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Selective Endothelin-A Receptor Antagonist (Diabetic Nephropathy) Pregnancy: Contraindicated — endothelin signalling critical for cardiovascular development. REMS programme with mandatory contraception and pregnancy testing required.

Atrasentan

Brand names: Zenaro

Adult dose

Dose: 0.75 mg once daily
Route: Oral
Frequency: Once daily
Max: 0.75 mg/day
Diabetic kidney disease (DKD) with proteinuria ≥0.7 g/g creatinine, eGFR 25–75 mL/min, on maximally tolerated RAAS blockade (ACEi or ARB). MHRA conditional approval 2024 under REMS programme. BNF 90 listed but prescribing specialist-only. Source: BNF 90; MHRA SPC Zenaro.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg
Route: N/A
Frequency: N/A
Max: N/A
Not licensed in paediatric diabetic nephropathy.

Dose adjustments

Renal

eGFR 25–75 mL/min: licensed range. Below eGFR 25: insufficient data — do not initiate. Above eGFR 75: limited evidence of benefit. Fluid retention risk is higher at lower eGFR.

Hepatic

Mild-moderate hepatic impairment: no dose adjustment. Severe hepatic impairment (Child-Pugh C): avoid — increased exposure and fluid retention risk.

Paediatric weight-based calculator

Not licensed in paediatric diabetic nephropathy.

Clinical pearls

  • SONAR trial (Lancet 2019): enrichment design — patients were first given atrasentan and only those who showed proteinuria reduction WITHOUT fluid retention were randomised. In this enriched population, atrasentan reduced the composite of doubling of serum creatinine or ESKD by 35% vs placebo. The enrichment design is critical — atrasentan is selective for patients who respond without fluid overload.
  • ETA selectivity — advantage over dual ERA: atrasentan is selective for ETA receptor (vs ETB). ETB activation promotes natriuresis (sodium excretion) and vasodilation — blocking ETB (as with non-selective ERAs) worsens fluid retention. Atrasentan's ETA selectivity spares ETB → less sodium retention than non-selective ERAs (bosentan, macitentan). Lower fluid retention rate than non-selective ERA is the critical safety advantage enabling use in CKD.
  • Position alongside SGLT2 inhibitors and finerenone: atrasentan represents a fourth mechanism-based therapy in diabetic CKD, complementing ACEi/ARB (RAAS), SGLT2 inhibitors, and finerenone (non-steroidal MRA). Whether combination of all four therapies provides additive benefit is under investigation — currently used as add-on to RAAS + SGLT2 inhibitor when proteinuria remains high.
  • Fluid retention monitoring: patients must weigh themselves daily at start of treatment. If weight gain >2 kg in 1 week — review and consider loop diuretic or stopping atrasentan. The SONAR enrichment protocol excluded patients who developed fluid retention in the run-in phase — real-world prescribers should be equally vigilant.
  • ERA class hepatotoxicity: ALT/AST must be checked at baseline and monthly for 3–6 months. If ALT >3× ULN — withhold and investigate. ERA-associated hepatotoxicity is a class effect (first seen with bosentan). Source: BNF 90; Heerspink et al. Lancet 2019 (SONAR); MHRA SPC Zenaro 2024.

Contraindications

  • Fluid overload or decompensated heart failure (fluid retention risk — absolute contraindication)
  • Serum albumin <30 g/L (increased fluid retention and oedema risk)
  • Concurrent dual RAAS blockade (ACEi + ARB) when adding atrasentan
  • Other endothelin receptor antagonists
  • Pregnancy (endothelin blockade — teratogenic; REMS programme required)

Side effects

  • Fluid retention and peripheral oedema (most common — ETA blockade promotes sodium and water retention in the kidney; incidence ~15% vs 5% placebo in SONAR)
  • Anaemia (endothelin modulates erythropoiesis — mild reduction in haemoglobin)
  • Elevated liver transaminases (ERA class — monitor monthly)
  • Nasopharyngitis, sinusitis
  • Heart failure hospitalisation (fluid retention risk — monitor weight and fluid status)

Interactions

  • Ciclosporin: significantly increases atrasentan exposure (P-gp/OATP inhibition) — contraindicated
  • Strong CYP3A4 inhibitors (clarithromycin, itraconazole): increase atrasentan — avoid or dose reduce
  • ACEi/ARB: background RAAS blockade is required (standard of care) — single RAAS agent only, not dual
  • Loop diuretics: may be needed to manage fluid retention during atrasentan treatment
  • Hepatotoxic drugs: additive liver injury risk — avoid concurrent hepatotoxic medications

Monitoring

  • Liver function tests (ALT, AST) at baseline and monthly for 6 months, then every 3 months
  • Body weight daily by patient (fluid retention monitoring — alert if >2 kg increase in 1 week)
  • Fluid balance and oedema assessment at each clinical visit
  • Urine ACR or proteinuria (treatment response — target ≥30% reduction at 3 months)
  • eGFR and serum electrolytes every 3 months
  • Pregnancy test before each prescription in women of childbearing potential (REMS)

Reference: BNFc; BNF 90; Heerspink et al. Lancet 2019 (SONAR trial); MHRA conditional approval SPC Zenaro 2024; KDIGO Diabetic Kidney Disease Guidelines 2022. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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