Journal Information
Vol. 29. Issue. 2.April 2009
Pages 95-184
Vol. 29. Issue. 2.April 2009
Pages 95-184
DOI: 10.3265/NEFROLOGIA.2009.29.2.4889.EN.FULL
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CMV disease resistant to Ganciclovir. Should valganciclovir plasma levels be monitored in high risk patients?
Enfermedad por CMV resistente a ganciclovir ¿Está indicado monitorizar niveles plasmáticos de valganciclovir en pacientes de alto riesgo ?
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Dear Editor,

We report the case of a patient who received a kidney transplant in June 2007. The donor was Ig G CMV positive and the recipient was negative. The immunosuppression consisted of steroids, mycophenolate (1g/day) and tacrolimus (0.1mg/12 h). Borderline/acute rejection occurred on the 11th day post-transplant and was successfully treated with steroids.

The patient was discharged with good renal function, Cr 0.9mg/dl on prophylactic treatment with valganciclovir, for six months having to repeatedly adjust the doses because of leucopenia. CMV viral load was negative whilst on treatment.

10 days after discontinuing treatment, the patient presented with diarrhoea, abdominal pain, fever, leucopenia and thrombocytopenia, and deterioration of renal function, blood and urine cultures were negative and CMV- PCR was positive, 101,000 copies/ml.

Treatment was started with valganciclovir and the dose of MMF was reduced. The fever subsided and the CMV viral load began to decrease.

The patient was discharged with stable kidney function (1mg/dl), without leucopenia and on treatment with valganciclovir.

A few days later, the patient presented with low fever, abdominal pain and persistent CMV viral load (4,900cop/ml). The patient received treatment with intravenous ganciclovir during 20 days until the CMV viral load was negative in blood. The patient was discharged without symptoms, with normal leucocyte count and on valganciclovir treatment.

Three days after discharge, the patient developed fever, epigastrium pain and leucopenia again. CMV- PCR was negative in blood. Screening for acute febrile illness was negative except for discreet hepatosplenomegaly. The upper endoscopy showed normal mucosa of which biopsies were taken. The qualitative PCR of the gastric tissue was positive for CMVand HSV 6. Intravenous gancyclovir was reinitiated. Non-specific abdominal pain persisted along with anaemia and leucopenia, needing treatment with granulocyte colony-stimulating factor, transfusion of erythrocyte concentrate. The patient continued to have low-grade fever. The CMV serum PCR remained negative.

Suspecting CMV disease resistant to ganciclovir, a drug resistance test was carried out on the gastric specimen. An L 595F mutation in UL97 was found.

The UL97 gene regulates the phosphorylation of the ganciclovir associated with resistance to it. We then began treatment with intravenous foscarnet and specific anti-CMV immunoglobulin 200mg/kg every three weeks. The patient became asymptomatic after 10 days of treatment with normal leukocyte count. The complications of this treatment included transient acute kidney failure at two weeks, with hypomagnesaemia and hypokalaemia.

The treatment continued for one month, followed by valganciclovir and foscarnet every 48 hours until the therapeutic levels of valganclovir were confirmed. Since then, the patient has remained asymptomatic and with excellent kidney function, six months after the episode.

The difficulty in diagnosing CMV Diease in this case was because of the false negative CMV viral load test requiring the confirmation of CMV and its resistance on gastric tissue. The resistance of the treatment was probably enhanced by inadequate doses of valganciclovir, which stresses the importance of monitoring vanganciclovir levels to ensure an adequate treatment thus avoiding the development of resistance to the treatment.

1.- Eid AJ, Arthus SK, Deziel PJ, Wilhelm MP, Razonable RR.Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes.Clin Transplant. 2008;22(2):162-70. [Pubmed]
2.- Nogueira E, Ozaki Ks; Vomitaba H, Granato CF, Camara MO, Pacheco-Silva A. The emergence of cytomegalovirus resistance to ganciclovir therapy in kidney transplant recipients.Int Immunopharmacol. 2006 ,20(6):2031-7
3.-Boivin G, Goyette N, Gilbert E, Covington E. Analysis of Cytomegalovirus DNA Polymerase (UL54) Mutations in Solid Organ Transplant Patients Receiving Valganciclovir Ganciclovir Prophylaxis. J Med Virol 2005; 77: 425-429. [Pubmed]
4.- Cervera C. Pineda M, Linares L, marcos MA, Ant??n A, Cof??n F, Ricart MJ, Navasa M, P??rez-Villa F, Fumarola T, Moreno A. Impact of valganciclovir prophylaxis on the development of severe late-cytomegalovirus disease in high-risk solid organ transplant recipients.Transplant Proc. 2007 Sep;39(7):2228-30 [Pubmed]
5.- A. Asberga, , A. Humar , H. Rollagc, A. G. Jardined, H. Mouase, M. D. Pescovitz;D. Sgarabottog, M. Tuncerh, I. L. Noronhai and A. Hartmannj, on behalf of the VICTOR Study Group. Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients American Journal of Transplantation 2007; 7: 2106??2113
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