Emerging paradigms of treating diabetic nephropathy.
Emerging paradigms of treating diabetic nephropathy.
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DOI：
10.1016/s2213-8587(18)30304-8
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发表时间：
2018-12
期刊：
影响因子：
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通讯作者：
Yongen Chang;H. Moradi;K. Kalantar-Zadeh
中科院分区：
文献类型：
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作者：
Yongen Chang;H. Moradi;K. Kalantar-Zadeh
2型糖尿病是慢性肾脏疾病的主要原因，包括终末期肾脏疾病。糖尿病肾病的预防和治疗几乎没有有效的治疗策略;主要策略是通过血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARB）调节肾素-血管紧张素醛固酮系统。这些药物具有肾脏保护作用，超出了其对血压的传统影响。血管紧张素通路调节剂和低蛋白饮食对肾小球内压有协同作用，前者使传出小动脉舒张，后者使传入小动脉收缩，从而改善肾小球超滤和减少蛋白尿。3然而，即使在最大化饮食和药物干预后，一些糖尿病肾病患者的蛋白尿仍可能持续，4联合ARB和ACE抑制剂或添加阿利吉仑5，6尚未显示出额外的益处。在过去的十年中，一些临床试验已经研究了使用新型药物改善糖尿病肾病患者蛋白尿和肾脏结局的潜在额外益处。抗氧化剂甲基巴多索龙（NCT 01351675）、内皮素受体拮抗剂阿伏生坦（NCT 00120328）和抗凝剂舒洛地特（NCT 00130312）的试验因不良事件风险增加或缺乏疗效而提前终止。在另一项试验中，7恩格列净（一种靶向钠-葡萄糖协同转运蛋白-2 [SGLT 2]的抗高血压药物）为2型糖尿病患者提供心脏和肾脏保护，尽管恩格列净组和安慰剂组之间发生蛋白尿的患者比例无显著差异。然而，在该试验7中，恩格列净组进展为大量白蛋白尿的患者比例低于安慰剂组。另一种SGLT 2抑制剂卡格列净产生了类似的结果。8表观遗传途径调节也可能成为慢性肾脏疾病的潜在治疗策略; apabetalone是一种新型的溴结构域和末端外蛋白抑制剂，在2期试验中降低了主要不良心脏事件的发生率，9，10在6个月治疗结束时减缓了估计肾小球滤过率（eGFR）的下降，并降低了碱性磷酸酶的血清浓度，不良心血管结局的替代标志物。10
Type 2 diabetes is the leading cause of chronic kidney disease, including end-stage renal disease, worldwide. Few effective therapeutic strategies exist for the prevention and treatment of diabetic kidney disease; the main strategy is modulation of the renin-angiotensinaldosterone system by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). These drugs have renal protective effects beyond their traditional effects on blood pressure. 1, 2 Angiotensinpathway modulators and low-protein diet have been shown to have a synergistic effect on intraglomerular pressure, with the former relaxing the efferent arteriole and the latter contracting the afferent arteriole, leading to amelioration of glomerular hyperfiltration and reduced proteinuria. 3 However, even after maximising dietary and pharmacological interventions, proteinuria might continue in some patients with diabetic kidney disease, 4 and combining ARBs and ACE inhibitors or adding aliskiren5, 6 have not been shown to provide additional benefits. Over the past decade, several clinical trials have investigated the potential added benefit of using novel pharmacotherapeutic drugs to improve proteinuria and renal outcomes in patients with diabetic kidney disease. Trials of the antioxidant bardoxolone methyl (NCT01351675), the endothelin-receptor antagonist avosentan (NCT00120328), and the anticoagulant sulodexide (NCT00130312) were terminated early because of an increased risk of adverse events or lack of efficacy. In another trial, 7 empagliflozin (an antihyperglycaemic drug targeting sodium-glucose co-transporter-2 [SGLT2]) provided both cardiac and renal protection in patients with type 2 diabetes, although there was no significant difference between empagliflozin and placebo groups in the proportion of patients who had incident albuminuria. However, the proportion of patients who progressed to macroalbuminuria in that trial7 was lower in the empagliflozin group than in the placebo group. Canagliflozin, another SGLT2 inhibitor, yielded similar results. 8 Epigenetic pathway modulation might also emerge as a potential therapeutic strategy for chronic kidney disease; apabetalone, a novel inhibitor of bromodomain and extra-terminal proteins, reduced the incidence of major adverse cardiac events in phase 2 trials, 9, 10 slowing the decline in the estimated glomerular filtration rate (eGFR) at the end of 6 months of treatment and lowering serum concentrations of alkaline phosphatase, a surrogate marker for adverse cardiovascular outcomes. 10