The role of pre-transplant antibodies in predicting chronic renal allograft injury

Continued rise in the incidence of late graft loss despite better immunosuppression and improvement in acute rejection rates has led to renewed interest in the effect of HLA antibodies on long term graft outcomes. The significance of pre—transplant HLA antibodies detected by the widely used CDC assay on early graft outcomes is well studied. However, a lot remains unknown about effects of pre—transplant antibodies detected by sensitive solid phase assays on early and late graft outcomes. This is due to increased use of these assays resulting in better detection of HLA and non HLA antibodies. Such antibodies are thought to be of low affinity and avidity. In addition, low sensitivity of conventional techniques for diagnosis of antibody mediated graft injury results in late diagnosis when interventions are unlikely to reverse graft failure. This thesis examines 3 aspects of antibody mediated graft injury, 1) effects of pre-transplant antibodies detected by Luminex (a solid phase assay) on histology and graft function outcomes, 2) use of electron microscopy in early diagnosis of chronic antibody mediated injury, and 3) the potential role of mycophenolate mofetil in amelioration of chronic graft injury

Epithelial-to-Mesenchymal Transition in Early Transplant Tubulointerstitial Damage

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation. Detection of EMT depended on the marker used; low levels of α-smooth muscle actin were found in 61% of biopsies, but the less specific marker S100 calcium binding protein-A4 (also known as Fsp1) suggested a higher incidence of EMT. The presence or development of TID did not correlate with EMT but instead significantly correlated with subclinical immune activity (P < 0.05). Among biopsies showing TID, microarray analysis revealed differential regulation of 127 genes at 1 mo and 67 genes at 3 mo compared with baseline; these genes were predominantly associated with fibrosis, tissue remodeling, and immune response. Of the 173 EMT-associated genes interrogated, however, only 8.1% showed an expression pattern consistent with EMT at 1 mo and 6.3% at 3 mo. The remainder were not differentially altered, or their changes in expression were opposite those expected to promote EMT. Quantitative reverse transcriptase–PCR revealed that the expression pattern of 12 EMT-associated genes was inconsistent over time, opposite that expected, or consistent with subclinical rejection or inflammation. In conclusion, EMT does not seem to play a significant role in the development of early allograft fibrosis

Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV

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