Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility
Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility
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DOI：
10.1093/qjmed/hct111
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发表时间：
2013-09-01
影响因子：
13.3
通讯作者：
Denton, C. P.
中科院分区：
文献类型：
--
作者：
Penn, H.;Quillinan, N.;Denton, C. P.
背景资料：我们研究了硬皮病肾危象（SRC）中内皮素-1（ET-1）水平和ET-1配体和受体组织表达，并在SRC中进行了一项非选择性ET-1受体拮抗剂波生坦的初步开放标签安全性研究[波生坦在肾病中的应用-1（BIRD-1）]。测量健康对照组（n = 20）或伴或不伴SRC的系统性硬化症（SSc）（n = 80）（包括肺动脉高压（PAH）病例）的血清ET-1水平。肾活检（n = 27）与SRC患者进行了染色内皮素配体和受体。6例SRC患者接受了6个月波生坦治疗。结果：SRC患者血清ET-1水平升高，但低于PAH患者。在SRC活检组织中，肾小球、肾小球和SRC标志性血管病变中ET-1和内皮素A、内皮素B受体表达均增加。在BIRD-1队列中，SRC时所有病例的血清ET-1均升高（中位健康对照为0.50 pg/ml; SRC为1.48 pg/ml; P < 0.0005），波生坦治疗后进一步升高（1.46 vs. 3.05 pg/ml; t检验P < 0.05）。波生坦的耐受性良好，没有明显的药物相关严重不良事件，与历史病例相比，长期结局有利。三名患者出现反弹高血压的波生坦和一个退出似乎进一步受益于维持therapy.Conclusions：ET-1配体轴的上调表明，ET-1受体阻滞剂是合乎逻辑的，波生坦治疗似乎是安全的SRC。未来的研究，以评估治疗效益和比较选择性或非选择性受体拮抗剂是合理的。
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.