尿毒症脑病发病机制的研究进展
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摘要
肾衰竭的并发症是导致病死率升高的常见原因,尿毒症脑病是终末期肾脏病的重要神经系统并发症,肾衰竭本身的心脑血管并发症的高风险增加了尿毒症脑病的发生。尿毒症脑病的发病机制目前尚不完全清楚。研究认为代谢紊乱、氧化应激、兴奋性和抑制性神经递质的失衡和血脑屏障的改变是主要致病因素,尽管在包括透析和移植在内的晚期慢性肾脏病的医学管理方面有所改进,但患者仍表现出许多神经系统症状,因此更多病理生理机制需要进一步研究。
The complications of renal failure are common causes of increased mortality. Uremic encephalopathy is an important neurological complication of end-stage renal disease. The high risk of cardiovascular and cerebrovascular complications caused by renal failure increases the occurrence of uremic encephalopathy. The pathogenesis of uremic encephalopathy is not completely clear at present. Metabolic disorders,oxidative stress,imbalance of excitatory and inhibitory neurotransmitters and changes of blood-brain barrier are the main pathogenic factors. Although medical management of advanced chronic kidney diseases including dialysis and transplantation has been improved,the patients still manifest many neurological symptoms,so more pathophysiological mechanisms need to be further studied.
The complications of renal failure are common causes of increased mortality. Uremic encephalopathy is an important neurological complication of end-stage renal disease. The high risk of cardiovascular and cerebrovascular complications caused by renal failure increases the occurrence of uremic encephalopathy. The pathogenesis of uremic encephalopathy is not completely clear at present. Metabolic disorders,oxidative stress,imbalance of excitatory and inhibitory neurotransmitters and changes of blood-brain barrier are the main pathogenic factors. Although medical management of advanced chronic kidney diseases including dialysis and transplantation has been improved,the patients still manifest many neurological symptoms,so more pathophysiological mechanisms need to be further studied.
引文
[1]Scaini G,Ferreira GK,Streck EL.Mechanisms underlying uremic encephalopathy[J].Rev Bras Ter Intensiva,2010,22(2):206-211.
[2]Murray AM,Bell EJ,Tupper DE,et al.The brain in kidney disease(BRINK)cohort study:Design and baseline cognitive function[J].Am J Kidney Dis,2016,67(4):593-600.
[3]Hocker SE.Renal disease and neurology[J].Continuum(Minneap Minn),2017,23(3,Neurology of Systemic Disease):722-743.
[4]Jabbari B,Vaziri ND.The nature,consequences,and management of neurological disorders in chronic kidney disease[J].Hemodial Int,2018,22(2):150-160.
[5]Park JW,Kim SU,Choi JY,et al.Reversible parkinsonism with lentiform fork sign as an initial and dominant manifestation of uremic encephalopathy[J].J Neurol Sci,2015,357(1/2):343-344.
[6]Lee J,Im K,Kwon K.Bilateral thalamic and basal ganglia lesions in an old woman:Unusual involvement of uremic encephalopathy[J].Acta Neurologica Belgica,2018,119(1):133-135.
[7]黄曌殊,范光明,沈金丹,等.尿毒症脑病的MRI及MRS研究[J].实用放射学杂志,2018,34(11):1670-1674.
[8]Baluarte JH.Neurological complications of renal disease[J].Semin Pediatr Neurol,2017,24(1):25-32.
[9]Bugnicourt JM,Godefroy O,Chillon JM,et al.Cognitive disorders and dementia in CKD:The neglected kidney-brain axis[J].J Am Soc Nephrol,2013,24(3):353-363.
[10]Brouns R,De Deyn PP.Neurological complications in renal failure:A review[J].Clin Neurol Neurosurg,2004,107(1):1-16.
[11]Hamed SA.Neurologic conditions and disorders of uremic syndrome of chronic kidney disease:Presentations,causes and treatment strategies[J].Expert Rev Clin Pharmacol,2018[2018-12-08].https://doi.10.1080/17512433.2019.1555468.[published online ahead of print Dec 2,2018]
[12]Barbosa PR,Cardoso MR,Daufenbach JF,et al.Inhibition of mitochondrial respiratory chain in the brain of rats after renal ischemia is prevented by N-acetylcysteine and deferoxamine[J].Metab Brain Dis,2010,25(2):219-225.
[13]Zhan M,Brooks C,Liu F,et al.Mitochondrial dynamics:Regulatory mechanisms and emerging role in renal pathophysiology[J].Kidney Int,2013,83(4):568-581.
[14]De Deyn PP,Vanholder R,Eloot S,et al.Guanidino compounds as uremic(neuro)toxins[J].Semin Dial,2009,22(4):340-345.
[15]Heidland A,Sebekova K,Klassen A,et al.Mechanisms of acute uremic encephalopathy:Early activation of Fos and Fra-2 gene products in different nuclei/areas of the rat brain[J].J Ren Nutr,2010,20(5 Suppl):S44-50.
[16]Adesso S,Paterniti I,Cuzzocrea S,et al.AST-120 reduces neuroinflammation induced by indoxyl sulfate in glial cells[J].J Clin Med,2018,7(10).pii:E365.
[17]Lin YT,Wu PH,Tsai YC,et al.Indoxyl sulfate induces apoptosis through oxidative stress and mitogen-activated protein kinase signaling pathway inhibition in human astrocytes[J].J Clin Med,2019,8(2).pii:E191.
[18]Adesso S,Magnus T,Cuzzocrea S,et al.Indoxyl sulfate affects glial function increasing oxidative stress and neuroinflammation in chronic kidney disease:Interaction between astrocytes and microglia[J].Front Pharmacol,2017,8:370.
[19]Fishman RA,Raskin NH.Experimental uremic encephalopathy.Permeability and electrolyte metabolism of brain and other tissues[J].Arch Neurol,1967,17(1):10-21.
[20]Fraser CL,Arieff AI.Metabolic encephalopathy as a complication of renal failure:Mechanisms and mediators[J].New Horiz,1994,2(4):518-526.
[21]文世杰,刘克辛.转运体在药物肾脏排泄中的重要作用[J].药物评价研究,2017,40(9):1216-1222.
[22]Seifter JL,Samuels MA.Uremic encephalopathy and other brain disorders associated with renal failure[J].Semin Neurol,2011,31(2):139-143.
[23]曾立.尿毒症脑病的诊治进展[D].重庆:重庆医科大学,2016.
[24]Nongnuch A,Panorchan K,Davenport A.Brain-kidney crosstalk[J].Crit Care,2014,18(3):225.
[25]Larson LM,Phiri KS,Pasricha SR.Iron and cognitive development:What is the evidence?[J].Ann Nutr Metab,2017,71 Suppl 3:25-38.
[26]Zheng G,Wen J,Lu H,et al.Elevated global cerebral blood flow,oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease:An MRI study[J].Eur Radiol,2016,26(6):1732-1741.
[27]Sonneville R,Verdonk F,Rauturier C,et al.Understanding brain dysfunction in sepsis[J].Ann Intensive Care,2013,3(1):15.
[28]Kawakami M,Hattori M,Ohashi W,et al.Role of G proteincoupled receptor kinase 2 in oxidative and nitrosative stressrelated neurohistopathological changes in a mouse model of sepsis-associated encephalopathy[J].J Neurochem,2018,145(6):474-488.
[29]Sofroniew MV.Astrocyte barriers to neurotoxic inflammation[J].Nat Rev Neurosci,2015,16(5):249-263.
[30]Cunningham C,Hennessy E.Co-morbidity and systemic inflammation as drivers of cognitive decline:New experimental models adopting a broader paradigm in dementia research[J].Alzheimers Res Ther,2015,7(1):33.
[31]Fujisaki K,Tsuruya K,Yamato M,et al.Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice:Neuroprotective effect of tempol[J].Nephrol Dial Transplant,2014,29(3):529-538.
[32]Galluzzi L,Blomgren K,Kroemer G.Mitochondrial membrane permeabilization in neuronal injury[J].Nat Rev Neurosci,2009,10(7):481-494.
[33]KovalˇcíkováA,GyurászováM,Vavrincová-Yaghi D,et al.Oxidative stress in the brain caused by acute kidney injury[J].Metab Brain Dis,2018,33(3):961-967.
[34]Jing W,Jabbari B,Vaziri ND.Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade,down-regulation of Nrf2 pathway and disruption of blood brain barrier[J].Am JTransl Res,2018,10(7):2137.
[35]Schieber M,Chandel NS.ROS function in redox signaling and oxidative stress[J].Curr Biol,2014,24(10):R453-R462.
[36]Eiserich JP,Butler J,van der Vliet A,et al.Nitric oxide rapidly scavenges tyrosine and tryptophan radicals[J].Biochem J,1995,310(Pt 3):745-749.
[37]Halliwell B.What nitrates tyrosine?Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo?[J].FEBS Lett,1997,411(2/3):157-160.
[38]Stenvinkel P.Inflammatory and atherosclerotic interactions in the depleted uremic patient[J].Blood Purif,2001,19(1):53-61.
[39]林叶.尿毒症脑病和细胞炎症因子[J].国际泌尿系统杂志,2012,32(2):265-269.
[40]Kalpana S,Dhananjay S,Anju B,et al.Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain:Molecular mechanisms of action of cobalt chloride[J].Toxicol Appl Pharmacol,2008,231(3):354-363.
[41]Liu M,Liang Y,Chigurupati S,et al.Acute kidney injury leads to inflammation and functional changes in the brain[J].J Am Soc Nephrol,2008,19(7):1360-1370.
[42]Justicia C,Panes J,Sole S,et al.Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats[J].J Cereb Blood Flow Metab,2003,23(12):1430-1440.
[43]殷英,徐米清,张亚杰.细胞间黏附分子-1在尿毒症大鼠脑组织中的表达及意义[J].广东医学,2012,33(24):3701-3703.
[44]Vecil GG,Larsen PH,Corley SM,et al.Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo[J].J Neurosci Res,2000,61(2):212-224.
[45]朱鸣,王小同,闵晶晶,等.丹参酮ⅡA对慢性肾功能衰竭大鼠认知障碍的神经保护作用及其机制[J].温州医科大学学报,2018,48(7):517-523,528.
[46]Deng G,Vaziri ND,Jabbari B,et al.Increased tyrosine nitration of the brain in chronic renal insufficiency:Reversal by antioxidant therapy and angiotensin-converting enzyme inhibition[J].J Am Soc Nephrol,2001,12(9):1892-1899.
[47]董晖,刘丽秋,时红娟,等.尿毒症脑病大鼠脑组织多巴胺、5-羟色胺含量变化及发病机制的探讨[J].中国实验诊断学,2010,14(1):42-45.
[48]Ksiazek A.Brain serotonin and catecholamine turnover in uremic rats[J].Nephron,1982,31(3):270-272.
[49]Ali F,Tayeb O,Attallah A.Plasma and brain catecholamines in experimental uremia:acute and chronic studies[J].Life Sci,1985,37(19):1757-1764.
[50]Ni Z,Smogorzewski M,Massry SG.Derangements in acetylcholine metabolism in brain synaptosomes in chronic renal failure[J].Kidney Int,1993,44(3):630-637.
[51]De Deyn PP,Macdonald RL.Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture[J].Ann Neurol,1990,28(5):627-633.
[52]商进春,刘丽秋.尿毒症脑病大鼠脑组织谷氨酸和γ-氨基丁酸浓度变化[J].西部医学,2007,19(3):353-355.
[2]Murray AM,Bell EJ,Tupper DE,et al.The brain in kidney disease(BRINK)cohort study:Design and baseline cognitive function[J].Am J Kidney Dis,2016,67(4):593-600.
[3]Hocker SE.Renal disease and neurology[J].Continuum(Minneap Minn),2017,23(3,Neurology of Systemic Disease):722-743.
[4]Jabbari B,Vaziri ND.The nature,consequences,and management of neurological disorders in chronic kidney disease[J].Hemodial Int,2018,22(2):150-160.
[5]Park JW,Kim SU,Choi JY,et al.Reversible parkinsonism with lentiform fork sign as an initial and dominant manifestation of uremic encephalopathy[J].J Neurol Sci,2015,357(1/2):343-344.
[6]Lee J,Im K,Kwon K.Bilateral thalamic and basal ganglia lesions in an old woman:Unusual involvement of uremic encephalopathy[J].Acta Neurologica Belgica,2018,119(1):133-135.
[7]黄曌殊,范光明,沈金丹,等.尿毒症脑病的MRI及MRS研究[J].实用放射学杂志,2018,34(11):1670-1674.
[8]Baluarte JH.Neurological complications of renal disease[J].Semin Pediatr Neurol,2017,24(1):25-32.
[9]Bugnicourt JM,Godefroy O,Chillon JM,et al.Cognitive disorders and dementia in CKD:The neglected kidney-brain axis[J].J Am Soc Nephrol,2013,24(3):353-363.
[10]Brouns R,De Deyn PP.Neurological complications in renal failure:A review[J].Clin Neurol Neurosurg,2004,107(1):1-16.
[11]Hamed SA.Neurologic conditions and disorders of uremic syndrome of chronic kidney disease:Presentations,causes and treatment strategies[J].Expert Rev Clin Pharmacol,2018[2018-12-08].https://doi.10.1080/17512433.2019.1555468.[published online ahead of print Dec 2,2018]
[12]Barbosa PR,Cardoso MR,Daufenbach JF,et al.Inhibition of mitochondrial respiratory chain in the brain of rats after renal ischemia is prevented by N-acetylcysteine and deferoxamine[J].Metab Brain Dis,2010,25(2):219-225.
[13]Zhan M,Brooks C,Liu F,et al.Mitochondrial dynamics:Regulatory mechanisms and emerging role in renal pathophysiology[J].Kidney Int,2013,83(4):568-581.
[14]De Deyn PP,Vanholder R,Eloot S,et al.Guanidino compounds as uremic(neuro)toxins[J].Semin Dial,2009,22(4):340-345.
[15]Heidland A,Sebekova K,Klassen A,et al.Mechanisms of acute uremic encephalopathy:Early activation of Fos and Fra-2 gene products in different nuclei/areas of the rat brain[J].J Ren Nutr,2010,20(5 Suppl):S44-50.
[16]Adesso S,Paterniti I,Cuzzocrea S,et al.AST-120 reduces neuroinflammation induced by indoxyl sulfate in glial cells[J].J Clin Med,2018,7(10).pii:E365.
[17]Lin YT,Wu PH,Tsai YC,et al.Indoxyl sulfate induces apoptosis through oxidative stress and mitogen-activated protein kinase signaling pathway inhibition in human astrocytes[J].J Clin Med,2019,8(2).pii:E191.
[18]Adesso S,Magnus T,Cuzzocrea S,et al.Indoxyl sulfate affects glial function increasing oxidative stress and neuroinflammation in chronic kidney disease:Interaction between astrocytes and microglia[J].Front Pharmacol,2017,8:370.
[19]Fishman RA,Raskin NH.Experimental uremic encephalopathy.Permeability and electrolyte metabolism of brain and other tissues[J].Arch Neurol,1967,17(1):10-21.
[20]Fraser CL,Arieff AI.Metabolic encephalopathy as a complication of renal failure:Mechanisms and mediators[J].New Horiz,1994,2(4):518-526.
[21]文世杰,刘克辛.转运体在药物肾脏排泄中的重要作用[J].药物评价研究,2017,40(9):1216-1222.
[22]Seifter JL,Samuels MA.Uremic encephalopathy and other brain disorders associated with renal failure[J].Semin Neurol,2011,31(2):139-143.
[23]曾立.尿毒症脑病的诊治进展[D].重庆:重庆医科大学,2016.
[24]Nongnuch A,Panorchan K,Davenport A.Brain-kidney crosstalk[J].Crit Care,2014,18(3):225.
[25]Larson LM,Phiri KS,Pasricha SR.Iron and cognitive development:What is the evidence?[J].Ann Nutr Metab,2017,71 Suppl 3:25-38.
[26]Zheng G,Wen J,Lu H,et al.Elevated global cerebral blood flow,oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease:An MRI study[J].Eur Radiol,2016,26(6):1732-1741.
[27]Sonneville R,Verdonk F,Rauturier C,et al.Understanding brain dysfunction in sepsis[J].Ann Intensive Care,2013,3(1):15.
[28]Kawakami M,Hattori M,Ohashi W,et al.Role of G proteincoupled receptor kinase 2 in oxidative and nitrosative stressrelated neurohistopathological changes in a mouse model of sepsis-associated encephalopathy[J].J Neurochem,2018,145(6):474-488.
[29]Sofroniew MV.Astrocyte barriers to neurotoxic inflammation[J].Nat Rev Neurosci,2015,16(5):249-263.
[30]Cunningham C,Hennessy E.Co-morbidity and systemic inflammation as drivers of cognitive decline:New experimental models adopting a broader paradigm in dementia research[J].Alzheimers Res Ther,2015,7(1):33.
[31]Fujisaki K,Tsuruya K,Yamato M,et al.Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice:Neuroprotective effect of tempol[J].Nephrol Dial Transplant,2014,29(3):529-538.
[32]Galluzzi L,Blomgren K,Kroemer G.Mitochondrial membrane permeabilization in neuronal injury[J].Nat Rev Neurosci,2009,10(7):481-494.
[33]KovalˇcíkováA,GyurászováM,Vavrincová-Yaghi D,et al.Oxidative stress in the brain caused by acute kidney injury[J].Metab Brain Dis,2018,33(3):961-967.
[34]Jing W,Jabbari B,Vaziri ND.Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade,down-regulation of Nrf2 pathway and disruption of blood brain barrier[J].Am JTransl Res,2018,10(7):2137.
[35]Schieber M,Chandel NS.ROS function in redox signaling and oxidative stress[J].Curr Biol,2014,24(10):R453-R462.
[36]Eiserich JP,Butler J,van der Vliet A,et al.Nitric oxide rapidly scavenges tyrosine and tryptophan radicals[J].Biochem J,1995,310(Pt 3):745-749.
[37]Halliwell B.What nitrates tyrosine?Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo?[J].FEBS Lett,1997,411(2/3):157-160.
[38]Stenvinkel P.Inflammatory and atherosclerotic interactions in the depleted uremic patient[J].Blood Purif,2001,19(1):53-61.
[39]林叶.尿毒症脑病和细胞炎症因子[J].国际泌尿系统杂志,2012,32(2):265-269.
[40]Kalpana S,Dhananjay S,Anju B,et al.Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain:Molecular mechanisms of action of cobalt chloride[J].Toxicol Appl Pharmacol,2008,231(3):354-363.
[41]Liu M,Liang Y,Chigurupati S,et al.Acute kidney injury leads to inflammation and functional changes in the brain[J].J Am Soc Nephrol,2008,19(7):1360-1370.
[42]Justicia C,Panes J,Sole S,et al.Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats[J].J Cereb Blood Flow Metab,2003,23(12):1430-1440.
[43]殷英,徐米清,张亚杰.细胞间黏附分子-1在尿毒症大鼠脑组织中的表达及意义[J].广东医学,2012,33(24):3701-3703.
[44]Vecil GG,Larsen PH,Corley SM,et al.Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo[J].J Neurosci Res,2000,61(2):212-224.
[45]朱鸣,王小同,闵晶晶,等.丹参酮ⅡA对慢性肾功能衰竭大鼠认知障碍的神经保护作用及其机制[J].温州医科大学学报,2018,48(7):517-523,528.
[46]Deng G,Vaziri ND,Jabbari B,et al.Increased tyrosine nitration of the brain in chronic renal insufficiency:Reversal by antioxidant therapy and angiotensin-converting enzyme inhibition[J].J Am Soc Nephrol,2001,12(9):1892-1899.
[47]董晖,刘丽秋,时红娟,等.尿毒症脑病大鼠脑组织多巴胺、5-羟色胺含量变化及发病机制的探讨[J].中国实验诊断学,2010,14(1):42-45.
[48]Ksiazek A.Brain serotonin and catecholamine turnover in uremic rats[J].Nephron,1982,31(3):270-272.
[49]Ali F,Tayeb O,Attallah A.Plasma and brain catecholamines in experimental uremia:acute and chronic studies[J].Life Sci,1985,37(19):1757-1764.
[50]Ni Z,Smogorzewski M,Massry SG.Derangements in acetylcholine metabolism in brain synaptosomes in chronic renal failure[J].Kidney Int,1993,44(3):630-637.
[51]De Deyn PP,Macdonald RL.Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture[J].Ann Neurol,1990,28(5):627-633.
[52]商进春,刘丽秋.尿毒症脑病大鼠脑组织谷氨酸和γ-氨基丁酸浓度变化[J].西部医学,2007,19(3):353-355.