MICA: Evaluation of the selective endothelin A-receptor antagonist zibotentan as a treatment for renal disease in systemic sclerosis (scleroderma)

系统性硬化症(SSC)，又称硬皮病，是一种严重的风湿病。尽管皮肤增厚或硬化几乎在所有病例中都会发生，这证明了“硬皮病”一词的合理性，但这种疾病远不止“皮肤深处”，因为它经常会导致包括心脏、肺、肾、肠道和血管在内的许多内部器官的损害。这很重要，因为虽然不常见，但它导致的死亡人数比其他任何风湿病都多，大约一半被诊断为硬皮病的患者最终死于这种疾病。它还会导致许多严重的非危及生命的问题，如疼痛、手功能丧失和残疾。硬皮病患者的肾脏通常会受到影响，主要有两种方式。首先，大约每8例严重系统性硬化症患者中就有1例发生肾功能衰竭，并伴有非常高的血压。这被称为硬皮病肾危机(SRC)。尽管以前通常是致命的，但现在大多数患者都能存活下来，但多达一半的患者可能会患有长期的肾功能衰竭，需要透析或移植。除了SRC，硬皮病还会以另一种更常见的方式影响肾脏。由于长期的血管损伤和疤痕形成(或纤维化)，硬皮病会导致长期的(慢性)肾脏损害。虽然这种慢性肾损伤不像SRC那样直接危及生命，但它可能会影响长期生存和生活质量，并对药物治疗或其他硬皮病并发症的严重程度产生重大影响。目前的应用将评估使用一种新药来阻断一种名为内皮素的特定蛋白质的潜在益处，这种蛋白质可能会导致系统性硬化症中的肾脏异常。内皮素是由血管衬里细胞产生的，高水平似乎会损害包括肾脏在内的组织。它通过两种特殊的细胞表面受体发挥作用，分别称为ET-A和ET-B。在SRC中，内皮素水平升高，有证据表明，在系统性硬化症的几个并发症中，内皮素活性增加。齐博坦是一种非常有效的药物，可以阻断内皮素的一种受体，即ET-A受体。这一点很重要，因为其他受体，特别是ET-B受体，可能对正常的肾脏功能很重要。因此，阻断ET-A有望改善SRC的预后，也可能逆转或预防不太严重的肾脏疾病。我们将通过首先确定系统性硬化症中肾脏疾病的最佳衡量标准来探索这一点，然后在患有中度肾脏疾病的SSC病例中进行齐宾坦与对照的临床试验。同时，我们将评估在SRC的标准治疗中加入齐博坦的益处，包括常规使用其他降压药，如ACE抑制剂。总之，这项工作的结果将确定阻断ET-A的益处，同时保留ET-B信号可能的有益效果，并可能与肾脏外硬皮病的并发症相关，以及与其他常见的医疗条件相关。

Systemic sclerosis (SSc), also called scleroderma, is a serious rheumatic disease. Although skin thickening, or hardening, occurs in almost all cases, justifying the term "scleroderma", the disease is much more than "skin-deep" since it often causes damage many internal organs including the heart, lungs, kidney, bowel and blood vessels. It is important because, although uncommon, it causes more deaths than any other rheumatic disease, with around half of the patients diagnosed with scleroderma eventually dying as a direct result of the condition. It also causes many severe non-life threatening problems such as pain, loss of hand function and disability. The kidneys are often affected in scleroderma and this can occur in two main ways. First, around 1 in 8 cases of severe systemic sclerosis develop kidney failure associated with very high blood pressure. This is called a scleroderma renal crisis (SRC). Although previously usually fatal, most patients now survive SRC but up to half can have long term renal failure and require dialysis or transplantation. In addition to SRC, scleroderma also affects kidneys in a second way that is much more frequent. Due to long term blood vessel damage and scarring (or fibrosis) scleroderma causes long term (chronic) renal damage. Although less immediately life-threatening than SRC this chronic renal damage may impact on long term survival and quality of life, and have a major effect on medication or the severity of other scleroderma complications.The present application will assess the potential benefit of using a novel drug to block a specific protein called endothelin that may be driving the renal abnormalities in systemic sclerosis. Endothelin is produced by blood vessel lining cells and high levels appear to damage tissues including the kidneys. It exerts its effect through two specific cell surface receptors termed ET-A and ET-B. Endothelin levels are increased in SRC and there is evidence for increased endothelin activity in several complications of systemic sclerosis. Zibotentan is a very potent drug that blocks one receptor for endothelin, the ET-A receptor. This is important as other receptors, specifically the ET-B receptor, may be important for normal kidney function. Thus blocking ET-A is expected to improve outcome in SRC and may also reverse or prevent less severe forms of renal disease. We will explore this by first defining the best measures of renal disease in systemic sclerosis and then undertake a clinical trial of zibtentan compared with control in cases of SSc that have moderate kidney disease. In parallel we will assess the benefit of adding zibotentan to standard treatments for SRC that include routine use of other blood pressure lowering drugs such as ACE inhibitors. Together the results of this work will define the benefit of blocking ET-A, whilst retaining the likely beneficial effects of ET-B signalling, and may have relevance for complications of scleroderma outside the kidney, and to other commoner medical conditions.