting the switching up of B cells to produce IgA, specifically pathogenic factor galactose-deficient IgA, or Gd-IgA1. Gd-IgA1 forms immune complexes in the kidneys that are then deposited within the glomeruli, triggering inflammation that ultimately leads to kidney damage and injury.

Therapeutically targeting APRIL presents a groundbreaking opportunity to disrupt this pathogenic process. By inhibiting APRIL, you reduce the production of Gd-IgA1, thereby preventing immune complex formation and subsequent kidney damage and injury. This approach has the potential to disrupt the pathogenic sequence that eventually leads to end-stage kidney disease.

What’s the current status of research on APRIL-targeted therapy for IgAN?

Several phase 2 and phase 3 clinical trials have been conducted, but while promising results have emerged, continued research remains crucial to uncovering opportunities for advancement in our understanding of IgAN, the potential of APRIL inhibition, and optimal treatment strategies for our patients.

What resources do you recommend for clinicians seeking to expand their knowledge of APRIL and IgAN?

The website DiscoverAPRILinIgAN.com is a valuable resource for healthcare professionals seeking news and information regarding APRIL and IgAN. For a greater understanding of nephrology in general, I personally recommend the Manual of Nephrology, written by the “god of nephrology,” Robert Schrier. I read the sixth edition back in 2005 when I was a medical student, and I’m very proud to have been co-editor of the ninth edition, which was just published. It’s an essential reference for medical students, residents, nephrologists, and other physicians engaged in kidney disease management.