Toward personalized medicine in renal transplantation.

BACKGROUND: The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. METHODS: Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with χ2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. RESULTS: Two patient groups were identified to show a difference in TRL dose requirements: a control (0.014-0.10 mg/kg/per day) and an high-dose group (0.14-0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P=.01 and P=.04) with the need for higher immunosuppressive doses (>0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. CONCLUSION: Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose.

Prophylactic therapy with valganciclovir in high-risk (cytomegalovirus D+/R-) kidney transplant recipients: a single-center experience.

BACKGROUND: A prospective study was performed in kidney transplant patients at risk of developing cytomegalovirus (CMV) infection (CMV D+/R-). They were treated with valganciclovir (VGC) for 3 months as prophylactic therapy. The aim was to determine the safety and efficacy of prophylactic therapy with VGC. METHODS: Antigenemia and/or polymerase chain reaction CMV was routinely performed every 2 weeks up to month 3, monthly to month 6, and every other month until the end of the first year posttranplantation, as well as when clinically indicated. RESULTS: From July 2007 to April 2010, 366 renal transplantations were performed at our center, including 34 (9%) high-risk patients for CMV infection. The median age was 47 years; 19 were males and 15 females. Twelve (35%) patients developed CMV infections: 10 (34%) gastrointestinal disease and 3 viral syndromes. The timing of the clinical manifestations was 16% (3/12) between months 1 and 3, 75% (8/12) between months 4 and 6, and 8% (1/12) in month 9 posttransplantation. CONCLUSION: Treatment with intravenous ganciclovir followed by oral VGC was successful in all patients. No opportunistic infections or allograft rejection were observed; only 1 patient developed thrombocytopenia as an adverse event to VGC.

Combination of everolimus and tacrolimus in kidney transplant patients with intolerance to mycophenolate mofetil/mycophenolic acid.

OBJECTIVE: Most immunosuppressive protocols in de novo renal transplantation include tacrolimus in combination with mycophenolate mofetil/mycophenolic acid (MMF/MPA) and prednisone. A variable percentage of patients show intolerance to MMF/MPA needing a reduction, interruption, or suspension of the drug, thereby exposing the patient to a greater risk of a rejection episode. The association of everolimus and tacrolimus may prove to be an alternative option in such cases. The aim of this study was to present our clinical experience, evaluating the incidence of graft rejection. PATIENTS AND METHODS: We performed a descriptive study of 19 kidney transplant patients from 2001-2008 who were treated with tacrolimus, MMF/MPA, and prednisone and displayed gastrointestinal or hematological adverse events to MMF/MPA, which were addressed with everolimus. We analyzed parameters up to 2 years after the change. RESULTS: The doses and levels of everolimus were increased progressively. At the same time, we decreased the doses and levels of tacrolimus. Renal function remained stable during the period and there was no case of a rejection episode during the 2 years. Only 5 patients (26%) showed side effects which were attributable to everolimus; 36% of patients required starting and/or increasing the erythropoietin dose, 15% required iron supplements, 15% required diuretics, and 31% began or increased treatment with statins. CONCLUSION: Our experience suggested that a combination of tacrolimus and everolimus may be a safe, effective alternative for kidney transplant patients who show intolerance to MMF/MPA.

Conversion to everolimus in kidney transplant recipients with decreased renal function.

Whenever graft function is good and proteinuria is under control, many reports describe the efficacy and safety of the conversion to Everolimus (EVL) among stable kidney recepients, simultaneously withdrawing the calcineurin inhibitor (CNI). However, there are few publications that evaluate the role of EVL in patients with decreased renal function. We describe our experience with 22 stable renal transplant recipients whose serum creatinine concentrations were >2 mg/dL and proteinuria <1000 mg/24 h who underwent an abrupt switch from a CNI to EVL. Conversion was simple, well-tolerated, and safe using an initial dose of 1-3 mg/d that was sufficient to achieve the recommended levels of 3-8 ng/dL. The adverse events were expected; most of them were of medium intensity. Globally, over the 24 months follow-up, there was improved renal function despite the initial creatinine. The improvement was greater when the switch was performed during the first year after transplantation. Two patients lost their grafts after a dramatic evolution with development of nephrotic syndrome and increasing creatinine. In our experience, conversion to EVL is a safe alternative among patients with chronic allograft nephropathy or nephrotoxicity due to CNI, even in patients with significantly decreased renal function at the time of the switch.

[Herpes simplex virus encephalitis in a renal transplant patient]. / Encefalitis por virus herpes simple en paciente portadora de trasplante renal. Estudio de un caso y revisión de la literatura.

The incidence of herpes simplex virus (HSV) encephalitis is estimated to occur annually in 2-4 cases per million population. HSV encephalitis is exceptional in renal transplant patients, we have found two previous reports after an extensive bibliography search. We report a case of a 47 years old women renal transplant recipient who presented 3 months after transplantation fever, stupor and aphasia. The diagnosis HSV encephalitis was achieved by PCR in cerebrospinal fluid and magnetic resonance imaging. She was treated with aciclovir for 4 weeks and recovered completely without neurologic sequelae.

Encefalitis por virus herpes simple en paciente portadora de trasplante renal. Estudio de un caso y revisión de la literatura / Herpes simplex virus encephalitis in a renal transplant patient

La incidencia estimada de encefalitis por virus herpes simple (VHS) es de 2-4casos anuales por millón de población general. La encefalitis por VHS en pacientestrasplantados es una complicación muy poco frecuente, de la que sólo hemosencontrado dos citas en la revisión bibliográfica realizada.Presentamos el caso de una paciente de 47 años que a los 3 meses del trasplanterenal presentó un cuadro de fiebre, estupor y afasia debido a una encefalitispor VHS. El diagnóstico se realizó mediante PCR en líquido cefalorraquídeoy resonancia magnética cerebral. La paciente fue tratada con aciclovir, recuperándosesin secuelas clínicas

The incidence of herpes simplex virus (HSV) encephalitis is estimated to occurannually in 2-4 cases per million population. HSV encephalitis is exceptional inrenal transplant patients, we have found two previous reports after an extensivebibliography search.We report a case of a 47 years old women renal transplant recipient who presented3 months after transplantation fever, stupor and aphasia. The diagnosis HSVencephalitis was achieved by PCR in cerebrospinal fluid and magnetic resonanceimaging. She was treated with aciclovir for 4 weeks and recovered completely withoutneurologic sequelae

Encefalitis por virus herpes simple en paciente portadora de trasplante renal. Estudio de un caso y revisión de la literatura / Herpes simplex virus encephalitis in a renal transplant patient

La incidencia estimada de encefalitis por virus herpes simple (VHS) es de 2-4casos anuales por millón de población general. La encefalitis por VHS en pacientestrasplantados es una complicación muy poco frecuente, de la que sólo hemosencontrado dos citas en la revisión bibliográfica realizada.Presentamos el caso de una paciente de 47 años que a los 3 meses del trasplanterenal presentó un cuadro de fiebre, estupor y afasia debido a una encefalitispor VHS. El diagnóstico se realizó mediante PCR en líquido cefalorraquídeoy resonancia magnética cerebral. La paciente fue tratada con aciclovir, recuperándosesin secuelas clínicas

The incidence of herpes simplex virus (HSV) encephalitis is estimated to occurannually in 2-4 cases per million population. HSV encephalitis is exceptional inrenal transplant patients, we have found two previous reports after an extensivebibliography search.We report a case of a 47 years old women renal transplant recipient who presented3 months after transplantation fever, stupor and aphasia. The diagnosis HSVencephalitis was achieved by PCR in cerebrospinal fluid and magnetic resonanceimaging. She was treated with aciclovir for 4 weeks and recovered completely withoutneurologic sequelae

Safety and efficacy of tacrolimus rescue therapy in 55 kidney transplant patients treated with cyclosporine.

To evaluate the efficacy and safety of conversion from cyclosporine to tacrolimus, we analyzed 55 kidney transplant patients who were converted due to cosmetic reasons in 42 patients, acute rejection in 2 patients, and other causes in 11 patients. At the doses and levels used, the development of diabetes mellitus was minimized. Disappearance of cosmetic side-effects and improvement of cardiovascular risk factors, together with conservation of renal function, encourage us to use tacrolimus as an efficacious and safe immunosuppressive therapy.

Análisis estadístico de la incidencia de cánceres "de novo" en pacientes trasplantados renales: una nueva metodología de estudio / Statistic analysis of cancer "de novo" incidence in renal transplant patients: a new study

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Presentación de cánceres en receptores trasplantados con órgano sólido / No disponible

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Alteraciones identificadas en la genética molecular de los trastornos tubulares que afectan al transporte de agua y electrolitos / Molecular basis of inherited tubular disorders affecting electrolytes and water transport

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Valoración del tratamiento sustitutivo integrado en pacientes en insuficiencia renal terminal: selección versus elección / Assessment of integrated replacement therapy in patients with terminal renal insufficiency: selection vs election

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A randomized trial comparing cyclosporine and steroids with cyclosporine, azathioprine, and steroids in cadaveric renal transplantation.

BACKGROUND: In renal transplantation, triple-drug therapy (low-dose cyclosporine [CsA] combined with azathioprine plus steroids) has been replacing double-drug therapy (CsA plus steroids) in clinical practice without much evidence in favor of either therapy. Previous trials comparing the two immunosuppressive regimens gave conflicting results. We attempted to determine whether triple therapy is at least equivalent to double therapy. METHODS: A randomized trial was performed in 250 adult cadaveric renal transplant recipients, comparing double therapy (CsA [10 mg/kg/day] plus prednisone) with triple therapy (CsA [6 mg/kg/day] plus azathioprine plus prednisone). The median follow-up time was 930 days. RESULTS: The incidence of acute rejection episodes refractory to treatment was 11% in double therapy and 4% in triple therapy (relative risk reduction: 64%; 95% confidence interval: 5-100%; P=0.035). Patients in the double therapy group required more intensive antirejection treatment, and their pathologic lesions were more severe. The proportion of patients with acute rejection was similar (double therapy: 45% vs. triple therapy: 40%) as was the incidence of chronic renal dysfunction (double therapy: 17% vs. triple therapy: 15.5%), the 4-year graft survival (double therapy: 71% vs. triple therapy: 83%, P=0.089), and patient survival (double therapy: 94% vs. triple therapy: 93%). In 29 patients (23%), 35 episodes of azathioprine-induced leukopenia were recorded, and in 9 of them azathioprine had to be discontinued. The incidence of other adverse events did not differ between the groups. CONCLUSIONS: Triple therapy caused fewer episodes of refractory acute rejection episodes and was as efficacious and safe as double therapy.