Blood glutathione as a marker of cardiac allograft vasculopathy in heart transplant recipients

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx). Between immunologic and non-immunologic factors, reactive oxygen species generation has been proposed as pathogenetic mechanism. This study was aimed at evaluating redox status in HTx recipients and verifying whether it could be independently associated with CAV. METHODS: Fifty-five consecutive male HTx recipients, median [interquartile range] age 60 yr [50, 64], underwent angiography 67 months [21, 97] after HTx to assess CAV, defined as significant stenosis in >or=1 epicardial vessel or any distal vessel attenuation. All patients underwent blood sampling 89 months [67, 119] after HTx for biochemical (glucose, creatinine, total and LDL cholesterol, and cyclosporin levels) and redox evaluation [plasma reduced and total homocysteine, cysteine, cysteinylglycine, glutathione, blood reduced glutathione (GSH(bl)) and vitamin E]. Univariate Odds Ratios (OR) with 95% confidence interval (95% CI, highest vs. lowest quartile) were estimated on the basis of a logistic regression analysis between clinical, conventional biochemical and redox data. Only the significant variables at univariate entered into multivariate analysis. RESULTS: CAV was documented in 15 (27%) patients. Univariate analysis showed that time from HTx to angiography (OR 3.97, 95% CI 1.15-14, p = 0.03) and GSH(bl) (OR 0.31, 95% CI: 0.14-0.70, p = 0.005) were significantly associated with CAV. However, multivariate analysis revealed GSH(bl) as the only independent predictor of CAV (OR 0.31, 95% CI: 0.13-0.74, p = 0.008). CONCLUSIONS: In HTx recipients reduced levels of GSH(bl) are independently associated with CAV. Given its potent intracellular scavenger properties, GSH(bl) may serve as a marker of antioxidant defence consumption, favouring CAV development.     

The changing pattern of humoral rejection in cardiac transplant recipients

BACKGROUND: Most humoral rejection (HR) episodes occur early after cardiac transplantation and are associated with hemodynamic compromise and poor prognosis. Late cases of HR (>6 months after transplant) have been reported. We examined the differences in clinical characteristics and outcomes in patients presenting with HR in the early (<6 months) and late transplant periods. METHODS: A retrospective chart review was performed of all cases of HR at a single large transplant center from January 1, 1995 to March 1, 2006. RESULTS: A total of 37 adult transplants had biopsy-proven HR; 13 patients had early HR and 24 patients had HR a mean of 5 yr after transplantation (range, 7 months to 17 yrs). Treatment for HR included plasmapheresis, cyclophosphamide, and rituximab. The age of the early and late humoral rejecters was similar (58+/-14 vs. 50+/-14 yrs; P=0.12). There was a trend toward more women in the early HR group (54% vs. 33%). Use of left ventricular assist devices was similar (38% vs. 33%). Early rejecters were more likely to have positive cross-matches (46% vs. 8%; P<0.01). Patients with late HR had a coexistent diagnosis of malignancy, or significant recent infection in 50% vs. 8% for early HR, suggesting an activation of a nonhuman leukocyte antigen antibody-mediated immune response to an acute illness. One-year survival after the diagnosis of HR was 78% for the both groups (P=NS). CONCLUSIONS: Humoral rejection occurs now more frequently in patients with remote transplants and is commonly associated with the presence of malignancy or infection.     

Donor cardiac troponin T: a marker to predict heart transplant rejection

Background. Noninvasive methodologies have shown poor sensitivity in predicting rejection when compared to serial endomyocardial biopsies. We studied the potential role of donor blood troponin T (Tn-T) as a marker for predicting heart transplant rejection.

Methods. Blood cardiac Tn-T was measured from 16 heart donors. Transplant rejection and cardiac function in the recipients were monitored for 1 year.

Results. When data were analyzed based on donor blood Tn-T levels, 6 patients who received hearts from donors with low Tn-T (<0.45 ± 0.1 ng/mL) showed no rejection, and patients whose hearts came from donors with higher Tn-T (6.01 ± 0.81 ng/mL) developed episodes of high-grade rejection (3A) within 38.5 ± 2.1 days after transplantation. Eight patients who received hearts from donors with intermediate levels of Tn-T (3.57 ± 0.55 ng/mL) showed mild rejection (grade 1). All recipients had qualitatively normal left ventricular systolic function by serial echocardiography. The mean donor ischemic time was 169 ± 47 minutes.

Conclusions. The quality of the donor heart is an important prognostic factor in heart transplantation. It may be possible to identify severely damaged donor organs before transplantation and avoid their use or to develop more aggressive strategies for reducing recurrent acute rejection episodes in high-risk patients.     

C4d: a marker for hepatic transplant rejection

BACKGROUND: Acute rejection is still a common complication of hepatic transplantation. The diagnosis, based on the histological examination of the graft, may be difficult to confirm in the setting of combined hepatitis C virus infection. The presence of C4d in the portal capillaries could facilitate differentiation between acute rejection and relapsed hepatitis C. The deposit of C4d provides evidence of activation of humoral immunity. To attempt to confirm this hypothesis, we searched for the presence of C4d in posttransplant hepatic biopsies. METHODS: Thirty-six biopsies from 34 patients were analyzed retrospectively. The samples had been requested for one of the following reasons: suspected rejection, relapsed hepatitis C infection, or systematic check-up 1 year after the transplant. RESULTS: C4d expression was common in biopsies classified as acute rejection (33%) and chronic rejection (100%). C4d was never detected in the event of recurrent hepatitis C infection without rejection. CONCLUSION: These results, which are comparable to recently published data, give credence to the theory that C4d could be used as a marker for rejection following hepatic transplantation.     

Subclinical rejection in tacrolimus-treated renal transplant recipients

BACKGROUND: Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%. The intent of our study was to determine the incidence of subclinical rejection in tacrolimus-treated renal allograft recipients. METHODS: We prospectively studied the incidence of subclinical rejection on surveillance biopsies performed 3 months after transplantation in 114 patients transplanted between September 1, 1998 and November 30, 2000. All patients received tacrolimus, mycophenolate mofetil, and prednisone, and 56% received antibody induction. RESULTS: Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5-7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone. CONCLUSIONS: The incidence of subclinical rejection early after kidney transplantation is extremely low in tacrolimus-treated patients in whom early rejections are aggressively treated, suggesting that surveillance biopsies may not be necessary with this regimen.     

Acute antibody-mediated rejection in kidney transplant recipients

Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention.     

Medium-term outcomes in cardiac transplant recipients in a single cardiac transplant center in Taiwan

This study retrospectively investigated the outcomes of cardiac transplantation in a single medical center in Taiwan. From February 1997 to December 2005, 214 orthotopic cardiac transplantations were performed in our institution. Cumulative survival rates were compared by gender, waiting status, blood type, ischemia time, donor gender, age, and cause of brain death. The cumulative survival rates were significant different among recipient waiting status (P = .0026), blood type (P = .0376), and donor age >40 years (P = .0260). The others parameters seem to not be different from the cumulative survival rate. There was a strong association between donors >40 years old and increased postoperative mortality. The age of a marginal donor seemed to be >40 years in this study.     

Acute antibody-mediated rejection in paediatric renal transplant recipients

Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1–8 weeks. At follow-up, 14, 15 and 22 months’ post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m² respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.     

原位心脏移植术后急性排斥反应的监测

为了探讨心脏移植术后急性排斥反应的监测指标，我们对３例原位心脏移植患者在发生急性中、重度排斥反应时出现的各种临床征象进行了分析，结果发现，心电图、超声心动图、单光子计算机体层扫描、外周血Ｔ淋巴细胞计数、Ｘ线影象等检查枯早期诊断急性排斥反应时产不是敏感指标，认为心的膜心甩活 诊断急性排斥反应的可靠指标     

Malignant neoplasms in cardiac transplant recipients

Purpose: Heart transplant recipients have an increased risk of posttransplantation lymphoproliferative disorders (PTLD) associated with monoclonal antilymphocyte (OKT₃) immunosuppression and Epstein-Barr viral (EBV) infections. These studies were undertaken to determine whether polyclonal antilymphocyte therapy can reduce the incidence of malignant neoplasia.Methods: We reviewed our experience with polyclonal induction therapy to assess the risk of malignant neoplasms in 223 transplant recipients between April 1985 and September 1998. Posttransplant immunosuppression therapy employed either polyclonal antilymphocyte or antithymocyte globulin given as 10mg/kg/day in divided doses for 3 days followed by cyclosporine, azothioprine, and steroids. OKT₃ was used in only 2 patients for persistent rejection.Results: Twenty-nine patients developed invasive malignant neoplasms (a mean of 57.9 months posttransplant; range 7 to 125). Invasive malignancies included carcinoma of the lung (7 patients), colon (3), kidney (3), bladder (2), prostate (1), squamous cell carcinoma of the tongue (1), malignant melanoma (2), Kaposi’s sarcoma (1), and squamous cell carcinoma of the anus (1). Five patients developed lymphoma: 3 patients had PTLD, 2 patients had Hodgkin’s and non-Hodgkin’s lymphoma. Positive EBV IgG titers (>4:1) were found in 3 patients, but only 1 of these developed PTLD and none of these patients received OKT₃. Of the 29 patients with invasive malignancy, 13 (45%) died secondary to their malignancy; 5 died of unrelated causes (sepsis, myocardial infarction, and organ failure); and 11 are alive after surgical excision and/or chemotherapy. The age-adjusted incidence of invasive neoplasm was 7.33 (95% 5.95 confidence interval 8.09) times as great as rates for the general population in the State of Michigan between 1988 and 1995.Conclusion: While induction polyclonal antilymphocyte therapy may reduce the risk of PTLD, the incidence of posttransplant malignancy remains high. A vigilant cancer surveillance protocol is mandatory in these high-risk patients.     

Neopterin as a new biochemical marker in the clinical monitoring of bone marrow transplant recipients

In previous reports we demonstrated that increased amounts of the pyrazinopyrimidine compound neopterin are released in the context of T lymphocyte activation. The aim of this investigation was twofold: (1) to define the contribution of hemopoetic cells to neopterin excretion, and (2) to search for the clinical utility of this biochemical marker in the monitoring of such patients. Thirteen patients were grafted with allogeneic, 1 with syngeneic, and 2 with autologous marrow. Urinary neopterin excretion was measured daily by means of high-performance liquid chromatography from the time before transplantation until the patients' discharge from the isolation unit. In all patients bone marrow aplasia was associated with depressed, and engraftment with increased, neopterin values. Rising neopterin levels invariably preceded the cytological definition of "take," on the average by seven days. After hematological reconstitution, neopterin excretion continuously declined in all 5 patients lacking infectious complications and/o-graft-versus-host disease (GVHD). A transitory increase of urinary neopterin followed by normalization was observed in 5 further patients. At the time of increased neopterin excretion, 4 experienced either herpetic infection or GVHD, both of which resolved promptly under the appropriate treatment. Neopterin values remained elevated after engraftment in 6 patients who suffered from persistent GVHD. Results of this pilot study suggest that (1) bone marrow derived cells are crucially involved in production of neopterin in vivo and (2) evaluation of neopterin excretion patterns after hemopoietic reconstitution enables one to discriminate between patients with and without an increased risk of developing GVHD or viral disease.