Veterans Affairs Hospital, Hines, Illinois; and Loyola University Medical Center, Maywood, Illinois.
Kidney360. 2020 Feb 28;1(4):292-299. doi: 10.34067/KID.0001252019. eCollection 2020 Apr 30.
Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration-approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.
糖尿病肾病（DKD）是美国和全球范围内导致终末期肾病（ESKD）的最常见原因。目前，DKD 的治疗包括严格控制血糖和通过肾素-血管紧张素-醛固酮系统（RAAS）阻断来使血压正常化。尽管 RAAS 阻滞剂可减缓疾病进展，但它们通常不能预防 ESKD，并且在 DKD 中使用这些药物的研究均未包括非蛋白尿患者，而目前在临床实践中，非蛋白尿患者所占比例越来越大。最近，使用胰高血糖素样肽-1 受体激动剂和钠-葡萄糖共转运蛋白-2（SGLT2）抑制剂的研究显示出了有益的肾脏作用，并且 SGLT2 抑制剂的益处可能扩展到非蛋白尿患者。然而，仍然需要开发 DKD 的新疗法，特别是在那些患有晚期疾病的患者中。慢性低度炎症在糖尿病患者的微血管并发症中的作用现已被广泛接受。正在进行大型临床试验，以评估实验性药物（如 bardoxolone 和 selonsertib）在炎症和氧化应激方面的作用。美国食品和药物管理局批准的非特异性磷酸二酯酶抑制剂己酮可可碱（PTX）已被证明通过抑制促炎细胞因子的产生，在动物和人类研究中具有抗炎作用。小型随机临床试验和荟萃分析表明，PTX 可能对 DKD 具有治疗益处，这提示一种临床上可获得的药物可能能够被重新用于治疗这种疾病。目前正在进行一项大型、多中心、随机临床试验，以确定该药物是否可以降低进入 ESKD 或死亡的时间，但结果还需要几年时间才能公布。目前，RAAS 阻断加 SGLT2 抑制被认为是 DKD 的标准治疗方法，但对于那些尽管优化了当前标准治疗方案但疾病仍在继续进展的患者，临床医生考虑添加 PTX 可能是合理的。
