Sci MT：建立肾脏衰竭的新血液检测法

近日，哈佛医学院等机构的研究人员发现，化学变性的血液蛋白与体内高量的代谢废物有关，而且它们可能导致严重的肾衰竭。文章发表在3月6日的Science Translational Medicion上。

肾功能衰竭中的病人无法排尿，导致其体液过度积聚和代谢废物的累积。病人必须通过移植来换肾或是通过频繁的透析治疗来去除多余的液体和废物。这些废物之一是尿素，这是一种在尿液中存在的化学物质。尽管尿素通常是无毒的，但它会降解成为更为有害的氰酸盐。氰酸盐会与血液蛋白上的氨基酸赖氨酸起反应，从而在这些蛋白质的表面上产生氨甲酰基团。

这种氨甲酰化可能会灭活这些蛋白质，或可能造成它们表现异常。氨甲酰化还与动脉粥样硬化和其它疾病有关。Anders Berg及其同事用质谱分析法在2组终末期肾脏疾病患者中研发出了一种检测血液蛋白的白蛋白氨甲酰化的测试方法。他们发现，高浓度的氨甲酰白蛋白与高浓度的尿素有关。

此外，在检测后一年之内死亡的病人其体内的白蛋白氨甲酰化比那些活得较长的病人的白蛋白氨甲酰化更为严重。在小鼠实验中，文章的作者证明，增加血液中氨基酸的浓度有助于减少氨甲酰化。

这些结果提示，氨基酸补充疗法可能对遏制肾脏病患者体内的血液蛋白氨甲酰化有益。

doi: 10.1126/scitranslmed.3005218

PMC:
PMID:

Carbamylation of Serum Albumin as a Risk Factor for Mortality in Patients with Kidney Failure

Anders H-Berg, Christiane Drechsler, Julia Wenger, Roberto Buccafusca, Tammy Hod, Sahir Kalim, Wenda Ramma, Samir M-Parikh, Hanno Steen, David J-Friedman, John Danziger, Christoph Wanner, Ravi Thadhani and S-Ananth Karumanchi.

Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys549. The proportion of serum albumin carbamylated on Lys549 (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.