Department of Vascular & Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiology, Bao Shan People's Hospital, Baoshan, Yunnan Province, China.
BMC Nephrol. 2021 Feb 23;22(1):66. doi: 10.1186/s12882-021-02268-3.
Sulfation of tyrosine, yielding O-sulfotyrosine, is a common but fixed post-translational modification in eukaryotes. Patients with increased circulating O-sulfotyrosine levels experience a faster decline in renal function with progression to end-stage renal disease (ESRD). In the present study, we measured serum O-sulfotyrosine levels in individuals with chronic kidney disease (CKD) and acute kidney injury (AKI) to explore its ability to differentiate AKI from CKD.
A total of 135 patients (20 with AKI and 115 with CKD) were recruited prospectively for liquid chromatography-mass spectrometry assessment of circulating O-sulfotyrosine. We also studied C57BL/6 mice with CKD after 5/6 nephrectomy (Nx). Blood samples were drawn from the tail vein on Day 1, 3, 5, 7, 14, 30, 60, and 90 after CKD. Serum separation and characterization of creatinine, blood urea nitrogen (BUN), and O-sulfotyrosine was performed. Thus, the time-concentration curves of the O-sulfotyrosine level demonstrate the variation of kidney dysfunction.
The serum levels of O-sulfotyrosine were markedly increased in patients with CKD compared with AKI. Median O-sulfotyrosine levels in CKD patients versus AKI, respectively, were as follows:243.61 ng/mL(interquartile range [IQR] = 171.90-553.86) versus 126.55 ng/mL (IQR = 48.19-185.03, P = 0.004). In patients with CKD, O-sulfotyrosine levels were positively correlated with creatinine, BUN, and Cystatin C (r = 0.63, P < 0.001; r = 0.49, P < 0.001; r = 0.61, P < 0.001, respectively) by the multivariate linear regression analysis (β = 0.71, P < 0.001; β = 0.40, P = 0.002; β = 0.73, P < 0.001, respectively). However, this association was not statistically significant in patients with AKI (r = - 0.17, P = 0.472; r = 0.11, P = 0.655; r = 0.09, P = 0.716, respectively). The receiver operating characteristic (ROC) analysis illustrated that the area under the curve was 0.80 (95% confidence interval [CI] 0.71-0.89; P < 0.001) and the optimal cut-off value of serum O-sulfotyrosine suggesting AKI was < 147.40 ng/mL with a sensitivity and specificity of 80.90 and 70.00% respectively. In animal experiments, serum levels of O-sulfotyrosine in mice were elevated on Day 7 after 5/6 nephrectomy (14.89 ± 1.05 vs. 8.88 ± 2.62 ng/mL, P < 0.001) until Day 90 (32.65 ± 5.59 vs. 8.88 ± 2.62 ng/mL, P < 0.001).
Serum O-sulfotyrosine levels were observed correlated with degrading renal function and in CKD patients substantially higher than those in AKI patients. Thus serum O-sulfotyrosine facilitated the differential diagnosis of AKI from CKD.
酪氨酸的硫酸化，生成 O-硫酸酪氨酸，是真核生物中常见但固定的翻译后修饰。循环 O-硫酸酪氨酸水平升高的患者在进展为终末期肾病 (ESRD) 时肾功能下降更快。在本研究中，我们测量了慢性肾脏病 (CKD) 和急性肾损伤 (AKI) 患者的血清 O-硫酸酪氨酸水平，以探讨其区分 AKI 与 CKD 的能力。
前瞻性招募了 135 名患者（20 名 AKI 和 115 名 CKD）进行液相色谱-质谱法评估循环 O-硫酸酪氨酸。我们还研究了 5/6 肾切除术 (Nx) 后 CKD 的 C57BL/6 小鼠。在 CKD 后第 1、3、5、7、14、30、60 和 90 天从尾静脉采血。进行血清分离和肌酐、血尿素氮 (BUN) 和 O-硫酸酪氨酸的特征分析。因此，O-硫酸酪氨酸水平的时间-浓度曲线表明肾功能障碍的变化。
与 AKI 相比，CKD 患者的血清 O-硫酸酪氨酸水平明显升高。与 AKI 相比，CKD 患者的 O-硫酸酪氨酸中位数分别为 243.61ng/mL（四分位距 [IQR] = 171.90-553.86）和 126.55ng/mL（IQR = 48.19-185.03，P=0.004）。在 CKD 患者中，O-硫酸酪氨酸水平与肌酐、BUN 和胱抑素 C 呈正相关（r=0.63，P<0.001；r=0.49，P<0.001；r=0.61，P<0.001，分别），多元线性回归分析（β=0.71，P<0.001；β=0.40，P=0.002；β=0.73，P<0.001，分别）。然而，在 AKI 患者中，这种相关性无统计学意义（r=-0.17，P=0.472；r=0.11，P=0.655；r=0.09，P=0.716，分别）。受试者工作特征 (ROC) 分析表明曲线下面积为 0.80（95%置信区间 [CI] 0.71-0.89；P<0.001），血清 O-硫酸酪氨酸的最佳截断值提示 AKI 为<147.40ng/mL，敏感性和特异性分别为 80.90%和 70.00%。在动物实验中，5/6 肾切除术后第 7 天小鼠血清 O-硫酸酪氨酸水平升高（14.89±1.05 与 8.88±2.62ng/mL，P<0.001），直至第 90 天（32.65±5.59 与 8.88±2.62ng/mL，P<0.001）。
血清 O-硫酸酪氨酸水平与肾功能下降有关，在 CKD 患者中明显高于 AKI 患者。因此，血清 O-硫酸酪氨酸有助于区分 AKI 与 CKD。
