RESUMEN
We determined peripheral blood (PB) and biopsy (Bx) RNA expression signatures in a Brazilian and US cohort of kidney transplant patients. Phenotypes assigned by precise histology were: acute rejection (AR), interstitial fibrosis/tubular atrophy/chronic rejection (CR), excellent functioning transplants (TX), and glomerulonephritis recurrence (GN). Samples were analyzed on microarrays and profiles from each cohort were cross-validated on the other cohort with similar phenotypes. We discovered signatures for each tissue: (1) AR vs TX, (2) CR vs TX, and (3) GN vs TX using the Random Forests algorithm. We validated biopsies signatures of AR vs TX (area under the curve [AUC] 0.97) and CR vs TX (AUC 0.87). We also validated both PB and Bx signatures of AR vs TX and CR vs TX with varying degrees of accuracy. Several biological pathways were shared between AR and CR, suggesting similar rejection mechanisms in these 2 clinical phenotypes. Thus, we identified gene expression signatures for AR and CR in transplant patients and validated them in independent cohorts of significantly different racial/ethnic backgrounds. These results reveal that there are strong unifying immune mechanisms driving transplant diseases and identified in the signatures discovered in each cohort, suggesting that molecular diagnostics across populations are feasible despite ethnic and environmental differences.
Asunto(s)
Biomarcadores/análisis , Etnicidad/genética , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Leucocitos Mononucleares/metabolismo , Transcriptoma , Adolescente , Adulto , Anciano , Biopsia , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Rechazo de Injerto/sangre , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenAsunto(s)
Lesión Renal Aguda/virología , Infecciones por Adenovirus Humanos/virología , Fiebre/virología , Trasplante de Riñón/efectos adversos , Nefritis Intersticial/virología , Infecciones Oportunistas/virología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inmunología , Infecciones por Adenovirus Humanos/diagnóstico , Infecciones por Adenovirus Humanos/tratamiento farmacológico , Infecciones por Adenovirus Humanos/inmunología , Adulto , Antivirales/uso terapéutico , Biopsia , Fiebre/diagnóstico , Fiebre/tratamiento farmacológico , Fiebre/inmunología , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Masculino , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/inmunología , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/inmunologíaRESUMEN
Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell-reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies.
Asunto(s)
Anticuerpos/sangre , Células Endoteliales/inmunología , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Trasplante de Riñón/inmunología , Brasil , Línea Celular , Pruebas Inmunológicas de Citotoxicidad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Prueba de Histocompatibilidad , Humanos , Inmunidad Humoral , Inmunoglobulinas Intravenosas/metabolismo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Sensitized patients (pts) may develop acute antibody-mediated rejection (AMR) due to preformed donor-specific antibodies, undetected by pre-transplant complement-dependent cytotoxicity (CDC) crossmatch (XM). We hypothesized that C4d staining in 1-h post-reperfusion biopsies (1-h Bx) could detect early complement activation in the renal allograft due to preformed donor-specific antibodies. METHODS: To test this hypothesis, renal transplants (n = 229) performed between June 2005 and December 2007 were entered into a prospective study of 1-h Bx and stained for C4d by immunofluorescence. Transplants were performed against a negative T-cell CDC-XM with the exception of three cases with a positive B-cell XM. RESULTS: All 229 1-h Bx stained negative for C4d. Fourteen pts (6%) developed AMR. None of the 14 protocol 1-h Bx stained positive for C4d in peritubular capillaries (PTC). However, all indication biopsies-that diagnosed AMR-performed at a median of 8 days after transplantation stained for C4d in PTC. CONCLUSIONS: These data show that C4d staining in 1-h Bx is, in general, not useful for the early detection of AMR when CDC-XM is negative.