终末期肾病患者血清Klotho蛋白水平与心血管疾病发生的关系
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摘要
目的:探讨终末期肾病(ESRD)患者血清Klotho蛋白与心血管疾病(CVD)的关系,分析Klotho蛋白对ESRD患者预后的影响。方法:收集50例接受规律血液透析> 3个月及50例腹膜透析> 3个月ESRD患者的临床资料,采用ELISA法检测患者每月血液透析或腹膜透析前血清Klotho蛋白水平,根据Klotho四分位数将患者分为Ⅰ组(Klotho Objective: To investigate the relation of serum Klotho protein with cardiovascular disease( CVD) in patients with end-stage nephropathy( ESRD) and to analyze the effect of Klotho protein on the prognosis of ESRD patients. Methods: Clinical data of 50 ESRD patients receiving regular hemodialysis for over 3 months and 50 ESRDpatients receiving peritoneal dialysis for over 3 monthswere collected,serum Klotho protein levels before hemodialysis or peritoneal dialysis were detected by ELISA.ESRD patients were categorized into four groups according to the quartiles of Klotho: groupⅠ( Klotho <358. 67 ng/L),groupⅡ( 358. 67 ng/L≤Klotho < 412. 46 ng/L),groupⅢ( 412. 46 ng/L≤Klotho <461. 51 ng/L),groupⅣ( Klotho≥461. 51 ng/L). The occurrence time of nonfatal CVD and all-cause mortality were recorded during the 24 months follow-up. Multivariate binary Logistic regression analysis was used to test the correlation between Klotho protein and nonfatal CVD events. Results: All 100 ESRD patients had serum Klotho protein concentration ranging from 310. 17 ng/L to 567. 68 ng/L.And 59 patients suffered from nonfatal CVD with 143 cases during the follow-up period. Low Klotho was the risk factors of coronary artery disease( OR = 0. 997,P = 0. 018) and peripheral artery occlusion( OR = 0. 997,P = 0. 047). The higher age was a risk factor for all newly developed non-fatal CVD in ESRD patients( OR = 1. 093,1. 076,1. 258,1. 099,P < 0. 05),and long-term dialysis was a risk factor for coronary artery disease( OR = 1. 003,P = 0. 011) and cerebrovascular accident( OR =1. 103,P = 0. 011). There were a total of 17 deaths of 100 ESRD patients,all-cause mortality and CVD mortality of the 4 groups were compared and the differences were statistically significant( P <0. 05). All-cause mortality in patients with ESRD of the group I,Ⅱ was significantly higher than that of groupⅣ( P < 0. 01). Conclusion: Low Klotho protein level is a risk factor for coronary artery disease and peripheral artery occlusion in ESRD patients. The lower the Klotho protein level is,the higher the mortality of ESRD patients will be.
引文
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[3]林文军,刘志红. Klotho-慢性肾脏病的心血管保护因子[J].肾脏病与透析肾移植杂志,2016,25(1):62-66.
[4] KIM H R,NAM B Y,KIM D W,et al. Circulatingα-Klotho levels in CKD and relationship to progression[J].Am J Kidney Dis,2013,61(6):899-909.
[5]KUROSU H,YAMAMOTO M,CLARK J D,et al. Suppression of aging in mice by the hormone Klotho[J]. Scienee,2005,309(5742):1829-1833.
[6]LI S A,WATANABE M,YAMADA H,et al. Immunohistochemical localization of Klotho protein in brain,kidney,and reproductive of mice[J]. Cell Struct Funct,2004,29(4):91-99.
[7]KOH N,FUJIMORI T,NISHIGUCHI S,et al. Severely reduced production of klotho in human chronic renal failure kidney[J]. Biochem Biophys Res Commun,2001,280(4):1015-1020.
[8]郑淑蓓,陈琰,潘敏,等.血清可溶性Klotho蛋白与维持性血液透析患者心血管疾病及预后的关系[J].中华肾脏病杂志,2017,33(4),264-270.
[9] ZUNUNI VABED S,NIKASA P,ARDALAN M. Klotho and renal fibrosis[J]. Nephrourol Mon,2013,5(5):946-948.
[10]GUTIERREZ O M. Fibroblast growth factor 23,klotho and disordered mineral metabolism in chronic kidney disease:unraveling the intricate tapestry of events and implications for therapy[J]. J Ren Nutr,2013,23(3):250-254.
[11]张亚璞,李建东,郭莉,等.终末肾脏病患者血管硬化的影响因素分析[J].贵州医科大学学报,2018,43(3),362-369.
[12]SPEER M Y,YANG H Y,BRABB T,et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries[J]. Circ Res,2009,104(6):733-741.
[13]FAUL C,AMARAL A P,OSKOUEI B,et al. FGF-23 induces left ventricular ypertrophy[J]. T J Clin Invest,2011,121(11):4393-4408.
[14]YOON H E,LIM S W,PIAO S G,et al. Statin upregulates the expression of Klotho,an anti-aging gene,in experimental cyclosporine nephropathy[J]. Nephron Exp Nephrol,2012,120(4):123-133.
[15]KARALLIEDDE J,MALTESE G,HILL B,et al. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes,systolic hypertension,and albuminuria[J]. Clin J Am Soc Nephrol,2013,8(11):1899-1905.
[16]ZHANG H,LI Y,FAN Y,et al. Klotho is a target gene of PPAR-gamma[J]. Kidney Int,2008,74(6):732-739.
[17]XIE J,YOON J,AN S W,et al. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate[J]. J Am Soc Nephrol,2015,26(5):1150-1160.
[18]HUM J M,O BRYAN L M,TATIPARTHI A K,et al.Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho[J]. J Am Soc Nephro I,2017,28(4):1162-1174.
[19]CHANG Q,HOEFS S,VAN DER KEMP A W,et al. The beta-glucuronidase k Jotho hydrolyzes and activates the TRPV5 cha Ilnel[J]. Science,2005,310(5747):490-493.
[20]XIE J,YOON J,AN S W,et al. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate[J]. J Am Soc Nephrol,2015,26(5):1150-1160.
[21]MALTESE G,PSEFTELI P M,RIZZO B,et al. The antiageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells[J]. J Cell Mol Med,2017,21(3):62l-627.
[22]KAPPELER L,DE MAGALLHAES FILHO C,LE BOUC Y,et al. Ageing genetics and the somatotropic axis[J].Med Sci,2006,22(3):259-265.
[23]WANG Y,SUN Z. Antiaging gene klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats[J]. J Hypertens,2014,32(8):1629-1636.
[2]KURO-OM,MATSUMURA Y AMAWA H,et al. Mutation of the mouse klotho gene leads to a syndrome resembling aging[J]. Nature,1997,390:45-51.
[3]林文军,刘志红. Klotho-慢性肾脏病的心血管保护因子[J].肾脏病与透析肾移植杂志,2016,25(1):62-66.
[4] KIM H R,NAM B Y,KIM D W,et al. Circulatingα-Klotho levels in CKD and relationship to progression[J].Am J Kidney Dis,2013,61(6):899-909.
[5]KUROSU H,YAMAMOTO M,CLARK J D,et al. Suppression of aging in mice by the hormone Klotho[J]. Scienee,2005,309(5742):1829-1833.
[6]LI S A,WATANABE M,YAMADA H,et al. Immunohistochemical localization of Klotho protein in brain,kidney,and reproductive of mice[J]. Cell Struct Funct,2004,29(4):91-99.
[7]KOH N,FUJIMORI T,NISHIGUCHI S,et al. Severely reduced production of klotho in human chronic renal failure kidney[J]. Biochem Biophys Res Commun,2001,280(4):1015-1020.
[8]郑淑蓓,陈琰,潘敏,等.血清可溶性Klotho蛋白与维持性血液透析患者心血管疾病及预后的关系[J].中华肾脏病杂志,2017,33(4),264-270.
[9] ZUNUNI VABED S,NIKASA P,ARDALAN M. Klotho and renal fibrosis[J]. Nephrourol Mon,2013,5(5):946-948.
[10]GUTIERREZ O M. Fibroblast growth factor 23,klotho and disordered mineral metabolism in chronic kidney disease:unraveling the intricate tapestry of events and implications for therapy[J]. J Ren Nutr,2013,23(3):250-254.
[11]张亚璞,李建东,郭莉,等.终末肾脏病患者血管硬化的影响因素分析[J].贵州医科大学学报,2018,43(3),362-369.
[12]SPEER M Y,YANG H Y,BRABB T,et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries[J]. Circ Res,2009,104(6):733-741.
[13]FAUL C,AMARAL A P,OSKOUEI B,et al. FGF-23 induces left ventricular ypertrophy[J]. T J Clin Invest,2011,121(11):4393-4408.
[14]YOON H E,LIM S W,PIAO S G,et al. Statin upregulates the expression of Klotho,an anti-aging gene,in experimental cyclosporine nephropathy[J]. Nephron Exp Nephrol,2012,120(4):123-133.
[15]KARALLIEDDE J,MALTESE G,HILL B,et al. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes,systolic hypertension,and albuminuria[J]. Clin J Am Soc Nephrol,2013,8(11):1899-1905.
[16]ZHANG H,LI Y,FAN Y,et al. Klotho is a target gene of PPAR-gamma[J]. Kidney Int,2008,74(6):732-739.
[17]XIE J,YOON J,AN S W,et al. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate[J]. J Am Soc Nephrol,2015,26(5):1150-1160.
[18]HUM J M,O BRYAN L M,TATIPARTHI A K,et al.Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho[J]. J Am Soc Nephro I,2017,28(4):1162-1174.
[19]CHANG Q,HOEFS S,VAN DER KEMP A W,et al. The beta-glucuronidase k Jotho hydrolyzes and activates the TRPV5 cha Ilnel[J]. Science,2005,310(5747):490-493.
[20]XIE J,YOON J,AN S W,et al. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate[J]. J Am Soc Nephrol,2015,26(5):1150-1160.
[21]MALTESE G,PSEFTELI P M,RIZZO B,et al. The antiageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells[J]. J Cell Mol Med,2017,21(3):62l-627.
[22]KAPPELER L,DE MAGALLHAES FILHO C,LE BOUC Y,et al. Ageing genetics and the somatotropic axis[J].Med Sci,2006,22(3):259-265.
[23]WANG Y,SUN Z. Antiaging gene klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats[J]. J Hypertens,2014,32(8):1629-1636.