For some patients with IgA nephropathy (IgAN), initial treatment with supportive care measures is not enough to control proteinuria, leaving these patients at high risk of kidney failure over time. In such cases, treatments that reduce proteinuria and slow the progression of kidney disease are necessary.

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of glomerular diseases from 2021 set the framework for determining IgAN therapy. The first step is to confirm that the patient has primary IgAN. Secondary IgAN is associated with liver cirrhosis, inflammatory bowel disease, and other causes, and then there is IgA vasculitis, which is a systemic disease. Once these have been ruled out, you can call it primary IgAN. The next step is to use the International IgAN Prediction Tool, which uses clinical and biopsy data to risk stratify patients and provide a risk estimate for renal progression over 5 years. Once this risk is established, the best therapy is determined by using a holistic approach, starting with supportive/conservative therapies before the consideration of other treatments.

For all patients with IgAN, the “low-hanging fruit” is blood pressure control to 120/80 mm Hg or better, lipid control, a healthy lifestyle, smoking cessation, and a heart-healthy, low-salt diet. If the patient’s proteinuria is greater than 0.5 g/day, then using an ARB or ACE inhibitor in the first line is appropriate. Now we have the SGLT2 inhibitor dapagliflozin that may be added. Occasionally we have used mineralocorticoid receptor antagonists such as eplerenone or spironolactone to further enhance the effect of nephroprotection and proteinuria reduction.

If a patient’s proteinuria stays above 0.75 g/day, one can consider them to be at a higher risk of renal progression compared with someone whose proteinuria has decreased to below 0.5 g. The first option is to enroll them in a clinical trial, if that is available. If that is not available, then targeted-release oral budesonide is another option, but that has to be weighed against systemic corticosteroids.

The large STOP-IgAN trial showed no difference in outcomes in patients who were given systemic immunosuppressants such as steroids and azathioprine in addition to supportive care vs those who received supportive care alone. The TESTING trial compared methylprednisolone with placebo and was stopped midway because of a high number of serious adverse events, including death in the corticosteroid arm. The investigators then modified the trial by reducing the dosage of steroids and adding antibiotic prophylaxis for subsequent participants. Ultimately, there was a clear signal that corticosteroids reduced the risk of IgAN progression, albeit with the risk of systemic side effects, predominantly with high-dose therapy. For patients with extremely high levels of proteinuria and very rapid progression, we typically use corticosteroids with or without cyclophosphamide or mycophenolate mofetil almost immediately. That is not based on good data, unlike the other trials.

There is a nice pipeline of drugs in phase 2 and 3 clinical trials for IgAN. We have seen the BAFF- and APRIL-targeting drugs atacicept, telitacicept, and povetacicept. These agents, along with the APRIL-only–targeting drugs sibeprenlimab and zigakibart (BION-1301), have shown a positive signal in phase 2 studies. That is very exciting because they address the root of IgAN: the production of abnormally glycosylated IgA. Agents targeting the complement pathway are also in development, and iptacopan is being evaluated in the phase 3 APPLAUSE-IgAN trial, with results anticipated at the end of 2024.