Pirfenidone: Anti-Scarring Drug for Diabetic Nephropathy

进展性糖尿病肾病的现有治疗方法包括抗高血压药物，如血管紧张素转换酶抑制剂（ACEi）和血管紧张素II受体阻滞剂（ARBs）。尽管最近的研究表明这种方法在1型和2型糖尿病患者中的效用，但这些药物在肾功能下降患者中阻止糖尿病肾病的效力尚不清楚。尽管肾素-盎格鲁-醛固酮系统的进一步改良可能被证明是有益的，但由于高钾血症、低血压和药物引起的肾灌注减少而导致肾功能下降的患者难以使用大剂量这些药物。认识到进行性糖尿病肾病主要是由于进行性肾小球硬化和小管间质纤维化，这一过程的介质和阻滞剂引起了人们的关注。我们之前的研究已经帮助确定了糖尿病肾脏中介导进行性基质沉积的一个关键因素是转化生长因子- α (TGF-a)。然而，TGF-a系统的直接抑制剂尚未用于临床试验。我们最近发现一种口服药物吡非尼酮，在糖尿病肾病小鼠模型发病后给药，对阻止进行性肾小球硬化非常有效。1型糖尿病和肾病患者的试验数据表明，该药耐受性良好。此外，最近一项针对晚期局灶性硬化患者的开放标签研究的初步数据表明，吡非尼酮可以降低肾功能下降的速度。然而，吡非尼酮的作用方式尚不清楚。基于动物模型和小型临床研究中令人鼓舞的数据，我们建议开展一项试验来评估吡非尼酮在1型和2型糖尿病和肾功能不全患者中的作用。我们提出一项随机、双盲、安慰剂研究来评估吡非尼酮是否会降低糖尿病肾病的进展率。此外，临床研究将确定是否可以使用TGF-a的一系列测量作为生物标志物来识别可能有肾功能快速下降的患者，并确定吡非尼酮的治疗益处是否确实是通过抑制TGF-a系统。

DESCRIPTION (provided by applicant): Existing treatment approaches for progressive diabetic nephropathy include anti-hypertensive agents such as angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs). Although recent studies demonstrate the utility of this approach in both type 1 and type 2 diabetic patients, the potency of these agents to arrest diabetic nephropathy in patients with declining renal function is not clear. Although, further modifications of the renin-Angll-aldosterone system may prove to be beneficial, high doses of these agents are difficult to use in patients with declining renal function due to hyperkalemia, low blood pressure, and drug-induced reduction of renal perfusion. The recognition that progressive diabetic nephropathy is largely due to progressive glomerulosclerosis and tubulointerstitial fibrosis has focused attention on mediators and blockers of this process. Our prior studies have helped to establish that a key factor in the mediation of progressive matrix deposition in the diabetic kidney is transforming growth factor-alpha (TGF-a). However, direct inhibitors of the TGF-a system are not yet available for clinical trials. We have recently identified that an orally administered drug, pirfenidone, is extremely potent to block progressive glomerulosclerosis when administered after the onset of disease in a mouse model of diabetic nephropathy. Pilot data in patients with type 1 diabetes and nephropathy indicate that this drug is well tolerated. In addition, preliminary data from a recent open-label study in patients with advanced focal scelrosis suggests that pirfenidone may lower the rate of decline of renal function. However, the mode of action of pirfenidone is unclear. Based on the encouraging data in animal models and small clinical studies, we propose to undertake a trial to evaluate the role of pirfenidone in patients with type 1 and type 2 diabetes and renal insufficiency. We propose a randomized, double-blind, placebo study to assess whether pirfenidone will lower the rate of progression of diabetic nephropathy. In addition, the clinical study will determine whether serial measures of TGF-a may be used as a biomarker to identify patients who may have a rapid decline in renal function and to determine if the therapeutic benefit of pirfenidone is indeed via inhibition of the TGF-a system.