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For two rare, understudied kidney diseases—IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS)—patients have long faced uncertain diagnosis and treatment. Now, a shared biological thread is opening the door to a treatment that can address both diseases by targeting pathways they have in common—angiotensin II and endothelin-1. 

With IgAN and FSGS, damage occurs to glomeruli, or the tiny filters inside the kidneys that remove waste from the blood while keeping protein and blood cells where they belong. When the filters break down, protein can leak into the urine, which is called proteinuria.  

Proteinuria is a marker of kidney injury and a driver causing kidney function to decline, pushing the organ toward failure over time. With greater understanding of the mechanism of disease, rare kidney therapies are moving toward more personalized medicine to specifically address implicated pathways. (See “When filters fail.”)  

As with most kidney diseases, issues arise in IgAN and FSGS as the kidneys’ ability to filter waste out of the blood is comprised. As kidney disease progresses toward kidney failure, often within 5–10 years, patients head towards potential dialysis or transplant. 

Different diseases, shared pathway 

“For a long time, rare kidney diseases have been viewed as following parallel tracks, rarely intersecting once diagnosed. But while they may start with distinct patterns, kidney diseases converge on common pathways of glomerular injury and progression,” said Jula Inrig, M.D., head of R&D and CMO at Travere Therapeutics. “IgAN and FSGS begin on different paths, but both can involve podocyte injury, disruption of the glomerular filtration barrier, proteinuria and progressive loss of kidney function. Looking across diagnoses helps us identify those shared mechanisms, potentially giving us more ways to intervene before irreversible damage occurs.” 

In IgAN, the body produces a flawed version of an antibody called galactose deficient IgA1, triggering the immune system to create a second antibody to attack it. Combined, these antibodies clump together and deposit in the kidneys’ glomeruli, setting off a cascade of damage that involves the signaling molecules angiotensin II and endothelin-1.  

Angiotensin II raises pressure in the glomeruli and contributes to scarring, while endothelin-1 drives inflammation and direct injury to the podocytes. Angiotensin II and endothelin-1 can also work together to damage podocytes, contributing to inflammation, scarring and worsening proteinuria. What’s more, angiotensin II can trigger the formation of endothelin-1, creating a feedback loop that can add to kidney injury. 

FSGS arises from injury to the podocytes themselves, whether from genetic factors, immune activity, or other causes. Chronic proteinuria contributes to further injury, creating a cycle of damage that accelerates disease progression. 

The barriers facing patients and providers haven’t been easy to overcome. Diagnosis for IgAN and FSGS typically requires a biopsy. These allow physicians to clearly differentiate IgAN from FSGS, but identifying specific subtypes of FSGS can be more difficult.  

While approved treatment options are more vast in the IgAN community, doctors don’t always have a clear playbook when it comes to FSGS, where there is currently only one approved medication. And overall, the rarity of these diseases has meant that large-scale clinical trials have been difficult. 

Historically, patients have received fragmented, symptom-focused care. FSGS treatment, for example, had centered on supportive care, including blood-pressure medications and low-salt diets, with no disease-specific drug approved until April 2026. 

But progress is possible, and recent advancements are changing the story not just for IgAN and FSGS but for the way the field looks at treatments for rare kidney disease. Other fields have increasingly looked beyond traditional disease labels to shared biology, and that same shift to biology-driven care has started to happen in rare kidney disease. 

“We’ve seen in oncology how understanding the biology that cuts across traditional disease categories can change the way therapies are developed,” Inrig said. “Kidney disease is different, but the principle is relevant.” 

Targeting the biology behind kidney damage 

With IgAN and FSGS, because the angiotensin II and endothelin-1 pathways can reinforce each other, targeting both simultaneously might offer a way to interrupt the cycle of glomerular injury more comprehensively than targeting either pathway alone. FILSPARI® (sparsentan) is designed to block both biological pathways with a single molecule.  

“FILSPARI is part of a much broader evolution in how rare kidney disease is understood,” said Inrig.  

Across both diseases, clinical trials have shown that FILSPARI can produce substantial and sustained reductions in proteinuria. In IgAN, the Phase 3 PROTECT trial pointed to greater proteinuria reduction and a slowing of kidney function decline versus maximum labeled-dose irbesartan. In FSGS, the Phase 2 DUET and Phase 3 DUPLEX studies showed greater and sustained reductions in proteinuria. In each clinical study, adverse events observed with sparsentan were similar to those observed with irbesartan. 

Meanwhile, the UK’s National Registry of Rare Kidney Diseases (RaDaR)—a large-scale real-world effort—showed that IgAN patients continue to progress to kidney failure at levels of proteinuria that were traditionally thought to be “safe.” This pushed the field to target lower proteinuria goals and now complete remission—less than 0.3 grams of protein per day. For FSGS, physicians agree in principle that achieving complete remission would be ideal. 

“FILSPARI was developed in parallel with the growing understanding that rare kidney disease progression has been flying under the radar,” Inrig said. “In that sense, it reflects the same shift among nephrologists: toward recognizing risk earlier, treating more proactively and setting more ambitious goals for reducing proteinuria and help preserve kidney function.” 

The medication is approved for use in both IgAN and FSGS, though for distinct purposes. In IgAN, FILSPARI is indicated to slow kidney function decline in adults with primary IgAN who are at risk for disease progression. In FSGS, it reduces proteinuria in adult and pediatric patients ages 8 years and older with FSGS without nephrotic syndrome.  

FILSPARI has Boxed Warnings for hepatotoxicity and embryo-fetal toxicity. It is contraindicated in patients who are pregnant and should not be co-administered with angiotensin receptor blockers, endothelin receptor antagonists, or aliskirin. Please see below for additional Warnings and Precautions and Important Safety Information. 

FILSPARI reflects a more mechanism-based approach to rare kidney disease. Simultaneously blocking ET-I and Ang-II addresses shared drivers of glomerular injury that are relevant in both IgA nephropathy and FSGS. 

“The future of rare kidney disease development will increasingly depend on identifying shared mechanisms of progression and asking where they may be therapeutically relevant,” said Inrig. “That approach could allow us to develop medicines more strategically across conditions and extend advances from one area of kidney disease into others.” 

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