Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies

Introduction: the impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain. Methods: we conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs. Results: patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively; P = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9; P < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8; P = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group, P = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively; P = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient. Conclusion: our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome

Could a loss of memory T cells limit responses to hepatitis C virus (HCV) antigens in blood leucocytes from patients chronically infected with HCV before and during pegylated interferon-a and ribavirin therapy?

The proportions and activation status of T cells may influence responses to hepatitis C virus (HCV) and treatment outcome in patients receiving pegylated interferon (IFN)-a/ribavirin therapy. We confirmed that IFN-? enzyme-linked immunospot (ELISPOT) responses to HCV are poor in HCV patients and showed that responses to HCV and cytomegalovirus (CMV) antigens decrease during therapy. This was most apparent in patients with sustained virological response (SVR). Baseline frequencies of CD4+ effector memory (TEM) T cells were lower in SVR than non-SVR. Proportions of CD4+ and CD8+ TEM and terminally differentiated effector memory (TEMRA) T cells declined on therapy in SVR, as did proportions of Fas+ CD8+ TEMRA T cells. Baseline frequencies of programmed death (PD)-1-expressing CD4+ TEM and T EMRA T-cells were higher in SVR. Therapy increased percentages of PD-1+ CD4+ central memory (TCM) T cells and PD-1+ CD8+ TEM and TEMRA T cells in SVR. We conclude that successful therapy depletes circulating antigen-specific CD4+ T cell responses. This paralleled decreases in proportions of effector memory T cells and higher percentages of CD4+ TCM T cells expressing PD-1. © 2010 British Society for Immunology

Cyclosporine versus everolimus:effects on the glomerulus

<p>Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single-center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n=16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n=7). All patients had been on the above-described maintenance immunosuppression for 18months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7mL/min/1.73m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14g/24h, p=0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected.</p>