Feasibility study of empagliflozin in patients with autosomal dominant polycystic kidney disease

项目总结 常染色体显性遗传性多囊肾病(ADPKD)是一种常见的遗传性疾病，可导致终末期肾病。 肾脏疾病的阶段。尽管进行了数十年的研究，托伐普坦是唯一被批准的ADPKD干预措施。 然而，托伐普坦并不针对ADPKD的心血管并发症，并且受到高成本的限制 以及限制依从性的副作用。因此，迫切需要一种可容忍的替代方案。 干预以减缓ADPKD的进展并改善血管健康。钠-葡萄糖共转运蛋白-2 抑制剂(SGLT2i)在蛋白尿型糖尿病和非糖尿病患者中有耐受性和安全性的跟踪记录。 糖尿病肾病。SGLT2i在这些条件下的试验非常令人鼓舞，这些 治疗极有可能成为糖尿病和非糖尿病肾脏疾病的标准护理； 然而，其作用机制尚未完全阐明，可能与疾病病因学无关。这个 SGLT2i的潜在益处尚未在ADPKD患者中进行检验，因为主要试验已经排除了这种情况 病人。SGLT2i对ADPKD患者也有潜在的好处，不仅仅是减缓肾脏的损失 功能，因为这类药物为CKD范围内的患者提供了心血管死亡益处。 在PKD动物模型中测试SGLT2i的效果的研究得出了相互矛盾的结果。五周的时间 使用SGLT1和SLGT2抑制剂Plorizon治疗可抑制HAN：SPRD的囊变 大鼠PKD模型。SGLT2i延缓囊性肾病进展的机制可能与 抑制囊上皮细胞增殖。SGLT2i还具有抗氧化和抗炎作用， 对于减少纤维化和改善血管健康很重要，这两种情况都发生在 ADPKD.虽然许多变化可能导致高血压患者动脉功能障碍的发展 ADPKD，其中最令人担忧的是大弹性动脉硬化的发展，典型的 以主动脉脉搏波速度(APWV)为评价指标。我们建议进行一项试点随机临床试验，以确定 阿帕格列星治疗ADPKD的安全性和耐受性。为了达到这一目标，我们将进行为期12个月的平行调查- 50例ADPKD患者的随机、双盲、安慰剂对照试验，EGFR为30-90 Ml/min/1.73m2。其次，探查终点将决定依帕格列酮对肾脏体积的影响， 肾功能、aPWV、血浆铜绿素水平、尿肾损伤分子-1(Kim-1)和生活质量。 具体目标1：从安全性和耐受性的角度确定处方依帕格列酮25的可行性 对于有进展风险的ADPKD患者，每天一次，EGFR为30-90毫升/分钟/1.73m2。 具体目标2：初步估计依帕格列星与安慰剂对12-14岁患者的疗效 A)磁共振成像显示的肾脏总体积，b)EGFR，c)血浆铜绿素水平的月份变化 (加压素分泌的标志物)，d)尿Kim-1(肾小管损伤的标志物)，e)aPWV；和f)ADPKD- ADPKD-Impact量表量化的特定健康相关生活质量(HRQOL)。

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end- stage kidney disease. Despite decades of research, tolvaptan is the only approved intervention in ADPKD. However, tolvaptan does not target cardiovascular complications of ADPKD and is constrained by high cost and side effects that limit adherence. Therefore, there is an urgent need for a well-tolerated alternative intervention to slow ADPKD progression and improve vascular health. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) have a track record of tolerability and safety in patients with proteinuric diabetic and non- diabetic kidney disease. Trials of SGLT2i in these conditions have been extremely encouraging, and these treatments are highly likely to become the standard of care for diabetic and non-diabetic kidney disease; however, the mechanisms of action are not fully elucidated, and may be non-specific to disease etiology. The potential benefit of SGLT2i has not been examined in patients with ADPKD, as major trials have excluded such patients. There are also potential benefits of SGLT2i to ADPKD patients beyond slowing loss of kidney function, as this class of drugs provide a cardiovascular mortality benefit for patients across the CKD spectrum. Studies testing the effects of SGLT2i in animal models of PKD have yield conflicting results. Five weeks of treatment with an SGLT1 and SLGT2 inhibitor phlorizon was shown to inhibit cystogenesis in the Han:SPRD rat model of PKD. The mechanisms by which SGLT2i slows cystic renal disease progression may be related to inhibition of cyst epithelial cell proliferation. SGLT2i have also antioxidant and anti-inflammatory actions, which are important for reducing fibrosis and improving vascular health, both of which occur in early stages of ADPKD. While many changes likely contribute to the development of arterial dysfunction in patients with ADPKD, among those of greatest concern is the development of stiffening of large elastic arteries, typically assessed by aortic pulse wave velocity (aPWV). We propose a pilot randomized clinical trial to determine the safety and tolerability of empagliflozin in ADPKD patients. To achieve this, we will conduct a 12-month parallel- group, randomized, double-blind, placebo-controlled trial in 50 ADPKD patients with an eGFR 30-90 mL/min/1.73m2. Secondary, exploratory endpoints will determine the effect of empagliflozin on kidney volume, kidney function, aPWV, plasma copeptin levels, urinary kidney injury molecule-1 (KIM-1) and quality of life. Specific Aim 1: To determine the feasibility, in terms of safety and tolerability, of prescribing empagliflozin 25 mg once a day in ADPKD patients at risk for progression with an eGFR of 30-90 mL/min/1.73m2. Specific Aim 2: To derive preliminary estimates of the effect of empagliflozin compared to placebo on 12- month change in a) total kidney volume by magnetic resonance imaging, b) eGFR, c) plasma copeptin levels (a marker of vasopressin secretion), d) urinary KIM-1 (a marker of tubular injury), e) aPWV; and f) ADPKD- specific health-related quality of life (HRQoL) as quantified by the ADPKD-Impact Scale.