Tailored immunosuppression after kidney transplantation - a single center real-life experience.

BACKGROUND: Kidney allograft survival continuously improved with introduction of novel immunosuppressants. However, also immunologically challenging transplants (blood group incompatibility and sensitized recipients) increase. Between 2006 and 2008, a new tailored immunosuppression scheme for kidney transplantation was implemented at the University Hospital in Zurich, together with an ABO-incompatible transplant program and systematic pre- and posttransplant anti-human leukocyte antigen (HLA) antibody screening by Luminex technology. This study retrospectively evaluated the results of this tailored immunosuppression approach with a particular focus on immunologically higher risk transplants. METHODS: A total of 204 consecutive kidney transplantations were analyzed, of whom 14 were ABO-incompatible and 35 recipients were donor-specific anti-HLA antibodies (DSA) positive, but complement-dependent cytotoxicity crossmatch (CDC-XM) negative. We analyzed patient and graft survival, acute rejection rates and infectious complications in ABO-compatible versus -incompatible and in DSA positive versus negative patients and compared those with a historical control group. RESULTS: Overall patient, death-censored allograft survival and non-death-censored allograft survival at 4 years were 92, 91 and 87%, respectively. We found that (1) there were no differences between ABO-compatible and -incompatible and between DSA positive and DSA negative patients concerning acute rejection rate and graft survival; (2) compared with the historical control group there was a significant decrease of acute rejection rates in sensitized patients who received an induction with thymoglobulin; (3) there was no increased rate of infection among the patients who received induction with thymoglobulin compared to no induction therapy. CONCLUSIONS: We observed excellent overall mid-term patient and graft survival rates with our tailored immunosuppression approach. Induction with thymoglobulin was efficient and safe in keeping rejection rates low in DSA positive patients with a negative CDC-XM.

Kidney paired donation: a plea for a Swiss National Programme.

Growing incidence of end-stage renal disease, shortage of kidneys from deceased donors and a better outcome for recipients of kidneys from living donor have led many centres worldwide to favour living donor kidney transplantation programmes. Although criteria for living donation have greatly evolved in recent years with acceptance of related and unrelated donors, an immunological incompatibility, either due to ABO incompatibility and/or to positive cross-match, between a living donor and the intended recipient, could impede up to 40% of such procedures. To avoid refusal of willing and healthy living donors, a number of strategies have emerged to overcome immunological incompatibilities. Kidney paired donation is the safest way for such patients to undergo kidney transplantation. Implemented with success in many countries either as national or multiple regional independent programmes, it could include simple exchanges between any number of incompatible pairs, incorporate compatible pairs and non-directed donors (NDDs) to start a chain of compatible transplantations, lead to acceptance of ABO-incompatible matching, and integrate desensitising protocols. Incorporating all variations of kidney paired donation, the Australian programme has been able to facilitate kidney transplantation in 49% of registered incompatible pairs. This review is a plea for implementing a national kidney paired donation programme in Switzerland.

Late antibody-mediated rejection by de novo donor HLA-DP-specific antibody after renal transplantation: a case report.

The role of donor HLA-DP-specific antibodies after renal transplantation is controversial, and only preformed HLA-DP-specific antibodies have been shown to mediate rejection. Here we present a case of late humoral rejection mediated by de novo donor HLA-DP-specific antibodies in a non-sensitized recipient. This unique case demonstrates the pathogenic role of de novo anti-DP antibodies and suggests that HLA-DP matching might be relevant for renal transplantation.

Donor-specific anti-HLA antibodies detected by Luminex: predictive for short-term but not long-term survival after heart transplantation.

In heart transplantation, the clinical significance of pretransplant donor-specific antibodies (DSA) detected by solid phase assay (SPA), which is more sensitive than the conventional complement-dependent cytotoxicity (CDC) assays, is unclear. The aim was to evaluate SPA performed on pretransplant sera for survival after heart transplantation. Pretransplant sera of 272 heart transplant recipients were screened for anti-HLA antibodies using CDC and SPA. For determination of pretransplant DSA, a single-antigen bead assay was performed. The presence of anti-HLA antibodies was correlated with survival. Secondary outcome parameters were acute cellular rejection, graft coronary vasculopathy and ejection fraction. In Kaplan-Meier analysis, SPA-screening did not predict survival (P = 0.494), this in contrast to CDC screening (P = 0.002). However, the presence of pretransplant DSA against HLA class I was associated with decreased short-term survival compared to non-DSA (P = 0.038). ROC curve analysis showed a sensitivity of 76% and specificity of 73% at a cutoff of 2000 MFI. In contrast, the presence of anti-HLA antibodies had no influence on long-term survival, rejection incidence, and graft function. Thus, detection of DSA class I in pretransplant serum is a strong predictor of short-term, but not long-term survival and may help in the early management of heart transplant patients.

Donor-specific antibody levels and three generations of crossmatches to predict antibody-mediated rejection in kidney transplantation.

BACKGROUND: This study evaluated the prognostic impact of pretransplant donor-specific anti-human leukocyte antigen antibodies (DSA) detected by single-antigen beads and compared the three generations of crossmatch (XM) tests in kidney transplantation. METHODS: Thirty-seven T-cell complement-dependent cytotoxicity crossmatch (CXM) negative living donor kidney recipients with a retrospectively positive antihuman leukocyte antigen antibody screening assay were included. A single-antigen bead test, a flow cytometry XM, and a Luminex XM (LXM) were retrospectively performed, and the results were correlated with the occurrence of antibody-mediated rejections (AMRs) and graft function. RESULTS: We found that (1) pretransplant DSA against class I (DSA-I), but not against class II, are predictive for AMR, resulting in a sensitivity of 75% and a specificity of 90% at a level of 900 mean fluorescence intensity (MFI); (2) with increasing strength of DSA-I, the sensitivity for AMR is decreasing to 50% and the specificity is increasing to 100% at 5200 MFI; (3) the LXM for class I, but not for class II, provides a higher accuracy than the flow cytometry XM and the B-cell CXM. The specificity of all XMs is increased greatly in combination with DSA-I values more than or equal to 900 MFI. CONCLUSIONS: In sensitized recipients, the best prediction of AMR and consecutively reduced graft function is delivered by DSA-I alone at high strength or by DSA-I at low strength in combination with the LXM or CXM.

Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses.

Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.

Rituximab and intravenous immunoglobulin treatment of chronic antibody-mediated kidney allograft rejection.

Kidney transplant rejections are classified into T-cell-mediated and antibody-mediated rejections (AMR). C4d staining on allograft biopsies and solid-phase assays to measure donor-specific alloantibodies have helped to precisely define the latter. Although for acute AMRs, therapy mainly relies on plasmapheresis or immunoadsorption, no studies for treatment of chronic AMR are available. Here, we report on four kidney allograft recipients suffering from chronic AMR 1 to 27 years posttransplant, who were treated with a combination of rituximab and intravenous immunoglobulin (IVIG). Rituximab/IVIG improved kidney allograft function in all four patients, whereas donor-specific antibodies were reduced in 2 of 4 patients. However, in one patient an acute rejection episode occurred 12 months after this treatment, and another patient had severe, possibly rituximab-associated lung toxicity. Thus, rituximab/IVIG may be a useful strategy for the treatment of chronic AMR, but further randomized multicenter studies are necessary to establish its efficacy and safety profile.