Atrasentan for IgA nephropathy: clinical trial results

Research-informed explainer — last updated April 12, 2026

Atrasentan is an endothelin A receptor antagonist that showed meaningful reductions in proteinuria in IgA nephropathy clinical trials, with the phase 3 ALIGN trial demonstrating significant decreases in urinary protein-to-creatinine ratio and a potential to slow kidney function decline. It represents one of several new targeted agents entering a field that, until recently, had few disease-modifying options beyond renin-angiotensin system (RAS) blockade.

This explainer provides context for what the atrasentan trials showed, where the drug fits in the treatment landscape for IgA nephropathy, and what the results mean for patients. It draws on research from glomerular disease specialists at Stanford and Boston University who have contributed foundational work on proteinuric kidney diseases.

What is IgA nephropathy?

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. It occurs when IgA — a type of antibody — deposits in the kidneys' filtering units (glomeruli), triggering inflammation that damages the delicate structures responsible for filtering blood. The signature feature is blood in the urine (hematuria), often accompanied by protein in the urine (proteinuria), which reflects ongoing glomerular injury.

The severity of IgAN varies widely. Some patients have a mild, stable course; others experience steady decline in kidney function over years, with a significant minority reaching end-stage kidney disease within 20 years. Persistently elevated proteinuria — particularly above 1 gram per day — is the strongest modifiable predictor of progression. This is why treatments that reduce proteinuria have become the key surrogate endpoint in IgAN trials.

Podocyte loss (podocytopenia) has been identified as a marker of disease severity in IgAN, with studies showing that fewer podocytes per glomerulus correlates with worse kidney function and more proteinuria [5]. Understanding this cellular vulnerability has shaped thinking about why some patients progress faster than others.

Why endothelin receptors are a target

Endothelin-1, a potent vasoconstrictor, contributes to glomerular hypertension and mesangial cell proliferation — two of the pathological processes that drive IgAN progression. Endothelin A receptors on mesangial cells and podocytes are upregulated in states of glomerular inflammation. Blocking these receptors with atrasentan relaxes the glomerular capillaries, reduces proteinuria-driving pressure, and may directly protect podocytes.

This adds to the mechanism of RAS blockade — ACE inhibitors and ARBs — which has been the cornerstone of IgAN management for decades. Preclinical research established that angiotensin II receptor blockade limits glomerular injury beyond its blood pressure effects, protecting glomerular architecture directly [4]. Atrasentan works through a complementary, non-overlapping pathway, which is why it was studied on top of existing RAS blockade.

What the clinical trials showed

Phase 2: ART trial

The ART trial was a phase 2, dose-finding study in patients with IgAN and proteinuria despite maximized RAS blockade. It examined three doses of atrasentan and established that 0.75 mg once daily produced the best balance of proteinuria reduction and fluid retention (a known on-target side effect of endothelin A antagonism). Proteinuria fell substantially at this dose, and there were no signals suggesting serious kidney harm.

Phase 3: ALIGN trial

The ALIGN trial enrolled patients with IgAN at high risk of progression — defined by persistent proteinuria above 1 g/day despite optimized RAS blockade. Patients were randomized to atrasentan 0.75 mg/day or placebo. The primary endpoint was change in urinary protein-to-creatinine ratio (UPCR) from baseline to 36 weeks.

Atrasentan significantly reduced UPCR compared to placebo. The reduction in proteinuria in the active arm was clinically meaningful given the well-established relationship between proteinuria levels and long-term kidney function decline. A kidney function composite — sustained 40% decline in eGFR or progression to kidney failure — was a secondary endpoint; longer follow-up data will be required to assess hard kidney outcomes definitively.

The main side effect observed was fluid retention and edema, consistent with the known pharmacology of endothelin A antagonism. Careful patient selection — excluding those with heart failure or significant fluid balance risk — and close monitoring helped manage this risk in the trials.

How atrasentan fits alongside other new treatments

IgAN therapy has changed substantially in recent years. Several disease-modifying agents are now available or in late-stage development:

SGLT2 inhibitors — Dapagliflozin and other SGLT2 inhibitors reduce proteinuria and slow eGFR decline through hemodynamic and anti-inflammatory effects in CKD broadly. The DAPA-CKD trial enrolled CKD patients regardless of underlying cause and found significant reductions in kidney disease progression endpoints with dapagliflozin [1]. A meaningful proportion of participants had non-diabetic CKD, and the benefit was consistent across causes. SGLT2 inhibitors are now standard of care for proteinuric CKD.

Sparsentan — A dual endothelin/angiotensin receptor antagonist, sparsentan combines both mechanisms in one molecule and received accelerated FDA approval for IgAN in 2023 based on proteinuria reduction data. It offers similar mechanistic coverage to atrasentan plus ARB, in a single pill.

Targeted-release budesonide (Nefecon) — An oral corticosteroid formulation that delivers drug to the gut-associated lymphoid tissue where galactose-deficient IgA1 production originates. It received accelerated approval for IgAN and addresses the upstream immune source of the disease rather than the downstream glomerular response.

BAFF/APRIL pathway inhibitors — Iptacopan (complement pathway) and atacicept (BAFF/APRIL) target the immune dysregulation driving IgA production and deposition.

Atrasentan occupies a specific role in this emerging landscape: it is most relevant for patients with high proteinuria burden who have already maximized RAS blockade and SGLT2 inhibitor therapy, or for whom sparsentan is not appropriate.

How CKD progression risk contextualizes the urgency of treatment

Large epidemiologic data established that even modest reductions in eGFR carry real risks of death, cardiovascular events, and hospitalization — and that these risks accumulate in a graded, dose-dependent way as kidney function falls [2]. For IgAN patients, this means that any treatment that durably reduces proteinuria and slows eGFR decline has meaningful real-world impact: each year of slower progression translates into lower cardiovascular risk and longer time before dialysis or transplantation becomes necessary.

Parallels in other glomerular diseases

Targeted therapy for glomerular diseases has accelerated broadly. In membranous nephropathy — the other major proteinuric glomerular disease — the discovery that most idiopathic cases are driven by autoantibodies to PLA2R (a receptor on podocyte surfaces) enabled rational immunotherapy [7]. Rituximab, which depletes B cells and reduces those antibodies, proved noninferior to cyclosporine at 12 months and superior at 24 months in the MENTOR trial [6]. Tracking anti-PLA2R antibody levels after rituximab treatment predicts clinical response earlier than waiting for proteinuria changes [9].

This model — a defined autoantigen, a measurable antibody, a targeted biologic — has become the template for glomerular disease drug development. IgAN researchers are applying similar logic, though the immune pathology is more complex.

Questions to ask your doctor

• What is my current proteinuria level, and has it been stable, worsening, or improving on my current RAS inhibitor regimen?
• Am I on an SGLT2 inhibitor, and if not, would it be appropriate to add one before considering atrasentan?
• Am I a candidate for sparsentan, targeted budesonide, or one of the newer immune-pathway agents given my specific proteinuria level and eGFR?
• What would my risk of reaching dialysis or transplant look like over the next 10 to 20 years on current versus more aggressive treatment?
• Do I have any heart failure, fluid retention, or other conditions that might affect how I tolerate an endothelin antagonist?
• Are there any clinical trials for IgAN treatments that I might be eligible for at a center that specializes in glomerular disease?

The bottom line

Atrasentan demonstrated meaningful proteinuria reduction in IgAN patients with high-risk, persistent disease despite optimized RAS blockade. It adds a complementary mechanism to existing therapy by blocking endothelin A receptors, reducing glomerular pressure and protecting podocytes. Within a rapidly expanding treatment landscape — one that now includes SGLT2 inhibitors, sparsentan, targeted budesonide, and complement pathway agents — atrasentan is most relevant for patients with significant residual proteinuria on maximized standard care. Decisions about which agents to add, in what order, are best made with a nephrologist who specializes in glomerular disease.