FSGS Treatment and Low IgAN Drug Uptake: Jai Radhakrishnan, MD, MS

Focal segmental glomerulosclerosis (FSGS) is not a single disease, and patients with and without full nephrotic syndrome may respond differently to therapy, according to Jai Radhakrishnan, MD, MS, professor of medicine and clinical chief of the Division of Nephrology at Columbia University Irving Medical Center. In an interview with The American Journal of Managed Care^®, Radhakrishnan discussed how FSGS phenotypes shape treatment response, why remission matters, and what limits uptake of newly approved immunoglobulin A nephropathy (IgAN) therapies.

Why FSGS Phenotype Shapes Response

Radhakrishnan explained that patients without the full nephrotic syndrome, meaning no low albumin and no edema, may still have extensive proteinuria. These patients essentially have what is called hemodynamically driven injury, in which glomerular hypertension and hyperfiltration lead to scarring. Endothelin and angiotensin II both drive this process.

“Blocking both these receptors rather than 1, either one alone, gives us a combined effect on slowing this progression from the damage,” Radhakrishnan said.

Patients with full nephrotic syndrome are different. Radhakrishnan said their disease is usually immune-mediated, with a circulating factor that causes direct damage. “Just by taking away the so-called hemodynamically driven injury, you’re not taking away the immune-mediated injury,” Radhakrishnan said, so the same treatment effect may not appear in this group.

Why Remission and GFR Slope Matter

In any glomerular disease, including FSGS, reaching complete or even partial remission is among the strongest predictors of long-term outcomes, Radhakrishnan said. Patients who see no effect on proteinuria from therapy have a high chance of progressing to kidney failure within 10 years or less. A protein level that drops below 0.3 signals that a patient will do very well.

Radhakrishnan cited complete remission in 20% of patients receiving sparsentan vs 6%, a 3-fold improvement in that end point. Still, proteinuria reduction is a surrogate. “The money is really in the glomerular filtration rate [(GFR)] slope,” Radhakrishnan said, adding that the goal is to flatten GFR decline and eventually reduce kidney failure events.

The difference in slope was not statistically significant, Radhakrishnan noted. The combination of a favorable trend in slope with a dramatic reduction in proteinuria led to the drug’s approval.

What Limits Uptake of New IgAN Therapies

Approved options do not guarantee use. Radhakrishnan pointed to an analysis presented at the National Kidney Foundation meeting a few months ago, which found that fewer than 5% of patients with IgAN were taking any of the newly approved drugs.

Radhakrishnan described several contributing factors. Drugs are arriving quickly, and “every time there’s a KDIGO guideline, it’s almost obsolete at that point,” Radhakrishnan said. That creates a lag between guidelines and practice, which has been shown in many disease states.

Thinking about risk has also changed. The proteinuria level at which risk begins is now understood to be 0.5 g rather than the 1 g once assumed, so the treatment target is below 0.5 g and ideally under 0.3 g in IgAN.

Volume is another barrier. Community nephrologists who see few patients with IgAN each year face added requirements, such as Risk Evaluation and Mitigation Strategies programs, liver monitoring, and surveillance for adverse effects. Radhakrishnan also noted that many of the approved drugs have only an interim analysis end point showing benefit, which supported approval but not final approval.

“There are lots of reasons, and these individual items need to be addressed to make sure patients get the right drug,” Radhakrishnan said.