• 1.

    Kohan DE, Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int 2014; 86:896904. doi: 10.1038/ki.2014.143

  • 2.

    Raina R, et al. The role of endothelin and endothelin antagonists in chronic kidney disease. Kidney Dis (Basel) 2020; 6:2234. doi: 10.1159/000504623

  • 3.

    Heerspink HJL, et al. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: A meta-analysis. J Am Soc Nephrol 2015; 26:20552064. doi: 10.1681/ASN.2014070688

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Coresh J, et al. Change in albuminuria and subsequent risk of end-stage kidney disease: An individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol 2019; 7:115127. doi: 10.1016/S2213-8587(18)30313-9

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Fernandez-Fernandez B, et al. Canagliflozin and renal events in diabetes with established nephropathy clinical evaluation and study of diabetic nephropathy with atrasentan: What was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan? Clin Kidney J 2019; 12:313321. doi: 10.1093/ckj/sfz070

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Mann JFE, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21:527535. doi: 10.1681/ASN.2009060593

  • 7.

    Dhaun N, et al. Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease. Hypertension 2011; 57:772779. doi: 10.1161/hypertensionaha.110.167486

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Heerspink HJL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomised, placebo-controlled trial. Lancet 2019; 393:19371947. doi: 10.1016/S0140-6736(19)30772-X

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Trachtman H, et al. DUET: A phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol 2018; 29:27452754. doi: 10.1681/ASN.2018010091

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Hogan J, et al. Complete remission of proteinuria in patients with focal segmental glomerulosclerosis treated with sparsentan, a dual endothelin and angiotensin receptor antagonist, in DUET trial (abstract). American Society of Nephrology (ASN) Annual Meeting (digital) 2020; SU-OR38. https://www.hdcn.com/xk/07or0038.htm

    • Search Google Scholar
    • Export Citation
  • 11.

    Komers R, et al. Study design of the phase 3 sparsentan versus irbesartan (DUPLEX) study in patients with focal segmental glomerulosclerosis. Kidney Int Rep 2020; 5:494502. doi: 10.1016/j.ekir.2019.12.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383:14361446. doi: 10.1056/NEJMoa2024816

New Studies in the Pipeline with Endothelin Inhibitors

  • 1 Marina Lopez-Martinez, MD, and María José Soler, MD, PhD, FERA, are with the Nephrology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, Barcelona, Spain.
Full access

Endothelin-1 (ET-1) plays a role in chronic kidney disease (CKD) progression (1). In the kidney, ET-1 binding of the endothelin A (ETA) receptor drives afferent arteriole vasoconstriction, cell proliferation, podocyte and glycocalyx damage, matrix accumulation, and proinflammatory effects, whereas binding of the endothelin B (ETB) receptor produces vasodilation, antifibrotic effects, and decreased sodium reabsorption and natriuresis (1, 2). Although renin-angiotensin-aldosterone system (RAAS) inhibition has proven a reduction of albuminuria and a proportional effect on kidney protection (3, 4), residual albuminuria still implies a significant risk of CKD progression (5

Endothelin-1 (ET-1) plays a role in chronic kidney disease (CKD) progression (1). In the kidney, ET-1 binding of the endothelin A (ETA) receptor drives afferent arteriole vasoconstriction, cell proliferation, podocyte and glycocalyx damage, matrix accumulation, and proinflammatory effects, whereas binding of the endothelin B (ETB) receptor produces vasodilation, antifibrotic effects, and decreased sodium reabsorption and natriuresis (1, 2). Although renin-angiotensin-aldosterone system (RAAS) inhibition has proven a reduction of albuminuria and a proportional effect on kidney protection (3, 4), residual albuminuria still implies a significant risk of CKD progression (5). Therefore, other therapies, such as endothelin receptor antagonists (ERAs), are currently being evaluated as promising treatments for different proteinuric nephropathies (1, 2).

The first phase 3 clinical trial of ERAs was the ASCEND study (A Study of Cardiovascular Events in Diabetes) (6), published in 2009. It compared, in 1392 patients with diabetic kidney disease, avosentan (ETA:ETB receptor blockade ≈ 50–300:1) with placebo in addition to continued angiotensin-converting enzyme inhibition (ACEi) and/or angiotensin receptor blockade (ARB) (Table 1). In patients who were treated with avosentan 25 mg/day, 50 mg/day, and placebo, the median reduction of the albumin-to-creatinine ratio (ACR) was 44.3%, 49.3%, and 9.7%, respectively (p < 0.0001). However, the trial was ended prematurely because of an excess of cardiovascular events with avosentan associated with fluid retention, which may be in part explained by the antinatriuretic effect secondary to the ETB receptor blockade (6). Since then, all future clinical trials have been designed to reduce cardiovascular events, by excluding patients with brain natriuretic peptide (BNP) ≥ 200 pg/mL or with a history of heart failure.

Table 1.

Randomized clinical trials with endothelin receptor antagonists in patients with kidney disease

Table 1.

Sitaxsentan (ETA:ETB receptor blockade ≈ 6000:1), at a dose of 100 mg daily, was studied in nondiabetic CKD patients (7). This ERA (Effects of Sitaxsentan on Proteinuria, 24-Hour Blood Pressure, and Arterial Stiffness in CKD Subjects [FCRD01]) was withdrawn due to two cases of fatal hepatic failure in 2010. The SONAR study (Study of Diabetic Nephropathy with Atrasentan) (8) included, after an enrichment period (excluding patients who did not have albuminuria reduction and/or edema), 2648 patients with diabetes who received either 0.75 mg of atrasentan (ETA:ETB receptor ≈ 1200:1) or placebo, on top of RAAS inhibition, during a median follow-up of 2.2 years. The primary outcome was the efficacy of atrasentan in delaying progression of CKD (composite endpoint): patients treated with atrasentan had a significantly lower risk of doubling serum creatinine or end stage kidney disease (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.49–0.88, p = 0.0047) compared with placebo. Adjudicated hospital admission for heart failure occurred in 3.5% of patients in the atrasentan group compared with 2.6% in the placebo group (HR 1.33, 95% CI 0.85–2.07, p = 0.65). This study was performed in a selected diabetic kidney disease group of patients without heart failure and normal BNP.

As additive effects on proteinuria were observed with ERA and ACEi/ARB, sparsentan, a molecule with a dual-acting angiotensin type 1 receptor blocker and highly selective ETA receptor antagonist (negligible ETB receptor blockade) has been recently evaluated in other proteinuric kidney diseases. DUET (Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis [FSGS]: A Randomized, Double-blind, Active-Control, Dose-Escalation Study) (9), a phase 2 trial, studied the effect of 200 mg, 400 mg, and 800 mg daily in primary FSGS. All doses of sparsentan compared with 300 mg of irbesartan achieved greater reductions in the protein-to-creatinine ratio (45% vs. 19% with 200 mg; 47% vs. 19% with 400 mg and 800 mg). Blood pressure was also reduced in the sparsentan group, and estimated glomerular filtration rate (eGFR) was stable in both treatments. The incidence of adverse events was similar between groups. Moreover, a post hoc analysis (DUET-Open-Label Extension [OLE]) concluded that 40% of patients treated with sparsentan achieved complete remission of proteinuria (≤0.3 g/g) on at least one occasion (10).

DUPLEX (Study of Sparsentan in Patients with Primary FSGS) (11) is the phase 3 study that will evaluate the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with irbesartan in patients with primary FSGS. Also, in immunoglobulin A (IgA) nephropathy, which is the most prevalent primary glomerulonephritis worldwide, the potential benefit of 200–400 mg of sparsentan on kidney function will be evaluated by analyzing changes in proteinuria and eGFR as compared to 150–300 mg of irbesartan in the PROTECT study (A Study of the Effect and Safety of Sparsentan in the Treatment of Patients with IgA Nephropathy; ClinicalTrials.gov: NCT03762850).

Sodium glucose co-transporter 2 inhibitors (SGLT2i) cause, through tubuloglomerular feedback, afferent arteriole vasoconstriction and have also proven kidney protection from CKD progression (12). Therefore, a potent antagonist of ETA with no effect on the ETB receptor (zibotentan) is being evaluated in ZENITH-CKD (Zibotentan and Dapagliflozin for the Treatment of CKD), a phase 2b study in patients with CKD and proteinuria (ClinicalTrials.gov: NCT04724837), as monotherapy and in addition to the SGLT2i, dapagliflozin. Zibotentan has already been studied in ZEBRA (Zibotentan Better Renal Scleroderma Outcome Study; ClinicalTrials.gov: NCT02047708), with positive results in the scleroderma renal crisis.

In conclusion, ERAs are a strategic therapy with promising effects on proteinuria and CKD progression. However, their incorporation into clinical practice has been delayed as a consequence of their adverse effects in terms of fluid retention. New molecules seem to achieve results with statistical power and safe results that will finally allow us to include them soon in day-to-day practice. In the near future, the treatment of patients with CKD is expected to mimic the sequential treatment offered currently for patients with heart failure.

References

  • 1.

    Kohan DE, Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int 2014; 86:896904. doi: 10.1038/ki.2014.143

  • 2.

    Raina R, et al. The role of endothelin and endothelin antagonists in chronic kidney disease. Kidney Dis (Basel) 2020; 6:2234. doi: 10.1159/000504623

  • 3.

    Heerspink HJL, et al. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: A meta-analysis. J Am Soc Nephrol 2015; 26:20552064. doi: 10.1681/ASN.2014070688

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Coresh J, et al. Change in albuminuria and subsequent risk of end-stage kidney disease: An individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol 2019; 7:115127. doi: 10.1016/S2213-8587(18)30313-9

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Fernandez-Fernandez B, et al. Canagliflozin and renal events in diabetes with established nephropathy clinical evaluation and study of diabetic nephropathy with atrasentan: What was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan? Clin Kidney J 2019; 12:313321. doi: 10.1093/ckj/sfz070

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Mann JFE, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21:527535. doi: 10.1681/ASN.2009060593

  • 7.

    Dhaun N, et al. Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease. Hypertension 2011; 57:772779. doi: 10.1161/hypertensionaha.110.167486

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Heerspink HJL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomised, placebo-controlled trial. Lancet 2019; 393:19371947. doi: 10.1016/S0140-6736(19)30772-X

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Trachtman H, et al. DUET: A phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol 2018; 29:27452754. doi: 10.1681/ASN.2018010091

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Hogan J, et al. Complete remission of proteinuria in patients with focal segmental glomerulosclerosis treated with sparsentan, a dual endothelin and angiotensin receptor antagonist, in DUET trial (abstract). American Society of Nephrology (ASN) Annual Meeting (digital) 2020; SU-OR38. https://www.hdcn.com/xk/07or0038.htm

    • Search Google Scholar
    • Export Citation
  • 11.

    Komers R, et al. Study design of the phase 3 sparsentan versus irbesartan (DUPLEX) study in patients with focal segmental glomerulosclerosis. Kidney Int Rep 2020; 5:494502. doi: 10.1016/j.ekir.2019.12.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383:14361446. doi: 10.1056/NEJMoa2024816

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