Targeting Inflammation and Fibrosis in IgA Nephropathy: Preclinical Data and Translational Biomarker Insights

In this issue we:

• Describe key inflammatory and fibrotic mechanisms in IgA nephropathy
• Share preclinical data from studies with sparsentan in mouse and rat models showing anti-fibrotic and anti-inflammatory effects independent of blood pressure reduction
• Explain the role of key urinary biomarkers in reflecting kidney-localized inflammation and fibrosis and understand their potential application to clinical studies

IgA nephropathy is the most common form of primary glomerulonephritis and is caused by the deposition of IgA in the glomerular mesangium.^2,3 This deposition triggers local inflammation and fibrotic remodeling that can lead to kidney damage, nephron loss, and progression to kidney failure.¹

ET-1 and Ang II are key mediators of disease progression.¹ Both have similar pathophysiological roles and together contribute to hypertension, glomerulosclerosis, and proteinuria, in addition to inflammation and fibrosis.^1,4,5

Renal inflammation occurs when ET-1 and Ang II stimulate the release of inflammatory signals, such as monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF).^5-8 These signals drive inflammation and trigger fibrosis by activating transcription growth factor-β (TGF-β), leading to fibroblast activation and matrix buildup.^9,10

Simultaneously, ET-1 and Ang II also induce oxidative stress, promoting upregulation of genes involved in fibrosis, inflammation, and tissue remodeling, further amplifying kidney damage over time.^5,9,11-13

In IgA nephropathy, sparsentan protects the glomerulus by simultaneously blocking the activity of ET-1 and Ang II.¹ To evaluate its intrarenal effects, several animal models mimicking key features of IgA nephropathy were used, including the gddY mouse, the IgA1-IgG engineered immune complex (EIC) mouse, and the anti-Thy1 rat.^12,14,15 These models reproduce hallmark features of the disease such as mesangial proliferation, inflammation, and fibrosis.^12,14,15

Across models, sparsentan consistently showed anti-inflammatory and anti-fibrotic activity.^12,14,15 In the EIC and gddY mouse models, sparsentan ameliorated expression of inflammatory, immune response, and proliferative gene pathways.^12,14 In the EIC model specifically, sparsentan also attenuated gene expression of C1q components of the classical complement pathway.¹² In the anti-Thy1 rat model, sparsentan led to dose-dependent reductions in glomerular macrophage infiltration.¹⁵

In addition to reducing inflammatory activity, sparsentan has demonstrated anti-fibrotic effects in preclinical models of IgA nephropathy.^14,15 In the anti-Thy1 rat model, treatment with sparsentan led to dose-dependent attenuations in interstitial myofibroblast activation.¹⁵ Similarly, in the gddY mouse model, sparsentan ameliorated the increase in mRNA expression of genes associated with profibrotic signaling pathways.¹⁴

These molecular changes were accompanied by improvements in histological markers of kidney injury across both models.^14,15

While kidney biopsy remains the gold standard for assessing inflammation and fibrosis in IgA nephropathy, its invasive nature limits its use for ongoing disease monitoring.¹⁸ Today, estimated glomerular filtration rate (eGFR) and proteinuria are the only validated biomarkers in clinical practice for IgA nephropathy.¹⁸ However, studies are increasingly investigating urinary biomarkers for noninvasive disease evaluation.¹⁶

Several interconnected urinary biomarkers have emerged as potential indicators of inflammation, immune activation, and fibrotic remodeling in IgA nephropathy.¹⁶

While not yet used in clinical decision-making, these biomarkers may provide insight into kidney-specific disease activity in ongoing studies.^16,17,19-23 In clinical studies, including the Phase 2 SPARTAN and Phase 3 TESTING trials, these biomarkers have been used to explore underlying inflammation, fibrosis, and kidney injury.^16,24