IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.     

Workshop on Late Renal Allograft Dysfunction

Despite continued improvement in incidence of acute immune injury and short-term graft survival, late allograft dysfunction remains a significant problem in the renal transplant population. Recent reports suggest that rates of renal function decline are quite varied in the overall recipient population, and that individual rates for many recipients may not change substantially over time. Moreover, analyses also reveal distinct predictive factors for both early and late functional decline. Long-term outcome studies for renal transplantation, however, might be significantly limited by incomplete data sets for assessing clinical endpoints. In view of the heterogeneous factors that may cause progressive allograft injury, more routine biopsy sampling would allow a more complete characterization of induced injuries. Elucidating mechanisms of renal fibrosis in response to injury, in experimental systems and humans, is also an important goal in better understanding chronic allograft damage. Regulation of cell senescence genes and epithelial to mesenchymal transition, studied in other models of renal fibrosis, are likely relevant to studies of renal allograft dysfunction. Recent technical advances in analyzing biological samples may play a pivotal role in identifying and validating surrogate markers of allograft function for future interventional trials in transplantation.     

Monitoring activated clotting time for combined heparin and aprotinin application: an in vitro evaluation of a new aprotinin-insensitive test using SONOCLOT

The kaolin-based activated clotting time (ACT) is commonly used for monitoring heparin-induced anticoagulation alone and combined with aprotinin during cardiopulmonary bypass. However, aprotinin prolongs ACT measurements. Recently, a new so-called 'aprotinin-insensitive' ACT test (SaiACT) has been developed for the SONOCLOT analyzer. In this study we evaluated and compared this new test for the SONOCLOT analyzer in vitro with an established kaolin-based ACT from HEMOCHRON (HkACT). Twenty-five patients undergoing elective valve surgery donated 80 mL of blood after induction of anesthesia. The blood was withdrawn in citrated tubes and processed to analyze effects of heparin (0, 1, 2, and 3 U x mL(-1)), aprotinin (0, 200 kIU x mL(-1)), and 25% hemodilution with calcium-free lactated Ringer's solution on ACT measurements. A total of 400 blood samples were analyzed and ACT was measured in a wide, clinically relevant range in duplicate with SaiACT and HkACT. Addition of aprotinin to heparinized blood samples induced no significant changes of SaiACT measurements. By contrast, HkACT readings increased significantly: aprotinin prolonged HkACT in heparinized blood samples by 20% +/- 37% (2 U x mL(-1)) and 24% +/- 18% (3 U x mL(-1)), respectively, and in vitro hemodilution increased this effect. IMPLICATIONS: Current standard techniques to measure heparin-induced anticoagulation during cardiopulmonary bypass are affected by aprotinin, a drug widely used in this setting. The aim of this study was to investigate in vitro a new, so-called 'aprotinin-insensitive' test from SONOCLOT to measure heparin-induced anticoagulation more reliably in combination with aprotinin.     

Endovascular management of traumatic thoracic aortic injuries.

BACKGROUND: Endovascular surgery has recently been extended to the treatment of blunt traumatic aortic injuries. Since most of these injuries occur at the aortic isthmus, graft fixation in proximity to the origin of the left subclavian artery (LSA) has been a concern. Covering the LSA with graft fabric lengthens the proximal fixation site and should minimize proximal endoleaks. We therefore wished to evaluate the feasibility and safety of endovascular repair of thoracic aortic injuries after blunt trauma, both with and without deliberate coverage of the LSA. METHODS: At a tertiary care teaching hospital in London, Ont., we reviewed our experience with endovascular repair of 7 traumatic aortic injuries. We reviewed the technical success rate and the incidence of left subclavian coverage. Major morbidity, including rates of paraplegia and death were noted. The patients were followed-up with serial CT to look for endoleaks, stent migration or aneurysm growth and to determine whether they had symptoms related to left subclavian coverage. RESULTS: The time from injury to treatment ranged from 7 hours to 7 days (mean 36 h). The mean Injury Severity Score was 36. All injuries were at the aortic isthmus, and among the 7 patients treated, 6 had deliberate coverage of the LSA. One patient underwent carotid-to-subclavian artery bypass, but the other 5 did not. There were no cases of paraplegia; 1 patient had symptoms of claudication in the left arm but did not want revascularization. No procedure-related complications occurred, and all patients survived the event. Follow-up ranged from 2 to 30 (mean 13) months, and no endoleaks, stent migration or aneurysm expansion were noted in follow-up. CONCLUSIONS: Although long-term results are unknown, we conclude that endovascular repair of traumatic aortic injuries after blunt trauma can be performed safely with low morbidity and mortality and that coverage of the LSA without revascularization is tolerated by most patients.     

Heart Rate and Energy Expenditure During Aqua Dynamics

In brief: The heart rate, oxygen uptake, and energy expenditure of three young women were measured during 20-minute low-gear, 30-minute middle-gear, and 60-minute high-gear aqua dynamics workouts. All three workouts were moderate in intensity, eliciting average heart rates of 132 to 143 beats min^?1 (70% to 77% HR max), average oxygen uptakes of 1.2 to 1.3 liters min^?1 (51% to 57% VO₂ max), and average energy expenditures of 5.9 to 6.5 kcals min^?1 The findings indicate that aqua dynamics could be a beneficial conditioning program for people who have relatively low physical work capacity and enjoy swimming but cannot conveniently engage in lap swimming.     

Bilateral testicular cancer: a preventable problem? Experience from a large cancer centre

OBJECTIVE: To report a retrospective review of patients with a testicular germ cell tumour treated in a large cancer centre who developed a second tumour, as 1.8-5% of such patients will subsequently develop a new primary tumour in the contralateral testis. PATIENTS AND METHODS: From a database of 570 men treated for testicular cancer in the West of Scotland between 1989 and 1998, all those who developed bilateral testicular tumours were identified. RESULTS: Nineteen men (3.3%) developed a second primary testicular malignancy; the mean age at diagnosis of the first tumour was 29.5 years, with the mean (range) interval to diagnosis of the second tumour of 76 (11-181) months (except for one man with synchronous tumours). The first tumour was teratoma in 11 and seminoma in seven; one patient had synchronous bilateral teratoma. The second primary was teratoma in 10 and seminoma in eight. Known risk factors for carcinoma in situ were present in nine patients, i.e. a small atrophic contralateral testis in five, a family history of testicular cancer in two, a history of infertility in two and unilateral undescended testis in one. Two patients had had contralateral testicular biopsies at the first diagnosis; both were negative for intratubular germ cell neoplasia (IGCN). Eight patients had chemotherapy to treat the first tumour and 14 for the second. All underwent bilateral orchidectomy. Overall, 18 of 19 men are alive and disease-free, with a median follow-up of 51 months. Pathology for 12 of the second testicular tumours was available for review; there was no IGCN in any of the slides from three patients, it was only present focally around the tumour in seven, and was diffuse in two patients. CONCLUSIONS: Chemotherapy for the first testicular tumour does not eliminate the risk of developing a contralateral tumour. Despite careful follow-up, in most patients the second primary tumour was not diagnosed early enough to avoid chemotherapy. The focal nature of IGCN in the second testis in most patients questions the value of biopsy of the contralateral testis. Improved methods of detecting patients at risk of second testicular tumours are needed.     

Myocardial T measurement in iron‐overloaded thalassemia: An ex vivo study to investigate optimal methods of quantification

Myocardial T measurement has been increasingly used for iron quantification to assess the risk of cardiac complications in thalassemia patients. In this study the noise effects were evaluated along with different curve‐fitting models on an iron overloaded ex vivo heart in order to determine the optimal method of T measurement and to help understand issues affecting reproducibility and accuracy. Gradient multiecho short axis images were acquired with differing numbers of excitations to generate varying signal‐to‐noise ratio (SNR) images. A noise correction method was implemented; linear and nonlinear curve‐fitting algorithms were compared and different curve‐fitting models (monoexponential, truncation, baseline subtraction, and offset) were evaluated. This study suggests that the T decay curve in an ex vivo heart can be fitted by a monoexponential model and accurate T measurements can be obtained with proper noise correction. With MRI noise, T is generally overestimated by including late low SNR data points, but underestimated by the offset or baseline subtraction models, which are in fact equivalent. In this situation the truncation model proves to be reproducible and more accurate than the other models. The study also shows that the nonlinear algorithm is preferred in T curve fitting. Magn Reson Med 60:350–356, 2008. © 2008 Wiley‐Liss, Inc.     

Monocyte Infiltration and Kidney Allograft Dysfunction During Acute Rejection

Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T-cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA-DR expression, increased with monocyte but not T-cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T-cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings.     

Obesity following kidney transplantation and steroid avoidance immunosuppression

Abstract:  Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 ± 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.