Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility

Area of Science:

• Nephrology
• Rheumatology
• Pharmacology

Background:

• Scleroderma renal crisis (SRC) involves elevated endothelin-1 (ET-1) levels.
• ET-1 ligand and receptor expression is increased in SRC kidney biopsies.
• Systemic sclerosis (SSc) patients with SRC exhibit higher ET-1 than healthy controls.

Purpose of the Study:

• To investigate ET-1 levels and tissue expression in SRC.
• To conduct a pilot safety study of bosentan in SRC patients.

Main Methods:

• Measured serum ET-1 in healthy controls, SSc patients, and SRC patients.
• Analyzed ET-1 and endothelin receptor expression in SRC renal biopsies.
• Administered bosentan to six SRC patients for six months and compared outcomes with historical controls.

Main Results:

• Serum ET-1 was elevated in SRC, with higher levels during bosentan therapy.
• Increased expression of ET-1, endothelin A, and endothelin B receptors was observed in SRC biopsies.
• Bosentan was well-tolerated, showing favorable long-term outcomes compared to historical SRC cases.

Conclusions:

• The upregulation of the ET-1 axis supports ET-1 receptor blockade as a therapeutic strategy in SRC.
• Bosentan treatment appears safe and potentially beneficial for SRC.
• Further research is warranted to evaluate therapeutic benefits and compare different receptor antagonists.