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Mechanisms Underlying Uremic Encephalopathy

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Mechanisms Underlying Uremic Encephalopathy 206 ARTIGO DE REVISÃO Giselli Scaini1, Gabriela Mecanismos básicos da encefalopatia urêmica Kozuchovski Ferreira2, Emilio Luiz Streck3,4 Mechanisms underlying uremic encephalopathy 1. Farmacêutica, Pós-graduanda RESUMO metabólitos, desequilíbrio entre os neuro- (Mestrado) do Laboratório de transmissores excitatórios e inibitórios, e Fisiopatologia Experimental, Programa Em pacientes com insuficiência renal, distúrbio do metabolismo intermediário de Pós-graduação em Ciências da a encefalopatia é um problema comum foram identificados como fatores contri- Saúde, Universidade do Extremo Sul que pode ser provocado pela uremia, de- buintes. A despeito do progresso continu- Catarinense. Criciúma (SC), Brasil. ficiência de tiamina, diálise, rejeição de ado na terapêutica, a maior parte das com- 2. Farmacêutica, Pós-graduanda transplante, hipertensão, desequilíbrios plicações neurológicas da uremia, como (Doutorado) do Laboratório de hidroeletrolíticos e toxicidades medica- a encefalopatia urêmica, não respondem Fisiopatologia Experimental, Programa mentosas. Em geral a encefalopatia se plenamente à diálise e muitas delas são de Pós-graduação em Ciências da apresenta como um complexo de sintomas desencadeadas ou agravadas pela diálise ou Saúde, Universidade do Extremo Sul que progride de uma leve obnubilação transplante renal. Por outro lado, estudos Catarinense. Criciúma (SC), Brasil. sensitiva até delírio e coma. Esta revisão prévios demonstraram que a terapia an- 3. Farmacêutico, Doutor do Laboratório discute questões importantes com relação tioxidante pode ser utilizada como terapia de Fisiopatologia Experimental, aos mecanismos de base da fisiopatologia coadjuvante para o tratamento destas com- Programa de Pós-graduação em Ciências da encefalopatia urêmica. A fisiopatologia plicações neurológicas. da Saúde, Universidade do Extremo Sul da encefalopatia urêmica é até hoje incerta, Catarinense. Criciúma (SC), Brasil. mas postula-se o envolvimento de diversos Descritores: Insuficiência renal/com- 4. Farmacêutico, Doutor do Instituto fatores; trata-se de um processo complexo plicações; Encefalopatias/etiologia; Ence- Nacional de Ciência e Tecnologia e provavelmente multifatorial. Distúrbios falopatias/fisiopatologia; Uremia/compli- Translacional em Medicina – INCT- hormonais, estresse oxidativo, acúmulo de cações TM - Universidade do Extremo Sul Catarinense - Criciúma (SC), Brasil. INTRODUÇÃO Como conseqüência dos numerosos avanços no diagnóstico e terapêutica pre- Recebido do Laboratório de coce de diversas doenças, a terapia intensiva desenvolveu-se como uma sub-especia- Fisiopatologia Experimental, Programa lidade em todas as disciplinas clínicas envolvidas no cuidado de doenças com risco de Pós-graduação em Ciências da à vida. Na neurologia, isto leva a um aumento nas unidades de terapia intensiva Saúde, Universidade do Extremo Sul neurológicas que lidam com uma ampla gama de doenças vasculares, infecciosas, Catarinense. Criciúma (SC), Brasil. imunológicas, metabólicas e doenças malignas não apenas como doenças primárias dos sistemas nervosos central e periférico e muscular mas também como afecções Submetido em 9 de maio de 2010 secundárias provocadas por outras doenças de órgãos ou sistemas.(1) Aceito em 15 de junho de 2010 A insuficiência renal aguda (IRA) é uma entidade clínica comum e crítica que afeta cerca de 5% a 7% de todos os pacientes hospitalizados.(2,3) Ela se associa com Autor para correspondência: diversos problemas, terapias e procedimentos clínicos. Apesar dos avanços no tra- Emilio Luiz Streck tamento clínico, a IRA ainda acarreta uma importante morbidade e uma taxa de Av. Universitária, 1105 CEP: 88806 - 000 - Criciúma (SC), Brasil. mortalidade de 20% a 70%. Infelizmente, isto não melhorou nos últimos anos em (4) Fone: +55 (48) 3431-2539 razão de uma população mais enferma e mais velha. E-mail: [email protected] Em pacientes com insuficiência renal, a encefalopatia é um problema comum que pode ser provocado pela uremia, deficiência de tiamina, diálise, rejeição de Rev Bras Ter Intensiva. 2010; 22(2):206-211 Mecanismos básicos da encefalopatia urêmica 207 transplante, hipertensão, desequilíbrios hidroeletrolíticos ou membranas da célula e organelas.(12-15) Diversos estudos de- toxicidade farmacológica.(5) Em geral a encefalopatia se apre- monstraram que esses produtos tóxicos provocam uma carga senta como um complexo de sintomas que progride desde inflamatória na IRC por meio da geração de um desequilíbrio uma leve obnubilação sensorial até delírio e coma. Ela se as- entre a maior produção de ROS e uma capacidade antioxi- socia frequentemente com cefaléia, anormalidades visuais, dante limitada ou diminuída.(16) tremor, flapping, mioclônus multifocal, coréia e convulsões. O óxido nítrico (NO), originalmente identificado como Estes sinais flutuam entre um dia e outro, e às vezes em in- fator relaxante derivado do endotélio, é hoje reconhecido tervalos de horas.(6) A encefalopatia urêmica pode acompa- como uma molécula crítica sinalizadora intra e intercelu- nhar a insuficiência renal aguda ou crônica, mas em pacien- lar que desempenha um papel fundamental na regulação tes com insuficiência renal aguda, os sintomas são em geral de uma ampla variedade de funções biológicas.(17) Além de mais pronunciados e progridem mais rapidamente.(6,7) Além suas importantes funções fisiológicas, o NO está envolvido do complexo de sintomas gerais da encefalopatia, podem ser em diversos processos patológicos que levam a citotoxicida- observados sinais motores focais e a síndrome urêmica con- de.(18,19) Com relação a isto, a interação do NO com ROS, vulsiva espástica.(6,8) Mesmo em pacientes com doença renal especialmente ânios superóxido, leva à geração de subpro- crônica neurologicamente assintomática, o comprometimen- dutos altamente reativos e citotóxicos, como o peroxidoni- to do processamento cognitivo pode ser evidenciado por po- trito, que podem reagir com DNA, lipídios e proteínas.(20,21) tenciais relacionados a evento. Esta revisão discute questões Por exemplo, o peroxidonitrito reage com a tirosina livre e importantes referentes aos mecanismos que fundamentam a resíduos de tirosina em moléculas protéicas para produzir fisiopatologia da encefalopatia urêmica. nitrotirosina. Alternativamente, as ROS podem ativar a ti- rosina para formar tirosil, um radical que, por sua vez oxida FISIOPATOLOGIA DA ENCEFALOPATIA URÊ- No para produzir nitrotirosina.(21,22) Mais ainda, a expressão MICA de NO sintetase neuronal (nNOS) está elevada no cérebro de ratos urêmicos.(23) Foi formulada a hipótese de que o au- A fisiopatologia da encefalopatia urêmica é até hoje incer- mento concomitante nas ROS com elevação da expressão ta, mas postula-se o envolvimento de diversos fatores;(9) trata- de nNOS no tecido cerebral na uremia pode favorecer a se de um processo complexo, e provavelmente multifatorial. geração ou acúmulo de nitrotirosina no cérebro urêmico. Distúrbios hormonais, estresse oxidativo, acúmulo de meta- Análise pelo método de Western blot revelou um aumento bólitos, desequilíbrio entre neurotransmissores excitatórios e acentuado no conteúdo de nitrotirosina no córtex cerebral inibitórios, e distúrbio do metabolismo intermediário foram de ratos com IRC. É também importante observar que o identificados como fatores contribuintes.(10) exame imuno-histoquímico do cérebro no grupo com IRC indicou uma associação de nitrotirosina com processos neu- Distúrbios hormonais ronais e membrana plasmática de células corticais.(24) Foram recentemente sugeridos efeitos tóxicos do parator- Sener et al.(25) também relataram aumento da peroxidação mônio (PTH) no sistema nervoso central (SNC).(9) Experi- lipídica, conteúdo de colágeno e atividade de mieloperoxida- mentações em animais relataram modificações bioquímicas se e diminuição dos níveis de glutationa (GSH). Neste estu- no cérebro, especialmente em modelos de IRA. Em insufi- do, os resultados demonstraram que a IRC em ratos levou a ciência renal aguda e crônica, o nível de PTH está elevado lesão oxidativa do tecido renal, assim como de tecidos do pul- com elevação concomitante do conteúdo de cálcio do córtex mão, coração e cérebro. Os danos teciduais observados foram cerebral. Esta hipótese é apoiada por um estudo que demons- acompanhados por elevação dos níveis séricos de mediadores a b trou que as anormalidades do conteúdo cerebral de cálcio em proinflamatórios (LTB4, TNF- , IL-1 and IL-6), enquan- cães com insuficiência renal podem ser prevenidas pela para- to as análises histológicas verificaram a gravidade da resposta tireoidectomia, de forma que estas modificações parecem ser sistêmica induzida pela IRC em todos os tecidos estudados. dependentes de PTH.(11) Diversos estudos revelaram que o estresse oxidativo e a formação de complexos de aminoglicosídeo-ferro por meio Estresse oxidativo da reação de Fenton dependente de ferro foram propostos Espécies reativas de oxigênio (ROS) são consideradas um como os principais mecanismos no desenvolvimento de IRC dos importantes mediadores para a fisiopatologia da encefa- induzida por gentamicina (GM).(26,27) Em um artigo recente, lopatia urêmica. As evidências de estresse oxidativo na insu- Petronilho et al.(28) demonstraram que o dano oxidativo indu- ficiência renal crônica (IRC) se baseiam na elevação dos pro- zido por GM é um evento precoce e que ocorre antes da ob- dutos de peroxidação lipídica, como resultado de lesão das servação do aumento nos níveis de uréia e creatinina, sugerin- Rev Bras Ter Intensiva. 2010; 22(2):206-211 208 Scaini
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