尿可溶性血管内皮生长因子受体-1与子痫前期的关系及意义
|
摘要
目的:子痫前期是妊娠期特有的疾病,虽然对其做了大量的研究,但是其病因及发病机制仍然不明。临床上常用的诊断方法为血压监测、尿蛋白分析和血清尿酸测定等,但是其特异度和敏感度不理想。目前研究认为促血管生成因子和抗血管生成因子失衡是子痫前期发病的重要原因,其中主要集中在胎盘产生的一种可溶性血管内皮生长因子受体-1 (soluble fms-like tyrosine kinase-1,sFlt-1)上。
sFlt-1是血管内皮生长因子(VEGF)的一种抑制性受体,可以通过结合VEGF和胎盘生长因子(PlGF)而抑制二者发挥生理性作用。实验显示子痫前期患者胎盘和血液中都有高浓度的sFlt-1存在,研究多集中在血循环中sFlt-1、VEGF和PlGF浓度的变化,发现血清sFlt-1在子痫前期患者和正常妊娠患者之间相比较有明显的升高,且可以用于判断该病的病情。我们研究尿中sFlt-1是否也会出现类似血液中的变化,是否可以用于该病的诊断;同时比较该因子与临床常用几种指标的优劣,寻求一种非侵入性、敏感度和特异度都较高的实验室诊断标志物。
方法:收集无其他合并症、未使用影响血管活性药物的重度子痫前期患者16例,非重度子痫前期患者13例,正常妊娠妇女即对照组15例。采用酶联免疫吸附试验(ELISA)测定上述孕妇入院随机尿液sFlt-1的含量;采用双缩脲比色法测定尿蛋白;采用磷钨酸还原法测定血清尿酸。
结果:(1)研究组与对照组在年龄、体重、孕产次和采样的孕周上差异无明显的统计学意义,重度子痫前期组分娩孕周明显小于非子痫前期和对照组;(2)血清尿酸在重度、非重度子痫前期患者与正常孕妇组分别是380、312、209umol/L,定性尿蛋白水平在各组间分别是2.88、1.31、0.37(P<0.05),差异有统计学意义;(3)尿液sFlt-1浓度在重度、非重度子痫前期组与正常孕妇组分别是2986.25±647、2189.38±658、1231.60±974mg/ml ,重度子痫前期组明显高于非重度子痫前期和对照组(P<0.05),且随着病情加重尿液sFlt-1逐渐增加;(4)定性尿蛋白和血清尿酸间存在相关性,定性尿蛋白和尿sFlt-1间存在相关性;(5)尿sFlt-1诊断重度子痫前期的敏感度和特异度优于定性尿蛋白和血清尿酸,同时尿sFlt-1≥2676mg/ml为切点,诊断重度子痫前期的准确性最佳。
结论:(1)sFlt-1在子痫前期的发病中起重要作用,尿sFlt-1可以用来判断子痫前期的病情;(2)尿sFlt-1测定是一种无创性的、快速的检验手段,且用于判断重度子痫前期病情时尿sFlt-1更优于定性蛋白尿;(3)尿sFlt-1≥2676mg/ml可以具有阳性意义。
Objective: Pre-eclampsia is a specific pathologic process of gestation period.Although amount of reseach have done about it,the etiology and pathogenesis of pre-eclampsia remains unclear.Clinical diagnostic methods are monitoring of blood pressure, analysis of urine protein, test of serum uric acid,but the specificity and sensitivity are not optimal.Update,the study showed that the imbalance between angiogenesis factor and antiangiogenic agent is the important reason.Among them,it focuses on soluble fms-like tyrosine kinase-1 (sFlt-1)generated by placenta.
sFlt-1 is inhibit receptor of vascular endothelial growth factor (VEGF). It can inhibit the physiologic action of VEGF and placental growth factor (PlGF) by combined them.
It was recently shown that concentration of sFlt-1 in placenta and blood of patients is high.So far the study is concentrated on the variety of sFlt-1,VEGF and PlGF in serum.And it is found that there exists singnifi– cant difference of sFlt-1 in serum between pre-eclampsia and normal pregnant.Meanwhile sFlt-1 indentify the degree of the disease. However,in our experiment, we sought to the possibly change of sFlt-1 in urine and the action of it.At the same time, in order to find out an noninvasive method,an experimental diagnostic mark with high specificity and sensitivity,we compared sFlt-1 with other clinical indexes.
Methods:Gathering the serum of 36 patients in pre-eclampsia without complications and using the drugs affecting the vacular activity, severe pre-eclampsia ,non severe pre-eclampsia and normal pregnant are 16、13and15 respectively.sFlt-1 is measured by ELISA,urine protein by biuret colorimetry, serum uric acid by phosphotungstic acid.
Results: (1)In severe pre-eclampsia,non severe pre-eclampsia and normal pregnant groups, the quanlity of urine protein is 2.88、1.31 and 0.37 respectively, the quanlity of uric acid in serum is 380、312 and 209umol/L respectively (P=0.004),There exists singnificantly difference(P<0.05). (2)the quanlity of sFlt-1 is 2986.25、2189.38 and 1231.60mg/ml respectively(P=0.000).There exists singnificantly difference (P<0.05). (3)Among them,there exist correlation ship.The r between urine protein and uric acid,urine protein and sFlt-1,uric acid and sFlt-1 is 0.582 and 0.325 respectively (P<0.05).(4)From the ROC curve,we can see that the specificity and sensitivity of sFlt-1 is the highest.
Conclusion: (1) sFlt-1 plays a important role in the creation of pre- eclampsia.And sFlt-1 indentify the degree of the disease.(2)Evaluation of sFlt-1 in urine is an noninvasive and quick meathod.The specificity and sensitivity of sFlt-1 are the much highest than another to identify the degree of severe pre-eclampsia.(3) sFlt-1 in casual urine has positive singnificance while larger than 2676mg/ml.
sFlt-1是血管内皮生长因子(VEGF)的一种抑制性受体,可以通过结合VEGF和胎盘生长因子(PlGF)而抑制二者发挥生理性作用。实验显示子痫前期患者胎盘和血液中都有高浓度的sFlt-1存在,研究多集中在血循环中sFlt-1、VEGF和PlGF浓度的变化,发现血清sFlt-1在子痫前期患者和正常妊娠患者之间相比较有明显的升高,且可以用于判断该病的病情。我们研究尿中sFlt-1是否也会出现类似血液中的变化,是否可以用于该病的诊断;同时比较该因子与临床常用几种指标的优劣,寻求一种非侵入性、敏感度和特异度都较高的实验室诊断标志物。
方法:收集无其他合并症、未使用影响血管活性药物的重度子痫前期患者16例,非重度子痫前期患者13例,正常妊娠妇女即对照组15例。采用酶联免疫吸附试验(ELISA)测定上述孕妇入院随机尿液sFlt-1的含量;采用双缩脲比色法测定尿蛋白;采用磷钨酸还原法测定血清尿酸。
结果:(1)研究组与对照组在年龄、体重、孕产次和采样的孕周上差异无明显的统计学意义,重度子痫前期组分娩孕周明显小于非子痫前期和对照组;(2)血清尿酸在重度、非重度子痫前期患者与正常孕妇组分别是380、312、209umol/L,定性尿蛋白水平在各组间分别是2.88、1.31、0.37(P<0.05),差异有统计学意义;(3)尿液sFlt-1浓度在重度、非重度子痫前期组与正常孕妇组分别是2986.25±647、2189.38±658、1231.60±974mg/ml ,重度子痫前期组明显高于非重度子痫前期和对照组(P<0.05),且随着病情加重尿液sFlt-1逐渐增加;(4)定性尿蛋白和血清尿酸间存在相关性,定性尿蛋白和尿sFlt-1间存在相关性;(5)尿sFlt-1诊断重度子痫前期的敏感度和特异度优于定性尿蛋白和血清尿酸,同时尿sFlt-1≥2676mg/ml为切点,诊断重度子痫前期的准确性最佳。
结论:(1)sFlt-1在子痫前期的发病中起重要作用,尿sFlt-1可以用来判断子痫前期的病情;(2)尿sFlt-1测定是一种无创性的、快速的检验手段,且用于判断重度子痫前期病情时尿sFlt-1更优于定性蛋白尿;(3)尿sFlt-1≥2676mg/ml可以具有阳性意义。
Objective: Pre-eclampsia is a specific pathologic process of gestation period.Although amount of reseach have done about it,the etiology and pathogenesis of pre-eclampsia remains unclear.Clinical diagnostic methods are monitoring of blood pressure, analysis of urine protein, test of serum uric acid,but the specificity and sensitivity are not optimal.Update,the study showed that the imbalance between angiogenesis factor and antiangiogenic agent is the important reason.Among them,it focuses on soluble fms-like tyrosine kinase-1 (sFlt-1)generated by placenta.
sFlt-1 is inhibit receptor of vascular endothelial growth factor (VEGF). It can inhibit the physiologic action of VEGF and placental growth factor (PlGF) by combined them.
It was recently shown that concentration of sFlt-1 in placenta and blood of patients is high.So far the study is concentrated on the variety of sFlt-1,VEGF and PlGF in serum.And it is found that there exists singnifi– cant difference of sFlt-1 in serum between pre-eclampsia and normal pregnant.Meanwhile sFlt-1 indentify the degree of the disease. However,in our experiment, we sought to the possibly change of sFlt-1 in urine and the action of it.At the same time, in order to find out an noninvasive method,an experimental diagnostic mark with high specificity and sensitivity,we compared sFlt-1 with other clinical indexes.
Methods:Gathering the serum of 36 patients in pre-eclampsia without complications and using the drugs affecting the vacular activity, severe pre-eclampsia ,non severe pre-eclampsia and normal pregnant are 16、13and15 respectively.sFlt-1 is measured by ELISA,urine protein by biuret colorimetry, serum uric acid by phosphotungstic acid.
Results: (1)In severe pre-eclampsia,non severe pre-eclampsia and normal pregnant groups, the quanlity of urine protein is 2.88、1.31 and 0.37 respectively, the quanlity of uric acid in serum is 380、312 and 209umol/L respectively (P=0.004),There exists singnificantly difference(P<0.05). (2)the quanlity of sFlt-1 is 2986.25、2189.38 and 1231.60mg/ml respectively(P=0.000).There exists singnificantly difference (P<0.05). (3)Among them,there exist correlation ship.The r between urine protein and uric acid,urine protein and sFlt-1,uric acid and sFlt-1 is 0.582 and 0.325 respectively (P<0.05).(4)From the ROC curve,we can see that the specificity and sensitivity of sFlt-1 is the highest.
Conclusion: (1) sFlt-1 plays a important role in the creation of pre- eclampsia.And sFlt-1 indentify the degree of the disease.(2)Evaluation of sFlt-1 in urine is an noninvasive and quick meathod.The specificity and sensitivity of sFlt-1 are the much highest than another to identify the degree of severe pre-eclampsia.(3) sFlt-1 in casual urine has positive singnificance while larger than 2676mg/ml.
引文
1. Lockwood CJ,Peters JH. Icreased plasma levels of ED1+cellular fibronectin precede the clinical signs of preeclampsia. Am J Obstet Gynecol,1990 Feb; 62(2): 658-62.
2. Neufeld G, Cohen T, Slraga N, et a1.The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis[J].Trends Cardiovasc Med,2002,12(1):13-19.
3. Roeckl W,Hecht D,Sztajer H,et a1.Differential binding characteristies and cellular inhibition by soluble VEGF receptors 1 and 2 [J] .ExpCA1Res. 1998,241(1):161-70.
4. Maynard SE,Venkatesha S,Thadhani R,et a1.Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of pre- eclampsia [J].Pediatr Res,2005,57(5pt 2):1R-7R.
5. Yuval Bdolah,S.Ananth Karumanchi,et al.Recent advances in under- standing of preeclampsia.Croat Med J.2005;46(5):728-736.
6. Cheung CY. J SocGynecol Invest.1997;4(4):169-177.
7. Witte L,Hicklin DJ,Zhu Z,et a1.Monoclonal antibodies targeting the VEGF receptor-2(FLK-1/KDR) as an anti-angiogenie therapeutic stratagy [J]. Cancer Metastasis Rev,1998,17 (2):155-159.
8. Zhou Y,McMaster M,Woo K,et a1.Vascular endothelial growth factor ligands and receptors that regu late human cytotrophoblast survival ale dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes and low platelet syndrome [J].Am J Pathol,2002,160(4):1405-1423.
9. Maynard SE,Min JY,Merchan J,et a1.Excess placental soluble fms- like tyrosine kinase 1(sFlt-1)may contribute to endothelial dysfunction hyper- tension,and proteinuria in preeclampsia.[J]. Clin Invest,2003,l11(5):649- 658.
10. Nagamatsu T,Fujii T,Kusumi M,et a1.Cytotrophoblasts upregulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen:an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology,2004,145(11):4838-4845.
11. Li H,Gu B,Zhang Y,et a1.Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta.Placenta,2005,26(2-3):210-217.
12. Rajakumar A,Brandon HM.Evidence for the functional activity of hypoxia- -inducible transcription factors overexpressed in preeclamptic placenta. P1acenta,2004,25:763-769.
13. Levine RJ,Maynard SE,Qian C,et a1.Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672-683.
14. Chikako HIRASHIMA,Akihide OHKUCHI,et a1.Establishing Reference Values for Both Total Soluble Fms-Like Tyrosine Kinase 1 and Free Placental Growth Factor in Pregnant Women. Hypertens Res 2005; 28(9): 727-732.
15. Akihide OHKUCHI,Chikako HIRASHIMA,et a1.Alterations in Placental Growth Factor Levels before and after the Onset of Preeclampsia Are More Pronounced in Women with Early Onset Severe Preeclampsia. Hypertens Res 2007,30(2):151-159.
16. Bdolah Y,Kanananchi SA,Sachs BP.Recent advances in understanding ofpreeclampsia [J].Croat Med J,2005,46(5):728-736.
17. Buhimschi CS,Norwitz ER,Funai E,et a1.Urinary angiogenie factors cluster hypertensive disorders and identify women with severe preeclampsia[J].Am J Obstet Gynecol,2005,192(3):734-741.
18. Geva E,Ginzinger DG,Zaloudek CJ,Moore DH,Byrne A,Jaffe RB.Human placental vascular development:vasculogenic and angiogenic(branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A,angiopoietin-1,andangiopoietin-2.[J] Clin Endocrinol Metab.2002; 87: 4213-24.
19. Goldman-Wohl DS,Ariel I,Greenfield C,Lavy Y,Yagel S.Tie-2 and angio- poietin-2 expression at the fetal-maternal interface:a receptor ligand model for vascular remodelling.Mol Hum Reprod.2000;6:81-7.
20. Dunk C,Shams M,Nijjar S,Rhaman M,Qiu Y,Bussolati B,et al. Angiopoietin- 1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development.Am J Pathol.2000;156:2185-99.
21. Wulff C,Wilson H,Dickson SE,Wiegand SJ,Fraser HM.Hemochorial placen- tation in the primate:expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy.Biol Reprod.2002; 66:802-12.
1. Simmons LA,Hennesy A,Gillin AG,et a1.Uterpoplacental blood flow and placental vascular endothelial factor in normotensive and preeclampsia pregnany.BJOG 2000;107:678-85
2. Lockwood CJ,Peters JH.Icreased plasma levels of ED1+cellular fibronectin precede the clinical signs of preeclampsia. Am J Obstet Gynecol,1990;62(2): 658-62
3. Ostendorf T,Kunter U,Eitner F,et a1.VEGF(165) mediates glomerular endothelial repair. J Clin Invest,1999;104:913-23.
4.乐杰,主编.妇产科学.第六版.北京:人民卫生出版社,2003.97-104.
5.朱晓平.妊娠高血压综合征患者血尿酸浓度检测临床价值探讨南京医科大学学报,2004;24(3):265.
6.刘铃,李克英,邓洪,等.监测血清尿酸值预测妊高征的临床意义[J].中国实用妇科与产科杂志,2004;20(2):95-96.
7. Richard L,Kendall,enneth A,et a1.Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA,1993,90: 10705-9.
8. Maynard SE,Min JY,Merchan J,et a1.Excess placental soluble fms- like tyrosine kinase 1(sFlt-1) may contribute to endothelial dysfunction hyper- tension,and proteinuria in preeclampsia.J Clin Invest,2003;l11(5): 649-658.
9. Thadhani R,Mutter WP,Wolf M,Levine RJ,Taylor RN,Sukhatme VP,et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.J Clin Endocrinol Metab,2004;89:770-5.
10. Sugimoto H,Hamano Y,Charytan D,et a1.Circulating vascular endothelial factor(VEGF) by anti-VEGF antibodies and soluble VEGF receptor (sFlt-1) induces proteinuria.J Biol Chem,2003;278:12605-8.
11. Levine RJ,Maynard SE,Qian C,et a1.Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med,2004; 350: 672-83.
12. Buhimschi CS,Norwitz ER,Funai E,et a1.Urinary angiogenie factors cluster hypertensive disorders and identify women with severe preeclampsia[J].Am J Obstet Gynecol,2005;192(3):734-41.
13. Garovic VD,Waqner SJ,Petrovic LM,et a1.Glomerular expression of nephrin and synaptopodin,but not podocin,is decreased in kidney sections fromwomen with preeclampsia.Nephrol Dial Transplant,2007 Apr;22(4):1136-43.
14. Gant NF,Chand S,Worley RJ,et al.A clinical test useul for predicting the development of acute hypertension in pregnancy. Am J Obstet Gynecol, 1974;120:1-7.
15. Meyer NL,Mercer BM,Friedman SA,Sibai BM.Urinary dipstic protein:a poor predictor of absent or severe proteinuria.Am J Obstet Gynecol, 1994;170: 137-41.
16. Hara A,Wada T,Furuichi K,et al . Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int.2006 Jun;69(11):1986-95.
17. Koga K,Osuga Y,Yoshino O,et al. Elevated serum soluble vascular endothelial factor receptor 1(sVEGFR-1) levels inwomen with preeclampsia. J Clin Endocrinol Metab 2003;88:2438-51.
18. Matsumoto K,Kanmatsuse K. Elevated vascular endothelial factor levels in the urine of patients with minimal change nephritic syndrome.Clin Nephrol 2001;66:269-74.
19. Rose EM,Steegers EA,Thomas CM,et al.High levels of urinary vascular endothelial growth factor in women with severe preeclampsia Int J Biol Markers,2004 Jan-Mar;19(1):72-5.
2. Neufeld G, Cohen T, Slraga N, et a1.The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis[J].Trends Cardiovasc Med,2002,12(1):13-19.
3. Roeckl W,Hecht D,Sztajer H,et a1.Differential binding characteristies and cellular inhibition by soluble VEGF receptors 1 and 2 [J] .ExpCA1Res. 1998,241(1):161-70.
4. Maynard SE,Venkatesha S,Thadhani R,et a1.Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of pre- eclampsia [J].Pediatr Res,2005,57(5pt 2):1R-7R.
5. Yuval Bdolah,S.Ananth Karumanchi,et al.Recent advances in under- standing of preeclampsia.Croat Med J.2005;46(5):728-736.
6. Cheung CY. J SocGynecol Invest.1997;4(4):169-177.
7. Witte L,Hicklin DJ,Zhu Z,et a1.Monoclonal antibodies targeting the VEGF receptor-2(FLK-1/KDR) as an anti-angiogenie therapeutic stratagy [J]. Cancer Metastasis Rev,1998,17 (2):155-159.
8. Zhou Y,McMaster M,Woo K,et a1.Vascular endothelial growth factor ligands and receptors that regu late human cytotrophoblast survival ale dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes and low platelet syndrome [J].Am J Pathol,2002,160(4):1405-1423.
9. Maynard SE,Min JY,Merchan J,et a1.Excess placental soluble fms- like tyrosine kinase 1(sFlt-1)may contribute to endothelial dysfunction hyper- tension,and proteinuria in preeclampsia.[J]. Clin Invest,2003,l11(5):649- 658.
10. Nagamatsu T,Fujii T,Kusumi M,et a1.Cytotrophoblasts upregulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen:an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology,2004,145(11):4838-4845.
11. Li H,Gu B,Zhang Y,et a1.Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta.Placenta,2005,26(2-3):210-217.
12. Rajakumar A,Brandon HM.Evidence for the functional activity of hypoxia- -inducible transcription factors overexpressed in preeclamptic placenta. P1acenta,2004,25:763-769.
13. Levine RJ,Maynard SE,Qian C,et a1.Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672-683.
14. Chikako HIRASHIMA,Akihide OHKUCHI,et a1.Establishing Reference Values for Both Total Soluble Fms-Like Tyrosine Kinase 1 and Free Placental Growth Factor in Pregnant Women. Hypertens Res 2005; 28(9): 727-732.
15. Akihide OHKUCHI,Chikako HIRASHIMA,et a1.Alterations in Placental Growth Factor Levels before and after the Onset of Preeclampsia Are More Pronounced in Women with Early Onset Severe Preeclampsia. Hypertens Res 2007,30(2):151-159.
16. Bdolah Y,Kanananchi SA,Sachs BP.Recent advances in understanding ofpreeclampsia [J].Croat Med J,2005,46(5):728-736.
17. Buhimschi CS,Norwitz ER,Funai E,et a1.Urinary angiogenie factors cluster hypertensive disorders and identify women with severe preeclampsia[J].Am J Obstet Gynecol,2005,192(3):734-741.
18. Geva E,Ginzinger DG,Zaloudek CJ,Moore DH,Byrne A,Jaffe RB.Human placental vascular development:vasculogenic and angiogenic(branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A,angiopoietin-1,andangiopoietin-2.[J] Clin Endocrinol Metab.2002; 87: 4213-24.
19. Goldman-Wohl DS,Ariel I,Greenfield C,Lavy Y,Yagel S.Tie-2 and angio- poietin-2 expression at the fetal-maternal interface:a receptor ligand model for vascular remodelling.Mol Hum Reprod.2000;6:81-7.
20. Dunk C,Shams M,Nijjar S,Rhaman M,Qiu Y,Bussolati B,et al. Angiopoietin- 1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development.Am J Pathol.2000;156:2185-99.
21. Wulff C,Wilson H,Dickson SE,Wiegand SJ,Fraser HM.Hemochorial placen- tation in the primate:expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy.Biol Reprod.2002; 66:802-12.
1. Simmons LA,Hennesy A,Gillin AG,et a1.Uterpoplacental blood flow and placental vascular endothelial factor in normotensive and preeclampsia pregnany.BJOG 2000;107:678-85
2. Lockwood CJ,Peters JH.Icreased plasma levels of ED1+cellular fibronectin precede the clinical signs of preeclampsia. Am J Obstet Gynecol,1990;62(2): 658-62
3. Ostendorf T,Kunter U,Eitner F,et a1.VEGF(165) mediates glomerular endothelial repair. J Clin Invest,1999;104:913-23.
4.乐杰,主编.妇产科学.第六版.北京:人民卫生出版社,2003.97-104.
5.朱晓平.妊娠高血压综合征患者血尿酸浓度检测临床价值探讨南京医科大学学报,2004;24(3):265.
6.刘铃,李克英,邓洪,等.监测血清尿酸值预测妊高征的临床意义[J].中国实用妇科与产科杂志,2004;20(2):95-96.
7. Richard L,Kendall,enneth A,et a1.Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA,1993,90: 10705-9.
8. Maynard SE,Min JY,Merchan J,et a1.Excess placental soluble fms- like tyrosine kinase 1(sFlt-1) may contribute to endothelial dysfunction hyper- tension,and proteinuria in preeclampsia.J Clin Invest,2003;l11(5): 649-658.
9. Thadhani R,Mutter WP,Wolf M,Levine RJ,Taylor RN,Sukhatme VP,et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.J Clin Endocrinol Metab,2004;89:770-5.
10. Sugimoto H,Hamano Y,Charytan D,et a1.Circulating vascular endothelial factor(VEGF) by anti-VEGF antibodies and soluble VEGF receptor (sFlt-1) induces proteinuria.J Biol Chem,2003;278:12605-8.
11. Levine RJ,Maynard SE,Qian C,et a1.Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med,2004; 350: 672-83.
12. Buhimschi CS,Norwitz ER,Funai E,et a1.Urinary angiogenie factors cluster hypertensive disorders and identify women with severe preeclampsia[J].Am J Obstet Gynecol,2005;192(3):734-41.
13. Garovic VD,Waqner SJ,Petrovic LM,et a1.Glomerular expression of nephrin and synaptopodin,but not podocin,is decreased in kidney sections fromwomen with preeclampsia.Nephrol Dial Transplant,2007 Apr;22(4):1136-43.
14. Gant NF,Chand S,Worley RJ,et al.A clinical test useul for predicting the development of acute hypertension in pregnancy. Am J Obstet Gynecol, 1974;120:1-7.
15. Meyer NL,Mercer BM,Friedman SA,Sibai BM.Urinary dipstic protein:a poor predictor of absent or severe proteinuria.Am J Obstet Gynecol, 1994;170: 137-41.
16. Hara A,Wada T,Furuichi K,et al . Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int.2006 Jun;69(11):1986-95.
17. Koga K,Osuga Y,Yoshino O,et al. Elevated serum soluble vascular endothelial factor receptor 1(sVEGFR-1) levels inwomen with preeclampsia. J Clin Endocrinol Metab 2003;88:2438-51.
18. Matsumoto K,Kanmatsuse K. Elevated vascular endothelial factor levels in the urine of patients with minimal change nephritic syndrome.Clin Nephrol 2001;66:269-74.
19. Rose EM,Steegers EA,Thomas CM,et al.High levels of urinary vascular endothelial growth factor in women with severe preeclampsia Int J Biol Markers,2004 Jan-Mar;19(1):72-5.