高原体外循环中应用乌司他丁对肾功能影响的实验研究
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摘要
目的探索高原体外循环对肾脏功能的影响,以早期发现高原体外循环后肾脏损害,观察乌司他丁对高原体外循环下肾脏及肾功能的影响并讨论其作用机制。
方法实验采用高原成年健康雄性杂种犬24只,随机均分为三组,建立高原体外循环肾脏缺血再灌注模型:假手术对照组(A组)、高原体外循环组(B组)、高原体外循环肾+乌司他丁组(C组),每组8只。B组、C组模拟临床浅低温体外循环120min后停止转流,恢复。肾脏正常血供,制作高原体外循环肾脏损伤模型;A组仅麻醉时间、创伤程度与B组和C组相同。C组分别在转流前30 min及转流结束时静脉注射乌司他丁20,000U/Kg,A组和B组静脉注射等量生理盐水。各组在转流结束后0、2、6、12、24h时取血、尿标本,测定以下指标:血尿素氮(BUN)、血肌酐(Cr)、血浆内皮素-1(Endothelin-1,ET-1)、尿N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-β-D-glucosaminidase,NAG)和γ-谷氨酰转肽酶(γ-glutamyltranspeptidase,γ-GTP),术后24h取左肾制备病理切片用于常规病理观察。
结果与A组比较:B组尿NAG、γ-GTP活性和血浆ET-1含量在各时相点均显著增高(P＜0.01),B组血清BUN、Cr浓度在12、24 h显著增高(P＜0.05,P＜0.01);C组尿NAG活性和血浆ET-1含量在各时相点均显著增高(P＜0.01),C组尿γ-GTP活性在0、12、24h明显高于A组(P＜0.01),而血清BUN、Cr浓度在各时相点均与A组无显著差异(P＞0.05)。与B组比较:C组尿NAG活性和血浆ET-1含量在各时相点均显著降低(P＜0.01),尿γ-GTP活性在6、12、24 h时显著降低(P＜0.05,P＜0.01),而血清BUN、Cr浓度仅在24 h显著降低(P＜0.01)。
病理组织学检查:A组未发现明显的肾脏组织形态学改变;B组可见肾脏点片状的近曲小管上皮细胞空泡变性和坏死,肾小管管腔扩张、其内可见管型和坏死脱落细胞,管周血管可见明显扩张、淤血,可见较多炎细胞浸润;C组可见肾脏有少量的近曲小管上皮细胞肿胀、颗粒变性,管型罕见,管周血管稍有淤血,少量炎细胞浸润。Paller评分:与A组比较,B组、C组得分显著高于A组(P＜0.01);与B组比较,C组得分显著低于B组(P＜0.01)。
结论
1、高原环境下进行体外循环,有一定的肾脏损伤,其中以肾功能损害较重,其机理可能与肾脏IRI有关。
2、内皮素-1可能是高原CPB后引发肾脏缺血再灌注损伤的重要因素。
3、尿酶(尿NAG、γ-GTP)可以先于常规指标(血BUN、Cr)发现高原CPB早期肾脏损害,且肾功能损伤程度与尿NAG水平呈正相关,肾脏损害因素作用时间与尿γ-GTP持续升高时间呈正相关。
4、乌司他丁可以对高原CPB后。肾脏及肾功能起到一定的保护作用,其机制可能是通过降低ET-1水平以减轻肾脏IRI。
Objective To investigate the effects on kidney during cardiopulmonary bypass at high altitude,to explore new predictors for early kidney damage during cardiopulmonary bypass at high altitude,and to research the effects and mechanism of ulinastatin on renal function during cardiopulmonary bypass at high altitude in dogs.
Methods Twenty-four male healthy dogs at high altitude were randomized into three groups:control group with sham operation(group A,n=8);renal ischemic reperfusion injury (IRI) group with cardiopulmonary bypass(CPB)(group B,n=8) and ulinastatin treatment group with CPB(group C,n=8).Blood samples and urine samples were harvested at 0,2,6, 12,24 h after CPB,and the concentrations of blood urea nitrogen(BUN),serum creatinine (Cr) and endothelin-1(ET-1),urine N-acetyl-β-D-glucosaminidase(NAG) and urine glutamyl transpeptidase(γ-GTP) were measured.Left kidney was obtained for pathological examination 24h after CPB.
Results Compared with group A,BUN and Cr levels were significantly higher at 12, 24 h after CPB in group B(P＜0.05,P＜0.01),NAG and ET-1 levels were significantly higher at 0,2,6,12,24 h after CPB in group C and in group B(P＜0.05,P＜0.01).γ-GTP levels were significantly higher at 0,2,6,12,24 h after CPB in group B(P＜0.01).γ-GTP levels were significantly higher at 0,12,24 h after CPB in group C(P＜0.05,P＜0.01). Compared with group B,BUN and Cr levels were significantly lower at 24 h after CPB in group C(P＜0.01),NAG and ET-1 levels were significantly lower at 0,2,6,12,24 h after CPB in group C(P＜0.01),γ-GTP levels were significantly lower at 6,12,24 h after CPB in group C(P＜0.05,P＜0.01).
Histopathological examination:There was no evident morphological change in group A.Proximal convoluted tubule endepidermis vacuolar developed degeneration and cellular necrosis,cast and necrosis cells occurred in the broadened lumens of nephric tubule,and blood vessel around the nephric tubule obviously demonstrated dilatation and congestion in group B.Proximal convoluted tubule endepidermis revealed cellular swelling,granular degeneration in group C.Cast and blood vessel congestion was rarely found in this group. The Paller scores of group C and group B are higher than group A(P＜0.01).The group B's score is higher than group C's(P＜0.01).
Conclusion
1、Earlier period kidney damage is definite during CPB at high altitude.The mechanism maybe relate with renal ischemic reperfusion injury.
2、ET-1 is possible an important initiating factor of renal ischemic reperfusion injury (IRI) after CPB at high altitude.
3、Urease(NAG,γ-GTP) increased at the earlier phase of kidney damage in comparison with other parameters during CPB at high altitude.The degree of injury of renal function is positive correlation with the NAG level in urine.The factor of causing kidney damage and increasedγ-GTP have a positive correlation in urine.
4、Ulinastatin can reduce the risk of renal dysfunction during CPB at high altitude. And decreased ET-1 level may be the mechanism of Ulinastatin to alleviate renal IRI.
方法实验采用高原成年健康雄性杂种犬24只,随机均分为三组,建立高原体外循环肾脏缺血再灌注模型:假手术对照组(A组)、高原体外循环组(B组)、高原体外循环肾+乌司他丁组(C组),每组8只。B组、C组模拟临床浅低温体外循环120min后停止转流,恢复。肾脏正常血供,制作高原体外循环肾脏损伤模型;A组仅麻醉时间、创伤程度与B组和C组相同。C组分别在转流前30 min及转流结束时静脉注射乌司他丁20,000U/Kg,A组和B组静脉注射等量生理盐水。各组在转流结束后0、2、6、12、24h时取血、尿标本,测定以下指标:血尿素氮(BUN)、血肌酐(Cr)、血浆内皮素-1(Endothelin-1,ET-1)、尿N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-β-D-glucosaminidase,NAG)和γ-谷氨酰转肽酶(γ-glutamyltranspeptidase,γ-GTP),术后24h取左肾制备病理切片用于常规病理观察。
结果与A组比较:B组尿NAG、γ-GTP活性和血浆ET-1含量在各时相点均显著增高(P＜0.01),B组血清BUN、Cr浓度在12、24 h显著增高(P＜0.05,P＜0.01);C组尿NAG活性和血浆ET-1含量在各时相点均显著增高(P＜0.01),C组尿γ-GTP活性在0、12、24h明显高于A组(P＜0.01),而血清BUN、Cr浓度在各时相点均与A组无显著差异(P＞0.05)。与B组比较:C组尿NAG活性和血浆ET-1含量在各时相点均显著降低(P＜0.01),尿γ-GTP活性在6、12、24 h时显著降低(P＜0.05,P＜0.01),而血清BUN、Cr浓度仅在24 h显著降低(P＜0.01)。
病理组织学检查:A组未发现明显的肾脏组织形态学改变;B组可见肾脏点片状的近曲小管上皮细胞空泡变性和坏死,肾小管管腔扩张、其内可见管型和坏死脱落细胞,管周血管可见明显扩张、淤血,可见较多炎细胞浸润;C组可见肾脏有少量的近曲小管上皮细胞肿胀、颗粒变性,管型罕见,管周血管稍有淤血,少量炎细胞浸润。Paller评分:与A组比较,B组、C组得分显著高于A组(P＜0.01);与B组比较,C组得分显著低于B组(P＜0.01)。
结论
1、高原环境下进行体外循环,有一定的肾脏损伤,其中以肾功能损害较重,其机理可能与肾脏IRI有关。
2、内皮素-1可能是高原CPB后引发肾脏缺血再灌注损伤的重要因素。
3、尿酶(尿NAG、γ-GTP)可以先于常规指标(血BUN、Cr)发现高原CPB早期肾脏损害,且肾功能损伤程度与尿NAG水平呈正相关,肾脏损害因素作用时间与尿γ-GTP持续升高时间呈正相关。
4、乌司他丁可以对高原CPB后。肾脏及肾功能起到一定的保护作用,其机制可能是通过降低ET-1水平以减轻肾脏IRI。
Objective To investigate the effects on kidney during cardiopulmonary bypass at high altitude,to explore new predictors for early kidney damage during cardiopulmonary bypass at high altitude,and to research the effects and mechanism of ulinastatin on renal function during cardiopulmonary bypass at high altitude in dogs.
Methods Twenty-four male healthy dogs at high altitude were randomized into three groups:control group with sham operation(group A,n=8);renal ischemic reperfusion injury (IRI) group with cardiopulmonary bypass(CPB)(group B,n=8) and ulinastatin treatment group with CPB(group C,n=8).Blood samples and urine samples were harvested at 0,2,6, 12,24 h after CPB,and the concentrations of blood urea nitrogen(BUN),serum creatinine (Cr) and endothelin-1(ET-1),urine N-acetyl-β-D-glucosaminidase(NAG) and urine glutamyl transpeptidase(γ-GTP) were measured.Left kidney was obtained for pathological examination 24h after CPB.
Results Compared with group A,BUN and Cr levels were significantly higher at 12, 24 h after CPB in group B(P＜0.05,P＜0.01),NAG and ET-1 levels were significantly higher at 0,2,6,12,24 h after CPB in group C and in group B(P＜0.05,P＜0.01).γ-GTP levels were significantly higher at 0,2,6,12,24 h after CPB in group B(P＜0.01).γ-GTP levels were significantly higher at 0,12,24 h after CPB in group C(P＜0.05,P＜0.01). Compared with group B,BUN and Cr levels were significantly lower at 24 h after CPB in group C(P＜0.01),NAG and ET-1 levels were significantly lower at 0,2,6,12,24 h after CPB in group C(P＜0.01),γ-GTP levels were significantly lower at 6,12,24 h after CPB in group C(P＜0.05,P＜0.01).
Histopathological examination:There was no evident morphological change in group A.Proximal convoluted tubule endepidermis vacuolar developed degeneration and cellular necrosis,cast and necrosis cells occurred in the broadened lumens of nephric tubule,and blood vessel around the nephric tubule obviously demonstrated dilatation and congestion in group B.Proximal convoluted tubule endepidermis revealed cellular swelling,granular degeneration in group C.Cast and blood vessel congestion was rarely found in this group. The Paller scores of group C and group B are higher than group A(P＜0.01).The group B's score is higher than group C's(P＜0.01).
Conclusion
1、Earlier period kidney damage is definite during CPB at high altitude.The mechanism maybe relate with renal ischemic reperfusion injury.
2、ET-1 is possible an important initiating factor of renal ischemic reperfusion injury (IRI) after CPB at high altitude.
3、Urease(NAG,γ-GTP) increased at the earlier phase of kidney damage in comparison with other parameters during CPB at high altitude.The degree of injury of renal function is positive correlation with the NAG level in urine.The factor of causing kidney damage and increasedγ-GTP have a positive correlation in urine.
4、Ulinastatin can reduce the risk of renal dysfunction during CPB at high altitude. And decreased ET-1 level may be the mechanism of Ulinastatin to alleviate renal IRI.
引文
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17.Rushitzka F,Shwa S,Gygi D,et al.Endothelial dysfunction in acute renal failure role of circulating and tissue endothelin-1.J Am Soc Nephrol,1999;10:953-959.
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7.马骏,刘立群,孙秀梅等.温度对体外循环期间氧代谢的影响.临床麻醉学杂志,2001:17:438-44l
8.吴新民,王东信,许幸等.冠心病冠脉搭桥术围术期的氧转运和氧消耗.中华麻醉学杂志,1998;18:331-332
9.Alwaidh MH,Cooke RW,Judd BA.Renal blood flow velocity in acute renal failure following cardiopulmonary bypass surgery.Act a Paediatr,1998;87:644-649.
10.马骏等.常温和低温体外循环期间犬肾脏灌注及氧代谢的变化.中华麻醉学杂志,2005;25:55-56
11.李佳春,李功宋主编.体外循环灌注学.第1版,人民军医出版社,1993.
12.Baartscheer A,Schumacher CA,et al.Increased Na+/H+-exchange activity is the cause of increased[Na~+]i and underlies disturbed calcium handling in the rabbit pressure and volume ovesload heart failure model,Cardiovascular Research,2003;57:1015-1024.
13.Wink da,Mitchell JB.Chemical biology of nitric oxide:insights into regulatory, cytotoxic,and cytoprotective mechanisms of nitric oxide.Free Radical Biology and Medicine,1998;25:434-456.
14.Camussi G,Ronco C,Montrucchio G,et al.Role of solule mediators in sepsis and renal failure.Kidney Int,1998;53:35-38
15.Wilhelm SM,Stowe NT,et al.The use of the endothelin receptor antagonist,tezosentan,before or after renal ischemia protects renal function.Transplantation,2001;71:211-216.
16.Toshiaki Ishizuka,Mitsuyo Takamizawa-Matsumoto,et al.Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor α-stimulated vascular endothelial cells.European Journal of Phamacology,1999;369:237-245.
17.Rushitzka F,Shwa S,Gygi D,et al.Endothelial dysfunction in acute renal failure role of circulating and tissue endothelin-1.J Am Soc Nephrol,1999;10:953-959.
18.Stammberger U,Giovanni L,et al.Combined treatment with Endothelin-1 and PAF-Antagonists reduces Posttransplant lung ischemia/reperfusion injury.The Journal of Heart and Lung Transplantation,1999;18(9):862-868.
19.Andersson LG,Bratteby LE,Ekroth R,et al.Renal function during cardiopulmonary bypass;Influence of pump flow and systemic blood pressure.Eur J Cardiothorac Surg,1994;8:597-602.
20.冯新为主编.肾功能不全,病理生理学,第2版.人民卫生出版社,1984:182
21.Joe R.Utley.Pathophysiology of cardiopulmonary bypass:A current review.The Australasian Journal of Cardiac and Thoracic Surgery,1992;1(2):46-52.
22.黄小蝶,叶小青,毕叔同 等.体外循环急性肾功能衰竭的预防.实用医学杂志,1996;12(7):462-464
23.Riden SP,Dillon MJ,Kind BF,et al.The beneficial effect of mannitol on postoperative renal function in children undergoing cardiopulmonary bypass surgery.Clin nephron,1984;21:148-151.
24.Graziani G,Karlberg H,John WH,et al.Dopamine and furosemide in olguric acute renal failure.Nephron 1984;37:39-44.
25.Marco Ranucci,Giorgio Soro,Nicoletta Barzaghi,Alessandro Locatelli,Gianbeppe Giordano,Angelo Vavassori,Aldo Manzato,Chiara Melchiorri,Tiziana Bove,Glauco Juliano,et al.Fenoldopam Prophylaxis of Postoperative Acute Renal Failure in High-Risk Cardiac Surgery Patients.The Annals of Thoracic Surgery,2004;78(4):1332-1337.
26.Murphy PG,Myers DS,Davies MJ,et al.The antioxidant potential of propofol (206-diso-propylpheonl)[J].Br J Anaesth,1992;68:613-619.
27.李治贵,黄海波,王泽华等.丙泊酚对家兔主动脉阻断所致脊髓损害的保护作用[J].中华麻醉学杂志,1999;19:352-354.
28.王泽华,殷振奎,黄海波等.丙泊酚对急性肾缺血再灌注过程脂质过氧化损伤的保护作用[J].临床麻醉学杂志,2001;17(11):619-621.
29.Zhou Tong,Li Xiao,Wu Pei,et al.Effect of anti-P-selectin monoclonal antibody on renal ischemia/reperfusion injury in rats[J].CM J 2000;113:790-793.
30.周同,李晓,张明钧 等.P-选择素及其单克隆抗体对肝肾缺血再灌注时细胞凋亡的影响[J].中国危重病急救医学,1999;11(4):213-215.
31.Bjornsson T D,Schneider D E,Hecht A R.Effects of N-deacetylation and N-desulfation of heparin on its anticoagulant activity and in vivo disposition[J].J Pharmacol Exp Ther,1998;245:804-808.
32.王锋,宋巍,周同等.N-去硫酸肝素对肾缺血再灌注损伤防治作用的研究[J].中国危重病急救医学,2002;14(4):198-200.
33.严博泉,姜佑三,权昌益等.腺苷和ATP对大鼠肾脏缺血再灌注损伤保护作用的比较[J].中国现代医学杂志,2000;10(10):12-14.
34.范明齐,王安静,王平贤等.应用钙离子拮抗剂保护离体肾的实验研究.中华器官移植杂志,2001;22(1):52-53.
35.Paller MS,Hoidal JR,Ferris TF.Oxygen free radicals in ischemic acute renal failure in the rat.J Clin Ivest,1984;74:1156-1162.
36.Shimazaki E,TanaKa H,Ohta S,et al.Effects of the antiprotease ulinastatin on mortality and oxidant injury in scalded rats.Arch Surg,1995;130:994-997.
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