Pos-378 Selective Eta Antagonist Atrasentan, Rapidly Reduces Albuminuria and Downregulates Intra-Renal Pro-Inflammatory and Pro-Fibrotic Transcriptional Networks in the Gddy Mouse Model of Spontaneous Iga Nephropathy

King, Alexandra; Oballa, Renata M.; Gunawan, Muhammad; Cox, Jason M.; Wu, J.; Chong, O.K.; Surendradoss, Jayakumar; Lester, Joanne; Nieh, C.; Kano, Toshiki; Suzuki, Yusuke

doi:10.1016/j.ekir.2021.03.396

Cited by 3 publications

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“…IgAN mouse models show that blocking ET A R can lead to significant decreases in proteinuria and glomerulonephritis. 31,32 However, use of drugs that target ET A R alone can lead to fluid retention, which, in some patients, has led to heart failure and hospitalisation. 33 Conversely, AT 1 R antagonists can lead to decreased sodium retention and promote fluid excretion.…”

Section: Bruce Hendrymentioning

confidence: 99%

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Roberts

2024

EMJ

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Immunoglobulin A nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. In some patients, it can progress rapidly, leading to proteinuria, kidney failure, and death. Standard of care is traditionally with an angiotensin converting enzyme inhibitor (ACEi), or an angiotensin II (Ang II) receptor blocker (ARB). More recently, drugs targeting both endothelin 1 (ET-1) and Ang II receptors have been developed, as overactivation of such is implicated in IgAN. Sparsentan is a dual ET Type A (ETAR) and Ang II subtype 1 receptor (AT1R) antagonist. The PROTECT study compared sparsentan with the ARB irbesartan, in patients with IgAN and with proteinuria of ≥1 g/day despite stable dose of ACEi/ARB for ≥90 days. Data presented at the 2023 American Society of Nephrology (ASN) Kidney Week showed that use of sparsentan led to sustained (>110 weeks) decreases in proteinuria, and a significantly greater preservation of kidney function, compared with irbesartan. The ongoing SPARTAN study is investigating the use of sparsentan in recently diagnosed, treatment-naïve patients with IgAN. Preliminary data in 12 patients showed rapid and sustained proteinuria reductions, with little change from baseline in estimated glomerular filtration rate (eGFR), body weight, or total body water mean at Week 36. In both studies, sparsentan was generally well-tolerated with, in PROTECT, a comparable safety profile to irbesartan. Data presented at the congress also showed that sparsentan consistently occupies AT1R at levels exceeding ETAR occupancy. This balance is hypothesised to contribute to sparsentan’s limited risk of fluid retention.

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Section: Bruce Hendrymentioning

confidence: 99%

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Roberts

2024

EMJ

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Targeting the Endothelin A Receptor in IgA Nephropathy

Kohan,

Barratt,

Heerspink

et al. 2023

Kidney International Reports

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The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy

Roberts¹

2022

EMJ Nephrol

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IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are rare primary glomerulopathies, though the incidence of IgAN is greater. Endothelin 1 (ET-1) and angiotensin II (Ang II) are implicated in the development and progression of IgAN and FSGS. Both conditions impact health-related quality of life (HRQoL) and may lead to kidney failure. IgAN and FSGS are both evidenced clinically by proteinuria, with a greater degree of such associated with more progressive disease and shorter times to kidney failure. Accordingly, the reduction of proteinuria in patients with these conditions is a key target. Currently, IgAN and FSGS treatments are unsuccessful or only partially successful in a number of patients. Immunosuppressant therapy is first-line for primary FSGS and utilised for patients with IgAN who remain at high risk of progression despite maximal supportive care; however, while effective, there is a significant risk of toxicity and relapse is frequent. A number of clinical trials are ongoing to investigate the use of non-immunosuppressive agents in the management of these conditions. The dual endothelin Type A receptor/Ang II subtype 1 receptor (ETAR/AT1R) antagonist (DEARA) sparsentan is currently being assessed as a means to control kidney disease progression. Interim study results show that sparsentan can lead to greater reductions in proteinuria than AT1R antagonism alone in IgAN and more patients reaching partial remission (PR) in FSGS. Herein, a symposium by leading experts at the European Renal Association (ERA) 59th Congress in Paris, 19th−22nd May 2022, is presented. It highlights IgAN and FSGS and the role of proteinuria in these conditions, and how targeting ET-1 and Ang II can lead to a reduction in proteinuria in IgAN and potential FSGS PR.

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Pos-378 Selective Eta Antagonist Atrasentan, Rapidly Reduces Albuminuria and Downregulates Intra-Renal Pro-Inflammatory and Pro-Fibrotic Transcriptional Networks in the Gddy Mouse Model of Spontaneous Iga Nephropathy

Cited by 3 publications

References 0 publications

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Targeting the Endothelin A Receptor in IgA Nephropathy

The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy

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