Proteinuria Response in Fibrillary GN: What Defines a Non-Responder

Andrew Bomback, MD, MPH, opens the segment by asking Gerald Appel, MD, how he defines a non-responder in fibrillary glomerulonephritis (FGN) in practice, how long patients should remain on therapy, and what numbers signal that treatment is not working.

Appel separates the question into two parts. Early response is measured by a reduction in proteinuria, which correlates with better outcomes across many glomerular diseases and appears to do so in FGN as well, with lower baseline proteinuria also associated with better outcomes. The ultimate endpoint, he explains, is the glomerular filtration rate and serum creatinine. With any new therapy, Appel expects to need 6 months to a year to see an initial signal and to gather data suggesting a patient is doing well long term without significant adverse effects.

The discussion shifts to where the FACT trial of ACTH with or without tacrolimus fits over longer follow-up. Bomback highlights a stark divergence between responders and non-responders over the 2 years patients were studied. At 24 months, none of the complete responders had reached end-stage kidney disease, suggesting that marked proteinuria reduction offered apparent protection against progression. In contrast, none of the non-responders showed a stable GFR, with 45% experiencing significant GFR decline and 55% progressing to end-stage kidney disease.

Bomback cautions that proteinuria is unlikely ever to be accepted as a formal surrogate endpoint in FGN. Unlike IgA nephropathy, where large natural history datasets allowed validation of proteinuria as a surrogate marker, the disease is simply too rare. Still, he emphasizes that there is a clear signal that early and significant proteinuria reduction offers the best chance of a good long-term kidney outcome, consistent with what clinicians see across many glomerular diseases.

The segment concludes with Bomback identifying the key open question in FGN management: which drug or combination of drugs can reliably achieve that early, significant drop in proteinuria.