Dept. of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Dept. of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Cell Signal. 2019 Mar;55:53-64. doi: 10.1016/j.cellsig.2018.12.001. Epub 2018 Dec 12.
Chronic kidney disease (CKD) is a global health problem with a profound impact on quality of life. Cardiovascular disease is established as a major cause of morbidity and mortality in patients with CKD. Dyslipidemia is frequently observed in CKD patients, suggesting a causal relation between dyslipidemia and cardiovascular disease in CKD patients. Currently, lipid-lowering drugs such as statins, are the primary choice for lipid lowering therapy in high-risk populations. Despite many studies showing CVD risk reduction with statins, CVD still remains the leading cause of the death in CKD. This underscores the need for new therapeutic approaches to reduce cardiovascular risk in CKD patients. Reduced lipoprotein lipase activity, increased very low-density lipoprotein production, increased proprotein convertase subtilisin kexin type 9 (PCSK9) expression and loss of hepatic heparan sulfate proteoglycans (HSPG) syndecan-1 have been associated with CKD-related dyslipidemia. Low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor-related protein 1 (LRP-1) and syndecan-1, are the most important hepatic receptors for lipoprotein clearance. However, their contributions to the pathogenesis of dyslipidemia and cardiovascular disease in CKD remain unclear. Interestingly, in CKD, increased plasma lipid levels are associated with elevated levels of PCSK9. This promotes the proteolysis of LDLR, suggesting a role for PCSK9 in CKD-associated dyslipidemia. Fully humanized monoclonal antibodies targeting PCSK9 have been approved by the US Food and Drug Administration and the European Medicines Agency as lipid lowering treatment for patients with hypercholesterolemia. In CKD sub-group analysis, ODYSSEY COMBO I and ODYSSEY COMBO II studies demonstrated strong reduction in LDL-C by alirocumab compared to placebo and ezetimibe and when added to statins. However, their efficacy in reducing plasma TG is controversial. Therefore, further research work is need for a detailed analysis on efficacy and safety of PCSK9 antibodies in CKD groups. Interestingly, novel findings on PCSK9 interaction with HSPG might shed new insight on altered lipid metabolism in CKD. In this review, we discuss various aspects of lipoprotein metabolism and hepatic lipoprotein receptor signaling pathways along with the concept of renal disease-related dyslipidemia. Furthermore, this review highlights the drawbacks of current lipid-lowering therapies and proposes novel approaches for lipid management in CKD.
慢性肾脏病（CKD）是一个全球性的健康问题，对生活质量有着深远的影响。心血管疾病已被确立为 CKD 患者发病率和死亡率的主要原因。CKD 患者常伴有血脂异常，表明血脂异常与 CKD 患者的心血管疾病之间存在因果关系。目前，降脂药物如他汀类药物是高危人群降脂治疗的首选。尽管许多研究表明他汀类药物可降低 CVD 风险，但 CVD 仍然是 CKD 患者死亡的主要原因。这凸显了需要新的治疗方法来降低 CKD 患者的心血管风险。脂蛋白脂酶活性降低、极低密度脂蛋白产生增加、前蛋白转化酶枯草溶菌素 kexin 9（PCSK9）表达增加和肝硫酸乙酰肝素蛋白聚糖（HSPG）syndecan-1 丢失与 CKD 相关的血脂异常有关。低密度脂蛋白受体（LDLR）、低密度脂蛋白受体相关蛋白 1（LRP-1）和 syndecan-1 是脂蛋白清除的最重要的肝受体。然而，它们对 CKD 患者血脂异常和心血管疾病的发病机制的贡献尚不清楚。有趣的是，在 CKD 中，血浆脂质水平升高与 PCSK9 水平升高相关。这促进了 LDLR 的蛋白水解，表明 PCSK9 在 CKD 相关的血脂异常中起作用。针对 PCSK9 的全人源化单克隆抗体已被美国食品和药物管理局和欧洲药品管理局批准为高胆固醇血症患者的降脂治疗药物。在 CKD 亚组分析中，ODYSSEY COMBO I 和 ODYSSEY COMBO II 研究表明，与安慰剂和依折麦布相比，alirocumab 可显著降低 LDL-C，并且当与他汀类药物联合使用时也是如此。然而，它们在降低血浆 TG 方面的疗效存在争议。因此，需要进一步的研究工作来详细分析 PCSK9 抗体在 CKD 组中的疗效和安全性。有趣的是，关于 PCSK9 与 HSPG 相互作用的新发现可能为 CKD 中改变的脂质代谢提供新的见解。在这篇综述中，我们讨论了脂蛋白代谢和肝脂蛋白受体信号通路的各个方面，以及肾脏疾病相关血脂异常的概念。此外，本文还强调了当前降脂治疗的局限性，并提出了 CKD 脂质管理的新方法。
