IgAN Was a Hot Topic at ASN Kidney Week

During an interview with Nephrology Times to discuss his Kidney Week abstracts, Jonathan Barratt, PhD, called IgA nephropathy (IgAN) “the world’s most important kidney disease.” Although the comment was tongue-in-cheek, he has a point, judging by the attention IgAN received at this year’s event.

Just consider the standing-room-only attendance on October 25 of the exhibitor spotlight Navigating IgA Nephropathy: Pathogenesis, the Role of APRIL, and Patient Case Study, sponsored by Otsuka. The discussion was led by Kenar D. Jhaveri, MD, and Heather Reich, MD, PhD, with the stated objectives of promoting (1) recognition of the disease burden and risk progression of IgAN; (2) understanding of the four-hit cascade in IgAN pathogenesis and the role of a proliferation-inducing ligand (APRIL); and (3) knowledge of the scientific evidence supporting the role of APRIL in pathogenesis.

When asked about IgAN being such a hot topic that it merited a session like this, in addition to the many abstracts presented on the topic, Dr. Jhaveri told Nephrology Times, “There probably should be more such sessions. It’s a relatively common glomerular disease in the world, so it’s important that people realize the change in the landscape of treatment.”

Disease Burden and Pathogenesis

During his segment, Dr. Jhaveri provided an overview of IgAN, stating that it is typically diagnosed in adults aged 20–40 years and usually leads to end-stage renal disease. He noted that the disease’s impact on patients is often overlooked, a sentiment echoed by Dr. Reich during her presentation. In fact, 30% of patients with IgAN have depression.

Although IgAN presentation is heterogeneous, hematuria and proteinuria are the most common manifestations, with the latter occurring in about 75% of patients, Dr. Jhaveri said. Proteinuria is, in his estimation, the key to treating IgAN and delaying disease progression—and the more that proteinuria is lowered, the more the risk of disease progression decreases. “I think if we can keep the GFR decline the lowest and the proteinuria the lowest, no matter which drug you use or combination of drugs down the road, that will delay kidney disease and dialysis, and that’s the key,” Dr. Jhaveri told Nephrology Times.

The 2021 KDIGO guidelines for the management of glomerular diseases call for lowering proteinuria to <1 g/d. However, a study utilizing data from the UK National Registry of Rare Kidney Diseases (RaDaR), of which Dr. Barratt is the IgAN Rare Disease Group lead, showed that 30% of patients who reach that goal still progress to ESRD within 10 years. Reducing proteinuria to <0.5 is a better target, Dr. Jhaveri said, and an upcoming revision to the KDIGO guidelines is expected to reflect this.

Role of APRIL in Pathogenesis

Dr. Reich began her segment with an overview of the four-hit cascade in IgAN pathogenesis. Notably, APRIL plays a role in every hit:

• Pre-hit 1: APRIL promotes Gd-IgA1 production
• Hit 1: Production of Gd-IgA1
• Hit 2: Anti-Gd-IgA1 autoantibodies synthesis
• Hit 3: Immune complex formation
• Hit 4: Immune complex deposition in mesangium

Dr. Reich pointed to several findings that reinforce the importance of APRIL in IgAN pathogenesis. One critical discovery occurred when genome-wide association studies identified a susceptibility locus in APRIL, TNFSF13, associated with IgAN. In addition, Dr. Reich noted that serum APRIL levels are elevated in IgAN patients, and therefore may serve as a predictor of kidney outcomes. Elevated APRIL levels correlate with Gd-IgA1, as APRIL promotes the production of pathogenic Gd-IgA1 and immune complex formation.

Looking to the Future

 Many current IgAN treatments target clinical manifestations of CKD rather than the underlying causes of IgAN. Given its prominent role in IgAN pathogenesis, APRIL has surfaced as a therapeutic target and is the focus of several clinical development programs. New treatments are emerging, and the landscape is changing quickly.

When asked which new treatment is most exciting to him, Dr. Jhaveri could not be pinned down to one. “I think the most exciting thing is to actually offer patients a lot more options, including clinical trials, for IgA compared to even 5 years ago or 6 years ago,” he remarked. “I think that’s the most exciting part, to actually have an armamentarium that I can choose from.”