HLA Mismatches Remain Risk Factors for Acute Kidney Allograft Rejection in Patients Receiving Quadruple Immunosuppression With Anti-Interleukin-2 Receptor Antibodies

Wissing, Karl Martin; Fomegne, Guy; Broeders, Nilüfer; Ghisdal, Lidia; Hoang, Anh Dung; Mikhalski, Dimitri; Donckier, Vincent; Vereerstraeten, Pierre; Abramowicz, Daniel

doi:10.1097/tp.0b013e31816349b5

Cited by 44 publications

(33 citation statements)

References 35 publications

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“…Although this is much higher than the 10 to 15% rejection incidence reported with a comparable quadruple immunosuppressive regimen in low-risk patients, 1,16 it is similar to recent data from other studies involving HLA-sensitized patients. [7][8][9][10] Our study was not powered to reveal significant differences in graft survival between the ATG and daclizumab arms, but post hoc analysis of the total patient population revealed that, when compared with patients who remained rejection-free, both graft function and graft survival were significantly lower among patients who experienced rejection.…”

Section: Discussionmentioning

confidence: 36%

“…Moreover, despite the availability of potent immunosuppressive drugs such as tacrolimus and mycophenolate mofetil (MMF), the negative impact of AR episodes on graft survival has remained important. 1 Acute rejection typically occurs during the first weeks after transplantation, and consequently, to suppress lymphocyte func-tion, many kidney transplant recipients receive induction therapy with either lymphocyte-depleting rabbit antithymocyte globulin (ATG) or nondepleting IL-2 receptor-antagonizing monoclonal antibodies (IL2RA mAbs). 2 Both types of anti-lymphocytes are equally effective in lowrisk recipients (i.e., patients with no previous exposure to HLA antigens).…”

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confidence: 99%

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Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

Noël

Abramowicz²,

Durand³

et al. 2009

Journal of the American Society of Nephrology

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186

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Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) Ͼ30%; peak PRA Ͼ50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P ϭ 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P ϭ 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P ϭ 0.037). In conclusion, among high-immunologicalrisk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsyproven acute rejection, but there is no significant benefit to one-year graft or patient survival.

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Section: Discussionmentioning

confidence: 36%

mentioning

confidence: 99%

Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

Noël

Abramowicz²,

Durand³

et al. 2009

Journal of the American Society of Nephrology

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186

161

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“…Matching at the HLA-ABDR loci remains the cornerstone of deceased donor kidney allocation in Australia and worldwide because of the association between incremental HLA-ABDR mismatches and increased risk of rejection and/or graft loss after kidney transplantation (1)(2)(3). Although differences in HLA-DQ matching between donors and recipients have been shown to be associated with adverse graft outcomes, matching at the HLA-DQ locus is not explicitly considered in the allocation algorithm for deceased donor kidney transplantation (4,5).…”

Section: Introductionmentioning

confidence: 99%

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Lim

Chapman

Coates

et al. 2016

CJASN

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Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P,0.01), late rejections (occurring .6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).Conclusions HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

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“…[11] Basiliximab binds specifically and with high affinity to IL-2Ra (dissociation constant [K D ] of 0.1 nmol L) on antigen-activated T lymphocytes and competitively inhibits IL-2 binding to the receptor, thereby inhibiting IL-2-mediated proliferation of T lymphocytes, a critical step in the cellular immune response involved in allograft rejection. [8,9] The specific epitope on IL-2Ra to which basiliximab binds is the seven amino acid string E-R-I-Y-H-F-V at positions [116][117][118][119][120][121][122] in the extracellular domain of the a-chain, which includes three of the IL-2 contact sites at amino acids I-Y-H (positions 118-120). [8,9] The specific epitope on IL-2Ra to which basiliximab binds is the seven amino acid string E-R-I-Y-H-F-V at positions [116][117][118][119][120][121][122] in the extracellular domain of the a-chain, which includes three of the IL-2 contact sites at amino acids I-Y-H (positions 118-120).…”

Section: Pharmacodynamic Propertiesmentioning

confidence: 99%

Basiliximab

McKeage

McCormack²

2010

BioDrugs

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Basiliximab (Simulect) is a recombinant chimeric murine/human IgG1 monoclonal anti-interleukin-2 receptor antibody that is indicated for the prevention of acute organ rejection in adult and pediatric renal transplant recipients in combination with other immunosuppressive agents. Induction therapy with two doses (day 0 and day 4) of intravenous basiliximab as part of double- or triple-immunotherapy regimens in adult renal transplant recipients reduces acute rejection episodes without increasing the incidence of adverse events. Compared with rabbit-derived antithymocyte globulin (RATG), basiliximab is generally associated with similar efficacy in standard-risk patients, but reduced efficacy in high-risk patients. Initial results indicate that induction with basiliximab is associated with a higher rate of biopsy-proven acute rejection than alemtuzumab induction. Basiliximab is generally associated with a tolerability profile that is similar to that reported with placebo, and better than that reported with RATG. As with other induction agents, basiliximab has not demonstrated improved graft or patient survival over the long term (periods of up to 7 years). Basiliximab induction allows for reduced dosage of corticosteroids or calcineurin inhibitors, while maintaining adequate immunosuppression, thereby reducing the potential for adverse effects associated with these coadministered agents. Thus, basiliximab provides an effective, well tolerated option for the prophylaxis of acute renal transplant rejection.

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HLA Mismatches Remain Risk Factors for Acute Kidney Allograft Rejection in Patients Receiving Quadruple Immunosuppression With Anti-Interleukin-2 Receptor Antibodies

Cited by 44 publications

References 35 publications

Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Basiliximab

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