背景:急性肾损伤(AKI)是一种急性发作的严重临床急症,快速进展和不良预后,在住院患者中发病率和死亡率都很高。DNA甲基化在肾脏疾病的发生和发展中起重要作用,在AKI患者中已经报道了异常甲基化和某些甲基化相关代谢物的改变。然而,AKI患者中甲基化相关代谢物的特异性改变未被明确研究.
方法:在本研究中,在倾向评分与年龄和高血压相匹配后,招募61名AKI和61名匹配的非AKI住院患者。采用UHPLC-MS/MS法对两组患者血浆和尿液中11种甲基化相关代谢物进行定量。
结果:某些甲基化相关中间体在血浆中上调(胆碱,三甲胺N-氧化物(TMAO),三甲基赖氨酸(TML),S-腺苷甲硫氨酸(SAM)和S-腺苷同型半胱氨酸(SAH))在AKI住院患者的尿液中下调(胆碱,甜菜碱,TMAO,二甲基甘氨酸(DMG),SAM和牛磺酸)。相关性分析显示血浆SAH之间有相对较强的相关性,SAM/SAH比值和肾功能指数(血清肌酐(SCr)和估计的肾小球滤过率(eGFR),r=0.523-0.616),尿中间体与肾功能指标的相关性弱于血浆。此外,受试者工作特征曲线(ROC)分析表明,血浆SAH和尿SAM/SAH比分别以AUC0.844和0.794代表最佳的区分效率。此外,二元回归分析的结果表明血浆胆碱,TMAO,TML,SAM和SAH是AKI的风险标志物(血浆上调,OR>1),尿胆碱,甜菜碱,TMAO,DMG和SAM是AKI的保护性标志物(尿液中的下调,OR<1),SAM/SAH比率是血浆和尿液中的保护性标记(在两种生物流体中都下调,血浆中OR=0.510,0.383-0.678,尿中OR=0.904,0.854-0.968),表明AKI的风险增加,当结合血浆和尿液水平的变化。
结论:对AKI住院患者的血浆和尿液样本的综合分析提供了对甲基化代谢改变的更广泛评估,提示AKI应激与甲基化能力改变密切相关。SAH的血浆水平和SAM/SAH比率以及尿SAM/SAH比率均与肾功能(SCr和eGFR)具有很强的相关性,并且在两个生物指标中区分AKI具有良好的准确性。在预测肾功能下降和为AKI的发病机制提供进一步的信息方面显示出有希望的前景。
BACKGROUND: Acute kidney injury (AKI) is a serious clinical emergency with an acute onset, rapid progression and poor prognosis, which has high morbidity and mortality in hospitalized patients. DNA methylation plays an important role in the occurrence and progression of kidney disease, and aberrant methylation and certain altered methylation-related metabolites have been reported in AKI patients. However, the specific alterations of methylation-related metabolites in the AKI patients were not investigated clearly.
METHODS: In this study, 61 AKI and 61 matched non-AKI inpatients were recruited after propensity score matching the age and hypertension. And 11 methylation-related metabolites in the plasma and urine of the two groups were quantified by using UHPLC-MS/MS method.
RESULTS: Certain methylation-relate intermediates were up-regulated in the plasma (choline, trimethylamine N-oxide (TMAO), trimethyl lysine (TML), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)) and down-regulated in the urine of AKI inpatients (choline,
betaine, TMAO, dimethylglycine (DMG), SAM and taurine). The correlation analysis revealed a relatively strong correlation between plasma SAH, SAM/SAH ratio and renal function index (serum creatinine (SCr) and estimated glomerular filtration rate (eGFR), r = 0.523-0.616), and the correlation of urinary intermediates with renal function index was weaker than that in the plasma. Furthermore, receiver operating characteristic (ROC) analysis showed that plasma SAH and urinary SAM/SAH ratio represented the best distinguishing efficiency with AUC 0.844 and 0.794, respectively. Moreover, the findings of binary regression analysis demonstrated plasma choline, TMAO, TML, SAM and SAH were the risk markers of AKI (up-regulation in plasma, OR > 1), urinary choline,
betaine, TMAO, DMG and SAM were protective markers of AKI (down-regulation in urine, OR < 1), and SAM/SAH ratio was a protective marker in plasma and urine (down-regulation in both two biofluids, OR = 0.510, 0.383-0.678 in plasma, OR = 0.904, 0.854-0.968 in urine), indicating the increased risk of AKI when combined with the alteration of plasma and urinary levels.
CONCLUSIONS: The comprehensive analysis of plasma and urine samples from AKI inpatients offers a more extensive assessment of methylated metabolic alterations, suggesting a close relationship between AKI stress and altered methylation ability. The plasma level of SAH and SAM/SAH ratio and urinary SAM/SAH ratio both showed a strong correlation with renal function (SCr and eGFR) and good accuracy for distinguishing AKI in the two biomatrices, which exhibited promising prospects in predicting renal function decline and providing further information for the pathogenesis of AKI.