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Matthew McIntosh

Bio: Matthew McIntosh is an academic researcher. The author has contributed to research in topics: Transplantation & Survival analysis. The author has an hindex of 9, co-authored 11 publications receiving 2490 citations.

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Journal ArticleDOI
TL;DR: There has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors since 1988.
Abstract: Background The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. Methods We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. Results From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased...

1,723 citations

Journal ArticleDOI
TL;DR: It is concluded that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD awaiting kidney transplants.
Abstract: Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] > or =50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean +/- SEM serum creatinine of 1.68 +/- 0.28 for IVIG versus 1.28 +/- 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.

392 citations

Journal ArticleDOI
TL;DR: For recipients on cyclosporine/mycophenolate mofetil/P with no AR at 90 days, the chance of developing subsequent AR is small; if P is tapered and withdrawn, the risk increases, but the majority remain free of acute and chronic rejection.
Abstract: BACKGROUND Prospective randomized trials have shown a reduced rate of acute rejection (AR) in mycophenolate mofetil-treated kidney transplant recipients. We hypothesized that this increased protection from AR could allow successful prednisone (P) withdrawal in cyclosporine/mycophenolate mofetil/P-treated recipients. METHODS A multicenter, prospective, randomized, double-blind trial of P withdrawal at 3 months post-transplant was initiated. Entry criteria were: primary transplant, adult, no AR by 90 days, mycophenolate mofetil dose > or =2 g/day, cyclosporine dose = 5-15 mg/kg/ day, P dose = 10-15 mg/day. Study participants were randomized to have P tapered over 8 weeks (beginning at 3 months posttransplant) to 0 vs. 10 mg/day. Prestudy power analysis determined 500 recipients should be randomized for 80% statistical power to test equivalence of the primary endpoint, AR, or treatment failure at 1 year posttransplant. By design, the study was to be stopped if interim data precluded reaching equivalence. An established data safety monitoring board monitored the study. RESULTS After 266 patients were enrolled, the patient enrollment was stopped (after safety monitoring board review) because of excess rejection in the P withdrawal group. The Kaplan-Meier estimate of the cumulative incidence of rejection or treatment failure within 1 year posttransplant (+/-95% confidence interval) for the maintenance group was 9.8% (4.4%; treatment failure, 14.9%); for the withdrawal group, 30.8% (21.0%; 39.3%). Treatment differences in the distribution of time to event were highly significant (P = 0.0007). Of note, risk was higher in blacks (39.6%) versus nonblacks (16.0%) (P<0.001). At 1 year post-transplant, there was no difference between groups in patient or graft survival. For the patients with functioning grafts at 6 months posttransplant, withdrawal patients had lower cholesterol (P = 0.0005), had higher creatinine (P = 0.03), and were less likely to use antihypertensives (P = 0.001). These differences persist to 1 yr posttransplant. CONCLUSIONS We conclude that for recipients on cyclosporine/mycophenolate mofetil/P with no AR at 90 days, the chance of developing subsequent AR is small; if P is tapered and withdrawn, the risk increases (but the majority remain free of acute and chronic rejection). After withdrawal, the risk of AR is different for blacks versus nonblacks. Withdrawal patients had a lower cholesterol level and less need for antihypertensives.

272 citations

Journal ArticleDOI
TL;DR: It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation, however, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.
Abstract: Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.

54 citations

Journal ArticleDOI
TL;DR: It is demonstrated that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction, and graft survival was inferior for children aged 6’yr or younger.
Abstract: Acute rejection leading to renal graft failure is more frequent among children. In patients treated with T cell antibody induction, retrospective data from the pediatric registry show a 22% reduction in the risk of graft failure. We conducted a randomized trial (n = 287) using OKT3 mAbs in one (OKT3) arm and intravenous cyclosporine in the other arm (CYS). Maintenance therapy consisted of randomized, double blind Sandimmune® or Neoral® together with prednisone and either azathioprine (AZA) or mycophenolate mofetil (MMF). Morbidity, mortality, rejection rates and adverse reactions in the two study arms were similar. Through 4 yr, graft failure was 27% in OKT3 and 19% in CYS (p = 0.15). One-year graft survival was 89.1% in OKT3 and 89.2% in CYS (p = .19). In multivariate analysis, OKT3 had a numerically inferior graft survival (RR = 1.4, CI 0.8–2.2, p = 0.22). In OKT3 graft survival was inferior for children aged 6 yr or younger. Our trial demonstrates that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction.

37 citations


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Journal ArticleDOI
TL;DR: This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.
Abstract: Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

1,342 citations

Journal ArticleDOI
TL;DR: This work analyzed data provided by the Scientific Registry of Transplant Recipients regarding all adult first renal transplants between 1995 and 2000 to investigate how acute rejection rates have evolved on a national level in the U.S and how this has impacted graft survival in the most recent era of kidney transplantation.

1,157 citations

Journal ArticleDOI
TL;DR: A systematic review of studies comparing adult chronic dialysis patients with kidney transplantation recipients for clinical outcomes found significantly lower mortality associated with transplantation, and the relative magnitude of the benefit seemed to increase over time.

1,027 citations

Journal ArticleDOI
TL;DR: Current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus and the purine-synthesis inhibitor mycophenolate mofetil are discussed, which inhibits the proliferation of T cells and B cells.
Abstract: This article provides a comprehensive, up-to-date review of methods to prevent early and late renal-allograft loss and to improve long-term outcomes in patients. The authors focus particular attention on the problem of late graft loss and discuss current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus, and the purine-synthesis inhibitor mycophenolate mofetil, which inhibits the proliferation of T cells and B cells.

830 citations

Journal ArticleDOI
TL;DR: In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength, which should help guide selection of acceptable grafts for sensitized patients.
Abstract: The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

706 citations