title: Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility.
abstract: BACKGROUND
  We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)].
  
  
  METHODS
  Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49).
  
  
  RESULTS
  Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy.
  
  
  CONCLUSIONS
  Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified.
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital and UCL Medical School, Pond Street, London NW3 2QG, UK. c.denton@ucl.ac.uk.
authors.forename: H
authors.initials: H
authors.lastname: Penn
authors.forename: N
authors.initials: N
authors.lastname: Quillinan
authors.forename: K
authors.initials: K
authors.lastname: Khan
authors.forename: K
authors.initials: K
authors.lastname: Chakravarty
authors.forename: V H
authors.initials: VH
authors.lastname: Ong
authors.forename: A
authors.initials: A
authors.lastname: Burns
authors.forename: C P
authors.initials: CP
authors.lastname: Denton
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D016022:Case-Control Studies; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000150:complications / Q000188:drug therapy*; D013449:Sulfonamides / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000077300:Bosentan