RESUMEN
AIM: Atypical haemolytic uraemic syndrome (aHUS) is a debilitating condition that can cause significant morbidity and mortality in children if not adequately and promptly treated. This report shares real-world data on the use of eculizumab in children with aHUS. METHODS: We report our experience with the use of eculizumab in 14 children with aHUS. RESULTS: The median age at aHUS diagnosis was 12 months (range: 2-108 months), with six (42.9%) patients presenting in infancy and six (42.9%) being males. Eculizumab therapy was associated with haematological and thrombotic microangiopathy responses in 14 (100%) and 13 (92.9%) patients after a median of 9 days (range: 7-12 days) and 9.5 days (range: 7-14 days), respectively. None of the six patients who were previously treated with plasma therapy required any further infusions. Of the six patients who previously required dialysis, only one patient continued to do so and eventually received a renal transplant. The median time to ≥25% decrease in serum creatinine level in the remaining patients was 16 days (range: 14-21 days), and estimated glomerular filtration rate increased from a median of 17-101 mL/min/1.73 m2 . The safety profile was similar to that reported in the literature, and 10 patients continue to receive therapy, with 3 being on the drug for 4 or more years. CONCLUSION: Our study adds to the growing body of evidence highlighting the efficacy and safety of eculizumab for the management of children with aHUS.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/farmacología , Evaluación de Resultado en la Atención de Salud , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Emiratos Árabes UnidosAsunto(s)
Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Linfadenopatía/etiología , Metástasis Linfática/diagnóstico , Sarcoma de Kaposi/diagnóstico , Biopsia , Niño , Diagnóstico Diferencial , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/etiología , Ganglios Linfáticos/patología , Linfadenopatía/tratamiento farmacológico , Linfadenopatía/patología , Metástasis Linfática/patología , Masculino , Síndrome Nefrótico/complicaciones , Sarcoma de Kaposi/complicaciones , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/patología , Sirolimus/uso terapéuticoAsunto(s)
Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Linfadenopatía/etiología , Profilaxis Antibiótica , Biopsia , Niño , Infecciones por Virus de Epstein-Barr/prevención & control , Infecciones por Virus de Epstein-Barr/virología , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Fallo Renal Crónico/etiología , Ganglios Linfáticos/patología , Linfadenopatía/patología , Masculino , Síndrome Nefrótico/complicaciones , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/virología , Valganciclovir/administración & dosificaciónRESUMEN
Immune cells utilize the IDO enzymatic conversion of trp to kyn to determine T-cell activation vs. anergy/apoptosis. In prior studies, urine IDO levels were higher in rejecting renal allografts than in stable state. However, urine IDO levels in healthy subjects or children are unknown. As a corollary to a larger longitudinal and prospective study of serum and urine IDO levels for transplant immune monitoring, here, we analyzed the difference between urine IDO levels in stable post-transplant vs. healthy children. IDO levels were measured by tandem mass spectrometry and expressed as kyn/trp ratios. We compared one-time urine samples, from 34 well children at general pediatric clinics, to the first-month post-transplant urine samples from 18 children, while in stable state (no acute rejection or major infection event in next 30 days). Urine kyn/trp ratios were significantly higher in stable children in first-month post-kidney transplant (median 16.6, range 3.9-44.0) vs. healthy children (median 9.2, range 3.51-17.0; p = 0.0057 by nonparametric Mann-Whitney test). Higher urine IDO levels even with stable transplant suggest a continuous ongoing low-grade allorecognition/inflammatory process. Our data also provide baseline urine IDO levels in healthy subjects for use in future studies.
Asunto(s)
Inmunosupresores/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/orina , Trasplante de Riñón/métodos , Insuficiencia Renal/cirugía , Insuficiencia Renal/orina , Adolescente , Anticuerpos/inmunología , Biopsia , Niño , Preescolar , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Antígenos HLA/inmunología , Humanos , Terapia de Inmunosupresión/métodos , Masculino , Prevalencia , Estudios Prospectivos , Receptores de TrasplantesRESUMEN
BACKGROUND: Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3-dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. METHODS: We prospectively tested 217 blood and 167 urine serial samples, collected monthly for 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR, MIE, or stable group (no events) in the next 30 days. RESULTS: Using absolute cutoffs and allocating to samples to AR, MIE, or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (P=0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (P=0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that, over time, serum kyn/trp ratios were higher before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). CONCLUSIONS: These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.
Asunto(s)
Adenosina Trifosfato/sangre , Linfocitos T CD4-Positivos/metabolismo , Enfermedades Transmisibles/etiología , Rechazo de Injerto/etiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Trasplante de Riñón/efectos adversos , Enfermedad Aguda , Adolescente , Análisis de Varianza , Biomarcadores/sangre , Biomarcadores/orina , Linfocitos T CD4-Positivos/inmunología , Niño , Enfermedades Transmisibles/sangre , Enfermedades Transmisibles/enzimología , Enfermedades Transmisibles/inmunología , Enfermedades Transmisibles/orina , Regulación hacia Abajo , Monitoreo de Drogas/métodos , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/enzimología , Rechazo de Injerto/inmunología , Rechazo de Injerto/orina , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/inmunología , Quinurenina/sangre , Quinurenina/orina , Estudios Longitudinales , Masculino , Espectrometría de Masas , Monitorización Inmunológica/métodos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Triptófano/sangre , Triptófano/orina , Regulación hacia ArribaRESUMEN
Surveillance testing for major viral infections such as CMV, EBV, and BKV early in their natural history course may allow for early intervention and prevention of FBVD, but the testing is expensive and optimal interval/frequency are uncertain. At our center we initiated routine monthly viral surveillance for CMV, EBV, and BKV in July 2008 for the first 12 months post-transplant. Here, we retrospectively analyzed for outcome of the patients who missed three or more surveillance tests in the first 12 months post-transplant vs. those who did not. Of 21 patients, five missed three or more surveillance tests. Two of those five developed FBVD (one BKV nephropathy and one EBV-PTLD). None of the 16 patients with more regular surveillance testing developed FBVD. The incidence of viral replication was similar in both groups. The odds ratio for FBVD if viral surveillance tests were missed was 23.57 (p-value of 0.047). In this small group of contemporaneous patients on identical immunosuppression, those patients who missed regular viral surveillance were more likely to develop FBVD. Prospective randomized trials to confirm the benefit of regular viral testing are recommended.
Asunto(s)
Virus BK , Infecciones por Citomegalovirus/prevención & control , Infecciones por Virus de Epstein-Barr/prevención & control , Trasplante de Riñón , Infecciones por Polyomavirus/prevención & control , Complicaciones Posoperatorias/prevención & control , Infecciones Tumorales por Virus/prevención & control , Adolescente , Virus BK/aislamiento & purificación , Niño , Preescolar , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/virología , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Oportunidad Relativa , Cooperación del Paciente , Infecciones por Polyomavirus/etiología , Infecciones por Polyomavirus/virología , Complicaciones Posoperatorias/virología , Estudios Retrospectivos , Resultado del Tratamiento , Infecciones Tumorales por Virus/etiología , Infecciones Tumorales por Virus/virología , Carga ViralRESUMEN
Infections have become as important an event as acute rejection posttransplant for long-term allograft survival. Less invasive biomarkers tested so far predict risk for one event or the other, not both. We prospectively tested blood and urine monthly for 12 months posttransplant from children receiving a kidney transplant. The IDO enzyme pathway was assessed by MS assays using the ratio of product l-kyn to substrate trp. Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with acute rejection or major infection events or stable group (no events) in the next 30 days. The 25 subjects experienced six discrete episodes of acute rejection in five subjects and 16 discrete events of major infection in 14 subjects (seven BK viruria, six cytomegaloviremia, one EB and cytomegaloviremia, and two transplant pyelonephritis). Mean serum kyn/trp ratios were significantly elevated in the group that experienced acute rejection (p = 0.02). Within-subject analyses revealed that over time, urine kyn/trp ratios showed an increase (p = 0.01) and blood CD4-ATP levels showed a decrease (p = 0.007) prior to a major infection event. These pilot results suggest that a panel of biomarkers together can predict over- or under-immunosuppression, but need independent validation.