Redução da imunossupressão, permitindo ao sistema imune do hospedeiro combater a infecção viral, é a estratégia mais frequentemente empregada, com algum sucesso. (68) (45) No entanto, redução da imunossupressão implica em aumento de risco de desenvolvimento rejeição aguda concomitante.(71)
(44)
Cidofovir, em uma dose 10-25% da dose usual (0,25-1mg/kg/dose) cada 1 a 3 semanas, tem sido usado com resultados satisfatórios. Em relato de dois casos de pacientes tratados inicialmente com redução da imunossupressão sem sucesso, baixas doses de cidofovir foram responsáveis por redução da presença de DNA viral e estabilização da função renal, sem toxicidade. (97) Em estudo não randomizado com acompanhamento médio de 2 anos, 8 pacientes foram tratados com cidofovir associado com diminuição da imunossupressão, não apresentando nenhuma perda de enxerto; 13 pacientes não receberam cidofovir, dos quais 9 apresentaram perda de enxerto com tempo médio de 8 meses (p=0,004). (98)
Tratamento com leflunomida, na dose diária de 20-60mg, em pacientes com nefropatia por BKV reduz significativamente a carga viral no sangue e na urina.
(99) (84)
Não houve diferença no tratamento com leflunomida, apenas, e leflunomida mais cidofovir em acompanhamento de 12 meses. Em acompanhamento de 6 a 40 meses, perda de enxerto ocorreu em 15%. Ausência de toxicidade renal e menor redução da imunossupressão são vantagens em relação ao uso de cidofovir isoladamente. (84)
Imunoglobulina humana (IVIG) tem sido usada para tratamento de nefropatia por BKV com resultados iniciais satisfatórios. Relato de oito casos de pacientes com nefropatia por BKV que receberam imunoglobulina humana revelou 88% destes com enxerto funcionante, porém, sem melhora da função renal, em acompanhamento médio de 15 meses. (83)
O uso de quinolonas pode estar associado com redução da carga viral na urina e no sangue. (100) Ciprofloxacina esteve associada com redução da reativação de BKV após transplante de medula óssea e, in vitro, comparada com cidofovir, ciprofloxacina apresentou inibição de BKV de maneira relativamente mais fraca, podendo, eventualmente, ter utilidade para profilaxia. (100)
O tratamento farmacológico da nefropatia por poliomavírus ainda necessita da realização de estudos randomizados e prospectivos, comparativos para melhor avaliação da eficácia das terapias existentes até o momento. (97) (98) (99) (84) (83)
(100)
1.9 Evolução e prognóstico
Estudos indicam um prognóstico ruim, com perda de enxerto renal variando de 10-80%. (68) (93) Análise de sobrevida de enxertos renais, através de curva de Kaplan-Meier, demonstrou que pacientes com nefropatia por BKV têm uma sobrevida de enxerto menor que pacientes controles apresentando disfunção renal, sem evidencias de BKV (p=0,0004). Em estudo retrospectivo comparativo evidenicou-se, ainda, sobrevida média de 47,8 meses e 88,7 meses, respectivamente, para pacientes com e sem presença de BKV. (44)
Na ausência de intervenção, perda de enxerto tem sido evidenciada
em aproximadamente 45% dos casos em uma média de 6 meses de diagnóstico. (71)
E, na ausência de medicamentos antivirais, terapia com redução da imunossupressão para nefropatia por BKV está associado com sobrevida do enxerto renal de 35 a 67% em 1 ano de diagnóstico. (52) (51) (84) Diagnóstico precoce de replicação de poliomavírus permite intervenção precoce com diminuição da perda de enxerto. (74) (68) (101) Entretando, conforme mencionado acima, a real eficácia destas terapias, ainda deverá ser estabelecida através de estudos adequadamente desenhados.
1.10 Transplantes na PUCRS
O Hospital São Lucas da PUCRS realiza transplantes renais desde 27 de abril de 1978 e, desde 17 de junho de 2002, realiza transplantes de pâncreas. Em 13 de fevereiro de 2003 realizou o primeiro transplante de pâncreas isolado do Rio Grande do Sul.
Até o presente momento, foram realizados, no Hospital São Lucas da PUCRS, 760 transplantes renais, sendo 47 transplantes simultâneos de pâncreas e rim, e 18 transplantes de pâncreas isolado. Destes, 563 foram com doadores falecidos, 174 com doadores vivos relacionados e 23 doadores vivos não- relacionados. Em 40 casos de doação renal com doador vivo, a retirada foi feita por videolaparoscopia.
Em novembro de 2003 foi realizado o primeiro diagnóstico de nefropatia por BKV em um paciente de 27 anos transplantado de pâncreas e rim há 4 meses, que apresentava biópsia renal com importante infiltrado túbulo-intersticial e destruição considerável de parênquima renal, e à imunohistoquímica (realizada pela Dra Marilda Mazzali, na UNICAMP) demonstrava grande quantidade de celularidade positiva para poliomavírus (Figura 5).
Figura 5 – Imunohistoquímica positiva para poliomavírus, em bióspia renal de paciente transplantado de pâncreas e rim do HSL-PUCRS. Aumento de 100x. (Cedido pela Dra. Marilda Mazzali).
1.11 Justificativa
A pesquisa de células decoy na urina é uma ferramenta clínica útil, principalmente como “screening”, de baixo custo e fácil disponibilidade, sem necessidade de equipamentos sofisticados. A importância deste teste, como já descrito, recai sobre a possibilidade de avaliar-se um sinal de replicação do poliomavírus no trato urinário, o que é um pré-requisito para doença viral (nefropatia por BK), de forma não invasiva.
No Brasil, apenas um estudo unicêntrico com 80 pacientes acompanhados prospectivamente avaliou a ocorrência de infecção por poliomavírus em transplantados renais. Seus dados, no entanto, são limitados pelo número de pacientes. Devido ao aumento da ocorrência desta patologia e a importância do seu diagnóstico em pacientes transplantados renais, consideramos importante a sua pesquisa em nosso meio.
1.12 Referências bibliográficas
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51. Barri YM, Ahmad I, Ketel BL, Barone GW, Walker PD, Bonsib SM, et al. Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy. Clin Transplant 2001;15(4):240-6.
52. Binet I, Nickeleit V, Hirsch HH, Prince O, Dalquen P, Gudat F, et al. Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation 1999;67(6):918-22.
53. Mengel M, Marwedel M, Radermacher J, Eden G, Schwarz A, Haller H, et al. Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant 2003;18(6):1190-6.
54. Buehrig CK, Lager DJ, Stegall MD, Kreps MA, Kremers WK, Gloor JM, et al. Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy. Kidney Int 2003;64(2):665-73.
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56. Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006;69(4):655-62.
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58. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, et al. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000;342(18):1309-15.
59. Hix JK, Braun WE, Isada CM. Delirium in a renal transplant recipient associated with BK virus in the cerebrospinal fluid. Transplantation 2004;78(9):1407- 8.
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64. Hariharan S, Cohen EP, Vasudev B, Orentas R, Viscidi RP, Kakela J, et al. BK virus-specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis. Am J Transplant 2005;5(11):2719-24.
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68. Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79(10):1277-86.
69. Drachenberg RC, Drachenberg CB, Papadimitriou JC, Ramos E, Fink JC, Wali R, et al. Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology. Am J Transplant 2001;1(4):373-81.
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73. Santos RL, Manfrinatto JA, Cia EM, Carvalho RB, Quadros KR, Alves-Filho G, et al. Urine cytology as a screening method for polyoma virus active infection. Transplant Proc 2004;36(4):899-901.
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77. Randhawa P, Vats A, Shapiro R. Monitoring for polyomavirus BK And JC in urine: comparison of quantitative polymerase chain reaction with urine cytology. Transplantation 2005;79(8):984-6.
78. Baldanti F, Fogazzi GB, Furione M, Saglimbeni L, Rovida F, Gatti M, et al. Quantification and identification of polyomavirus DNA in blood and urine of renal transplant recipients. Diagn Microbiol Infect Dis 2006.
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80. Ryschkewitsch C, Jensen P, Hou J, Fahle G, Fischer S, Major EO. Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 2004;121(2):217-21.
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83. Sener A, House AA, Jevnikar AM, Boudville N, McAlister VC, Muirhead N, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation 2006;81(1):117-20.
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91. Trofe J, Gaber LW, Stratta RJ, Shokouh-Amiri MH, Vera SR, Alloway RR, et al. Polyomavirus in kidney and kidney-pancreas transplant recipients. Transpl Infect Dis 2003;5(1):21-8.
92. Kang YN, Han SM, Park KK, Jeon DS, Kim HC. BK virus infection in renal allograft recipients. Transplant Proc 2003;35(1):275-7.
93. Kim HC, Hwang EA, Kang MJ, Han SY, Park SB, Park KK. BK virus infection in kidney transplant recipients. Transplant Proc 2004;36(7):2113-5.
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and SV40 co-infection in polyomavirus nephropathy. Transplantation
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96. Maiza H, Fontaniere B, Dijoud F, Pouteil-Noble C. Graft dysfunction and polyomavirus infection in renal allograft recipients. Transplant Proc 2002;34(3):809- 11.
97. Kadambi PV, Josephson MA, Williams J, Corey L, Jerome KR, Meehan SM, et al. Treatment of refractory BK virus-associated nephropathy with cidofovir. Am J Transplant 2003;3(2):186-91.
98. Kuypers DR, Vandooren AK, Lerut E, Evenepoel P, Claes K, Snoeck R, et al. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. Am J Transplant 2005;5(8):1997-2004.
99. Williams JW, Javaid B, Kadambi PV, Gillen D, Harland R, Thistlewaite JR, et al. Leflunomide for polyomavirus type BK nephropathy. N Engl J Med 2005;352(11):1157-8.
100. Leung AY, Chan MT, Yuen KY, Cheng VC, Chan KH, Wong CL, et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2005;40(4):528-37.
101. Drachenberg CB, Papadimitriou JC, Wali R, Nogueira J, Mendley S, Hirsch HH, et al. Improved outcome of polyoma virus allograft nephropathy with early biopsy. Transplant Proc 2004;36(3):758-9.
2 OBJETIVOS
2.1 Principal
Avaliar a prevalência de células decoy na urina de pacientes transplantados (transplante renal, pancreático ou pâncreas-rim) do Hospital São