RESUMEN
BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.
Asunto(s)
Anticuerpos/sangre , Glomerulonefritis por IGA/epidemiología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Adulto , Aloinjertos/inmunología , Aloinjertos/patología , Biopsia , Brasil/epidemiología , Europa (Continente)/epidemiología , Femenino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Supervivencia de Injerto , Humanos , Incidencia , Riñón/patología , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/cirugía , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adulto , Brasil , Europa (Continente) , Femenino , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Plasmaféresis , Recurrencia , Retratamiento , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Rituximab/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.
Asunto(s)
Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Antígenos CD/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Cadenas alfa de Integrinas/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
El trasplante renal de donante vivo permite una mejor individualización de la inmunosupresión sobre la base de criterios clínicos e inmunológicos. Por ejemplo, permite la administración de agentes inmunosupresores días antes del trasplante y prevenir así mejor el rechazo agudo en los casos en los que el riesgo inmunológico lo requiera. Dada la escasa evidencia al respecto, no se recomienda la inmunosupresión previa al trasplante de manera indiscriminada en todos los receptores. En los receptores HLA idénticos relacionados con su donante, se recomienda iniciar la pauta con tacrolimus y un derivado de ácido micofenólico y valorar la suspensión de tacrolimus a partir del sexto mes postrasplante. En las parejas no HLA idénticas, se recomienda inducción con basiliximab, excepto en aquellos de alto riesgo inmunológico, en los que se aconseja timoglobulina. La utilización de un riñón procedente de un donante con criterios expandidos requiere reducir la dosis habitual de tacrolimus para optimizar la función renal. En general, y dependiendo del riesgo inmunológico, se recomienda la suspensión de los esteroides a partir del tercero al sexto mes postrasplante. El trasplante renal de donante vivo con anticuerpos específicos de donante preformados o ABO-incompatible es posible mediante la realización de técnicas de desensibilización como la plasmaféresis o la inmuno adsorción específica, así como la administración de gammaglobulina o rituximab, además de la inmunosupresión convencional...