Division of Nephrology and Hypertension, University of California Irvine, Orange, CA, U.S.A.
Clin Sci (Lond). 2017 Jan 1;131(1):3-12. doi: 10.1042/CS20160203.
Blood levels of urea rise with progressive decline in kidney function. Older studies examining acute urea infusion suggested that urea was well-tolerated at levels 8-10× above normal values. More recent in vitro and in vivo work argue the opposite and demonstrate both direct and indirect toxicities of urea, which probably promote the premature aging phenotype that is pervasive in chronic kidney disease (CKD). Elevated urea at concentrations typically encountered in uremic patients induces disintegration of the gut epithelial barrier, leading to translocation of bacterial toxins into the bloodstream and systemic inflammation. Urea induces apoptosis of vascular smooth muscle cells as well as endothelial dysfunction, thus directly promoting cardiovascular disease. Further, urea stimulates oxidative stress and dysfunction in adipocytes, leading to insulin resistance. Finally, there are widespread indirect effects of elevated urea as a result of the carbamylation reaction, where isocyanic acid (a product of urea catabolism) alters the structure and function of proteins in the body. Carbamylation has been linked with renal fibrosis, atherosclerosis and anaemia. In summary, urea is a re-emerging Dark Force in CKD pathophysiology. Trials examining low protein diet to minimize accumulation of urea and other toxins suggest a clinical benefit in terms of slowing progression of CKD.
血液中的尿素水平随着肾功能的逐渐下降而升高。早期研究检查急性尿素输注表明，尿素在正常水平的 8-10 倍以上是可以耐受的。最近的体外和体内研究结果则相反，证明了尿素具有直接和间接的毒性，这可能会促进慢性肾脏病（CKD）中普遍存在的过早衰老表型。在尿毒症患者中常见的浓度下，升高的尿素会导致肠道上皮屏障解体，导致细菌毒素转移到血液中并引发全身炎症。尿素诱导血管平滑肌细胞凋亡和内皮功能障碍，从而直接促进心血管疾病。此外，尿素刺激脂肪细胞中的氧化应激和功能障碍，导致胰岛素抵抗。最后，由于氨基甲酰化反应，尿素水平升高会产生广泛的间接影响，其中异氰酸（尿素分解代谢的产物）会改变体内蛋白质的结构和功能。氨基甲酰化与肾纤维化、动脉粥样硬化和贫血有关。总之，尿素是 CKD 病理生理学中重新出现的暗物质。研究检查低蛋白饮食以尽量减少尿素和其他毒素的积累，表明在减缓 CKD 进展方面具有临床益处。
