Changes and Clinical Significance of Serum Cys C, β 2-MG, MCP-1 and Ang Ⅱ Levels in Patients with Chronic Renal Failure
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摘要:
目的 探讨慢性肾功能衰竭（CRF）患者血清膀胱抑素C（Cys C）、β2-微球蛋白（β2-MG）、单核细胞趋化蛋白-1（MCP-1）、血管紧张素Ⅱ(AngⅡ)水平变化，分析其与CRF患者预后的关系。 方法 选择2017年1月至2019年1月深圳市南山区蛇口人民医院肾内科收治的68例CRF患者（CRF组）和50例健康体检者（对照组），检测血清Cys C 、β2-MG、MCP-1、ANG Ⅱ水平，比较组间差异。以CRF患者随访期间发生全因死亡为终点事件，分析Cys C 、β2-MG、MCP-1、ANG Ⅱ与CRF患者预后的关系。 结果 随访中位时间18（13～25）个月，23例死亡（死亡组），50例存活（存活组）。死亡组血清CysC、β2-MG、MCP-1、ANG Ⅱ水平均高于存活组和对照组，差异有统计学意义（P < 0.05）。CRF患者血清CysC、β2-MG、MCP-1、ANG Ⅱ水平随着慢性肾脏疾病（CKD）分级增加而升高，差异有统计学意义（P < 0.05），血清CysC、β2-MG、MCP-1、ANG Ⅱ水平与肾小球滤过率（eGFR）均呈负相关（r = −0.435、−0.406、−0.621、−0.594，P < 0.05），与尿白蛋白/肌酐比值（ACR）呈正相关（r = 0.406、0.435、0.562、0.503，P < 0.05）。ROC分析结果显示CysC、β2-MG、MCP-1、ANG Ⅱ预测CRF患者预后的曲线下面积（AUC）分别为0.681（95%CI：0.551～0.811）、0.649（95%CI：0.510～0.789）、0.917（95%CI：0.852～0.981）、0.838（95%CI：0.733～0.942）。Kaplan-Meier生存分析结果显示高水平CysC、β2-MG、MCP-1、ANG Ⅱ组患者生存时间短于低水平CysC、β2-MG、MCP-1、ANG Ⅱ组，差异有统计学意义（P < 0.05）。多因素COX风险回归分析高水平CysC、β2-MG、MCP-1、ANG Ⅱ是CRF全因死亡的独立危险因素（P < 0.001）。 结论 血清CysC、β2-MG、MCP-1、ANG Ⅱ水平与CRF患者肾损伤程度和不良预后密切相关，可作为CRF预后评估的辅助指标。 Abstract:Objective To investigate the changes of serum cystatin C（Cys C）, β 2-microglobulin（β 2-MG）, monocyte chemoattractant protein-1（MCP-1）and angiotension Ⅱ（ANG Ⅱ）levels in patients with chronic renal failure（CRF）, and analyze the relationship between them and the prognosis of CRF patients. Methods From January 2017 to January 2019, 68 CRF patients（CRF group）and 50 healthy people（control group）were selected from the nephrology department of our hospital. The levels of Cys C, β 2-MG, MCP-1 and ANG Ⅱ in serum were measured, and the differences between the two groups were compared. The end point was all-cause death, the relationship between Cys C, β 2-MG, MCP-1, ANG Ⅱ and the prognosis of CRF patients was analyzed. Results The median follow-up time was 18（13-25）months, 23 cases died（death group）, 50 cases survived（survival group）. The serum levels of CysC, β 2-MG, MCP-1 and ANG Ⅱ in the death group were higher than those in the survival group and the control group（P < 0.05）. The levels of CysC, β 2-MG, MCP-1 and ANG Ⅱ in CRF patients increased with the increase of CKD grading（P < 0.05）. Serum CysC, β 2-MG, MCP-1, ANG Ⅱwere negatively correlated with estimated glomerular filtration rate（EGFR）（r = -0.435, -0.406, -0.621, -0.594, P < 0.05）, and positively correlated with urinary albumin / creatinine ratio（ACR）（r = 0.406, 0.435, 0.562, 0.503, P < 0.05）. ROC analysis showed that AUC of CysC, β 2-MG, MCP-1 and ANG Ⅱ were 0.681（95% CI: 0.551-0.811）, 0.649（95% CI: 0.510-0.789）, 0.917（95% CI: 0.852-0.981）and 0.838（95% CI: 0.733-0.942）, respectively. Kaplan-Meier survival analysis showed that the survival time of high level CysC, β 2-MG, MCP-1, ANG Ⅱ group was shorter than that of low level CysC, β 2-MG, MCP-1, ANG Ⅱ group（P < 0.05）. Multivariate Cox regression analysis showed high levels of CysC, β 2-MG, MCP-1 and ANG Ⅱ were independent risk factors for all-cause death of CRF（P < 0.001）. Conclusion The serum levels of CysC, β 2-MG, MCP-1 and ANG Ⅱ are closely related to the degree of renal injury and poor prognosis in CRF patients, which can be used as an auxiliary index for the prognosis evaluation of CRF. -
Key words:
- Chronic renal failure /
- Cys C /
- β 2-MG /
- MCP-1 /
- ANG Ⅱ /
- All cause death
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图 1 各参数预测CRF患者预后的ROC图
Figure 1. ROC diagram of each parameter predicting the prognosis of CRF patients
图 2 CRF患者生存曲线
a：不同CysC水平生存曲线；b：不同β2-MG水平生存曲线；c：不同MCP-1水平生存曲线；d：不同ANG Ⅱ水平生存曲线。
Figure 2. Survival curve of CRF patients
表 1 基线资料（
$\bar x\pm s $ ）Table 1. Baseline data（
$\bar x\pm s $ ）项目 死亡组（n = 23） 存活组（n = 45） 对照组（n = 50） F/t/χ2 P 性别[n（%）] 男 13（56.52） 29（64.44） 32（64.00） 0.470 0.791 女 10（43.48） 16（35.56） 18（36.00） 年龄（岁） 65.13 ± 4.18∆▲ 61.21 ± 5.49 60.35 ± 5.13 6.352 0.000 体质量（kg/m2） 25.50 ± 1.85 26.13 ± 2.31 25.31 ± 2.29 1.035 0.439 收缩压（mmHg） 145.16 ± 11.56∆▲ 135.13 ± 8.49∆ 120.32 ± 6.35 13.265 0.000 舒张压（mmHg） 76.23 ± 5.65∆ 77.14 ± 6.34∆ 53.26 ± 4.28 10.249 0.000 高血压[n（%）] 16（69.57）▲ 17（37.78） − 5.340 0.021 糖尿病[n（%）] 15（65.22）▲ 14（31.11） − 7.239 0.007 高血脂[n（%）] 10（43.48） 13（28.89） − 0.405 0.525 吸烟史[n（%）] 14（60.87）∆▲ 9（20.00） 8（16.00） 17.531 0.000 心肌梗死[n（%）] 13（56.52）▲ 11（24.44） − 6.858 0.009 脑卒中[n（%）] 6（26.09）▲ 3（6.67） − 4.999 0.025 TC（mmol/L） 5.47 ± 0.39∆ 5.12 ± 0.35∆ 4.03 ± 0.21 5.263 0.000 TG（mmol/L） 1.65 ± 0.71∆ 1.69 ± 0.81∆ 1.32 ± 0.36 4.235 0.003 HDL-C（mmol/L） 1.03 ± 0.46∆ 1.06 ± 0.43∆ 1.65 ± 0.13 6.359 0.000 LDL-C（mmol/L） 3.92 ± 0.65∆ 3.85 ± 0.51∆ 2.24 ± 0.28 4.523 0.001 CysC（mg/L） 2.43 ± 0.65∆▲ 1.09 ± 0.36∆ 0.73 ± 0.29 13.265 0.000 β2-MG（g/mL） 4.16 ± 0.65∆▲ 2.51 ± 0.45∆ 1.13 ± 0.29 21.352 0.000 MCP-1（pg/mL） 235.16 ± 35.26∆▲ 195.26 ± 32.56a 153.26 ± 20.46 17.598 0.000 AngⅡ（ng/L） 92.35 ± 13.26∆▲ 72.35 ± 9.35∆ 34.16 ± 5.23 26.351 0.000 eGFR[mL/（min·（1.73 m2）] 42.35 ± 6.59∆▲ 73.26 ± 12.64∆ 112.65 ± 15.37 53.264 0.000 ACR（mg/g） 305.26 ± 35.26∆b 165.26 ± 16.05∆ 3.26 ± 0.25 105.341 0.000 与对照组比较，∆P < 0.05；与存活组比较，▲P < 0.05。 
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表 2 不同CKD分期CRF患者血清CysC、β2-MG、MCP-1、ANG Ⅱ水平差异（
$\bar x \pm s$ ）Table 2. The difference of serum CysC，β2-MG，MCP-1，ANG Ⅱ levels in CRF patient in different CKD stage （
$\bar x \pm s $ ）CKD分期 n CysC（mg/L） β2-MG（g/mLL） MCP-1（pg/mL） AngⅡ（ng/L） Ⅲ期 21 0.95 ± 0.25 2.13 ± 0.35 186.26 ± 18.52 63.25 ± 7.49 Ⅳ期 28 1.36 ± 0.43∆ 3.26 ± 0.59∆ 209.35 ± 24.16∆ 81.24 ± 10.25∆ Ⅴ期 19 2.45 ± 0.69∆▲ 3.82 ± 0.65∆▲ 232.74 ± 34.26∆▲ 95.67 ± 13.65∆▲ F 13.265 15.243 21.352 16.592 P 0.000 0.000 0.000 0.000 与Ⅲ期组比较，∆P < 0.05；与Ⅳ期组比较，▲P < 0.05。
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表 3 生存分析资料及比较
Table 3. Survival analysis and comparison
指标 水平 血清检测水平 n 生存时间（月） Log-Rank （χ2，P） CysC 低水平 < 1.95 mg/L 29 25.13 ± 3.26 10.141， 0.000 高水平 ≥1.95 mg/L 39 18.35 ± 2.35 β2-MG 低水平 < 3.61 g/mL 37 24.13 ± 2.69 9.754， 0.002 高水平 ≥3.61 g/mL 31 18.34 ± 2.01 MCP-1 低水平 < 216.35 pg/mL 28 24.31 ± 2.69 12.554， 0.000 高水平 ≥216.35 pg/mL 40 17.34 ± 2.03 ANG Ⅱ 低水平 < 85.34 ng/L 33 25.03 ± 2.15 6.580， 0.010 高水平 ≥85.34 ng/L 35 18.34 ± 1.69
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表 4 影响CRF患者预后的单因素和多因素COX风险回归模型
Table 4. Univariate and multivariate cox regression model of factors influencing the prognonsis of CRF patients
因素 单因素 多因素 RR 95%CI P值 RR 95%CI P值 收缩压 1.035 0.524～1.954 0.096 − − − 合并糖尿病 1.135 0.352～1.795 0.071 − − − 吸烟史 1.092 0.231～1.809 0.085 − − − 既往脑卒中 1.139 0.512～1.972 0.069 − − − ACR 1.126 0.633～2.251 0.057 − − − eGFR 1.625 1.035～16.254 0.002 − − − 既往心肌梗死 1.825 1.165～18.351 0.000 − − − 年龄 1.532 1.325～13.265 0.005 − − − 合并高血压 1.603 1.425～15.625 0.003 − − − CysC 1.998 1.324～20.112 0.000 1.824 1.325～18.245 0.000 β2-MG 1.856 0.625～1.824 0.000 1.623 1.135～13.265 0.000 MCP-1 2.056 1.325～10.254 0.000 2.016 1.854～25.352 0.000 ANG Ⅱ 1.936 1.542～15.342 0.000 1.822 1.354～19.547 0.000
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