Managing Non-Responders in Glomerular Disease: Proteinuria Targets by Disease

Andrew Bomback, MD, MPH, broadens the discussion beyond fibrillary glomerulonephritis (FGN) to glomerular disease as a whole. With more therapies approved and more options available, he asks Gerald Appel, MD, how he approaches patients who do not respond to treatment, whether he follows a standard approach or decides case by case, and whether he routinely rebiopsies before moving to second-line therapy.

Appel explains that the answer depends on the specific disease, both in terms of which drugs to use and how low proteinuria must go. Proteinuria reduction is the common thread, but the target that matters, and the evidence behind it, differs from disease to disease. In IgA nephropathy, he notes, there is now fairly clear evidence that lowering proteinuria below 0.5 g per day, or to a protein-to-creatinine ratio below 0.5, makes a long-term difference, citing data from the UK RaDaR registry and from Kaiser Permanente in California. In lupus nephritis, achieving lower proteinuria within the first 6 months and the first year likewise predicts long-term outcomes.

Other diseases raise harder questions about how far to push treatment. Appel offers the example of a patient with membranous nephropathy whose proteinuria falls to about 1 g and asks whether the immunosuppressive agent that achieved that response should be continued, stopped, or given at spaced-out intervals. For diseases like these, he suggests, the depth of remission worth pursuing is still an open clinical question.

He argues that these decisions still require individualized therapy based on the specific disease and the specific drug, including whether that drug has evidence that it targets disease pathogenesis. That evidence exists for membranous nephropathy, lupus nephritis, and IgA nephropathy, Appel notes, but not yet for FGN, where the rarity of the disease has limited the data available to guide clinicians.