Andrew Bomback, MD, MPH, is an assistant professor of medicine at Columbia University Medical Center.

Andrew Bomback, MD, MPH

Asked by Gerald Appel, MD, how he would design the next trial in fibrillary glomerulonephritis (FGN), drawing on his experience helping secure FDA approval of two drugs for C3 glomerulopathy, Andrew Bomback, MD, MPH, begins by emphasizing why the completion of the FACT trial matters. The trial signals to drug developers that FGN is a disease in need of therapies with patients who can be enrolled, and that even in an ultra-rare disease, a study can be completed and could potentially support a drug approval.

Designing the Next Fibrillary GN Trial: B-Cell Agents and T-Cell Engagers

The biggest obstacle, Bomback explains, is that even with DNAJB9 as a reliable diagnostic marker, it remains unclear which cell type produces the fibrils, so he has no definitive answer on which agent to test. Given the signal seen with rituximab, he suggests that newer B-cell agents targeting APRIL or BAFF/APRIL could be reasonable candidates. While FGN is likely autoimmune, whether it is driven by B cells or T cells is uncertain. For that reason, he is drawn to the T-cell engagers used in lupus nephritis, if more safety experience accrues, because they act on both T-cell and B-cell pathways. He stresses that there is clearly a population of patients willing to participate in trials.

Appel agrees that patients are engaged, noting that they often read about their disease. He adds that while there were no glomerular centers when Columbia founded the first around 2000, many now see patients with FGN. A multicenter collaborative study, similar to efforts in C3 glomerulonephritis and dense deposit disease, could enroll a few patients from each center for a controlled trial against placebo or nonspecific therapy, with biopsies before and after treatment to assess changes in the fibrils.

Appel supports testing anti-B-cell agents and newer drugs acting on T cells and B cells, including those used in IgA nephropathy, pointing to the smudgy IgG seen on FGN biopsies as a possible clue to pathogenesis.

In closing, Bomback notes that the FACT trial, while not a perfect answer, shows that some patients benefit from treatment and underscores that lowering proteinuria as quickly and efficiently as possible gives patients the best chance of avoiding end-stage kidney disease. Appel adds that their insights reflect long experience at a glomerular center rather than data validated in hundreds or thousands of patients.

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Discover which therapeutic targets and multicenter trial designs Columbia experts see as the next step for fibrillary glomerulonephritis research.

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.

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

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.

Explore how proteinuria targets and treatment decisions for non-responders differ across IgA nephropathy, lupus nephritis, and membranous nephropathy.

Gerald Appel, MD, opens the segment by highlighting an added benefit of nonspecific therapy in fibrillary glomerulonephritis (FGN). Beyond reducing proteinuria, agents such as ACE inhibitors, angiotensin receptor blockers, and certain antidiabetic drugs also lower cardiovascular risk, including stroke and myocardial infarction. Appel calls this a real long-term positive of the approach, because cardiovascular disease is the leading cause of death in patients with kidney dysfunction.

Fibrillary GN: Cardiovascular Protection and Recurrence After Kidney Transplant

Appel describes how that consideration shapes drug selection in similar diseases. In younger patients with less cardiovascular concern, he may choose certain agents, while in older patients or those with diabetes, he favors drugs that also protect against future cardiovascular events.

The conversation then shifts to kidney transplantation. Appel notes that it has long been cited that about 50% of patients with FGN experience recurrence after transplant, and he asks Andrew Bomback, MD, MPH, whether that matches his experience.

Bomback says he has read the same statistics, but they do not match what he has seen. Over the past 15 years at Columbia, he can recall only one case of recurrent FGN, even as more patients with FGN have proceeded to transplant. He considers several possible explanations without endorsing any: the shift from cyclosporine to tacrolimus, from azathioprine to mycophenolate, or changes in induction therapy. Whatever the cause, he has not observed the 50% recurrence rate reported in the literature in Columbia's transplant population.

Appel agrees that recurrence has been far less common in his experience. He recalls one patient who lost a kidney donated by her husband to recurrence after about 8 years. Bomback observes that such cases stand out precisely because they are unusual. Appel adds that the true recurrence rate appears lower than historically reported and would be a worthwhile question for future study.

Understand how nonspecific therapy lowers cardiovascular risk in fibrillary glomerulonephritis and why transplant recurrence may be lower than reported.

Asked by Gerald Appel, MD, about the role of nonspecific therapy, Andrew Bomback, MD, MPH, describes a growing number of patients with fibrillary glomerulonephritis (FGN) who have done well on conservative, nonimmunosuppressive treatment alone. The patients he feels most optimistic about, he notes, present with subnephrotic proteinuria and preserved or only mildly reduced GFR.

Conservative Therapy in Fibrillary GN: A Four-Drug Kidney-Protective Approach

For these patients, Bomback uses a four-drug foundation: an ACE inhibitor or angiotensin receptor blocker; either a mineralocorticoid receptor antagonist or an endothelin receptor antagonist; an SGLT2 inhibitor; and, whenever possible, a GLP-1 receptor agonist. He tells patients that getting all four on board gives the kidney a strong foundational therapy against progression.

Bomback reports following several patients on this regimen, chosen for various reasons over immunosuppression, for 4 to 6 years, with nearly flat GFR decline and well-controlled proteinuria. He believes this expansive approach to conservative therapy makes sense even for more severe cases in which immunosuppression is used.

Appel agrees that this holds across many glomerular diseases where the best course is uncertain, but he raises a practical concern. Most of these agents lower blood pressure, and in IgA nephropathy clinicians have had difficulty combining them, sometimes struggling to add even two drugs in patients with low baseline blood pressure. He asks how Bomback sequences the medications.

Bomback explains that the challenge differs in FGN. His patients with FGN tend to be 10 to 20 years older than his patients with IgA nephropathy, who are typically younger, healthier, and more likely to start with low blood pressure. Because many patients with FGN arrive having read a grim prognosis online, he tells them he will start all four drugs at once rather than stagger them, to begin kidney protection as soon as possible, and he finds that most accept this strategy.

He agrees that endothelin receptor antagonists pose the greatest challenge because of relative hypotension, but notes this has been less of an issue in his older FGN population.

Discover the four-drug conservative regimen one Columbia nephrologist uses to slow fibrillary glomerulonephritis progression without immunosuppression.

Andrew Bomback, MD, MPH

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