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慢性肾脏病(chronic kidney disease,CKD)已经成为一种常见病,在全球影响8%~16%的成年人健康[1]。CKD病人进入终末期肾病(ESRD)者大部分选择血液透析(hemodialysis,HD)治疗,自体动静脉内瘘(arteriovenous fistulas, AVF)是HD病人长期透析的最理想的血管通路,而内瘘血管钙化是其失功主要原因之一。血管钙化主要指血管在多种因素作用下引起血管僵硬度增加,血管的弹性降低,可引起血栓形成,斑块破裂等后果[2]。内瘘血管钙化极易造成内瘘血管血栓栓塞、透析时血流动力学异常等各种危险因素引起HD病人无法透析威胁生命。探讨内瘘血管钙化相关影响因素变得尤为重要,其中有研究[3]指出,骨形态发生蛋白-2(BMP-2)/Smad信号通路参与成纤维细胞生长因子21(FGF-21)对血管钙化的抑制作用。由于内瘘血管的特殊性,关于FGF-21及BMP-2在内瘘血管钙化作用研究鲜见报道。本研究旨在探讨FGF-21、BMP-2在维持性血液透析病人自体AVF血管钙化中的作用及其与内瘘血管钙化的相关性。
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初次内瘘组、内瘘修复组和对照组3组间比较,除性别、GLU水平差异无统计学意义外(P>0.05), 其他临床相关指标差异均有统计学意义(P < 0.01)(见表 1)。
指标 对照组
(n=20)初次内瘘组
(n=20)内瘘修复组
(n=20)F P MS组内 男[n;百分率(%)] 10(50.00) 9(45.00) 13(65.00) 1.74* >0.05 — 年龄/岁 45.20±12.05 56.80±10.89△△ 54.40±10.18△△ 6.12 < 0.01 122.476 P/(mmol/L) 1.30±0.09 1.64±0.03△△ 2.13±0.67△△## 35.78 < 0.01 0.173 Ca/(mmol/L) 2.29±0.10 2.08±0.15△△ 2.15±0.22# 15.56 < 0.01 0.028 GLU/(mmol/L) 5.45±2.05 5.85±3.41 6.00±2.40 0.41 >0.05 7.220 TC/(mmol/L) 4.88±0.91 3.62±1.10△△ 3.94±0.96△△ 16.83 < 0.01 0.985 BUN/(mmol/L) 5.16±1.07 25.94±9.69△△ 22.71±6.14△△ 39.64 < 0.01 44.226 SCr/(μmol/L) 61.85±8.41 571.95±212.39△△ 774.85±227.19△△# 83.68 < 0.01 32 254.597 ALP/(U/L) 57.10±17.02 80.60±31.96△ 98.00±40.04△△ 16.94 < 0.01 971.589 PTH/(ng/L) 47.61±4.05 164.24±95.76△△ 333.94±235.46△△# 33.19 < 0.01 21 544.362 25-羟-VD/(ng/mL) 25.18±2.14 18.02±5.17△△ 15.41±5.93△△ 27.66 < 0.01 22.154 FGF-21/(pg/mL) 50.09±9.46 180.43±110.87△△ 292.42±217.55△△ 37.54 < 0.01 19 903.652 BMP-2/(pg/mL) 6.49±1.24 41.22±25.31△△ 43.17±20.05△△ 38.48 < 0.01 348.072 baPWV/(cm/s) 1 273.70±174.43 1 699.50±237.37△△ 1 794.00±124.48△△ 31.80 < 0.01 34 087.319 *示χ2值; q检验:与对照组比较△P < 0.05,△△P < 0.01;与初次内瘘组比较#P < 0.05,## P < 0.01 表 1 临床相关指标的比较(x±s)
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观察组40例中内瘘血管钙化病人共24例,发生率达60.00%。内瘘血管钙化病人血FGF-21、BMP-2、P、PTH、SCr水平及baPWV值均明显高于内瘘血管无钙化病人(P < 0.05~P < 0.01),Ca水平明显低于无钙化组(P < 0.01), 其他临床指标相比较差异均无统计学意义(见表 2)。
指标 无钙化组
(n=16)轻、中度组
(n=15)重度组
(n=9)F P MS组内 男[n;百分率(%)] 10(62.50) 7(46.70) 5(55.50) 0.79* >0.05 — 年龄/岁 52.3±12.83 57.53±8.17 58.22±8.54 1.35 >0.05 107.803 P/(mmol/L) 1.53±0.17 1.85±0.47△ 2.55±0.58△△## 21.95 < 0.01 0.165 Ca/(mmol/L) 2.16±0.14 2.15±0.20 1.94±0.20△△## 17.43 < 0.05 0.031 GLU/(mmol/L) 5.63±2.07 6.40±3.85 5.65±2.61 0.31 >0.05 8.824 TC/(mmol/L) 3.76±1.08 3.71±0.92 3.94±1.21 0.44 >0.05 1.113 BUN/(mmol/L) 23.99±9.20 23.26±8.44 26.69±5.80 0.51 >0.05 68.492 SCr/(μmol/L) 578.81±243.56 625.87±152.61 926.11±184.39△△## 9.46 < 0.01 40 211.380 ALP/(U/L) 82.69±21.22 87.93±39.72 103.33±51.92 0.67 >0.05 1 362.280 PTH/(ng/L) 180.93±95.87 194.47±134.07 461.28±274.29△△## 4.24 < 0.05 26 794.571 25-羟-VD/(ng/mL) 17.20±4.69 16.71±5.26 15.58±8.03 2.20 >0.05 33.309 FGF-21/(pg/mL) 105.15±41.33 210.93±69.77△△ 512.28±155.75△△## 29.87 < 0.01 7 779.578 BMP-2/(pg/mL) 22.58±6.72 45.22±12.11△△ 71.99±18.82△△## 36.31 < 0.01 150.427 baPWV/(cm/s) 1 628.80±207.50 1 822.80±145.12△△ 1 829.00±133.5△△ 6.33 < 0.05 29 282.587 *示χ2值; q检验:与无钙化组比较△P < 0.05,△△P < 0.01;与轻、中度组比较## P < 0.01 表 2 临床相关指标在观察组不同亚组间的比较(x±s)
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观察组与对照组baPWV存在明显差异,初次内瘘组baPWV为(1 699.50±237.37)cm/s, 内瘘修复组为(1 794.00±124.48)cm/s, 对照组为(1 273.70±174.43)cm/s, 差异有统计学意义(P < 0.01);内瘘血管钙化病人baPWV大于非钙化血管病人(P < 0.01)(见表 1、2)。
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Spearman相关分析显示,观察组病人内瘘血管钙化与血清FGF-21、BMP-2、P、SCr、PTH、baPWV均呈正相关(rs=0.850、0.769、0.718、0.433、0.441、0.457,P < 0.01),与Ca、GLU、TC、BUN、ALP、25-羟-VD、性别、年龄指标无相关性(rs=-0.398、-0.113、0.014、0.244、0.006、-0.278、0.084、0.133,P>0.05)。
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通过观察所有AVF血管钙化的标本,FGF-21及BMP-2在钙化血管壁上均有所表达,大都表现于血管中膜,重度钙化血管表达量明显大于轻、中度钙化血管(见图 1~2)。重度钙化组FGF-21、BMP-2阳性表达高于轻、中度钙化组(P < 0.05)(见表 3)。
分组 n S/FGF-21 S/BMP-2 重度钙化组 9 10.67±0.67 9.67±0.60 轻、中度钙化组 15 8.53±0.27 8.26±0.11 t — 2.96 2.29 P — < 0.05 < 0.05 表 3 重度钙化组与轻、中度钙化组免疫组化表达比较(x±s)
FGF-21、BMP-2在维持性血液透析病人自体动静脉内瘘血管钙化中的作用
Effect of the FGF-21 and BMP-2 on vascular calcification of autologous arteriovenous fistula in maintenance hemodialysis patients
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摘要:
目的探讨成纤维细胞生长因子-21(FGF-21)及骨形态发生蛋白-2(BMP-2)在维持性血液透析病人自体动静脉内瘘血管钙化中的作用。 方法选取蚌埠医学院第一附属医院肾病科维持性血液透析的病人中行内瘘修复术及慢性肾脏病4~5期初次内瘘术者各20例为观察组,并选取同期健康体检中心年龄、性别与之相匹配的健康人群20名为对照组。在观察组建立自体动静脉内瘘手术时留取修剪下的内瘘血管组织(初瘘病人的头静脉组织,修瘘病人的“静脉动脉化”的头静脉),行茜素红S染色检测有无钙化,并计算钙化积分进行钙化分级(重度钙化组和轻、中度钙化组、无钙化组)。收集所有研究对象临床基本资料、血清生化指标及肱踝脉搏波传导速度(baPWV)值;酶联免疫吸附法测定所有研究对象FGF-21和BMP-2血清浓度;免疫组织化学检测观察组内瘘血管壁上FGF-21和BMP-2的表达情况。 结果观察组血清FGF-21和BMP-2水平明显高于对照组(P < 0.01)。随着血管钙化程度加重FGF-21和BMP-2在血清中水平越高,FGF-21及BMP-2在钙化程度越高的血管壁上的免疫组织表达也越强(P < 0.05)。观察组血清FGF-21、BMP-2、血磷、肌酐、甲状旁腺激素水平及baPWV值与内瘘血管钙化呈正相关(rs=0.850、0.769、0.718、0.433、0.441、0.457,P < 0.01)。 结论FGF-21及BMP-2与维持性血液透析病人自体动静脉内瘘血管钙化存在一定的相关性,可作为监测内瘘血管钙化的参考依据。 -
关键词:
- 血液透析 /
- 血管钙化 /
- 动静脉内瘘 /
- 成纤维细胞生长因子-21 /
- 骨形态发生蛋白-2
Abstract:ObjectiveTo investigate the effects of fibroblast growth factor-21(FGF-21) and bone morphogenetic protein-2(BMP-2) on vascular calcification of autologous arteriovenous fistula(AVF) in maintenance hemodialysis patients. MethodsTwenty maintenance hemodialysis patients treated with internal fistula repair and 20 patients treated with primary internal fistula operation at stage 4-5 of chronic kidney disease in the Department of Nephrology of The First Affiliated Hospital of Bengbu Medical College were selected as the observation group, and 20 healthy people matched with age and gender in the health examination center were selected as the control group.The internal fistula blood vessels from establishing autogenous arteriovenous fistula operation(cephalic vein tissue of early fistula patients or arterialized venous cephalic vein of repairing fistula patients) were stained with alizarin red S to detect the presence of calcification, and calculate the calcification score for calcified stage(including severe calcification group, light and moderate calcification group and noncalcification group).The clinical data, serum biochemical parameters, and brachial and ankle pulse wave conduction velocity(baPWV) in all cases were collected.The serum concentrations of FGF-21 and BMP-2 in all cases were determined by ELISA, the immunohistochemistry was used to detect the expression levels of FGF-21 and BMP-2 in the vascular wall of internal fistula in the observation group. ResultsThe serum levels of FGF-21 and BMP-2 in observation group were significantly higher than those in control group(P < 0.01).With the aggravation of vascular calcification, the serum levels of FGF-21 and BMP-2 increased, and the expression levels of FGF-21 and BMP-2 in the immune tissue of the vascular wall with higher calcification degree also increased(P < 0.05).The levels of FGF-21, BMP-2, serum phosphorus, creatinine, parathyroid hormone and baPWV in the observation group were positively correlated with the vascular calcification of internal fistula(rs=0.850, 0.769, 0.718, 0.433, 0.441 and 0.457, respectively)(P < 0.01). ConclusionsThe levels of FGF-21 and BMP-2 are correlated with the vascular calcification of autologous arteriovenous fistula in patients with maintenance hemodialysis, which can be used as the reference for monitoring the vascular calcification of internal fistula. -
表 1 临床相关指标的比较(x±s)
指标 对照组
(n=20)初次内瘘组
(n=20)内瘘修复组
(n=20)F P MS组内 男[n;百分率(%)] 10(50.00) 9(45.00) 13(65.00) 1.74* >0.05 — 年龄/岁 45.20±12.05 56.80±10.89△△ 54.40±10.18△△ 6.12 < 0.01 122.476 P/(mmol/L) 1.30±0.09 1.64±0.03△△ 2.13±0.67△△## 35.78 < 0.01 0.173 Ca/(mmol/L) 2.29±0.10 2.08±0.15△△ 2.15±0.22# 15.56 < 0.01 0.028 GLU/(mmol/L) 5.45±2.05 5.85±3.41 6.00±2.40 0.41 >0.05 7.220 TC/(mmol/L) 4.88±0.91 3.62±1.10△△ 3.94±0.96△△ 16.83 < 0.01 0.985 BUN/(mmol/L) 5.16±1.07 25.94±9.69△△ 22.71±6.14△△ 39.64 < 0.01 44.226 SCr/(μmol/L) 61.85±8.41 571.95±212.39△△ 774.85±227.19△△# 83.68 < 0.01 32 254.597 ALP/(U/L) 57.10±17.02 80.60±31.96△ 98.00±40.04△△ 16.94 < 0.01 971.589 PTH/(ng/L) 47.61±4.05 164.24±95.76△△ 333.94±235.46△△# 33.19 < 0.01 21 544.362 25-羟-VD/(ng/mL) 25.18±2.14 18.02±5.17△△ 15.41±5.93△△ 27.66 < 0.01 22.154 FGF-21/(pg/mL) 50.09±9.46 180.43±110.87△△ 292.42±217.55△△ 37.54 < 0.01 19 903.652 BMP-2/(pg/mL) 6.49±1.24 41.22±25.31△△ 43.17±20.05△△ 38.48 < 0.01 348.072 baPWV/(cm/s) 1 273.70±174.43 1 699.50±237.37△△ 1 794.00±124.48△△ 31.80 < 0.01 34 087.319 *示χ2值; q检验:与对照组比较△P < 0.05,△△P < 0.01;与初次内瘘组比较#P < 0.05,## P < 0.01 表 2 临床相关指标在观察组不同亚组间的比较(x±s)
指标 无钙化组
(n=16)轻、中度组
(n=15)重度组
(n=9)F P MS组内 男[n;百分率(%)] 10(62.50) 7(46.70) 5(55.50) 0.79* >0.05 — 年龄/岁 52.3±12.83 57.53±8.17 58.22±8.54 1.35 >0.05 107.803 P/(mmol/L) 1.53±0.17 1.85±0.47△ 2.55±0.58△△## 21.95 < 0.01 0.165 Ca/(mmol/L) 2.16±0.14 2.15±0.20 1.94±0.20△△## 17.43 < 0.05 0.031 GLU/(mmol/L) 5.63±2.07 6.40±3.85 5.65±2.61 0.31 >0.05 8.824 TC/(mmol/L) 3.76±1.08 3.71±0.92 3.94±1.21 0.44 >0.05 1.113 BUN/(mmol/L) 23.99±9.20 23.26±8.44 26.69±5.80 0.51 >0.05 68.492 SCr/(μmol/L) 578.81±243.56 625.87±152.61 926.11±184.39△△## 9.46 < 0.01 40 211.380 ALP/(U/L) 82.69±21.22 87.93±39.72 103.33±51.92 0.67 >0.05 1 362.280 PTH/(ng/L) 180.93±95.87 194.47±134.07 461.28±274.29△△## 4.24 < 0.05 26 794.571 25-羟-VD/(ng/mL) 17.20±4.69 16.71±5.26 15.58±8.03 2.20 >0.05 33.309 FGF-21/(pg/mL) 105.15±41.33 210.93±69.77△△ 512.28±155.75△△## 29.87 < 0.01 7 779.578 BMP-2/(pg/mL) 22.58±6.72 45.22±12.11△△ 71.99±18.82△△## 36.31 < 0.01 150.427 baPWV/(cm/s) 1 628.80±207.50 1 822.80±145.12△△ 1 829.00±133.5△△ 6.33 < 0.05 29 282.587 *示χ2值; q检验:与无钙化组比较△P < 0.05,△△P < 0.01;与轻、中度组比较## P < 0.01 表 3 重度钙化组与轻、中度钙化组免疫组化表达比较(x±s)
分组 n S/FGF-21 S/BMP-2 重度钙化组 9 10.67±0.67 9.67±0.60 轻、中度钙化组 15 8.53±0.27 8.26±0.11 t — 2.96 2.29 P — < 0.05 < 0.05 -
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