Intravenous Immunoglobulin Reduces Anti-HLA Alloreactivity and Shortens Waiting Time to Cardiac Transplantation in Highly Sensitized Left Ventricular Assist Device Recipients

John, Ranjit; Lietz, Katherine; Burke, Elizabeth; Ankersmit, Jan; Mancini, Donna; Suciu‐Foca, Nicole; Edwards, Niloo M.; Rose, Eric A.; Öz, Mehmet C.; Itescu, Silviu

doi:10.1161/01.cir.100.suppl_2.ii-229

Cited by 105 publications

(83 citation statements)

References 26 publications

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“…The use of plasmapheresis and IVIG likely impacted on the depth without affecting breadth (hence, although some patients did not have a large change in percentage PRA, that does not mean antibody quantity was not reduced). Moreover, whereas the degree of antibody reduction after IVIG has been shown to be time-dependent with maximal reduction at 1 week after treatment, 21 higher doses have been shown to have a more permanent effect on antibody reduction, and continued use after transplant might be effective because of its potent antiinflammatory effect where antibody-mediated mechanisms are present. 28 Nonetheless, even with pretreatment, continuing interventions after transplantation are clearly required to control rebound B-cell and plasma cell activity to prevent AMR as has been reported by others.…”

Section: Pretreatmentmentioning

confidence: 99%

Pediatric Heart Transplantation in Human Leukocyte Antigen–Sensitized Patients

Pollock-BarZiv

Hollander²,

Ngan³

et al. 2007

Circulation

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Background— There is an elevated risk for poor outcomes after heart transplant (HTx) in patients sensitized to human leukocyte antigens including graft dysfunction, acute cellular and antibody-mediated (AMR) rejection, and cardiac allograft vasculopathy. We report our experience with human leukocyte antigens–sensitized pediatric HTx recipients. Methods and Results— We identified pediatric HTx patients with elevated pre-HTx Panel Reactive Antibody (Class I/II; >10%), or a positive T- or B-cell crossmatch. Thirteen patients met criteria (5 female, 39%). The median age at HTx was 7 months (3.5 months to 15.5 years). Nine were infants who had prior palliation for congenital heart disease. Four were older patients (median 7.3 years; 4.8 to 15.5 years): 2 had congenital heart disease (Fontan), 2 were re-HTx. B-cell therapies were used in all patients, guided by assessment of CD19+ and CD20+ cells. Immunosuppression included thymoglobulin induction, and tacrolimus, mycophenolate mofetil, and steroids. Daily plasmapheresis ± intravenous immunoglobulin G was used if there was a positive crossmatch on day 1, with a gradual, biopsy-guided weaning schedule. Rituximab was used when AMR was detected on biopsy: more recently (n=3), used empirically perioperatively. AMR was confirmed in 9 patients within median 0.9 months post-HTx. Seven had early acute cellular rejection (≥ ISHLT Grade 2 R) with no hemodynamic compromise or graft dysfunction. There were 4 deaths post-HTx (range, 11 days to 9 months). The median follow-up of 9 survivors was 1.7 years (0.3 to 3.7 years). Of 7 patients >6 months post-HTx, no AMR or cardiac allograft vasculopathy was observed at a mean of 1.9+1.1 years post-HTx and no cardiac allograft vasculopathy. Conclusions— Despite aggressive management, acute cellular rejection and AMR occurred frequently early post-HTx. An algorithm of B cell–directed strategies can be effective in managing these patients with reasonable intermediate-term outcomes.

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Section: Pretreatmentmentioning

confidence: 99%

Pediatric Heart Transplantation in Human Leukocyte Antigen–Sensitized Patients

Pollock-BarZiv

Hollander²,

Ngan³

et al. 2007

Circulation

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“…We have previously demonstrated that this regimen, when given before the transplant, reduces the waiting time to the level in nonsensitized patients. 21 The posttransplant use of cyclophosphamide has also prevented induction of anti-HLA class II antibodies, prolonged the rejection-free interval, and reduced cumulative rejections to levels in nonsensitized patients. 22 The results of this study imply that taken together, these therapeutic strategies have reduced the adverse outcomes conferred by sensitization.…”

Section: Discussionmentioning

confidence: 99%

Impact of Current Management Practices on Early and Late Death in More Than 500 Consecutive Cardiac Transplant Recipients

John¹,

Rajasinghe²,

Chen³

et al. 2000

Annals of Surgery

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ObjectiveTo study risk factors for early and late death after heart transplantation in the current era. Summary Background DataThe current cardiac transplant population differs from earlier periods in that an increasing number of sicker patients, such as those with ventricular assist device (LVAD) support, prior cardiac allotransplantation, and pulmonary hypertension, are undergoing transplantation. In addition, sensitized patients constitute a greater proportion of the transplanted population. Emphasis has been placed on therapies to prevent early graft loss, such as the use of nitric oxide and improved immunosuppression, in addition to newer therapies. MethodsFive hundred thirty-six patients undergoing heart transplantation between 1993 and 1999 at a single center were evaluated (464 adults and 72 children; 109 had received prior LVAD support and 24 underwent retransplantation). The mean patient age at transplantation was 44.9 years. Logistic regression and Cox proportional hazard models were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, LVAD, retransplantation, pretransplant pulmonary vascular resistance, and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies). ResultsThe rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children. The actuarial survival rate of the 536 patients was 83%, 77%, and 71% at 1, 3, and 5 years, respectively, by Kaplan Meier analysis. Risk factors adversely affecting survival included the year of transplant, donor age, and donor-recipient gender mismatching. Neither early nor late death was influenced by elevated pulmonary vascular resistance, sensitization, prior LVAD support, or prior cardiac allotransplantation. ConclusionsPreviously identified risk factors did not adversely affect shortor long-term survival of heart transplant recipients in the current era. The steady improvement in survival during this period argues that advances in transplantation have offset the increasing acuity of transplant recipients.

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“…28 Although IVIg stimulates the production of IgM anti-idiotypic-blocking antibodies to HLA in recipient serum, 12 this immunomodulatory mechanism is unlikely to account for the rapid, transient, and nonsustained clinical effect on reduction in anti-HLA alloreactivity that has been observed when using IVIg in sensitized cardiac transplant recipients. 29 In contrast, our combined IVIg/intravenous cyclophosphamide regimen seemed to have a prolonged inhibitory effect on CD4 T-cell activation, as defined by sustained prevention of both T-cell-mediated allograft rejection and induction of anti-HLA class II antibodies after transplantation. This immunomodulatory effect suggests that the principal component of the regimen responsible for these effects is cyclophosphamide.…”

Section: Discussionmentioning

confidence: 76%

Intravenous Pulse Administration of Cyclophosphamide Is an Effective and Safe Treatment for Sensitized Cardiac Allograft Recipients

et al. 2002

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Background-The proportion of cardiac transplant recipients with preexisting sensitization to HLA alloantigens has been increasing. Sensitization prolongs duration to obtaining a donor and predicts poorer long-term allograft survival because of increased risk of cellular rejections. We investigated the effect of cyclophosphamide pulse therapy in sensitized cardiac allograft recipients. Methods and Results-Pretransplant and posttransplant outcomes were compared between 88 cardiac allograft recipients at risk for sensitization and 26 sensitized recipients treated with intravenous cyclophosphamide pulse therapy together with intravenous immune globulin before transplant and as part of a cyclosporine-based triple immunosuppressive regimen after transplant. Preformed IgG anti-HLA antibodies predicted longer duration to transplantation, earlier cellular rejection, and 2.7-fold higher cumulative rejection frequency (Pϭ0.002). Before transplant, cyclophosphamide reduced waiting time and mortality to levels in nonsensitized patients. After transplant, cyclophosphamide prevented induction of IgG anti-HLA class II antibodies and interleukin-2 receptor-positive T-cell outgrowth from biopsy sites (both PϽ0.01), prolonged the rejection-free interval (Pϭ0.009), and reduced cumulative rejections to levels in nonsensitized patients (Pϭ0.003). By multivariable analysis, the risk of rejection was 3.7-fold higher in patients treated with mycophenolate mofetil than patients treated with cyclophosphamide (Pϭ0.019). There were no differences in infectious or other significant complications. Conclusions-Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized cardiac transplant recipients. When used after transplantation as part of triple immunosuppression, cyclophosphamide is superior to mycophenolate mofetil in reducing rejection. The mechanism may involve prevention of diversification of the recipient immune response to donor HLA class II molecules.

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Intravenous Immunoglobulin Reduces Anti-HLA Alloreactivity and Shortens Waiting Time to Cardiac Transplantation in Highly Sensitized Left Ventricular Assist Device Recipients

Cited by 105 publications

References 26 publications

Pediatric Heart Transplantation in Human Leukocyte Antigen–Sensitized Patients

Pediatric Heart Transplantation in Human Leukocyte Antigen–Sensitized Patients

Impact of Current Management Practices on Early and Late Death in More Than 500 Consecutive Cardiac Transplant Recipients

Intravenous Pulse Administration of Cyclophosphamide Is an Effective and Safe Treatment for Sensitized Cardiac Allograft Recipients

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