Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8 T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients

Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8 T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients

Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation

Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation

OPTN/SRTR 2011 Annual Data Report: Kidney

ABSTRACT  A shortage of kidneys for transplant remains a major problem for patients with end-stage renal disease. The number of candidates on the waiting list continues to increase each year, while organ donation numbers remain flat. Thus, transplant rates for adult wait-listed candidates continue to decrease. However, pretransplant mortality rates also show a decreasing trend. Many kidneys recovered for transplant are discarded, and discard rates are increasing. Living donation rates have been essentially unchanged for the past decade, despite introduction of desensitization, non-directed donations, and kidney paired donation programs. For both living and deceased donor recipients, early posttransplant results have shown ongoing improvement, driven by decreases in rates of graft failure and return to dialysis. Immunosuppressive drug use has changed little, except for the Food and Drug Administration approval of belatacept in 2011, the first approval of a maintenance immunosuppressive drug in more than a decade. Pediatric kidney transplant candidates receive priority under the Share 35 policy. The number of pediatric transplants peaked in 2005, and decreased to a low of 760 in 2011. Graft survival and short-term renal function continue to improve for pediatric recipients. Postransplant lymphoproliferative disorder is an important concern, occurring in about one-third of pediatric recipients.

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Página original: http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fajt.12019

Machine perfusion versus cold storage for the preservation of kidneys from donors >=65 years allocated in the Eurotransplant Senior Programme

Background

In the Eurotransplant Senior Programme (ESP), kidneys from donors aged ≥65 years are preferentially allocated locally and transplanted into patients aged ≥65 years on dialysis. The purpose of this study was to analyse whether the results of transplantation in the ESP can be improved by preservation of organs by hypothermic machine perfusion (MP) compared with simple cold storage (CS).

Methods

Overall, 85 deceased heart-beating donors ≥65 years of age were included in this analysis with follow-up until 1 year post-transplant. For each donor, one kidney was randomly assigned to preservation by CS and the contralateral kidney to MP from organ procurement until transplantation. Delayed graft function (DGF), primary non-function (PNF) and 1-year patient and graft survival rates were evaluated as primary and secondary endpoints.

Results

The median recipient age was 66 years in both groups and the median cold ischaemia time was 11 h for MP and 10.5 h for CS (P = 0.69). The DGF rate was 29.4% for MP and 34.1% for CS (P = 0.58). Only extended duration of cold ischaemia time was an independent risk factor for the development of DGF (odds ratio 1.2, P < 0.0001). PNF was significantly reduced (3.5% MP versus 12.9% CS, P = 0.02). The 1-year patient and graft survival rates were similar for MP and CS (94% versus 95% and 89 versus 81%, P > 0.05). The 1-year graft survival rate was significantly improved after MP in recipients who developed DGF (84% MP versus 48% CS, P = 0.01).

Conclusions

Continuous pulsatile hypothermic MP for kidneys from donors aged ≥65 years can reduce the rate of never-functioning kidneys and improve the 1-year graft survival rate of kidneys with DGF. In this small cohort, the known advantage of MP for the reduction of DGF could not be confirmed, possibly due to relatively short cold ischaemia times.

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Página original: http://ndt.oxfordjournals.org/cgi/content/short/27/12/4458?rss=1

Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients

Background: In renal transplant recipients, mammalian target of rapamycin (mTOR) inhibitors have been reported to protect against cytomegalovirus (CMV) disease. Here, we questioned whether mTOR inhibitors specifically influence human CMV-induced T-cell responses. Methods: We studied renal transplant recipients treated with prednisolone, cyclosporine A (CsA), and mycophenolate sodium (MPS) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus, which is an mTOR inhibitor (P/EVL; n=10), prednisolone/CsA (P/CsA; n=7), or prednisolone/MPS (P/MPS; n=9). All patients were CMV-IgG positive before transplantation. CMV reactivation was detectable in the first 6 months after transplantation and not thereafter. None of the patients included in this study suffered from CMV disease. Both CD27-CD8+ and CD27-CD28-CD4+ effector-type T-cell counts, known to be associated with CMV infection, were measured before transplantation and at 6 and 24 months after transplantation. Additionally, we determined both number and function of CMV-specific CD8+ T cells at these time points. Results: The number of total CD8+ T cells, CD27-CD8+ T cells, and CD28-CD4+ T cells increased significantly after switch to therapy with P/EVL but not after switch to P/CsA or P/MPS. Specifically, CMV-specific CD8+ T-cell counts significantly increased after switch to therapy with P/EVL. Furthermore, the mTOR inhibitor sirolimus strongly inhibited alloresponses in vitro, whereas it did not affect CMV-specific responses. Conclusion: We observed a significant increase in (CMV-specific) effector-type CD8+ and CD4+ T-cell counts in everolimus-treated patients. These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients. (C) 2012 Lippincott Williams & Wilkins, Inc.

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Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Everolimus_Treated_Renal_Transplant_Recipients.98779.pdf

Effects of HLA-Matched Blood Transfusion for Patients Awaiting Renal Transplantation

Background: HLA sensitization in potential renal transplant recipients hinders opportunities of receiving suitable organs. To alleviate this, we sought to determine if supplying closely HLA Class I matched leukodepleted blood would minimize sensitization. Methods: Patients received HLA selected or random units of packed red cells. Selected units were sourced from blood donors included in the British Bone Marrow Registry and had no HLA-A and HLA-B mismatches where available, or alternatively, no HLA antigens with more than five immunogenic triplet mismatches as determined by the HLAMatchmaker algorithm. Posttransfusion antibody screening confirmed development of de novo Class I and Class II HLA-specific IgG antibody(s) or increases in preexisting antibody levels of at least 20%. Results: Thirty-seven and 31 patients received HLA selected (mean, 2.5 units) and random (mean, 3.4 units) blood, respectively. A total of 20 of 37 (54.1%) patients receiving selected units and 10 of 31 (32.3%) patients receiving random units were previously sensitized. No patient receiving HLA selected units demonstrated any change in antibody levels. In patients who received random units, 7 of 31 demonstrated changes in antibody levels with three developing de novo HLA-specific antibodies and four an increase in panel reactive antibody (PRA) of at least 20% (P=0.002). Conclusions: The risk of developing HLA-specific antibody is significantly reduced in renal patients awaiting transplantation when transfused with HLA selected units of blood compared with random units. With planning, access to HLA typed blood is achievable as many blood transfusion centers recruit donors for stem cell donor registries.

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Página original: http://journals.lww.com/transplantjournal/Fulltext/2012/12150/Effects_of_HLA_Matched_Blood_Transfusion_for.6.aspx

HTLV-1 in Solid-Organ Transplantation: Current Challenges and Future Management Strategies

Human T-cell lymphotrophic virus (HTLV)-1 has been reported after solid-organ transplantation, with a related fatal outcome in less than five cases. The natural history of HTLV-1 transmission from donor to recipient is unknown in this setting, because available screening platforms are suboptimal in low-prevalence areas and there is a lack of long-term follow-up. Minimizing organ wastage due to false-positive screening and avoiding donor-derived HTLV-associated diseases remain the goal. To date, only six HTLV-naive organ recipients from four donors (only one had confirmed HTLV) have developed HTLV-associated disease after transplantation. All of these cases were described in countries or from donors from HTLV-endemic regions. To the best of our knowledge, there have been no reported cases of donor-derived HTLV-1–associated death after organ transplantation in the world. Based on data from low-prevalence countries (Europe and the United States) and the current shortage of donor organs, it appears plausible to authorize the decision to transplant an organ without the prior knowledge of the donor's HTLV-1 status. Currently, it is not possible to exclude such transmission and recipients should be informed of the possible inadvertent transmission of this (and other) infections at the time of consent. In those cases where HTLV-1 transmission does occur, there may be a therapeutic window in which use of antiviral agents (i.e., zidovudine and raltegravir) may be of benefit. The development of national/international registries should allow a greater understanding of the extent and consequences of transmission risk and so allow a more evidence-based approach to management.

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Página original: http://journals.lww.com/transplantjournal/Fulltext/2012/12150/HTLV_1_in_Solid_Organ_Transplantation___Current.1.aspx

Is Cytomegalovirus Prophylaxis Dispensable in Patients Receiving an mTOR Inhibitor-Based Immunosuppression? A Systematic Review and Meta-Analysis

Background: Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation. Cytomegalovirus causes increased morbidity, mortality, and reduced allograft survival. Prophylaxis may help control the virus but is associated with substantial side effects and does not completely prevent virus reactivation; relapses after cessation of the prophylaxis are frequent. Experimental and clinical data suggest that mTOR inhibitors may have an anti-CMV effect. Here, we present a meta-analysis of clinical trials after solid organ transplantation and describe potential mechanisms involved in the anti-CMV effect of mTOR-inhibitors. Methods: The current literature was reviewed for randomized controlled trials in solid organ transplantation comparing an mTOR-I with a non-mTOR-I (CNI based) treatment. The scientific quality of the trials was assessed by the Jadad score, the use of an effective allocation concealment (AC) and the existence of an intention-to-treat (ITT) analysis. Cytomegalovirus incidence was assessed in studies comparing 1) an mTOR-I-based with a CNI-based immunosuppression (10 trials, n=3,100 patients) and 2) an mTOR-I/CNI combination therapy with a CNI-based immunosuppression (15 trials, n=7,100 patients). Results: In the first meta-analysis, CMV events after solid organ transplantation occurred significantly more often under CNIs (RR=2.27). The second meta-analysis comparing the mTOR-I + CNI combination with a CNI treatment in 15 trials of kidney, heart, and liver transplantation showed again a higher CMV incidence when patients received an mTOR-I free immunosuppression (RR=2.45). Conclusions: mTOR-inhibitor treatment either alone or in combination with CNIs reduces significantly the CMV incidence after organ transplantation. With the use of an mTOR-inhibitor, CMV prophylaxis may be dispensible. (C) 2012 Lippincott Williams & Wilkins, Inc.

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Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Is_Cytomegalovirus_Prophylaxis_Dispensable_in.98791.pdf

The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3–8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.

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Página original: http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fj.1600-6143.2012.04334.x

Effect on Kidney Graft Survival of Reducing or Discontinuing Maintenance Immunosuppression After the First Year Posttransplant

Background. Data are scarce concerning the impact of maintenance immunosuppression dose reductions posttransplant. Methods. Graft survival according to dose reduction or discontinuation of calcineurin inhibitors or mycophenolate mofetil (MMF) after the first year posttransplant was evaluated in 25,045 patients undergoing kidney transplantation during 1996 to 2005. No patient in this analysis had experienced a rejection and all had good graft function before dose reduction. Results. Reduction of cyclosporine (CsA) dose to less than or equal to 150 mg/day, tacrolimus to less than or equal to 2 mg/day, or MMF to less than or equal to 1.0 g/day in patients on CsA or less than or equal to 0.5 g/day in patients on tacrolimus during the second year posttransplant was associated with a statistically significant reduction in graft survival (hazard ratios between 1.37 and 1.65). Withdrawal of CsA, tacrolimus, or MMF during year 2 was also associated with an increase in the risk of graft loss compared with continuing treatment (hazard ratio 1.52-1.73). Conclusions. This observational analysis indicates that in kidney transplant patients with good graft function, withdrawing maintenance CsA, tacrolimus or MMF, or reducing the dose of these agents below certain thresholds after the first year posttransplant is associated with a significant risk of graft loss. (C) 2008 Lippincott Williams & Wilkins, Inc.

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Página original: http://journals.lww.com/transplantjournal/Fulltext/2008/08150/Effect_on_Kidney_Graft_Survival_of_Reducing_or.1.aspx

Preformed Complement-Activating Low-Level Donor-Specific Antibody Predicts Early Antibody-Mediated Rejection in Renal Allografts

Background: Donor-specific anti-HLA antibodies (DSA) are a major cause of alloimmune injury. Transplant recipients with negative complement-dependent cytotoxic crossmatch (CDC-XM) and donor cell-based flow cytometric crossmatch (flow-XM) but low level DSA (i.e., by Luminex) have worse outcomes compared with nonsensitized patients. The aim of this study was to establish whether complement-activating ability in this low-level DSA, present before transplantation, as determined by this technique is important in dictating pathogenicity. Methods: We retrospectively studied 52 patients with preformed DSA detected by single-antigen flow cytometric fluorescent beads (SAFBs). Patients were transplanted using a steroid-sparing regimen consisting of alemtuzumab induction, 1 week of corticosteroids and tacrolimus monotherapy.Fifteen (29%) of 52 patients experienced antibody-mediated rejection (AMR), whereas 37 (71%) patients did not. There were no demographic differences between patients with AMR and those without. Pretransplant sera were retested using a modified (SAFB) assay, which detects the presence of the complement fragment C4d as a result of DSA-induced complement activation. Results: C4d+DSA were detected in 10 (19%) of 52 patients. Biopsy-proven AMR occurred in 7 (70%) of the 10 patients with C4d+DSA and in 8 (19%) of 42 patients with C4d-DSA. AMR-free survival was worse in patients with C4d+DSA (P<0.001). Conclusions: The ability of preformed, low-level, DSA to trigger C4d fixation in vitro in patients with negative conventional crossmatch tests is predictive for AMR. C4d SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression. (C) 2012 Lippincott Williams & Wilkins, Inc.

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Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Preformed_Complement_Activating_Low_Level.98796.pdf

Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up

Summary

Delayed graft function (DGF) has a negative impact on graft survival in donation after brain death (DBD) but not for donation after cardiac death (DCD) kidneys. However, older donor age is associated with graft loss in DCD transplants. We sought to examine the interaction between donor age and DGF in DBD kidneys. This is a single-center, retrospective review of 657 consecutive DBD recipients transplanted between 1990 and 2005. We stratified the cohort by decades of donor age and studied the association between DGF and graft failure using Cox models. The risk of graft loss associated with DGF was not significantly increased for donor age below 60 years (adjusted hazard ratio [aHR] 1.12, 1.51, and 0.90, respectively, for age <40, 41–50 and 51–60 years) but significantly increased after 60 years (aHR 2.67; P = 0.019). Analysis of death-censored graft failure yielded similar results for donor age below 60 years and showed a substantially increased risk with donors above 60 years (aHR 6.98, P = 0.002). This analysis reveals an unexpectedly high impact of older donor age on the association between DGF and renal transplant outcomes. Further research is needed to determine the best use of kidneys from donors above 60 years old, where DGF is expected.

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Página original: http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Ftri.12016