Exploring the Mechanism of Sparsentan in IgAN: Including a Spotlight on Urinary sCD163, a Key Marker of Inflammation

In this issue we:

• Discuss the importance of targeting inflammation in IgA nephropathy by inhibition of endothelin-1 (ET-1) and angiotensin II
• Learn how the urinary soluble CD163 (u-sCD163) inflammatory biomarker can measure IgA nephropathy progression, severity, and remission
• Highlight data from the interim analysis of the Phase 2 SPARTAN study demonstrating the anti-inflammatory effect of sparsentan

Ang II and ET-1 are key disease mediators that contribute to the progression of IgA nephropathy.¹ They upregulate each other and exert an additive effect driving ongoing kidney damage.^1-3

Ang II impacts nearly the entire kidney through activation of angiotensin II subtype 1 receptors (AT₁R), and ET-1 activity in the kidney is mostly mediated through the endothelin type A receptor (ET_AR).¹

Both Ang II and ET-1 have similar pathophysiological functions within the kidney that contribute to actions such as vasoconstriction, inflammation, and cellular proliferation.^1,4,5 Collectively, these effects contribute to hypertension, glomerulosclerosis, proteinuria, and tubulointerstitial fibrosis.^1,4,6

Preclinical data suggest that increased ET-1 leads to inflammation, particularly in the glomerulus.^7-10

Within the glomerulus, ET-1 is constitutively expressed in all cells and is involved in the homeostasis of glomerular structure and filtration function.⁷ Findings indicate that ET-1 increases glomerular permeability to proteins and renal inflammation.^7-10

• Mesangial cells: Increased ET-1 causes cellular proliferation, contraction, and increased extracellular matrix accumulation.^7,10 Excessive ET-1 activity in mesangial cells may be strongly indicative of glomerular damage.¹⁰

• Endothelial cells and podocytes: Increased ET-1 production leads to glomerular inflammation and injury, sclerosis, and podocyte injury, all contributing to proteinuria.⁷

• Glycocalyx: The IgA nephropathy-prone gddY mouse model demonstrated an upregulation of ET-1 and ET_AR and a decrease in the glycocalyx area.⁸

Ultimately blocking ET_AR could mediate glomerular damage and the proinflammatory effects of ET-1.^7-9/

Several biomarkers have been associated with inflammation in IgA nephropathy including urinary soluble CD163 (u-sCD163).^12,15,16

CD163 is a transmembrane protein expressed during the healing phase of inflammation.¹² It is a marker of alternatively activated macrophages and inflammation in several proinflammatory diseases.^13,17,18

In the kidney, CD163 has been correlated with macrophage infiltration and is associated with active lesions.¹⁵

In IgA nephropathy, u-sCD163 has been associated with inflammation in the TESTING and NEFIGAN studies.^15,16

The recent Phase 2 SPARTAN interim analysis, presented at ASN Kidney Week 2024 and WCN 2025, assessed u-sCD163 as an inflammation biomarker in patients with IgA nephropathy treated with sparsentan.¹⁹

Early mouse models of IgA nephropathy found that sparsentan decreased glomerular macrophage infiltration and attenuated immune-complex mediated mesangial cellularity.^21,22 Recent IgA nephropathy mouse models have demonstrated that treatment with sparsentan can attenuate gene expression specific to immune and inflammatory pathways, including inflammatory pathway gene markers.^8,20

Interim u-sCD163 data from SPARTAN (n=11), a Phase 2, open-label, single-arm multicenter trial, demonstrated the anti-inflammatory effect of sparsentan.¹⁹

Findings showed a rapid and sustained reduction of u-sCD163 with sparsentan treatment.¹⁹ At Week 24, there was a 50% reduction in u-sCD163 from baseline indicating a reduction in inflammation in patients.¹⁹

The SPARTAN study will continue to evaluate additional biomarkers to better elucidate the additional mechanistic actions of sparsentan, a novel, non-immunosuppressive Dual Endothelin Angiotensin Receptor Antagonist (DEARA).^1,19,23

Over the last two decades, preclinical data has implicated ET-1 in renal inflammation.^7,9,10 Recently, biomarker data from the SPARTAN interim analysis demonstrated sparsentan’s anti-inflammatory effect in humans, supporting data from early mouse models of IgA nephropathy that showed attenuation of immune and proinflammatory signaling with sparsentan.^8,19,20