The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia
The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia
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DOI：
10.1046/j.1523-1755.2002.00600.x
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发表时间：
2002-11-01
影响因子：
19.6
通讯作者：
Hakim, RM
中科院分区：
文献类型：
--
作者：
Himmelfarb, J;Stenvinkel, P;Hakim, RM
心血管疾病是尿毒症患者死亡的主要原因。在透析患者的大型横断面研究中，发现传统的心血管风险因素如高血压和高胆固醇血症的预测能力较低，而炎症和营养不良的标志物与心血管死亡率高度相关。然而，尿毒症、炎症和营养不良与心血管并发症增加的疾病过程的病理生理学尚不清楚。我们在此提出一个假说，即氧化应激及其后遗症的增加是尿毒症患者动脉粥样硬化和心血管疾病发病率和死亡率增加的主要原因。这一假设是基于以下研究得出的结论：尿毒症患者在肾脏替代治疗之前和之后的氧化负荷增加，这可通过多种氧化应激生物标志物的浓度升高得到证明。这一假说还提供了一个框架来解释激活的吞噬细胞在氧化应激和炎症（来自感染和非感染原因）之间提供的联系，以及营养不良（如低浓度白蛋白和/或抗氧化剂所反映的）导致尿毒症心血管疾病负担增加的协同作用。我们进一步提出，保留尿毒症溶质，如β-2微球蛋白，晚期糖基化终产物（AGE），半胱氨酸，同型半胱氨酸，这是底物的氧化损伤，进一步促进促动脉粥样硬化环境的尿毒症。透析治疗，其作用是降低氧化底物的浓度，改善氧化还原平衡。然而，与透析治疗相关的过程，例如长期使用血管通路导管和使用生物不相容的透析膜，可能导致促炎和促氧化状态，从而导致促动脉粥样硬化状态。尿毒症患者的抗氧化治疗策略处于非常早期的阶段;尽管如此，早期研究表明，在减少心血管并发症方面可能具有显著疗效。
Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.