Recipients Of First Transplants Research Articles

Variations in Risk of Cancer and Death From Cancer According to Kidney Allograft Function, Graft Loss, and Return to Dialysis.

Cancer incidence and mortality may change with varying kidney allograft function and after graft loss. We aimed to quantify cancer incidence and mortality during periods with a functioning graft and after graft loss. We included all adult Australians aged 20 and above who commenced kidney replacement therapy between 1982 and 2014 using data from Australia and New Zealand Dialysis and Transplant Registry. We calculated the standardized incidence ratios and standardized mortality ratios (standardized against the Australian general population) for dialysis patients and transplant recipients during periods with a functioning graft and after graft loss. A total of 44 765 dialysis patients without transplants, 13 443 with first kidney transplants, 2951 after first graft loss, 1010 with second transplants, and 279 after second graft loss were followed for 274 660 patient-years. Cancer incidence and mortality (per 100 000 patient-years) were 1564 and 760 in dialysis patients, 1564 and 689 in recipients of first transplants, 1188 and 390 after first graft loss, 1525 and 693 after second transplants, and 1645 and 779 after second graft loss. Cancer standardized incidence ratios and standardized mortality ratios (95% confidence intervals) were 1.15 (1.11-1.20) and 1.29 (1.21-1.36) for dialysis patients, 2.03 (1.94-2.13) and 2.50 (2.33-2.69) for recipients following their first transplant, 1.55 (1.29-1.85) and 1.40 (1.00-1.90) after first graft loss, 2.18 (1.79-2.63) and 3.00 (2.23-3.96) for second transplants, 2.59 (1.56-4.04) and 3.82 (1.75-7.25) after second graft loss. In kidney transplant recipients, cancer incidence and mortality are highest during periods with a functioning graft and remained higher than in the general population even after graft loss.

Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation.

Although venous thromboembolism rates and risk factors are well described in patients with cancer, there are limited data on the incidence, risk factors and outcomes of thrombosis after allogeneic stem cell transplantation, a curative therapy for patients with hematologic malignancies. We aimed to determine the incidence and risks associated with venous thrombosis in allogeneic stem cell transplants. We studied 2276 recipients of first transplant between 2002–2013 at our institution with a median follow up of 50 months (range 4–146). Using pharmacy records and subsequent chart reviews, 190 patients who received systemic anticoagulation for venous thrombosis were identified. The 1-and 2-year cumulative incidence of all venous thrombotic events were 5.5% (95% confidence interval (CI) 4.6–6.5%) and 7.1% (95% CI 6.1–8.2%), respectively. There was no difference in age, sex, body mass index, diagnosis, disease risk index, conditioning intensity, donor type or graft source between transplant recipients with and without subsequent thrombosis. In multivariable models, both acute and chronic graft-versus-host disease were independently associated with thrombosis occurrence (Hazard ratio (HR)=2.05, 95% CI 1.52–2.76; HR=1.71, 95% CI 1.19–2.46, respectively). Upper extremity thrombosis differed from all other thromboses in terms of timing, risk factors and clinical impact, and was not associated with non-relapse mortality (HR=1.15; 95% CI 0.69–1.90), unlike all other thromboses which did increase non-relapse mortality (HR=1.71; 95% CI 1.17–2.49). In subgroup analysis evaluating conventional thrombosis predictors by comparing patients with and without thrombosis, a history of prior venous thrombosis was the only significant predictor. Venous thromboembolism has a high incidence after allogeneic stem cell transplant and is associated with graft-versus-host disease and non-relapse mortality.

First in Man Evaluation of the Safety and Potential Efficacy of TOL101 Induction to Prevent Kidney Transplant Rejection

Purpose: Induction remains a potent tool for the prevention of early rejection episodes following kidney transplantation. However, current induction therapies are associated with significant short and long-term safety issues. TOL101, through its specificity for the αβTCR and absence of mitogenicity, has the potential to be safer and better tolerated. TOL101 is currently in Phase 2 testing, and interim safety and potential efficacy results of the study are presented here. Methods: The study was designed to enroll up to 42 subjects in Part A, beginning with a 1/10 the minimally anticipated biologic effect level. Eligible subjects were low-risk for acute rejection, i.e., recipients of first transplant, living (LD) and SCD, crossmatch negative, ABO compatible with < 20% PRA, and ranging in age from 35-55 years. The following safety parameters were evaluated: clinical adverse events, standard laboratory evaluations, cytokine release syndrome, malignancies, and infections. The ability of TOL101 to modulate the T-lymphocyte count was also assessed by measuring peripheral blood CD3 counts. Maintenance therapy was tacrolimus, mycophenolate, and steroids. Results: Several i.v doses (delivered days 0-5) ranging from 0.28-42mg of TOL101 have been tested in 23 subjects who received LD kidneys, with increasing doses showing greater effects in downregulating the ab-TCR+ T cell population. There have been no deaths or graft losses up to 6 months. There have been few infusion reactions, mild in severity, including skin rash at 42mg. There was one SAE (pneumonia) and two treated acute rejections. Malignancies or serious infections have not been observed. Cytokine release syndrome coupled with significant increases in measured cytokines, and HAMA formation has not been observed. The initial plasma elimination half life appears to range from 15-20 hours. Conclusions: TOL101 appears to be a safe and well tolerated induction agent at doses that have substantial T-cell modulating effects.

Outcomes of renal transplantation in recipients with peak panel reactive antibody &gt;30% under tacrolimus-based immunosuppression

Renal transplant recipients with high panel reactive antibodies (PRA) have worse outcomes than those with lower PRA. High PRA re-transplant recipients are thought to have worse outcomes than high PRA first transplant recipients. In this study, we examined outcomes of renal transplantation recipients with a peak PRA >30% and compared the outcomes of first and re-transplanted recipients. Survival outcomes between recipients of first transplants (n=68) and re-transplants (n=155) operated between June 1990 and August 2000 were compared. Sub-group analysis was done based on patient's gender, race and first/re-transplant. All patients received tacrolimus-based immunosuppression. No difference in graft survival was noted between first and re-transplanted patients. Ten-year patient survival was better in the re-transplanted group (p<0.004). Factors affecting patient survival on univariate analysis were age >55 years (p=0.015), deceased donor transplant (p=0.009), first transplant patient (p=0.004) and diabetes mellitus (DM) as the cause of End Stage Renal Disease (ESRD) (p=0.005). On multivariable analysis, factors affecting patient survival were number of the transplant (re-transplant versus first transplant, Relative risk [RR]=0.54, p=0.009) and cause of ESRD (DM versus no DM, RR=1.91, p=0.012).Diabetes as a cause for ESRD was the only factor affecting graft survival on univariate(p=0.015) and multivariable analysis (DM versus no DM, RR=1.63, p=0.017). High PRA recipients of first transplants had poorer patient survival than high PRA re-transplants. On multivariable analysis, diabetes etiology of ESRD and first transplantation were found to be independent risk factors for poorer patient survival.

Patient Survival and Cardiovascular Risk After Kidney Transplantation: The Challenge of Diabetes

An increasing proportion of kidney recipients have diabetes mellitus (DM). Herein, we assessed the impact of DM on morbidity and mortality. The study included 933 recipients of first transplants. DM was present in 212 (23%). Compared to non-diabetics (NoDM), DM were older, heavier and had more pretransplant cardiovascular (CV) disease (16% vs. 48%, p < 0.0001). DM had reduced survival (5 years, 93% vs. 70%, p < 0.0001) and higher incidence of CV events (9% vs. 37%, p < 0.0001). CV disease was the most common cause of death in DM (61%) but not in NoDM (26%). Mortality from infections was also higher in DM (p = 0.001). In NoDM, survival related to recipient age (hazard ratio (HR) = 1.07, p < 0.0001) and dialysis pretransplant HR = 2.21, p = 0.01, while in DM, survival related to dialysis (HR = 2.89, p = 0.01) and pretransplant CV disease (HR = 2.79, p = 0.007). In NoDM, the incidence of posttransplant CV events was related to traditional CV risk factors, while in DM only the pretransplant CV history related to this outcome. In conclusion, survival differs between NoDM and DM recipients quantitatively, by cause of death and by risk factors. In NoDM, survival is excellent, and the main threat to survival relates to immunosuppression. In DM, survival is inferior primarily due to CV disease generally present prior to transplantation.

EFFICACY OF REJECTION PROPHYLAXIS WITH OKT3 IN RENAL TRANSPLANTATION

The results of renal cadaver transplants performed between 1984 and 1994 and reported to the Collaborative Transplant Study were analyzed to examine the effect of rejection prophylaxis with OKT3. OKT3 prophylaxis with sequential (i.e., delayed) addition of cyclosporine (CsA), compared with immunosuppressive treatment that included CsA but not OKT3, resulted in a significantly higher overall 3-year graft survival rate in recipients of first transplants (75 +/- 1% vs. 71 +/- 1%, respectively; P < 0.0001) and in recipients of retransplants (68 +/- 2% vs. 62 +/- 1%, respectively; P < 0.001). In contrast, the simultaneous administration of OKT3 and CsA from the first posttransplant day did not result in improved graft survival over treatment with CsA alone. Graft survival rates were significantly associated with matching for HLA-A, -B, and -DR antigens in both first and retransplant recipients treated with a sequential protocol of OKT3/CsA (P < 0.01). Among patients with preformed panel reactive lymphocytotoxic antibodies > 50%, significantly better 3-year graft survival rates were obtained with sequential OKT3/CsA than were achieved without OKT3 in first transplant recipients (80 +/- 5% vs. 63 +/- 1%, respectively; P < 0.001) and in retransplant recipients (73 +/- 5% vs. 58 +/- 1%, respectively; P < 0.01). Significantly improved 3-year graft survival rates with OKT3 and sequential CsA were likewise obtained in two other groups of high-risk patients: black recipients (P < 0.001) and pediatric recipients (P < 0.01). The results demonstrate an advantage for OKT3 prophylaxis in conjunction with delayed CsA therapy among renal transplant recipients at high immunological risk, particularly among presensitized patients.

Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors. The UNOS Scientific Renal Transplant Registry.

The importance of HLA histocompatibility typing to the outcome of transplantation of cadaveric kidneys has been controversial. Four years ago, a prospective trial began in all U.S. transplantation centers to determine whether the results of transplantation would improve with the nationwide shipment of kidneys from cadaveric donors to waiting patients undergoing dialysis when there was a match at the HLA-A, B, and DR loci. A total of 1386 cadaveric kidneys were shipped from 108 organ centers to 198 transplantation centers and distributed among HLA-matched recipients, 1004 of whom were receiving a first transplant and 382 of whom were receiving a subsequent transplant. Graft survival in these recipients was compared with that in 22,188 recipients of first transplants and 3950 recipients of subsequent transplants whose HLA antigens differed from those of the donor. The rate of graft survival at one year in recipients of HLA-matched first transplants was 88 percent, as compared with 79 percent in the recipients of mismatched grafts (P less than 0.001). The estimated half-life of the kidney after the first year was 17.3 years for matched grafts, as compared with 7.8 years for mismatched grafts (P = 0.003). Among paired kidneys from 470 donors, one-year graft survival was 87 percent in the recipients of matched first grafts, as compared with 80 percent in the recipients of the contralateral kidneys, who did not have HLA matches with the donors. In donors and recipients matched for the more highly defined split Class I and Class II HLA antigens, the rate of graft survival after one year was as high as 90 percent. The collaborative renal-transplantation program for HLA matching of donors and recipients yielded an increased rate of one-year graft survival and an estimated half-life for matched grafts twice that for mismatched grafts. An increased role for HLA matching in kidney allocation is therefore indicated.

IMPROVED SURVIVAL-RATES IN PRESENSITISED RECIPIENTS OF KIDNEY TRANSPLANTS BY IMMUNOSUPPRESSION WITH MATERNAL-SOURCE GAMMA-GLOBULIN

The effect on cadaver-kidney transplant survival-rates of a γ-globulin concentrate, prepared from clotted blood centrifugally expressed from placental tissue recovered from post-partum women, was evaluated in a prospective controlled trial in 195 patients who were also given a standard immunosuppressive regimen. Allograft-survival rates were analysed according to whether or not the recipient had lymphocytotoxic antibodies before transplantation (responders) and whether the graft was a first or second transplant. The graft-survival rate was improved in responder-type recipients of first transplants who had received the γ-globulin concentrate as adjunctive therapy (control group 28·8±10·1% vs. γ-globulin 55·5±9·7% at 2 years, P<0·05). The survival-rate of grafts in non-responders was not affected by administration of γ-globulin and data on its use in recipients of a second graft were insufficient for analysis. These results suggest that the γ-globulin concentrate was suppressing immunological responses associated with humoral-type rejection.