Kalim Sahir, Trottier Caitlin A, Wenger Julia B, Wibecan Josh, Ahmed Rayhnuma, Ankers Elizabeth, Karumanchi S Ananth, Thadhani Ravi, Berg Anders H
Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and.
Department of Medicine, Division of Nephrology and Center for Vascular Biology Research and.
Clin J Am Soc Nephrol. 2016 Oct 7;11(10):1809-1816. doi: 10.2215/CJN.02390316. Epub 2016 Jul 21.
Carbamylation describes a post-translational protein modification associated with adverse outcomes in ESRD, but the risk implications of changes in carbamylation over time are not well understood.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated the 1-year natural history of protein carbamylation in patients initiating maintenance hemodialysis and determined the prognostic value of longitudinal carbamylation changes in relation to mortality. In a nested patient-control study, we measured serial carbamylated albumin concentrations in select participants from a large incident dialysis cohort followed from 2004 to 2005 (=10,044); 122 individuals who survived at least 90 days but died within 1 year of initiating hemodialysis (patients) were randomly selected along with 244 individuals who survived for at least 1 year (controls; matched for demographics). Carbamylated albumin concentration was measured using plasma collected at dialysis initiation and every subsequent 90-day period until 1 year or death.
Baseline carbamylated albumin concentration was similar between controls and patients (mean±SD; 18.9±0.7 and 19.8±1.1 mmol/mol, respectively; =0.94). From dialysis initiation to day 90, carbamylated albumin concentration markedly fell in all patients, with controls -9.9±0.8 mmol/mol (<0.001) and patients -10.0±1.2 mmol/mol (<0.001). Adjusted repeated measures analysis of carbamylated albumin concentration from dialysis initiation to 1 year or death showed that the mean change (95% confidence interval) in carbamylated albumin concentration from baseline to final measure differed significantly between groups (-9.3; 95% confidence interval, -10.8 to -7.7 for controls and -6.3; 95% confidence interval, -7.7 to -2.8 for patients; <0.01). There were no such between-group differences in blood urea levels, Kt/V, or normalized protein catabolic rate. Mortality prediction assessed using statistics showed that carbamylated albumin concentration, when modeled continuously as the difference from baseline to final, improved a fully adjusted model from 0.76 to 0.87 (0.03).
Protein carbamylation decreased with dialysis initiation, and a greater reduction over time was associated with a lower risk for mortality. Carbamylation changes were able to predict individuals' mortality risk beyond traditional variables, including markers of dialysis adequacy and nutrition.
氨甲酰化描述了一种与终末期肾病不良结局相关的翻译后蛋白质修饰，但随着时间推移氨甲酰化变化的风险影响尚未得到充分理解。
设计、研究地点、参与者及测量方法：我们调查了开始维持性血液透析患者蛋白质氨甲酰化的1年自然病程，并确定了氨甲酰化纵向变化与死亡率相关的预后价值。在一项嵌套病例对照研究中，我们测量了2004年至2005年纳入的大型新发病例透析队列（n = 10,044）中部分参与者的系列氨甲酰化白蛋白浓度；随机选择了122例在开始血液透析后至少存活90天但在1年内死亡的个体（患者）以及244例存活至少1年的个体（对照；按人口统计学特征匹配）。使用透析开始时及随后每90天采集的血浆测量氨甲酰化白蛋白浓度，直至1年或死亡。
对照组和患者的基线氨甲酰化白蛋白浓度相似（均值±标准差；分别为18.9±0.7和19.8±1.1 mmol/mol；P = 0.94）。从透析开始至第90天，所有患者的氨甲酰化白蛋白浓度均显著下降，对照组下降9.9±0.8 mmol/mol（P < 0.001），患者下降10.0±1.2 mmol/mol（P < 0.001）。对从透析开始至1年或死亡期间氨甲酰化白蛋白浓度进行的调整后重复测量分析显示，两组从基线到最终测量的氨甲酰化白蛋白浓度平均变化（95%置信区间）存在显著差异（对照组为 -9.3；95%置信区间为 -10.8至 -7.7，患者组为 -6.3；95%置信区间为 -7.7至 -2.8；P < 0.01）。在血尿素水平、Kt/V或标准化蛋白分解代谢率方面，两组之间不存在此类差异。使用C统计量评估的死亡率预测显示，将氨甲酰化白蛋白浓度作为从基线到最终的差值进行连续建模时，可使完全调整模型的C统计量从0.76提高至0.87（P = 0.03）。
蛋白质氨甲酰化随着透析开始而降低，且随着时间推移更大程度的降低与较低的死亡风险相关。氨甲酰化变化能够预测个体的死亡风险，其预测能力超过包括透析充分性和营养指标在内的传统变量。
