Abbott Laboratories, Abbott Park, IL 60064, United States.
Life Sci. 2012 Oct 15;91(13-14):739-42. doi: 10.1016/j.lfs.2012.01.011. Epub 2012 Feb 2.
Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan.
UACR was reduced in the 0.75 mg and 1.75 mg groups (42% and 35% vs placebo, P<0.011) over the 8 week treatment period. Edema was reported in 21 subjects: 62% of edema events emerged during the first 4 weeks. There were no significant changes in serum hsCRP, IL-6, NT-pro-BNP, ET-1, urine TGFb or MCP-1. Urine NGAL was reduced 24% in the 1.75 mg group (P=0.044). Hispanic subjects (58% of total) tended to have greater UACR reductions than non-Hispanics (0.75 mg dose: Hispanic: 41-60%; non-Hispanic: 18-37%; P=0.012 and 0.048 vs placebo, respectively) without different rates of edema. Mean UACR reduction in subjects receiving maximum doses of RAS inhibitors (38%) was 32% and 35% in the 0.75 and 1.75 mg groups, respectively, and similar to overall UACR changes.
Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN.
糖尿病患者慢性肾脏病（CKD）的进展是一个日益严重的问题。糖尿病与内皮素-1（ET-1）升高和内皮素 A 受体（ETAR）在肾脏中的表达增强有关。高度选择性的 ETAR 拮抗剂阿曲生坦可降低糖尿病肾病（DN）患者的蛋白尿。
这是一项针对接受肾素-血管紧张素系统（RAS）抑制剂治疗、肾小球滤过率（eGFR）>20ml/min 且尿白蛋白/肌酐比值（UACR）为 100-3000mg/g 的 2 型糖尿病患者的随机、双盲试验，患者被随机分配至安慰剂、0.25、0.75 或 1.75mg 阿曲生坦组。
在 8 周的治疗期间，0.75mg 和 1.75mg 组的 UACR 降低（与安慰剂相比分别降低 42%和 35%，P<0.011）。有 21 例患者出现水肿：62%的水肿事件发生在治疗的前 4 周。血清 hsCRP、IL-6、NT-pro-BNP、ET-1、尿 TGFb 或 MCP-1 无明显变化。1.75mg 组尿 NGAL 降低 24%（P=0.044）。西班牙裔患者（占总人数的 58%）比非西班牙裔患者（0.75mg 剂量：西班牙裔：41-60%；非西班牙裔：18-37%；P=0.012 和 0.048 分别与安慰剂相比）的 UACR 降低幅度更大，且水肿发生率无差异。接受最大剂量 RAS 抑制剂治疗的患者（38%）的平均 UACR 降低率分别为 0.75mg 和 1.75mg 组的 32%和 35%，与总体 UACR 变化相似。
水肿的形成呈剂量依赖性，且发生较早。尿 NGAL 的减少需要进一步研究肾小管疾病的缓解。基于种族的 UACR 反应需要进一步描述。结果表明，阿曲生坦可能与 RAS 抑制联合治疗糖尿病肾病具有协同作用。
