Nefropatia induzida pelos meios de contraste radiológico após cateterismo cardíaco diagnóstico e terapêutico
Hospital Universitário Evangélico de Curitiba e Hospital de Clínicas da UFPR - Curitiba, PR
É estimado que o número de cateterismos cardíacos diagnósticos e terapêuticos nos países ocidentais seja, respectivamente, de 6.000 e 2.000 procedimentos por milhão de habitantes por ano, com uma demanda anual de 1.800 toneladas de iodo em todo o mundo para a fabricação dos meios de contraste (MC). Além disso, o número destes procedimentos tem aumentado progressivamente, e a população submetida a eles é cada vez mais idosa e com mais co-morbidades1,2.
Atualmente, os MC de baixa osmolaridade são utilizados em aproximadamente 75% dos pacientes e o uso dos MCs iso-osmolares, teoricamente menos tóxicos, está se tornando mais freqüente 1. Apesar da evolução no desenvolvimento de novos MC, eles permanecem como a terceira principal causa de insuficiência renal aguda (IRA) adquirida em ambiente hospitalar (10% dos casos), aumentando substancialmente o tempo de internação, os custos do atendimento e a morbimortalidade intra-hospitalar3-6.
Esta revisão tem como principal objetivo abordar aspectos importantes sobre a nefropatia induzida por meio de contraste radiológico (NIMC) após cateterismo cardíaco, incluindo definição, patogênese, incidência, fatores de risco, apresentação clínica, prevenção, tratamento e prognóstico.
Não há um consenso quanto à definição de NIMC, até o momento. A mais utilizada é o declínio agudo da função renal, manifestado por um aumento relativo da creatinina sérica de 25% ou um aumento absoluto de 0,5 mg/dl, 48 a 72 horas após a administração de contraste, na ausência de outras causas. São também aceitos como conceito, em alguns estudos, aumentos da creatinina sérica de 50% e de 1 mg/dl1,2,6-8.
Acredita-se que a patogênese da NIMC seja multifatorial. Há contribuição de fatores vasculares (hemodinâmicos) e tubulares. Entretanto, os mecanismos fisiopatológicos exatos não são completamente compreendidos.
Um dos mecanismos implicados na patogênese da IRA induzida pelos MC é seu efeito vasoconstritor, promovendo isquemia medular, o qual tornou-se objeto de intenso estudo atualmente8,9. Na verdade, após a injeção de MC, há uma resposta bifásica, constituída por um breve período de vasodilatação inicial, com duração de segundos, levando a um aumento no fluxo sangüíneo renal; seguido por períodos variáveis de vasoconstrição e conseqüente redução no fluxo e na taxa de filtração glomerular10,11.
O efeito vasoconstritor é mais pronunciado na presença de certas drogas como antiinflamatórios não-hormonais; todavia o uso de vasodilatadores como a dopamina e o peptídio natriurético atrial, de modo interessante, pode exacerbar a isquemia medular devido à redistribuição do fluxo sangüíneo da medula para o córtex10-13. A depleção do espaço extracelular em animais também torna estas alterações hemodinâmicas mais pronunciadas e persistentes, alcançando até 24 horas de duração14.
A vasoconstrição parece estar relacionada a: mudanças na pressão intracapsular renal, alterações agudas na perfusão renal, secundárias a vasodilatação inicial, efeitos diretos dos MCs na contratilidade dos músculos lisos promovidos por alterações na hidratação intracelular, efeitos secundários dos MCs na contratilidade dos músculos lisos em decorrência da liberação de substâncias vasoativas, alterações nas concentrações intracelulares de cálcio e agregação de células sangüíneas na circulação medular8,10-13.
A redução no fluxo sangüíneo renal pode ser o resultado da própria osmolaridade do MC15. Foi demonstrado que a pressão intra-renal e o fluxo sangüíneo são inversamente proporcionais, ou seja, quando a pressão intra-renal aumenta, o fluxo sangüíneo diminui e vice-versa16. Portanto, parece possível que as reduções do fluxo sangüíneo e da taxa de filtração glomerular possam ser explicadas pelo aumento da pressão hidrostática intratubular induzido pela hiper-osmolaridade dos MCs1,8. Este fenômeno é corroborado pela importante redução destes efeitos quando são usados MCs de baixa osmolaridade8.
O efeito direto da osmolaridade dos MCs sobre as células dos músculos lisos vasculares, promovendo vasoconstrição, é outro provável componente das alterações hemodinâmicas8,10-13. O cálcio pode ser um dos mediadores deste fenômeno, devido à demonstração de que alguns de seus antagonistas atenuam a vasoconstrição associada à administração de MC17.
A adenosina é um vasodilatador na circulação periférica; no córtex renal, entretanto, promove vasoconstrição18. Estudos realizados em cães demonstraram que o antagonista da adenosina teofilina e o agonista dipiridamol promovem atenuação e acentuação, respectivamente, do efeito vasoconstritor induzido pelos MC19. Entretanto, são necessárias pesquisas adicionais para esclarecer a contribuição da adenosina.
Peptídios como endotelina, angiotensina II, vasopressina, peptídio natriurético atrial e bradicinina possuem importantes funções na fisiologia renal. A endotelina, um potente vasoconstritor, diminui o fluxo sangüíneo e a taxa de filtração glomerular20. Numerosos estudos sugerem que a endotelina pode desempenhar um papel importante nas alterações hemodinâmicas induzidas pelos MC, os quais estimulariam a sua liberação pelas células endoteliais, promovendo um aumento das suas concentrações plasmática e urinária21-24. Contra a importância da endotelina como mediadora da redução do fluxo sangüíneo renal causada pelos MC está sua ação predominante sobre a arteríola eferente, como a angiotensina II, o que, classicamente, é considerado como promotor de aumento da fração de filtração. Isto não é compatível com os efeitos previamente descritos 15. Em suma, novos estudos deverão ser realizados para confirmar o papel da endotelina nas alterações vasculares mediadas pelos MC.
A possibilidade de a angiotensina II ser um dos mediadores da vasoconstrição é contraditória. Há estudos utilizando bloqueadores da angiotensina II ou dos seus receptores contra esta hipótese25 e a favor26. São necessários estudos controlados em humanos para avaliar definitivamente o papel deste peptídio na patogênese da IRA induzida pelos MC.
Alterações promovidas pelos MC sobre substâncias vasodilatadoras também contribuem para a ocorrência de IRA. É reconhecida a diminuição da síntese de óxido nítrico no córtex renal após a administração de MC27. Adicionalmente, a inibição farmacológica da produção de prostaglandinas vasodilatadoras e de óxido nítrico aumenta a nefrotoxicidade dos MCs13,28. A disfunção do endotélio causada por diabetes, hipertensão arterial e doença aterosclerótica, com conseqüente redução na liberação de vasodilatadores, pode ser a explicação para o risco aumentado de IRA induzida pelos MC que apresentam estes pacientes2.
Foi especulado que a vasoconstrição induzida pelos MC poderia ser resultado de um mecanismo de "feedback" túbulo-glomerular, o qual é desencadeado pela mácula densa, ao entrar em contato com soluções hipertônicas. A angiotensina II, a adenosina e o cálcio participariam como mediadores intermediários, promovendo a vasoconstrição da arteríola aferente, o que leva a redução da taxa de filtração glomerular e a aumento da resistência vascular renal. Há crescente evidência de que a adenosina seria o principal mediador do "feedback" túbulo-glomerular8.
Possíveis efeitos tóxicos diretos dos MCs sobre a função tubular têm sido menos investigados recentemente, mas incluem: injúria celular direta, obstrução tubular e alterações osmóticas8.
Foi demonstrado que os MC reduzem a função secretora dos túbulos proximais dos néfrons corticais, sugerindo um efeito tóxico independente das alterações hemodinâmicas 29. Há evidências da ocorrência de injúria celular direta, pela demonstração de alterações no metabolismo energético das células dos túbulos proximais, pela liberação de enzimas intracelulares e pelas mudanças histológicas produzidas pelos MC30. Entre estas, destaca-se a vacuolização das células dos túbulos proximais ("nefrose osmótica"), que provavelmente se deve ao acúmulo de lisossomos gigantes. Esta é mais pronunciada com o uso de MC iso-osmolares, é completamente reversível e não está necessariamente relacionada com a evolução para IRA1,8,31.
Estudos avaliando pacientes com mieloma múltiplo que desenvolveram IRA induzida pelos MC descreveram uma precipitação maciça de proteína de Bence-Jones, causando obstrução tubular. Inicialmente, pensou-se que este seria o mecanismo responsável pelo risco particularmente alto apresentado por estes pacientes32,33. Contudo, esta precipitação é improvável com os novos contrastes e em pacientes bem hidratados. Além disso, não foi comprovada a importância da precipitação da mucoproteína de Tamm-Horsefall e de cristais de ácido úrico como coadjuvantes da NIMC34,35.
Argumentos que defendem a possibilidade da obstrução tubular como causa primária da IRA induzida pelos MC incluem a observação de que os nefrogramas estão usualmente densos, imediatamente após o exame, e os rins estão bilateralmente aumentados, simulando uma obstrução ureteral aguda. Se prolongada, esta poderia levar a uma diminuição sustentada do fluxo sangüíneo renal8. Todavia, não existe evidência patológica para comprovar este mecanismo como principal agente etiológico da NIMC2,11.
Uma proteinúria importante, mas transitória, ocorre após angiografia em animais e humanos com o uso de agentes hipertônicos35,36. Entretanto, não está confirmado se este aumento transitório da permeabilidade da membrana basal glomerular possui um papel importante na promoção da NIMC. Também houve grande interesse na excreção urinária de várias enzimas tubulares como indicador de injúria destas células, mas a especificidade tanto da enzimúria, quanto da proteinúria é questionada2,8,37,38. Portanto, parece não haver vantagens na monitorização destas anormalidades urinárias em pacientes submetidos a exames contrastados2.
Infelizmente, é difícil dissociar por completo os efeitos verdadeiros da injúria tubular direta, dos efeitos secundários da isquemia renal, a qual pode causar danos celulares como resultado da peroxidação de lipídios, associada à produção aumentada e remoção reduzida de radicais livres de oxigênio9. A importância das espécies reativas do oxigênio como fatores na patogênese da NIMC, foi comprovada em estudos nos quais se utilizaram animais8,9,14,39. A administração de catalase 14 ou superóxido dismutase38 ou a quelação do ferro com deferoxamina40 podem melhorar as alterações hemodinâmicas e funcionais induzidas pelos MC.
Em resumo, as evidências favorecem a isquemia medular como o fator fisiopatológico central para a indução de IRA pelos MC. O papel dos prováveis mediadores deste processo não é completamente conhecido. A isquemia medular pode ser resultado do desequilíbrio entre fatores vasoconstritores e vasodilatadores agindo independentemente no córtex e na medula renal. Portanto, alterações no metabolismo das prostaglandinas, óxido nítrico, endotelina, adenosina ou outros poderiam contribuir. Na verdade, a ocorrência de NIMC não apresenta necessariamente os mesmos mecanismos fisiopatológicos em todos pacientes. Além disso, pacientes com disfunção das células endoteliais, por exemplo diabéticos, hipertensos ou com doença aterosclerótica, poderiam possuir uma sensibilidade aumentada para o desenvolvimento de IRA após exames contrastados2.
A incidência de NIMC varia substancialmente em vários estudos, dependendo dos critérios diagnósticos utilizados e dos fatores de risco individuais apresentados pelos pacientes1,9. Estima-se que ocorra em 1% a 6% 41,42 dos indivíduos em grupos não selecionados; porém, pode acometer até 40% a 90% 12,43-46 dos pacientes de alto risco, particularmente aqueles com insuficiência renal crônica (IRC) e diabetes melito (DM). A incidência de IRA induzida pelos MC também é variável de acordo com a definição utilizada: 2,0% (aumento de 1,0 mg/dl na creatinina sérica) 47; 3,3% (aumento de 0,5 mg/dl na creatinina sérica) 48; e 14,5% (aumento de 25% na creatinina sérica) 49.
Em um estudo com 1.077 indivíduos submetidos a cateterismo cardíaco com MC não-iônico, foi demonstrado que 73% dos pacientes apresentaram um discreto aumento da creatinina sérica, o qual foi transitório e sem significado clínico, na grande maioria dos casos41.
Foram reconhecidos, entretanto, certos grupos com maior probabilidade para o desenvolvimento de IRA após exames contrastados e vários fatores de risco foram sugeridos, incluindo: IRC preexistente, DM, volume do MC administrado, desidratação, doença aterosclerótica, insuficiência cardíaca congestiva1,9, síndrome nefrótica, cirrose hepática, uso concomitante de drogas nefrotóxicas, uso de MC de alta osmolaridade1, idade, sexo masculino, mieloma múltiplo9, hipoalbuminemia e hiponatremia45. Após intervenções coronárias também são citados como fatores de risco para NIMC: hipertensão arterial sistêmica; procedimentos emergenciais; uso de balão intra-aórtico47; infarto agudo do miocárdio nas 24 horas precedentes; falta de sucesso do procedimento; intervenções em coronária esquerda; presença de complicações coronárias, vasculares periféricas e sistêmicas relacionadas ao procedimento48. É de fundamental relevância identificar os pacientes com tais fatores, para a implementação de medidas profiláticas vigorosas.
A maioria dos estudos mais recentes confirmou a IRC como o mais importante fator de risco para NIMC, seguida pelo DM 2,41,43-51. Todas as pesquisas comparando pacientes com e sem IRC demonstraram uma probabilidade maior de NIMC no primeiro grupo41,44-46,48,52.
Estudos prospectivos envolvendo cerca de 9000 pacientes submetidos a cateterismo cardíaco demonstraram um aumento exponencial do risco de IRA, nos casos em que a creatinina sérica antes do exame era superior a 1,2 mg/dl, chegando a um índice de 30,6% em pacientes com creatinina basal maior que 3,0 mg/dl. Os indivíduos com creatinina sérica maior que 1,5 mg/dl apresentaram um risco 21 vezes maior de IRA induzida pelo MC, quando comparados àqueles com função renal normal41,48,50.
Segundo Bartholomew e cols.47, em uma pesquisa envolvendo 20.479 pacientes submetidos a intervenções coronárias, a incidência de IRA após o procedimento é inversamente proporcional ao "clearance" de creatinina: maior ou igual a 90 ml/min: 0,6%; de 60 a 89 ml/min: 1,4% e menor que 60 ml/min: 6,4 por cento. Manske e cols. estudaram um grupo de 59 pacientes diabéticos insulino-dependentes com "clearance" de creatinina médio de 14 ml/min submetidos a coronariografia. Destes, 50% apresentaram agudização da insuficiência renal. Dez pacientes necessitaram diálise durante o acompanhamento; 7 deles, nos primeiros 6 dias após o exame43.
A grande maioria dos estudos confirmou que o risco de IRA induzida por MC é similar nos indivíduos com DM sem IRC e naqueles sem DM41,46,50,52. Por outro lado, quase todas as pesquisas evidenciaram uma forte associação entre DM com disfunção renal preexistente e IRA induzida pelo MC12,44,46,49-51. McCullough e cols.49 analisaram 1.826 pacientes consecutivos submetidos a intervenção coronária, detectando NIMC em 14,5% dos casos e necessidade de diálise em 0,77% do total. A diálise foi necessária em 43% dos pacientes diabéticos com clearance de creatinina menor ou igual a 20 ml/min, mas não foi requerida por nenhum indivíduo com clearance maior que 47 ml/min.
No estudo de Rudnick e cols.50, com 1.196 pacientes submetidos a cateterismo cardíaco, foram obtidas as seguintes incidências de NIMC: DM e função renal normal: 0,6%; IRC isolada: 6%; DM e IRC: 19,7 por cento. Dados concordantes foram encontrados por Barret e cols.51 ao avaliarem 249 casos: creatinina sérica menor que 2,25 mg/dl sem DM: 6%; creatinina sérica menor que 2,25 mg/dl com DM: 11%; creatinina sérica maior que 2,25 mg/dl sem DM: 16,7%; e creatinina sérica maior que 2,25 mg/dl com DM: 33,3% de incidência de NIMC.
Em suma, pacientes diabéticos com função renal normal, apesar de merecerem cuidados especiais, apresentam risco baixo para o desenvolvimento de IRA induzida pelos MC. Porém, os diabéticos com IRC representam um grupo com risco extremamente alto e, portanto, medidas profiláticas sempre devem ser adotadas.
Várias pesquisas correlacionaram o volume do MC administrado com o risco de IRA43,44,45,49,50,52-54. Dos 1.826 pacientes submetidos a procedimentos coronários percutâneos avaliados por McCullough e cols. 49, houve necessidade de diálise em 14 casos, nos quais o volume de MC empregado foi sempre maior ou igual a 100 ml por paciente. Outras pesquisas, no entanto, demonstraram que mesmo volumes menores de MC podem induzir insuficiência renal e necessidade de diálise43,55. No estudo de Manske e cols. 43, 26% dos indivíduos diabéticos insulino-dependentes, com IRC avançada, avaliados, apresentaram agudização do quadro, ao receberem menos de 30 ml de MC no cateterismo cardíaco. Quando a dose excedeu 30 ml, esta taxa aumentou para 79 por cento. Para cada 5 ml de MC utilizado a mais, o risco de IRA aumentou 65 por cento.
Cigarroa e cols.54 dividiram pacientes com creatinina sérica maior que 1,8 mg/dl em dois grupos: o primeiro, sem limite para o volume de MC administrado e o segundo com limite, de acordo com o peso e com a creatinina sérica do indivíduo. A incidência de IRA, nos dois grupos, foi de 26% e 2%, respectivamente. Todos os pacientes que desenvolveram NIMC eram diabéticos.
Diante destes achados, recomenda-se a utilização da menor quantidade possível de MC, inclusive com a suspensão da ventriculografia de rotina nos pacientes de alto risco.
A Foram obtidos resultados semelhantes, em importantes pesquisas, comparando a nefrotoxicidade de MC de baixa e alta osmolaridade. Na meta-análise de Barrett e Carlisle 56, abrangendo 31 estudos controlados, randomizados com um total de 5.146 pacientes, 22 favoreceram os MC de baixa osmolaridade. Entretanto, os autores detectaram uma redução estatisticamente significante na incidência de NIMC com o uso de MC de baixa osmolaridade, somente no grupo de indivíduos com creatinina sérica maior que 1,35 mg/dl ou taxa de filtração glomerular menor que 70 ml/min antes do exame contrastado.
No estudo de Rudnick e cols.50 com 1.196 casos, não foi observada diferença quanto a nefrotoxicidade de MC de baixa e alta osmolaridade (respectivamente iohexol e diatrizoato), nos pacientes com função renal normal, o que reflete o baixo risco apresentado por estes indivíduos. Nos pacientes de maior risco, a incidência de NIMC foi significativamente menor, quando foi usado MC de baixa osmolaridade: 12,2% contra 27% nos indivíduos com IRC isolada e 33,3% contra 47,7% naqueles com a combinação de IRC e DM.
Um estudo multicêntrico envolvendo 1.194 pacientes submetidos a coronariografia eletiva comparou o diatrizoato (MC de alta osmolaridade) e o iohexol (MC de baixa osmolaridade). Entre os indivíduos com IRC e DM, a freqüência de NIMC foi de 27% e 12%, respectivamente57.
Contrariando as evidências anteriores, através da compilação de três estudos51,58,59, totalizando 657 pacientes com creatinina sérica maior que 1,35 mg/dl, foi confirmado um benefício menos importante dos MCs de baixa osmolaridade nos indivíduos com função renal anormal, questionando-se uma relação custo-benefício efetiva. Entretanto, menos de 20% dos casos avaliados apresentavam comprometimento renal severo (creatinina sérica maior que 2,25 mg/dl).
Outros estudos também falharam em confirmar uma superioridade inquestionável dos MCs de baixa osmolaridade. Através da análise prospectiva de 443 pacientes submetidos a cateterismo cardíaco recebendo de forma randomizada iopamidol (baixa osmolaridade) ou diatrizoato (alta osmolaridade), Schwab e cols. 60 observaram uma diferença não significativa de NIMC entre os dois grupos. Houve um aumento na creatinina sérica maior ou igual a 0,5 mg/dl em 10,2% dos indivíduos que receberam diatrizoato contra 8,2% no grupo do iopamidol. Em relação aos 160 pacientes considerados como de alto risco por apresentarem DM, insuficiência cardíaca congestiva e/ou IRC, foram obtidas incidências de 17% e 15%, respectivamente nos grupos dos MCs de alta e baixa osmolaridade. Somente 5% dos casos possuíam creatinina sérica maior que 3 mg/dl.
Quanto aos MCs iso-osmolares, em duas meta-análises com 18 e 14 estudos respectivamente, comparando-os aos de baixa osmolaridade, não houve diferença significativa na freqüência de IRA61,62. Uma pesquisa prospectiva, randomizada, com 856 indivíduos de alto risco submetidos a intervenção coronária utilizando iodixanol (MC iso-osmolar) ou ioxaglato (MC de baixa osmolaridade), apesar de ter detectado uma expressiva redução de 45% em importantes eventos adversos intra-hospitalares, também não demonstrou diferença em relação à incidência de NIMC63.
O estudo multicêntrico publicado por Aspelin e cols.64, envolvendo 129 pacientes com DM e creatinina sérica de 1,5 a 3,5 mg/dl submetidos a angiografia coronária ou aorto-femoral, contrariou os resultados supracitados. No grupo em que foi utilizado iodixanol, um MC iso-osmolar, a incidência de agudização da IRC foi de 3%, contra 26% naqueles em que foi empregado o iohexol (MC de baixa osmolaridade). Outra pesquisa com os mesmos MCs e um total de 124 indivíduos com creatinina sérica maior que 1,7 mg/dl, também demonstrou menor nefrotoxicidade do iodixanol em relação ao iohexol: incidência de NIMC de 3,7% e 10%, respectivamente65.
Novos estudos deverão ser realizados, principalmente com pacientes de alto risco, para comparação mais consistente entre MC de osmolaridade diferente. Nos indivíduos com IRC isolada ou combinada ao DM, a utilização de MC de baixa osmolaridade é recomendada. Considerando seu custo 3 a 5 vezes maior em relação aos MCs de alta osmolaridade9, o uso rotineiro de MC de baixa osmolaridade, nos pacientes com função renal normal, não é justificado. Em relação aos MCs iso-osmolares, as evidências são contraditórias.
A desidratação é reconhecida como fator de risco para NIMC66. Entretanto, nos estudos mais recentes, é difícil analisar a desidratação como variável independente, em virtude dos rigorosos protocolos de hidratação utilizados9.
A administração concomitante de MC e drogas nefrotóxicas, como antiinflamatórios não-hormonais e aminoglicosídeos e, possivelmente, a prescrição aguda de inibidores da enzima conversora do angiotensinogênio, devem ser evitadas. Nos pacientes com nefropatia diabética tratados com tais medicamentos para reduzir a proteinúria, se a pressão arterial estiver controlada, provavelmente não há necessidade de suspendê-los antes do exame contrastado1.
O mieloma múltiplo tradicionalmente foi considerado um fator de risco independente para IRA induzida por MC33. Uma revisão de estudos envolvendo um total de 476 indivíduos com esta doença falhou em confirmar esta afirmação67. Acredita-se que o risco elevado provavelmente esteja relacionado à insuficiência renal subjacente e/ou à depleção de volume, com subseqüente deposição intratubular aumentada de cadeias leves filtradas66,67.
A insuficiência cardíaca congestiva foi considerada um fator de risco independente para NIMC por alguns estudos45,53,68,69, porém não por todos41,70. Muitos pacientes destas pesquisas estavam tomando diuréticos previamente ao cateterismo ou estavam inadequadamente hidratados por receio de precipitar edema pulmonar agudo após o exame. Portanto, depleção do espaço extracelular e ativação de mecanismos vasoconstritores renais poderiam ter influenciado no desencadeamento de IRA induzida pelos MCs e, conseqüentemente, nos resultados dos estudos supracitados2.
Foi observado por alguns estudos que a idade avançada está associada a um risco aumentado de NIMC4,71 e que os pacientes idosos submetidos a cateterismo cardíaco apresentam maior probabilidade de desenvolverem complicações em geral72,73. Entretanto, Rich e cols.45, em um estudo prospectivo abrangendo 183 indivíduos com 70 anos de idade ou mais submetidos a cateterismo cardíaco, demonstraram que a incidência e o curso clínico da IRA induzida pelo MC nestes pacientes são similares aos dos mais jovens. Como as pessoas idosas são mais propensas a apresentar fatores de risco para NIMC, como IRC, DM e depleção, o risco pode realmente ser mais elevado nesta população; porém, a idade avançada, isoladamente, não deve ser considerada uma contra-indicação para exames contrastados45.
Outros fatores de risco como, por exemplo, doença aterosclerótica41 e sexo masculino44 não foram considerados fatores de risco independentes em estudos mais recentes.
A IRA induzida pelos MCs é assintomática, não oligúrica e reversível na maioria dos pacientes. A creatinina sérica usualmente aumenta em 24 a 72 horas após a exposição ao MC, alcança seu valor máximo em 3 a 5 dias (geralmente um aumento de 0,5 a 3 mg/dl) e então retorna ao seu valor inicial em 7 a 14 dias8,9,74,75.
A NIMC também pode ocorrer como uma forma mais severa de IRA, particularmente nos pacientes de alto risco. Nestas situações, ocorre oligúria 24 horas após a administração do MC, com um aumento da creatinina sérica geralmente excedendo 5 mg/dl8,9. A oligúria é transitória na grande maioria dos casos, usualmente persistindo por 2 a 5 dias. O pico de creatinina sérica acontece em 5 a 10 dias e tipicamente retorna ao valor inicial em 14 a 21 dias8.
A urinálise freqüentemente apresenta padrão de necrose tubular aguda, podendo demonstrar células epiteliais tubulares e cilindros granulosos grosseiros9, mas o sedimento urinário pode ser completamente inespecífico e a proteinúria é mínima2. Foi demonstrado que a excreção fracionada de sódio é baixa por alguns, mas não por todos os estudos66. Concentração urinária de sódio baixa e excreção fracionada de sódio extremamente baixa podem ocorrer nos pacientes com IRA severa induzida pelos MCs durante a fase oligúrica74. Entretanto, alterações em parâmetros urinários como as alterações na excreção fracionada de sódio, proteinúria transitória e enzimúria não se mostraram úteis para confirmar o diagnóstico de NIMC38,74,75.
É importante lembrar que os pacientes com doença aterosclerótica submetidos a angiografia também apresentam risco aumentado para o desenvolvimento de IRA secundária a fenômeno ateroembólico76. Em contraste à NIMC, a doença ateroembólica promove IRA tardia (7 dias a semanas após o exame contrastado). Freqüentemente, está associada a breves períodos de eosinofilia, hipocomplementemia e outras evidências de fenômeno ateroembólico, tais como livedo reticular, isquemia ou infarto gastrintestinal. O quadro clínico da IRA provocada por ateroembolismo é mais prolongado e, freqüentemente, está associado a mínima recuperação da função renal9.
Ao contrário da maioria das outras formas de IRA adquiridas em hospital, a NIMC pode ser prevenida. Várias medidas profiláticas têm sido propostas, a partir dos crescentes conhecimentos sobre a patogênese desta enfermidade.
Em relação ao volume e à osmolaridade dos MCs, já discutidos previamente, não serão adicionados novos comentários.
A acetilcisteína, além de antioxidante, apresenta propriedades vasodilatadoras por aumentar a expressão da enzima óxido nítrico sintetase 77,78 e poderia prevenir a NIMC, tanto por reduzir o dano oxidativo direto quanto por melhorar as condições hemodinâmicas nos rins.
Nos anos de 2002 a 2005, apesar de alguns estudos terem falhado em comprovar a eficácia da acetilcisteína79-84, foram publicadas quatro meta-análises85-88 favoráveis à utilização deste medicamento para a prevenção da IRA induzida pelos MC.
Dos ensaios que não obtiveram resultados satisfatórios, destaca-se o estudo multicêntrico brasileiro publicado recentemente por Gomes e cols.84, o qual incluiu 156 indivíduos submetidos a cateterismo cardíaco ou intervenção coronária, utilizando apenas MC de baixa osmolaridade. Não houve diferença quanto à incidência de NIMC entre o grupo que recebeu o medicamento e os pacientes que receberam placebo.
Na meta-análise publicada por Alonso e cols.85, oito estudos controlados, randomizados, foram avaliados, abrangendo 885 pacientes com creatinina maior ou igual a 1,2 mg/dl ou clearance de creatinina inferior a 70 ml/min. A acetilcisteína reduziu o risco de NIMC.
Em outra meta-análise abrangendo cinco pesquisas prospectivas, randomizadas, foi identificada uma redução de 20% na taxa de NIMC no grupo dos pacientes submetidos a tratamento profilático com acetilcisteína, quando comparado aos indivíduos que receberam placebo86.
Birck e cols.87 e Isenbarger e cols.88, após análise dos mesmos sete estudos randomizados, comparando acetilcisteína e hidratação com hidratação isolada em 805 indivíduos com IRC, confirmaram a eficácia da acetilcisteína. Os primeiros demonstraram uma significativa redução de 56% no risco relativo de agudização da IRC com o uso preventivo deste medicamento. O segundo grupo de pesquisadores concluiu que a cada 9 pacientes tratados com a droga, um caso de NIMC é evitado.
A maioria dos ensaios incluídos nas meta-análises supracitadas empregou a dose de 600 mg duas vezes por dia, a partir do dia anterior ao exame contrastado. Briguori e cols. 89 compararam esta posologia com seu dobro (1.200 mg duas vezes por dia) em um estudo que totalizou 224 pacientes com creatinina sérica maior ou igual a 1,5 mg/dl ou "clearance" de creatinina menor que 60 ml/min. A freqüência de NIMC foi menor no grupo de pacientes que recebeu a dose dobrada (3,5% contra 11%), porém esta diferença só foi significativa quando a quantidade de MC empregada foi igual ou maior a 140 ml.
Nos casos emergenciais, nos quais não há tempo para a administração oral da acetilcisteína, foi proposta a utilização endovenosa da droga. Na pesquisa de Webb e cols. 81, 487 indivíduos com IRC foram divididos em dois grupos: hidratação isolada e hidratação associada a acetilcisteína 500 mg via endovenosa, imediatamente antes da administração do MC em dose única. Foi indicada a interrupção precoce do estudo devido à inefetividade do medicamento. Contrariando estes resultados, porém com apenas 80 casos submetidos à hidratação ou à administração endovenosa de acetilcisteína 150 mg/kg 30 minutos imediatamente antes e 50 mg/kg após o exame contrastado, outro estudo obteve resultados favoráveis. A freqüência de NIMC foi de 21% e 5%, respectivamente90. É importante ressaltar a dose mais elevada e o uso da droga antes e após a administração do MC neste segundo ensaio.
Ochoa e cols.91 avaliaram a administração via oral abreviada de acetilcisteína em altas doses (1.000 mg uma hora antes e quatro horas após coronariografia e/ou intervenção coronária) em 80 pacientes com IRC. Obtiveram taxas de NIMC de 8% no grupo medicado e de 25% nos indivíduos que receberam placebo, sugerindo a eficácia do esquema profilático proposto.
Apesar de sua efetividade ter sido questionada por alguns estudos, o benefício da utilização profilática da acetilcisteína contra a NIMC foi confirmado pelas meta-análises comentadas. Além disso, características como baixo custo, ampla disponibilidade, administração via oral e efeitos adversos limitados fortalecem o seu emprego com este propósito. Vários esquemas posológicos foram usados; entretanto, o mais estudado foi 600 mg duas vezes por dia, a partir do dia anterior ao exame contrastado com duração de dois dias.
O ácido ascórbico apresenta propriedades antioxidantes e tem sido utilizado seguramente como suplemento dietético. Foi realizado um ensaio randomizado, controlado por placebo, para avaliar a sua eficácia como agente profilático para a NIMC. Este estudo avaliou 231 pacientes com creatinina sérica maior ou igual a 1,2 mg/dl, submetidos a coronariografia e/ou intervenções coronárias. A dose de vitamina C utilizada foi de 3 g, pelo menos duas horas antes da administração do MC e 2 g na noite e na manhã após o procedimento. Agudização da IRC ocorreu, respectivamente, em 9% e 20% dos indivíduos que receberam o ácido ascórbico e o placebo. Tais resultados sugerem que a vitamina C é efetiva na prevenção da NIMC, além de ser segura, bem tolerada, barata e amplamente disponível; porém, são necessários estudos com maior número de pacientes para confirmar esta hipótese 92.
A teofilina e a aminofilina foram avaliadas quanto a um possível efeito protetor contra a nefrotoxicidade dos MCs. Apesar de alguns ensaios terem sugerido a eficácia da teofilina 93,94, outros não obtiveram resultados favoráveis 95,96; portanto, estudos prospectivos maiores são necessários para definir a importância dos antagonistas da adenosina, neste contexto.
Existem dois receptores para a endotelina: ET-A e ET-B. Em ratos, observou-se que apresentavam funções diferenciadas: o receptor ET-A é vasoconstritor, sendo encontrado no músculo liso; o receptor ET-B promove vasodilatação através da liberação de óxido nítrico e prostaciclina e é encontrado nas células endoteliais 97. Entretanto, ambos subtipos de receptores foram envolvidos com a ação vasoconstritora da endotelina em vasos sangüíneos humanos 98.
Estudos em animais demonstraram que um antagonista seletivo dos receptores ET-A preveniu o aumento da creatinina após a administração de MC 99; entretanto, o bloqueio dos receptores ET-B não resultou em proteção renal 100.
Wang e cols. 101 realizaram uma pesquisa randomizada, controlada por placebo, para avaliar a efetividade de um antagonista misto dos receptores ET-A e ET-B (SB290670), na prevenção da NIMC. O estudo totalizou 158 indivíduos com creatinina sérica maior ou igual a 2,0 mg/dl, submetidos a cateterismo cardíaco. A freqüência de agudização da IRC foi maior nos pacientes que receberam a droga em relação ao grupo placebo (56% contra 29%, respectivamente), revelando seu efeito deletério.
Fica evidente, portanto, que novos estudos são necessários para determinar se antagonistas específicos dos receptores da endotelina são úteis no manejo preventivo da NIMC.
Pequenas pesquisas prospectivas demonstraram que os antagonistas dos canais de cálcio atenuaram a redução na taxa de filtração glomerular após a exposição a MC 102,103. Entretanto, outros estudos não comprovaram redução na freqüência de NIMC com o uso profilático destes medicamentos 104,105. Devido ao pequeno número de ensaios clínicos, todos com um número reduzido de pacientes e com resultados contraditórios, é necessário um grande estudo para avaliar definitivamente a eficácia dos antagonistas dos canais de cálcio na prevenção da IRA induzida pelos MCs em pacientes de alto risco.
A arginina é o substrato para a síntese do óxido nítrico. A administração endovenosa de 300 mg/kg desta substância, durante a coronariografia, foi avaliada através de um ensaio randomizado, controlado por placebo, quanto à sua efetividade na prevenção da NIMC em pacientes com IRC. Não foi demonstrado benefício com a utilização desta estratégia 106.
Recentemente, foi publicado um estudo prospectivo, randomizado, comparando a utilização de bicarbonato de sódio e cloreto de sódio, ambos em concentração de 154 mEq/l, para hidratação profilática antes da exposição a MC. Foram incluídos 119 indivíduos com creatinina sérica maior ou igual a 1,1 mg/dl, dos quais desenvolveram NIMC oito pacientes (13,6%) que receberam cloreto de sódio contra apenas um (1,7%), no grupo do bicarbonato de sódio. Apesar da necessidade de confirmar estes resultados através de um ensaio com maior número de casos, a infusão de bicarbonato de sódio pode constituir um método seguro, prático, barato e simples, para prevenir a IRA induzida pelos MCs 107.
A utilização de manitol e furosemida foi comparada ao uso isolado de solução salina como tentativa de prevenir a NIMC, não apresentando os efeitos desejados e podendo, inclusive, ser deletéria 12,108,109.
Stevens e cols. 110 demonstraram que uma diurese forçada, induzida pela administração de furosemida, manitol e baixa dose de dopamina, associada à tentativa de manutenção do volume intravascular com solução cristalóide endovenosa, promoveu modesta proteção contra a NIMC. Este achado foi mais evidente no grupo de pacientes em que o fluxo urinário médio superou 150 ml/h.
Pelo exposto acima, o uso rotineiro de manitol e furosemida como agentes profiláticos não é recomendado. Deve ser lembrado que ambos podem promover depleção do espaço extracelular, comprovadamente aumentando o risco de nefrotoxicidade pelos MCs.
A dopamina estimula de forma não seletiva dois tipos de receptores: DA-1 e DA-2; além de atuar sobre os receptores adrenérgicos alfa e beta, quando utilizada em altas doses. A ativação dos receptores DA-1 promove aumento do fluxo sangüíneo renal e natriurese, em contraste com a estimulação dos receptores DA-2 e adrenérgicos, a qual está associada à vasoconstrição 9.
Vários investigadores testaram a eficácia da dopamina na prevenção da NIMC. Weisberg e cols.12 confirmaram o aumento do fluxo sangüíneo renal; porém, obtiveram maior incidência de agudização de IRC no grupo de pacientes diabéticos tratados com este medicamento. Em outros estudos, não foi demonstrada vantagem com o uso da dopamina, quando comparada à hidratação isolada para a profilaxia da NIMC95,111. Abizaid e cols. 95 descreveram, inclusive, efeitos deletérios quando esta é utilizada no tratamento da IRA estabelecida, causada pelo MC.
Contrariando os achados destes pesquisadores, dois ensaios prospectivos demonstraram que a dopamina, utilizada na dose de 2,5 a 3,0 µg/kg/min 12 a 24 horas após a exposição ao MC, preveniu a nefrotoxicidade em indivíduos com disfunção renal leve112,113. Porém, os resultados destes estudos são limitados, pelo pequeno número de pacientes e curto período de seguimento.
Diante das evidências contraditórias, o uso rotineiro da dopamina com a intenção de evitar a NIMC não é recomendado.
O fenoldopan é um agonista seletivo dos receptores dopaminérgicos DA-1, aprovado para o tratamento de emergências hipertensivas, através da administração endovenosa. Apresenta potente ação vasodilatadora arteriolar sistêmica e renal e não estimula os receptores DA-2 e adrenérgicos, mesmo em doses altas114.
Foram publicados alguns estudos randomizados, controlados por placebo, para avaliar o efeito desta droga na profilaxia da NIMC. Tumlin e cols.115 realizaram um ensaio com 45 pacientes com creatinina sérica maior ou igual a 2,0 mg/dl, comparando fenoldopan na dose de 0,1 µg/kg/min e hidratação com hidratação isolada. A incidência de agudização da IRC foi de 21% no grupo tratado com o medicamento e 41% nos pacientes que receberam apenas solução salina.
No estudo de Kini e cols.116, foi comparada a freqüência de NIMC após intervenção coronária entre 150 pacientes que receberam fenoldopan e um grupo-controle histórico, de 150 indivíduos. Os valores obtidos foram 4,7% e 18,8%, respectivamente.
Opondo-se aos resultados anteriores, uma pesquisa multicêntrica falhou em demonstrar a eficácia do fenoldopan na prevenção da NIMC. Foram estudados 315 indivíduos com "clearance" de creatinina inferior a 60 ml/min, randomizados para receber a droga na dose de até 0,1 µg/kg/min ou placebo117.
A comparação do fenoldopan com a acetilcisteína também apresentou resultados heterogêneos. No ensaio de Briguori e cols.118, 192 pacientes com IRC foram divididos em dois grupos: acetilcisteína 1.200 mg, duas vezes ao dia, e fenoldopan 0,1 µg/kg/min; ambos associados à hidratação. A primeira droga foi mais efetiva com uma incidência de NIMC de 4,1% contra 13,7%. Outra pesquisa com 123 indivíduos portadores de IRC obteve resultados desfavoráveis à acetilcisteína e ao fenoldopan, quando comparados à hidratação; com freqüências de agudização da IRC de: 17,7%, 15,7% e 15,3%, respectivamente119.
Devido aos resultados contraditórios obtidos até o momento, são necessários novos estudos para avaliar de forma definitiva a eficácia do fenoldopan na prevenção da NIMC.
Questionou-se sobre a possibilidade de a hemodiálise profilática prevenir uma deterioração adicional da função renal em pacientes de alto risco, quando iniciada imediatamente após a administração do MC. Vários estudos comprovaram que esta estratégia reduz significativamente os níveis plasmáticos do MC; porém, não reduz a freqüência de IRA 120-124.
Marenzi e cols.125 avaliaram a efetividade da hemofiltração, uma forma de terapia de substituição renal contínua, na profilaxia da NIMC. Foram incluídos no ensaio 114 indivíduos com creatinina sérica maior que 2,0 mg/dl submetidos a intervenção coronária. No grupo da hemofiltração, apenas 5% dos participantes apresentaram piora da função renal; tal índice alcançou 50% no grupo controle. As taxas de mortalidade intra-hospitalar e no período de um ano também favoreceram esta modalidade de tratamento: 2% contra 14% e 10% contra 30%, respectivamente. É importante lembrar que a hemofiltração é um procedimento invasivo e de alto custo. Sua relação custo-benefício ainda não foi determinada, porém pode ser adequada nos pacientes de risco elevado.
Nas últimas décadas, a grande maioria dos grandes estudos sobre nefrotoxicidade dos MCs incorporou protocolos de hidratação, confirmando a recomendação de que todos os pacientes deveriam recebê-la por via oral ou endovenosa, ainda que não existam ensaios clínicos comparando de forma direta a sua utilização ou não. Particularmente, nos pacientes com alto risco para NIMC, esta estratégia deve ser iniciada antes e mantida após a administração do potencial agente nefrotóxico por via endovenosa.
O objetivo clínico é manter um balanço positivo de fluidos, com um alto débito urinário. Ainda não foi definido o esquema ideal; porém, muitos foram empregados com taxas de infusão de 100 a 150 ml/h ou 1,0 a 1,5 ml/kg/h, voltados a atingir volumes urinários de 75 a 125 ml/h 12,41,46,60,108. É de fundamental importância monitorizar rigorosamente o balanço hídrico total, para ajustar a hidratação conforme necessário.
Em uma pesquisa prospectiva, randomizada envolvendo 1.620 pacientes submetidos a angioplastia coronária, Mueller e cols. 126 avaliaram dois regimes de hidratação: solução salina isotônica e soro hipotônico (cloreto de sódio 0,45% mais glicose 5%), iniciados na manhã do procedimento eletivo ou imediatamente antes nos casos emergenciais. A freqüência de NIMC foi significativamente menor no grupo do soro isotônico (0,7% contra 2,0%). Três subgrupos pré-definidos foram beneficiados, em particular, pela hidratação isotônica: mulheres, diabéticos e os que receberam 250 ml ou mais de contraste.
O peptídio natriurético atrial foi avaliado quanto a um possível efeito protetor contra a NIMC em um estudo prospectivo envolvendo 247 pacientes com IRC randomizados para receber três doses distintas desta substância ou placebo. Com nenhuma das doses testadas foi comprovada proteção contra a nefrotoxicidade do MC, inclusive no grupo de indivíduos diabéticos127. Portanto, não há evidências que suportem o uso do peptídio natriurético atrial para a profilaxia da NIMC.
O uso profilático da prostaglandina E1 foi avaliado em um ensaio duplo-cego, randomizado abrangendo 117 pacientes com creatinina sérica maior ou igual a 1,5 mg/dl, submetidos a diversos exames contrastados. Foram testadas doses de 10, 20 e 40 ng/kg/min, via endovenosa, iniciadas 1 hora antes do procedimento, com duração total da infusão de 6 horas. A administração do medicamento a 20 ng/kg/min foi superior, de forma estatisticamente significante, ao placebo e às outras doses, na prevenção da NIMC128. Entretanto, são necessários estudos maiores para confirmar definitivamente estes resultados.
Nos serviços de Hemodinâmica e Cardiologia Intervencionista dos dois hospitais que participaram desta revisão, procura-se utilizar a menor quantidade possível de MC, suspender o uso concomitante de drogas nefrotóxicas e estratificar o risco de NIMC em todos pacientes que serão submetidos a cateterismo cardíaco diagnóstico e/ou terapêutico. Naqueles com baixo risco para IRA induzida pelo MC, estimula-se a hidratação via oral. Nos indivíduos com alto risco, é realizada hidratação com solução salina isotônica endovenosa, na dose de 1000 ml, 12 horas antes e 12 horas depois da exposição ao MC, com monitorização cuidadosa do balanço hídrico; além da administração de acetilcisteína 600 mg, via oral, a cada 12 horas, iniciada 24 horas antes do cateterismo, com duração de dois dias. Nos pacientes que não suportam hidratação tão rigorosa, são utilizadas quantidades menores de solução salina isotônica, de acordo com parâmetros clínicos.
O tratamento da NIMC estabelecida compreende medidas conservadoras e diálise, dependendo da severidade da disfunção renal e das complicações resultantes8.
O manejo conservador é feito com a monitorização diária do peso do paciente, com a avaliação cuidadosa do seu balanço hídrico, infusão de solução salina e aferição periódica de eletrólitos séricos, creatinina e uréia. A ingestão protéica deve ser limitada a aproximadamente 0,5 g/kg/dia.
Os pacientes que desenvolvem IRA após a utilização de MC podem necessitar de diálise em 0,44% a até 25% dos casos, nos subgrupos de alto risco5,49,68,129-132. A diálise é indicada quando ocorre hiperpotassemia severa, acidose metabólica ou sobrecarga de volume não responsivas às medidas conservadoras. Sinais e sintomas de uremia também constituem indicação de tratamento dialítico. A fase de recuperação pode ser complicada por diurese acentuada e conseqüentes depleção extracelular e perda de eletrólitos, exigindo detecção precoce e os devidos cuidados corretivos8.
A NIMC aumenta o tempo de internação e a morbimortalidade intra-hospitalar, em médio e em longo prazo48.
A mortalidade intra-hospitalar nos casos de NIMC varia de 7,1%, em situações não emergenciais, a até 66%, nos pacientes de alto risco com infarto agudo do miocárdio e IRC5,48,49,133. Em um ano, pode atingir 12,1% a 37,7 por cento48,68,134. A mortalidade intra-hospitalar entre pacientes que necessitaram de diálise por IRA induzida por MC varia entre 22,6% e 39%49,68,130, podendo atingir 45,2% ao final de um ano68.
Levy e cols.5 avaliaram 16.248 pacientes submetidos a procedimentos que envolviam o uso de MC. A mortalidade, nos indivíduos com e sem IRA induzida pelo MC, foi de 34% e 7%, respectivamente. Foram identificados os eventos que contribuíram para a morbidade e para a mortalidade nos pacientes com disfunção renal: sepse, sangramento, coma e insuficiência respiratória.
No estudo prospectivo de Freeman e cols.130 foram analisadas 16.592 intervenções coronárias, sendo verificada NIMC necessitando diálise em 0,44% dos casos. A mortalidade intra-hospitalar, neste grupo de pacientes atingiu 39%; apenas 1,4% dos indivíduos que não apresentaram esta complicação faleceu. Em outra pesquisa totalizando 20.479 pacientes submetidos a angioplastia coronária, os indivíduos que desenvolveram IRA após o procedimento apresentaram uma chance 15 vezes maior de hospitalização prolongada (superior a quatro dias) e de eventos cardíacos maiores (morte, infarto agudo do miocárdio e re-oclusão do vaso submetido a angioplastia)47.
No ensaio retrospectivo de Rihal e cols.48, com 7.586 pacientes consecutivos submetidos a intervenção coronária, 22% dos indivíduos que desenvolveram IRA após o procedimento faleceram durante a hospitalização; contra somente 1,4%, no grupo sem piora da função renal. Entre os sobreviventes com NIMC, as taxas de mortalidade em 1 e 5 anos foram 12,1% e 44,6%, respectivamente; muito maiores que 3,7% e 14,5%, encontradas nos pacientes sem IRA.
Após avaliação de 1.826 pacientes consecutivos submetidos a intervenção coronária, McCullough e cols.49 obtiveram incidência de NIMC de 14,5% e de NIMC necessitando diálise de 0,77 por cento. As taxas de mortalidade intra-hospitalar nos grupos sem IRA, com IRA e com IRA necessitando diálise foram: 1,1%, 7,1% e 35,7%, respectivamente.
Gruberg e cols.68 estudaram retrospectivamente as implicações prognósticas da agudização da IRC após administração de MC em 439 pacientes com creatinina sérica maior ou igual a 1,8 mg/dl, submetidos a intervenções coronárias. Dos 161 indivíduos (37%) que desenvolveram NIMC, 19% necessitaram diálise e 14,9% faleceram durante o internamento, contra apenas 4,9% daqueles que não evoluíram com piora da função renal. Em um ano, a mortalidade foi de 45,2% nos pacientes que necessitaram diálise, 35,4% nos que não precisaram deste tipo de tratamento e 19,4% nos indivíduos em que não houve piora da creatinina sérica.
O impacto da insuficiência renal preexistente e do desenvolvimento subseqüente de NIMC em 2.082 pacientes submetidos a angioplastia coronária primária para o tratamento do infarto agudo do miocárdio foi avaliado por Sadeghi e cols.134. As taxas de mortalidade em 30 dias (16,2% contra 1,2%) e em um ano (23,3% contra 3,2%) foram significativamente maiores nos indivíduos que evoluíram com IRA após a intervenção coronária.
Em conclusão, os conhecimentos sobre a NIMC vêm crescendo substancialmente, mas permanece grande quantidade de dúvidas a serem esclarecidas em vários aspectos, desde a sua patogênese até o seu tratamento; além da persistência de elevados índices de morbimortalidade. São ainda necessários estudos detalhados para que a profilaxia e o tratamento desta entidade possam ser realizados de maneira mais eficaz.
Declaro não haver conflitos de interesses pertinentes.
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Frederico T. Ultramari Rua Tomazina, 395 80540-160 – Curitiba, PR E-mail:
Recebido em 25/03/05
Aceito em 12/08/05
Contrast media-induced nephropathy following diagnostic and therapeutic cardiac catheterization
Hospital Universitário Evangélico de Curitiba e Hospital de Clínicas da UFPR - Curitiba, PR - Brazil
It is estimated that 6,000 and 2,000 cardiac catheterization procedures per million inhabitants/year are performed in Western countries for diagnostic and therapeutic purposes. In order to perform these procedures, 1,800 tons of iodine are required all over the world to manufacture contrast media (CM). The number of procedures that require the use of contrast media (or dye) has increased over time, and the population submitted to it is growing older, presenting more comorbidities1, 2.
Currently low-osmolar contrast media are used in approximately 75% of patients and the iso-osmolar contrast media, allegedly less toxic are becoming more popular1. In spite of development of new contrast media, they still represent the third main cause of nosocomial-acquired acute renal failure (ARF) (10% of cases), substantially increasing hospitalization period, care costs and in-hospital morbi-mortality 3-6.
The main goal is to address important aspects about the contrast-medium induced nephropathy (CMIN) that follows cardiac catheterization, including its definition, pathogenesis, incidence, risk factors, clinical picture, prevention, treatment and prognosis.
To date, no consensus has been established regarding the definition of CMIN. The most used is the marked impairment of renal function related to a 25% increase in serum creatinine levels or an absolute increase of 0.5 mg/dL, 48 to 72 hours after the administration of contrast medium and in the absence of other causes. Some studies have used a 50% increase in serum creatinine level and 1 mg/dL to determine CMIN1,2,6-8.
It is believed that the pathogenesis of CMIN is multifactorial. Vascular (hemodynamic) and tubular factors contribute to its development. However, the accurate pathophysiological mechanisms have not yet been clearly understood.
One of the mechanisms involved in the contrast medium-induced acute renal failure (CMIARF) is the medium vasoconstrictive effect, which leads to medullar ischemia. Today, vasoconstriction is the subject of many studies8,9. Actually, medium injection is followed by biphasic response – initial vasodilation that lasts only some seconds, but that increases renal blood flow, followed by variable periods of vasoconstriction and subsequent flow and glomerular filtration rate reduction 10,11.
The vasoconstrictive effect is stronger in the presence of nonsteroidal anti-inflammatory drugs (NSAIDS); however, the use of vasodilators such as dopamine and atrial natriuretic peptide can accentuate medullar ischemia due to redistribution of the blood flow from the medulla to the cortex10-13. Depletion of extracellular space in animals also enhances the more severe and persistent changes that can last up to 24 hours14.
Vasoconstriction seems to be related to changes in the renal intracapsular pressure, acute changes in renal perfusion secondary to initial vasodilation, direct effects of contrast media in smooth muscle contractility caused by changes in intracellular hydration, secondary effects of contrast media on smooth muscle contractility due to the release of vasoactive substances, changes in intracellular concentrations of calcium and aggregation of blood cells in the medullar flow 8,10-13.
Decreased renal blood flow may be a consequence of the osmolarity of contrast media15. It has been shown that intrarenal pressure and blood flow are inversely related, i.e., when intrarenal pressure increases, blood flow diminishes and vice versa16. Therefore it seems that decreased blood flow and glomerular filtration rate can be explained by increased intratubular hydrostatic pressure induced by hyper-osmolar contrast media1,8. This phenomenon is supported by important reduction of these effects when low-osmolar contrast media are used 8.
Direct effect of contrast media osmolarity on vascular smooth muscle cells resulting in vasoconstriction is another possible component of hemodynamic changes 8,10-13. Calcium may be another mediator of this phenomenon because it has been demonstrated that some of its antagonists reduce vasoconstriction associated with administration of contrast media17.
Adenosine is a vasodilator that acts on peripheral circulation; however it promotes vasoconstriction at the renal cortex18. Studies carried out in dogs have shown that adenosine antagonist, theophiline, and its agonist, dipiridamol weaken and accentuate, respectively, the contrast medium-induced vasoconstrictive effect19. However, further research is necessary to better understand the role played by adenosine.
Peptides such as endothelin, angiotensin II, vasopressine, atrial natriuretic peptide and bradikinin play important roles in renal physiology. Endothelin, a powerful vasoconstrictive agent, reduces the blood flow and the glomerular filtration rate20. Many studies suggest that endothelin may play an important role in CM-induced hemodynamic changes, which would stimulate its release by endothelial cells, increasing its plasma and urinary levels. In contrast to the importance of endothelin as a mediator in the decrease of renal blood flow caused by CM is its prevailing action on the efferent arteriole such as angiotensin II, which is classically considered to increase filtration fraction. This is not consistent with the previously described effects15. To sum up, new studies should be performed to confirm the role played by endothelin in CM-mediated vascular changes.
It is unclear if angiotensin is a vasoconstriction mediator. Studies with angiotensin II blockers or its receptors for and against this hypothesis are being carried out. Controlled studies with human beings are necessary to definitely evaluate the role played by this peptide in the pathogenesis of CM-induced ACF.
Changes caused by contrast media on vasodilator substances also contribute to the occurrence of ARF. Nitric oxide synthesis reduction at the renal cortex after CM administration is well-known27. Additionally, pharmacological inhibition of vasodilator prostaglandin and nitric oxide increase MC nephotoxicity13,28. Endothelium dysfunction caused by diabetes, hypertension and atherosclerotic disease, with subsequent reduction of vasodilator release may explain the increased risk of CM-induced ARF presented by these patients 2.
It has been suggested that CM-induced vasoconstriction could be caused by a tubuloglomerular feedback mechanism, triggered by the macula densa when in contact with hypertonic solutions. Angiotensin II, adenosine and calcium would participate as intermediate mediators promoting vasoconstriction of the afferent arteriole causing the reduction of glomerular filtration rate and the increase of the renal vascular resistance. There is increasing evidence that adenosine is the main mediator of the tubuloglomerular feedback8.
Possible direct toxic effects of CM on tubular function has been less studied recently, but they include: direct cellular injury, tubular obstruction and osmotic changes8.
It has been shown that contrast media reduce the secreting function of the proximal tubules of cortical nephrons, suggesting an independent toxic effect caused by hemodynamic changes29. There is evidence of direct cellular injury, shown by changes in the energy metabolism of cells in the proximal tubules, release of intracellular enzymes and CM-produced histological changes30. Among them, it is worth highlighting the proximal renal tubule vacuolization (osmotic nephrosis) which is probably caused by increase of giant lysosomes. This is enhanced by using iso-osmolar CM, is completely reversible and is not necessarily related to the progress to ARF1,8,31.
Studies that have evaluated patients with multiple myeloma and who developed CM-induced ARF describe massive deposition of Bence-Jones protein, causing tubular obstruction. At first it was thought that this mechanism was responsible for the particularly high risk presented by these patients 32,33. However, it is unlikely that this deposition will take place with the new contrast media and affect well-hydrated patients. Furthermore, the importance of the deposition of the Tamm-Horsfall protein and uric acid crystals in CMIN has not been proved34,35.
Arguments used to defend possible tubular obstruction as the primary cause of CMIARF include the observation that nephrograms are usually dense immediately after the procedure and both kidneys are enlarged, simulating acute ureteral obstruction. Maintenance of this picture for a long period of time could result in a sustained reduction of the renal blood flow8. However, there is no pathological evidence to prove that this mechanism is the main etiological agent of CMIN2,11.
Important but transient proteinuria affect animals and human beings following angiography with hypertonic agents35,36. However, whether this transient increase in the permeability of the glomerular basal membrane plays an important role in promoting CMIN or not is unclear. Urinary excretion of many tubular enzymes as indication of these cells’ injury has also drawn much interest, but specificity both of enzimuria and proteinuria is debated 2,8,37,38. Therefore it seems that there are no advantages in monitoring these urinary abnormalities in patients that undergo dye-based tests 2.
Unfortunately, it is difficult to totally dissociate the true effects of direct tubular injury from the secondary effects of renal ischemia, which can cause cellular damage due to lipid peroxidation, associated with increased production and reduced removal of oxygen free radicals9. The importance of oxygen reactive species as factors related to the pathogenesis of the CMIN has been shown in experimental studies8,9,14,39. Administration of catalase14 or dismutase superoxide38 or deferoxamine iron chelation40 can improve the CM-induced hemodynamic and functional changes.
To sum up, evidences favor medullar ischemia as the central pathophysiological factor of CMIARF. The role of possible mediators involved in this process is still unclear. Medullar ischemia may be caused by the unbalance between vasoconstrictive and vasodilator factors, independently acting on the renal cortex and medulla. Therefore, changes in the metabolism of prostaglandins, nitric oxide, endothelin, adenosine or other substances can contribute to it. Actually the pathophysiological mechanisms of CMIN are not necessarily the same in all patients. In addition to that, patients with endothelial cell dysfunction, such as individuals with diabetes, hypertension or atherosclerotic disease may be more sensitive to developing ACF following dye-based tests2.
Incidence of CMIN varies substantially among several studies, depending on the diagnostic criteria used and individual risk factors presented by the patients1,9. It is estimated that it affects 1% to 6%41,42 of individuals in non-selected groups, but it may affect up to 40% to 90%12,43-46 of high risk patients, especially those with chronic renal failure (CRF) and diabetes mellitus (DM). The incidence of CMIARF also varies depending on the definition used: 2.0% (1.0 mg/dL increase in serum creatinine)47; 3.3% (0.5 mg/dL increase in serum creatinine)48; and 14.5% (25% increase in serum creatinine)49.
A study with 1,077 individuals submitted to cardiac catheterization with nonionic contrast agent revealed that although 73% of them presented a discreet transient increase of serum creatinine, this had no clinical impact in most cases41.
However, groups with higher likelihood of developing ARF following dye-based exams have been determined as well as possible risk factors such as pre-existing ARF, DM, volume of CM administered, dehydration, atherosclerotic disease, congestive heart failure1,9, nephritic syndrome, liver cirrhosis, concurrent use of nephrotoxic drugs, use of high-osmolar CM1, age, male gender, multiple myeloma 9, hypoalbuminemia and hyponatremia45. Other risk factors for CMIN are suggested following coronary interventions: systemic arterial hypertension, emergency procedures, intra-aortic balloon47; onset of acute myocardial infarction 24 hours before the procedure, unsuccessful procedure; interventions on the left coronary artery; presence of coronary, peripheral and systemic vascular complications related to the procedure48. It is key to identify patients that present any of these risk factors in order to implement severe prophylactic measures.
The majority of most recent studies confirmed that CRF is the most important risk factor of CMIN, followed by DM2,41,43-51. Results of all studies that compared patients with and without CRF have pointed that the first group was more likely to develop CMIN41,44-46,48, 52.
Prospective studies involving approximately 9,000 patients that underwent cardiac catheterization presented an exponential increase in their risk to develop ARF when serum creatinine before the procedure was above 1.2 mg/dL, attaining a 30.6% index in patients with basal creatinine above 3.0 mg/dL. Subjects with serum creatinine higher than 1.5 mg/dL had a 21-fold increase in their risk of developing CMIARF compared to those whose renal function is normal41,48,50.
According to a study carried out by Bartholomew et al47 with 20,479 patients that had undergone coronary interventions, the incidence of ARF following the procedure is inversely proportional to the creatinine clearance: higher or equal to 90 mL/min: 0.6%; between 60 to 89 mL/min: 1.4%, and lower than 60 mL/min: 6.4%. Manske et al studied a group of 59 insulin-dependent diabetic patients with a mean creatinine clearance of 14 mL/min who have undergone coronary angiography. Out of those patients, 50% presented recurrence of renal failure. Ten patients had to be submitted to dialysis during the follow-up, and 7 of them in the first six days following the procedure43.
Most studies confirmed that the risk of developing MCIARF is similar in diabetic individuals without CRF and in non-diabetic subjects41,46,50,52. On the other hand, almost every study has evidenced a strong association between DM with pre-existing renal dysfunction and CMIARF12,44,46,49-51. McCullough et al49 examined 1,826 consecutive patients submitted to coronary intervention. In their study, 14.5% of patients developed CMIN and 0.77% had to undergo dialysis. This latter procedure was required by 43% of diabetic patients with creatinine clearance below or equal to 20 mL/min, but by no patient whose clearance was above 47 mL/min.
Rudnick et al50 performed a study with 1,196 patients that underwent cardiac catheterization. The incidence of MCIN observed by them was DM and normal renal function: 0.6%; isolated CRF: 6%; DM and CRF: 19.7%. Results obtained by Barret et al51 with 249 patients supported those findings; the incidence of MCIN in their series was: non-diabetic patient with serum creatinine level lower than 2.25 mg/dL: 6%; diabetic patient with serum creatinine level lower than 2.25 mg/dL: 11%; non-diabetic patient with serum creatinine above 2.25 mg/dL: 16.7%; and diabetic patient with serum creatinine above 2.25 mg/dL: 33.3%.
In conclusion, although diabetic patients with normal renal function require special care, their risk to develop CMIARF is low. However, diabetic individuals with CRF represent a group whose risk is extremely high and therefore, prophylactic measures should be always adopted.
Several studies pointed a correlation between the volume of contrast media administered and risk to develop ARF43,44,45,49,50,52-54. Out of the 1,826 patients submitted to percutaneous coronary interventions examined by McCullough et al49, 14 individuals had to undergo dialysis. The volume of MC administered to each of them had been always equal or higher than 100 mL. However, other studies have shown that even smaller volumes of CM may induce renal failure and consequently dialysis 43,55. Manske et al43 found that 26% of the insulin-dependent diabetic patients with advanced chronic renal failure studied had a recurrence episode when less than 30 mL of CM was injected during cardiac catheterization. When the dose was above 30 mL, this rate went up to 79%. For each extra 5 mL of CM, the risk for ARF increased 65%.
Cigarroa et al54 classified patients with serum creatinine level above 1.8 mg/dL in two groups: the first without any limits regarding the volume of CM administered and the second with restricted volume, according to the individual’s weight and serum levels of creatinine. The incidence of ARF in both groups was 26% and 2%, respectively. All patients that developed CMIN were diabetic.
In light of these findings, the lowest possible volume of CM is recommended, as well as the ruling out of routine ventriculography in high-risk patients.
Similar results comparing different osmolar contrast media and nephrotoxicity were found in relevant studies. The meta-analysis carried out by Barret and Carlisle56 showed that out of the 31 controlled, randomized studies totaling 5,146 patients 22 favored the low osmolar CM. But the authors observed a statistically significant reduction in CMIN incidence when low osmolar CM was administered only when serum creatinine level was above 1.35 mg/dL or when glomerular filtration rate was lower than 70 mL/min before contrast was administered.
Rudnick et al50 have examined 1,196 individuals and found no difference between low and high osmolar CM and nephrotoxicity (iohexol and diatrizoate, respectively) in patients with normal renal function, which reflects the low risk presented by these individuals. For higher risk patients, the incidence of CMIN was significantly lower when low-osmolar CM was used: 12.2% vs. 27% in individuals with CRF and 33.3% vs. 47.7% in diabetic individuals with CRF.
A multicentric study with 1,194 patients who had undergone scheduled coronary angiography compared diatrizoate (high osmolar CM) and iohexol (low osmolar CM). CMIN affected 27% (diatrizoate) and 12% (iodexol) of individuals that presented both CRF and DM57.
Contrary to previous evidence, data from three studies51,58,59 with 657 patients whose serum creatinine level was above 1.35 mg/dL pointed out a less important benefit of low osmolar contrast media in individuals with impaired renal function and discussed its cost-effectiveness. However, less than 20% of the cases evaluated presented severe renal impairment (serum creatinine level above 2.25 mg/dL).
Other studies also failed to support an indisputable advantage of low osmolar CM. A prospective randomized study of 443 patients that underwent cardiac catheterization receiving either iopamidol (low osmolar) or diatrizoate (high osmolar) carried out by Schwab et al60 revealed a non-significant difference of CMIN between the two groups. Serum creatinine level increase of at least 0.5 mg/dL was observed in 10.2% of subjects that had been given diatrizoate vs. 8.2% among those that had received iopamidol. As for 160 individuals considered high risk patients because they had DM, congestive heart failure and/or CRF, 17% of those that had received high osmolar CM vs. 15¨% of those that had received low osmolar CM developed CMIN. Only 5% of this sample had serum creatinine higher than 3 mg/dL.
Two meta-analyses studies examined 18 and 14 studies comparing iso-osmolar to low-osmolar CM. No significant difference was found regarding ARF61,62. A prospective, randomized study with 856 low risk individuals who underwent coronary intervention with administration of iodixanol (iso-osmolar CM) or ioxaglate (low-osmolar CM) did not reveal any difference regarding the incidence of CMIN, although the study did show an expressive 45% reduction in important in-hospital adverse events63.
A multicentric study published by Aspelin et al64 evaluated the effect of coronary or aortofemoral angiographic studies on 129 diabetic patients with serum creatinine level between 1.5 and 3.5 mg/dL, but results did not support the findings above mentioned. The incidence of renal failure recurrence in patients with chronic renal failure was 3.0% when iodixanol, an iso-osmolar contrast medium was used, compared to 26% when iodehol (low-osmolar CM) was administered. Another study evaluated the same media in a total of 124 individuals with serum creatinine above 1.7 mg/dL. It also showed that iodixanol was less nephrotoxic than iohexol with CMIN incidence of 3.7 and 10%, respectively65.
Further studies are necessary, especially with high risk patients for comparing contrast media with different osmolarity. Low-osmolar CM should be used in the presence of CRF or of CRF plus DM. Considering that low osmolar CMs cost three to five-fold more than high osmolar CMs9, the regular use of low-osmolar CMs in patients with normal renal function is not justified. Evidence about iso-osmolar contrast media is controversial.
Dehydration is a known risk factor for CMIN66. However, most recent studies have found it difficult to consider dehydration as an independent variable due to the strict hydration protocols used 9.
Concurrent administration of CM and nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs and aminoglycosides, and possible acute prescription of angiotensin-converting enzyme inhibitors should be avoided. Patients with diabetic nephropathy that undergo therapy with drugs to reduce proteinuria, but that present normal blood pressure may not need to discontinue their use before a contrast-based test 1.
Multiple myeloma has been traditionally considered an independent risk factor for CMIARF33. A study review totaling 476 subjects with this condition failed to confirm that67. It is possible that high risk is related to an underlying renal failure and/or volume depletion, resulting in increased intratubular deposition of filtered light chains66,67.
Congestive heart failure has been considered an independent risk factor for CMIN by some studies45,53,68,69; however, this was not supported by others41,70. Many subjects of those studies were receiving diuretics before cardiac catheterization or were not adequately hydrated due to the fear that it could trigger an acute pulmonary edema after the procedure. Therefore, depletion of extracellular space and activation of renal vasoconstrictive mechanisms could be related to triggering CMIARF and consequently the results mentioned2.
Some studies have found that older age is associated with an increased risk for CMIN4,71 and that elderly patients submitted to cardiac catheterization are more likely to develop further general complications72,73. However, Rich et al45 conducted a prospective study and examined the incidence and clinical course of CMIARF in 183 individuals whose age was at least 70 years and who have had been submitted to cardiac catheterization – results of this study were similar for older and younger patients. As older subjects are more likely to present risk factors for CMIN, such as CRF, DM and depletion, risk may be really higher in this population; however, older age as an isolated variable should not be considered a counter-indication for exams that require contrast media45.
Other risk factors, such as atherosclerotic disease41 and male gender44 have not been considered independent risk factors in more recent research.
Medium-contrast induced acute renal failure is asymptomatic, non-oliguric and reversible in most patients. Serum creatinine usually increases 24 to 72 hours after the patient has been exposed to the medium contrast and reaches its peak in 3 to 5 days (usually a 0.5 – 3.0 mg/dL increase), and is lowered to its initial level in 7-14 days8,9,74,75.
A more severe form of ARF due to CMIN can be also observed, especially in high risk patients. In this case, oliguria is observed 24 hours following the administration of the CM, and serum creatinine level is usually above 5 mg/dL8,9. Oliguria is transient in most cases, and is usually present for 2 – 5 days. Serum creatinine peak is observed within 5 – 10 days and lowers to its initial value 14 – 21 days later8.
Urinalysis usually shows a pattern of acute tubular necrosis. It may also show tubular epithelial cells and coarse granular cylinders9, but the urinary sediment may be non- specific with minimal proteinuria2. Some studies pointed that the fractional excretion of sodium is low, but this has not been confirmed by others66. Low urinary sodium concentration and extremely low fractional excretion of sodium may be present in severe CMIARF during the oliguric stage74. However, changes in urinary standards such as fractional excretion of sodium, transient proteinuria and enzimuria have not proved to be useful to confirm the diagnosis of CMIN38,74,75.
It is important to mention that patients with atherosclerotic disease who underwent angiography also present high risk for developing secondary ARF due to an atheroembolic event76. Differently from CMIN, renal atheroembolic disease causes late ARF (7 days to weeks following the contrast-based test). It is often associated with short periods of eosinophilia, hypocomplementemia and other evidence of atheromatous emboli event, such as livedo reticularis, ischemia or gastrointestinal infarction. The clinical picture of ARF caused by atheromatous embolism lasts longer and is often associated with minimal recovery of the renal function9.
In contrast to most of the other forms of nosocomial-acquired ARF, CMIN can be prevented. Several prophylactic measures have been proposed based on better understanding about the pathogenesis of this condition.
No other remarks related to volume and osmolarity of contrast media, previously discussed, will be added.
In addition to being an antioxidant, acetylcysteine has vasodilator properties. It increases the expression of the nitric oxide synthase77,78 and could prevent CMIN both by reducing the direct oxidative damage and by improving the kidney hemodynamic status.
From 2002 to 2005, four meta-analysis studies have presented results favorable to the use of acetylcysteine to prevent CMIARF85-88, although some studies have failed to prove its efficacy79-84.
Out of the studies that have not presented favorable results, the Brazilian multicentric study recently published by Gomes et al84 stands out. The sample consisted of 156 subjects submitted to cardiac catheterization or coronary intervention in which only low-osmolar CM was used – no difference was found regarding CMIN incidence between the group that received the drug and the placebo group.
A meta-analysis conducted by Alonso et al85 examined eight randomized controlled studies with 885 patients whose serum creatinine level was equal to or above 1.2 mg/dL or whose creatinine clearance was lower than 70 mL/min. acetylcysteine reduced the risk for CMIN.
Five prospective, randomized studies were examined by another meta-analysis research, which revealed a 20% reduction of CMIN in the group of patients that had received prophylactic treatment with acetylcysteine as compared to the placebo group86.
Birck et al87 and Isenbarger et al88 analyzed the same seven randomized studies comparing acetylcysteine and hydration, with the latter as a single variable in 805 subjects with CRF and confirmed the efficacy of this drug. Birck et al observed a 56% reduction in the relative risk of renal failure recurrence in patients with CRF when this medication was used as preventive therapy. The second group of researchers concluded that for each 9 patients treated with acetylcysteine, one case of CMIN is prevented.
The dose used in most of the studies included in the above mentioned meta-analyses was 600 mg twice a day, from the day before the dye was administered. Briguori et al89 compared this to a higher dose (1,200 mg twice a day, or twice as much) in a sample of 224 patients whose serum creatinine was equal to or above 1.5 mg/dL or whose creatinine clearance was lower than 60 mL/min. CMIN frequency was lower in the group of patients that had received the higher dose (3.5% vs. 11%), but this difference was significant only when the volume of dye used was equal to or higher than 140 mL.
At emergency situations, endovenous administration has been proposed since there is not enough time for oral administration of acetylcysteine. Webb et al81 distributed 487 subjects in two groups: hydration and hydration associated with a single dose of 500 mg IV of acetylcysteine immediately before the administration of the dye. Early discontinuation of the study was recommended owing to lack of effectiveness of the drug. In contrast, another study presented favorable results, although the sample consisted of only 80 individuals submitted to hydration or to the IV administration of acetylcysteine – 150 mg/kg, 30 minutes immediately before and 50 mg/kg following the procedure using the dye. CMIN affected 21% and 5% of the population, respectively90. It is important to highlight the highest dose and the use of the drug before and after injection of contrast medium.
Ochoa et al91 evaluated the oral administration of acetylcysteine in high doses (1,000 mg one hour before and four hours following coronary angiography and/or coronary intervention) in 80 patients with CRF. Their results pointed to an 8% incidence of CMIN in the group that received the drug vs. 25% in the placebo group, suggesting that the proposed prophylactic regimen is effective.
Although some studies debated the effectiveness of acetylcysteine, the benefit of the prophylactic use of acetylcysteine to prevent CMIN was confirmed by the meta-analysis studies mentioned. Furthermore, characteristics such as low cost, high availability, oral administration and limited adverse effects favor its use for this purpose. Several dose regimens were used however, the most studied was 600 mg twice a day, for two days, starting on the day before the procedure.
Ascorbic acid has antioxidant properties and has been used as a nutritional supplement. A randomized, placebo-controlled study evaluated its efficacy to prevent CMIN. This study evaluated 231 patients whose serum creatinine was equal to or higher than 1.2 mg/dL and who had undergone coronary angiography and/or coronary interventions. The dose of vitamin C used was 3 g, at least two hours before the contrast medium was injected plus 2 g at night and in the morning following the procedure. Recurrence of renal failure in CRF patients affected 9% and 20%, respectively, of the sample that received ascorbic acid and the placebo group. Such results suggest that vitamin C is effective to prevent CMIN, in addition to being safe, well-tolerated, inexpensive and widely available; however, further studies are required with a larger number of patients to confirm this hypothesis92.
A possible protective role of theophylline and aminophylline against contrast medium-induced nephrotoxicity was studied. Some research have suggested theophylline’s efficacy93,94, but this has not been confirmed by some other studies95,96; therefore larger prospective studies are necessary to define the importance of adenosine antagonists in this context.
There are two receptors for endothelin: ETA e ETB. Experimental studies with rats have shown that they played different roles: ETA receptor is vasoconstrictive and is found in the smooth muscle whereas ETB receptor promotes vasodilation via the release of nitric oxide and prostacyclin and is found in endothelial cells97. However, both subtypes are involved in endothelin’s vasoconstrictive action in human blood vessels98.
Experimental studies have pointed that a selective antagonist of the ETA receptors prevented creatinine increase after the administration of contrast medium99; however blockage of ETB receptors did not promote any renal protection100.
Wang et al101 conducted a randomized, placebo-controlled study to evaluate the effectiveness of a mixed ETA/ETB receptor antagonist, (SB290670), to prevent MCIN. The sample comprised 158 individuals whose serum creatinine level was equal to or above 2.0 mg/dL and who had undergone cardiac catheterization. Recurrence of renal failure in patients with CRF was higher in patients that received the drug vs. the placebo group (56% vs. 26%), determining its harmful effect.
It is clear, then, that further studies are required to determine if specific antagonists of endothelin receptors are useful in the preventive management of CMIN.
Few prospective studies have shown that the calcium channel antagonists have attenuated the glomerular filtration rate reduction following exposure to a contrast medium102,103. However, other studies did not prove a reduced incidence rate of CMIN with prophylactic use of these drugs104,105. Because of the small number of clinical trials, all of them with a reduced number of patients and controversial results, an in-depth study with a large number of subjects is required to adequately evaluate the efficacy of calcium channel blockers to prevent CMIARF in high risk patients.
Arginine is the substrate for the nitric oxide production. The effectiveness of the IV administration of 300 mg/kg of arginine during coronary angiography was evaluated by a randomized, placebo-controlled study to prevent CMIN in patients with CRF. No benefit has been observed106.
Recent results from a prospective, randomized study with a total of 119 individuals whose serum creatinine was equal to or above 1.1 mg/dL were published. It compared the use of sodium bicarbonate and sodium chloride, both at a concentration level of 154 mEq/L, as a prophylactic hydration procedure following exposure to contrast medium. Eight patients out of the group that had received sodium chloride developed CMIN (13.6%) compared to only one (1.7%) from the sodium bicarbonate group. Although further studies with larger samples are necessary to confirm these results, the infusion of sodium bicarbonate represents a safe, practical, inexpensive and simple method to prevent ARF induced by contrast media107.
Manitol and furosemide were compared to saline solution to prevent CMIN. Results were not effective; on the contrary, it is possible that they might be harmful12,108,109.
Stevens et al110 have shown that forced diuresis, induced by the administration of furosemide, manitol and low dose of dopamine associated with the attempt to maintain the intravascular volume with IV crystalloid solution promoted mild protection against CMIN. This finding was more evident in the group of patients whose mean urinary flow was above 150 mL/h.
Based on that, the routine use of manitol and furosemide as prophylactic agents is not recommended. It should be mentioned that both substances may deplete the extracellular space therefore increasing nephrotoxicity risk promoted by contrast media.
Dopamine stimulates two types of receptors DA1 and DA2 in a non- selective manner, in addition to act on alpha and beta adrenergic receptors when administered in high doses. Activation of DA1 receptors increases renal blood flow and natriuresis in contrast to stimulation of DA2 and adrenergic receptors, associated with vasoconstriction9.
Several researchers have studied dopamine’s efficacy to prevent CMIN. Weisberg et al12 confirmed increased renal blood flow; however, their results have shown a higher incidence of recurrence in diabetic patients treated with this drug. Some other studies did not prove any advantage when dopamine was used compared to hydration as a prophylactic measure against CMIN95,111. Abizaid et al95 have described some harmful effects when dopamine is used to treat established ARF, caused by contrast medium.
In contrast to findings of those researchers, two prospective trials have shown that dopamine, administered at a dose of 2.5 – 3.0 µg/kg/min, 12 to 24 hours following CM exposure, prevented nephrotoxicity from affecting individuals with mild renal dysfunction 112,113. But results from these studies are limited because of the small number of patients and short follow-up.
In the light of controversial evidence, routine use of dopamine with intention to avoid CMIN is not recommended.
Fenoldopan is a selective dopamine-1 receptor agonist. It has been approved to manage hypertensive emergencies via intravenous administration. It has a powerful vasodilator action both systemic and on the renal arterioles, but it does not stimulate adrenergic and DA2 receptors even when high doses are given114.
Some randomized, placebo-controlled studies to evaluate the prophylactic effect of this drug against CMIN have been published. Tumlin et. al.115 conducted a trial with 45 patients whose serum creatinine level was equal to or higher than 2.0 mg/dL. They compared a dose of 0.1 µg/kg/min of fenoldopan to hydration as a single variable. Incidence of renal failure recurrence in patients with CRF was 21% in the fenoldopan group and 41% in the group that received only saline solution.
Kini et al116 compared the frequency of CMIN following coronary intervention in 150 patients that had received fenoldopanwith another 150 in the control group. Results were 4.7% and 18.8%, respectively.
Contrary to the previous results presented, a multicentric study has failed to prove the efficacy of fenoldopan to prevent CMIN. A sample of 315 individuals with creatinine clearance lower than 60 mL/min were randomly selected to receive either the drug, at a dose of up to 0.1 µg/kg/min or placebo117.
The comparison between fenoldopan and acetylcysteine was also controversial Briguori et al118 studied 192 patients with CRF who were randomly assigned to two groups: acetylcysteine: 1,200 mg, twice a day, and fenoldopan: 0.1 µg/kg/min; both related to hydration. Efficacy of acetylcysteine was higher, with incidence of CMIN of 4.1% vs. 13.7%. Another study examined 123 individuals with CRF and the results were unfavorable to acetylcysteine and to fenoldopan when compared to hydration. Recurrence rates were 17.7%, 15.7% and 15.3%, respectively119.
Because of the controversial results that have been found to date, further studies are necessary to provide a final evaluation of the efficacy of fenoldopan to prevent CMIN.
Prophylactic hemodialysis was considered to prevent further impairment of the renal function in high risk patients when performed immediately following the dye administration. Several studies have proved that this strategy significantly reduces the plasma levels of contrast medium; however, it does not affect the frequency of Acute Renal Failure120-124.
Marenzi et al have evaluated the effectiveness of hemofiltration, a therapeutical procedure to provide continuous renal replacement to prevent CMIN. They examined 114 individuals with serum creatinine above 2.0 mg/dL that had undergone coronary intervention. In the hemofiltration group, renal functional became poorer only for 5% of participants; whereas this happened in 50% of those in the control group. In-hospital mortality rate and within a year also indicated better results for hemofiltration: 2% vs. 14% and 10% vs. 30%. It is important to emphasize that hemofiltration is an invasive procedure with high costs. Its cost-effectiveness has not been determined yet, but it can be suitable for high risk patients.
Over the last decades, most large studies about CM nephrotoxicity have incorporated hydration protocols, confirming the recommendation that all patients should be hydrated, either orally or via IV, although there are no clinical trials directly comparing its use. This strategy should be introduced intravenously before and maintained after the administration of the potential nephrotoxic agent, especially for patients at high risk of developing CMIN.
The clinical goal is to maintain a positive fluid balance, with high urinary output. The ideal regimen has not been determined yet; however, many have been used, with infusion rates varying from 100 to 150 mL/h or 1.0 to 1.5 mL/kg/h, aiming to produce urinary volumes of 75 to 125 mL/h12,41,46,60,108. Close monitoring of total fluid balance is key to adjust hydration as necessary.
A prospective, randomized study with 1,620 patients who had undergone coronary angioplasty was performed by Mueller et al126, who evaluated two hydration regimens: isotonic and hypotonic saline solution (sodium chloride: 0.45% and glucose 5%). Liquids were offered in the morning of the scheduled procedure or immediately before it in emergency cases. CMIN was significantly lower in the group that received isotonic saline solution (0.7% against 2.0%). Three pre-defined subgroups have benefited from receiving isotonic hydration: women, diabetic patients and those who received 250 mL or more of contrast medium.
The possible protecting effect of this peptide in CMIN was examined in by a prospective study with 247 patients with CRF who were randomly assigned to receive three different doses of this substance or placebo. None of the three doses evaluated proved its protective role against contrast medium nephrotoxicity, even among diabetic patients127. Therefore, there is no evidence to support the use of atrial natriuretic peptide as prophylactic agent against CMIN.
A double-blind, randomized study evaluated the prophylactic use of prostaglandin E1 (PGE1) in 117 patients with serum creatinine level equal to or above 1.5 mg/dL who had undergone several tests that required administration of contrast medium. Doses of 10, 20 and 40 ng/kg/min of IV PGE1 administered one hour before the procedure for six hours. The 20 ng/kg/min dose presented better and statistically significant results compared to all the other groups to prevent CMIN128. However, further studies are required to confirm these results.
The Hemodynamics and Interventional Cardiology services of the two hospitals that participated in this review seek to use the least possible amount of contrast medium, to discontinue the concurrent use of nephrotoxic drugs and to stratify the risk of developing CMIN in all patients that are going to be submitted to cardiac catheterization, either for diagnosis and/or therapeutical purposes. Oral hydration is encouraged to patients with low risk of developing CMIARF. The procedure for high risk patients involves intravenous hydration with an isotonic saline solution, at the dose of 1,000 mL, 12 hours before and 12 hours following exposure to the dye, with close monitoring of fluid balance in addition to administration of acetylcysteine, 600 mg orally every 12 hours, for two days, starting 24 hours before catheterization. Less volume of isotonic saline solution, based on clinical parameters, is given to patients who cannot bear such a hydration program.
Established treatment of CMIN encompasses conservative measures and dialysis in accordance to the severity of renal dysfunction and the resulting complications8.
Conservative management involves daily monitoring of the patient’s weight, with close assessment of fluid balance, infusion of saline solution and periodical measurement of serum electrolytes, such as creatinine and urea. Protein intake should be limited to approximately 0.5 g/kg/day.
Out of the patients who developed ARF after being exposed to contrast medium, 0.44% to 25% of them may need to undergo dialysis in the subgroups at high risk 5,49,68,129-132. Dialysis is indicated in the presence of severe hyperkalemia, metabolic acidosis or volume overload that do not respond to conservative measures. Signs and symptoms of uremia also indicate dialysis. Recovery may be hard due to increased diuresis and resulting extracellular depletion and electrolyte loss, which require early detection and adequate corrective measures8.
Contrast-medium induced nephrotoxicity increases hospitalization period and in-hospital morbidity and mortality in the medium and long run48.
In-hospital mortality of patients with CMIN varies from 7.1%, in non-emergency situations, up to 66%, in high risk patients with acute myocardial infarction and chronic renal failure5,48,49,133. In one year, it can attain levels of 12.1% to 27.7%48,68,134. In-hospital mortality rate of patients that require dialysis owing to CMIARF varies from 22.6% to 39%49,68,130, and may affect 45.2% in one year68.
Levy et al5 evaluated 16,248 patients who underwent procedures that required administration of contrast medium. Mortality rate in individuals with and without CMIARF was 34% and 7%, respectively. Events that contributed to higher levels of morbidity and mortality of patients with renal dysfunction were sepsis, bleeding, coma and respiratory failure.
A prospective study by Freeman et al examined 16,592 coronary interventions. The study revealed a 0.44% incidence of CMIN that required dialysis. The in-hospital mortality rate in this group of patients was 39% but only 1.4% of the subjects that did not present this complication died. Another study with 20,479 patients who had been submitted to coronary angioplasty has demonstrated that patients that had developed ACF following the procedure had a 15-fold increased chance of longer hospitalization (over four days) and were more likely to present major cardiac events (death, acute myocardial infarction and re-occlusion of the vessel submitted to angioplasty)47.
A retrospective trial by Rihal et al48 with 7,586 consecutive patients submitted to coronary intervention have shown that 22% of the subjects who developed ARF after the procedure died during hospitalization compared to only 1.4% among those others whose renal function had not worsened. Mortality rates at 1 and 5 years of CMIN survivors were respectively 12.1% and 44.6%, much higher than 3.7% and 14.5% observed in patients without acute renal failure.
After having evaluated 1,826 consecutive patients submitted to coronary intervention, McCullough et al49 found an incidence rate of 14.5% for CMIN and of 0.77% for dialysis-required CMIN. In-hospital mortality rates among patients without ARF, with ARF and among those with ARF that required dialysis were 1.1%, 7.1% and 35.7%.
Gruberg et al68 have retrospectively studied the prognostic implications of renal failure recurrence after the administration of contrast media in 439 patients whose serum creatinine level was equal to or above 1.8 mg/dL and that had undergone coronary interventions. Out of the 161 (37%) individuals who developed CMIN, 19% required dialysis and 14.9% died during hospitalization compared to only 4.9% of those whose renal function had not worsened. Within a year, mortality rate attained 45.2% in patients that needed to undergo dialysis, 35.4% in those that did not require that procedure and in 19.4% of individuals whose serum creatinine profile had not worsened.
The impact of pre-existing renal failure and subsequent development of CMIN in 2,082 patients submitted to primary coronary angioplasty to treat acute myocardial infarction was assessed by Sadeghi et al134. Mortality rates at 30 days (16.2% vs.1.2%) and at one year (23.3% vs. 3.2%) were significantly higher in individuals that developed acute renal failure after coronary intervention.
To conclude, knowledge about CMIN has significantly increased, but there are still many questions to be clarified, regarding many aspects, from its pathogenesis to therapy, not to mention the consistent high morbidity and mortality rates. Further detailed studies are required in order to implement a more effective prophylactic measure and to improve its treatment.
No potential conflict of interest relevant to this article was reported.
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Mailing Address: Frederico T. Ultramari Rua Tomazina, 395 80540-160 – Curitiba, PR - Brazil E-mail:
Received on 03/25/05
Accepted on 08/12/05 12/08/05
A desidratação é reconhecida como fator de risco para NIMC66. Entretanto, nos estudos mais recentes, é difícil analisar a desidratação como variável independente, em virtude dos rigorosos protocolos de hidratação utilizados9.
Mailing Address:
Frederico T. Ultramari
Rua Tomazina, 395
80540-160 – Curitiba, PR - Brazil
E-mail:
Received on 03/25/05
Accepted on 08/12/05 12/08/05