RESUMO
Transplant glomerulopathy (TG) is a lesion with specific morphology and strong evidence of an immune mechanism. The incidence of TG is approximately 20% by 5 years after transplantation. TG is characterized by proteinuria, hypertension and declining graft function. Appearances on light microscopy include thickened capillary walls and double contours, with reduplication or lamination of the glomerular basement membrane on electron microscopy. TG is associated with acute rejection, the antibody status before transplantation and de novo HLA antibodies. HLA class II and/or donor-specific antibodies incur additional risks. Desensitization protocols do not always prevent the development of TG in highly sensitized individuals. Associations between TG, past or current C4d and the presence of alloantibodies are recognised, however, C4d in the peri-tubular capillaries or glomeruli is not a prerequisite at the time of diagnosis. Clinical observation and animal models suggest that TG arises as a consequence of chronic endothelial cell (EC) injury by the humoral arm of the immune system. In some cases, this follows a period of EC accommodation after an episode of acute injury. Proposed treatments include augmentation of background immunosuppression, and trials of monoclonal therapies targeted at CD20-positive B cells are underway.
Assuntos
Nefropatias/etiologia , Glomérulos Renais/patologia , Transplante de Rim/imunologia , Complicações Pós-Operatórias/etiologia , Animais , Linfócitos B/imunologia , Complemento C4b/imunologia , Via Clássica do Complemento , Endotélio Vascular/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Antígenos HLA/imunologia , Humanos , Hipertensão Renal/etiologia , Imunossupressores/uso terapêutico , Incidência , Isoanticorpos/imunologia , Nefropatias/epidemiologia , Nefropatias/imunologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/imunologia , Transplante de Rim/patologia , Macaca fascicularis , Modelos Imunológicos , Fragmentos de Peptídeos/imunologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/prevenção & controle , Proteinúria/etiologia , Ratos , Ratos Endogâmicos LewRESUMO
BACKGROUND: The relationship between humoral rejection and human leukocyte antigen (HLA) antibodies is established. Proteinuria is the hallmark of glomerular injury. The relationship between HLA antibody and proteinuria was explored in renal transplant recipients developing de novo donor-specific antibodies (DSA) and nondonor-specific antibodies (NDSA). METHODS: Seventy-two patients with de novo HLA antibody (38 DSA and 34 NDSA) were identified from 475 prevalent renal transplant recipients (15.2%). Antibody surveillance occurred every 6 months, with specificity characterized by a combination of enzyme-linked immunosorbent assay, flow-bead cytometry, and Luminex bead analysis. Pooled analysis of every glomerular filtration rate (GFR) and urinary protein estimation in a 48-month window around the date of antibody detection was performed (4004 and 2084 measurements, respectively). RESULTS: GFR slope (-5.85 vs. -3.21 mL/min/1.73 m per year) and graft failure rate (29% vs. 9%, P=0.039) were worse in patients with DSA. Three-year graft survival after antibody detection was worse in patients with DSA (69.5% vs. 91.1%, P=0.035). Patients with DSA had significantly more proteinuria than those with NDSA and 205 control patients with no alloantibodies, from 6 months before antibody detection (0.91 vs. 0.39 g/L, P=0.015). Graft failure was more likely in patients with DSA with excess of 0.2 g/L at antibody detection (42% vs. 0%, P=0.008). CONCLUSIONS: Proteinuria is associated with DSA detection and is likely to be an important factor that determines rapid GFR decline and earlier graft failure in patients developing de novo HLA antibodies.