Antithrombin therapy in pancreas retransplantation and pancreas-after-kidney/pancreas-transplantation-alone patients.

Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities. AT reduces ischemia/reperfusion injury and has been successfully used in patients with simultaneous pancreas kidney transplantation. This study retrospectively analyzes prophylactic high-dose AT application in patients with solitary pancreas transplantation traditionally related to suboptimal results. In our center, 31 patients received solitary pancreas transplantation between 7/1994 and 7/2005 (pancreas retransplantation, PAK/PTA). The perioperative treatment protocol was modified in 5/2002 now including application of 3000 IU. AT was given intravenously before pancreatic reperfusion (AT, n = 18). Patients receiving standard therapy served as controls (n = 13). Daily blood sampling was performed during five postoperative days. Standard coagulatory parameters and number of transfused red blood cell units were not altered by AT. In AT patients serum amylase (p < 0.01) and lipase (p < 0.01) on postoperative days 1, 2 and 3 were significantly reduced. Our actual perioperative management protocol including high dose AT application in human solitary pancreas transplantation reduced postoperative liberation of pancreatic enzymes in this pilot study. Prophylactic AT application should deserve further clinical testing in a randomized controlled trial.

Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow.

PURPOSE: To study the invasion-related molecule urokinase-type plasminogen activator receptor (u-PAR) expressed by disseminated tumor cells as a biologic predictor of poor survival in a large prospective series of patients with gastric cancer. PATIENTS AND METHODS: In 156 gastric cancer patients (prospective series), disseminated tumor cells in the bone marrow and the u-PAR expressed by these tumor cells were determined by cytokeratin (CK) 18 immunocytochemistry and u-PAR/CK18 double immunocytochemistry. RESULTS: In contrast to the mere detection of disseminated tumor cells at primary surgery, the additional evidence of u-PAR on these cells correlated significantly with pathologic T stage (P =.0474) and the expression of u-PAR (P =.0093) and plasminogen-activator inhibitor 1 (P =.0145) in the primary tumor (immunohistochemistry, chi(2)). Kaplan-Meier analysis revealed no association with prognosis for the mere detection of disseminated tumor cells. In contrast, a significant association was seen between detection of u-PAR on these cells and shorter disease-free (P <.0001) and overall survival (P <.0001). Multivariate analysis revealed that u-PAR on disseminated tumor cells at the time of primary surgery is an independent prognostic factor for disease-free (95% confidence interval [CI], 1.72 to 3.21; P =.024) and overall survival (P =.0049; relative risk, 2.89; 95% CI, 1.92 to 4.30). CONCLUSION: This is the first large study to show that u-PAR, detected on disseminated tumor cells in the bone marrow, is an independent prognostic parameter in gastric cancer, in contrast to the mere detection of minimal residual disease (MRD). u-PAR may be a promising marker to define a critical subpopulation of disseminated tumor cells and a target to eliminate MRD. Molecular phenotyping of MRD is critical for defining its individual clinical relevance.

Single-shot antithrombin in human pancreas-kidney transplantation: reduction of reperfusion pancreatitis and prevention of graft thrombosis.

Reperfusion pancreatitis and graft thrombosis often induce early graft loss in simultaneous pancreas-kidney (SPK) transplantation. Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities that reduces experimental ischemia/reperfusion injury. This study retrospectively analyses prophylactic high-dose AT application in patients with first SPK. In an university transplantation center, 53 consecutive patients with SPK were studied without randomization. In one group, 3000 IU of AT was given intravenously before pancreatic reperfusion (AT, n = 24). Patients receiving standard therapy including postoperative AT supplementation (controls, n = 29) served as controls. Daily blood sampling was performed as a part of the clinical routine during four postoperative days. There were no differences in demographic and laboratory parameters [donor/recipient age, ischemia time, perfusion solution, body weight, mismatches] between both groups. Baseline creatinine values were lower in the control group versus AT group (P < 0.05). Coagulatory parameters and bleeding incidence were not influenced by AT, while incidence of graft thrombosis was reduced (control: 7/29; AT: 4/24; relative reduction of risk: -33%; P < 0.05). Single-shot AT application during SPK modulated serum lipase activity on postoperative days 2 and 3, and minimized risk for graft thromboses without increasing perioperative bleeding. This new concept should deserve testing in a prospective clinical trial.

Rejection after simultaneous pancreas-kidney transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK. METHODS: The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids. RESULTS: After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors. CONCLUSION: Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.

A calcineurin antagonist-free induction/maintenance strategy for immunosuppression in elderly recipients of renal allografts from elderly cadaver donors: long-term results from a prospective single centre trial.

BACKGROUND: With the aim to improve the inferior outcomes in elderly recipients of kidneys from elderly cadaver donors, we applied and investigated a therapeutic regimen consisting of calcineurin inhibitor (CNI)-free, mycophenolate mofetil (MMF)-based immunosuppressive (i.s.) induction/maintenance protocol. In this article, we report the long-term results of this clinical trial. METHODS: A total of 89 recipients (mean age: 63.8 yr) of kidneys from cadaver donors (mean age: 66.8 yr) were consecutively recruited for this 5-yr, prospective, open, single centre, pilot trial. Induction therapy consisted of MMF and steroids in conjunction with a short course (4-10 d) of rabbit antithymocyte globulin (ATG). Maintenance treatment was performed with MMF/steroids or MMF alone under strict therapeutic drug monitoring by aiming target mycophenolic acid (MPA)-trough levels between 2 and 6 mg/mL. RESULTS: Cumulative 5-year patient and renal allograft survival was 87.69% and 69.81%, respectively. Acute rejection episodes occurred in 23.6% (21 patients). Long-term function of the old renal allografts proved to be satisfactory as reflected by serum creatinine-values of 1.53 mg/dL and urea-values of 57.9 mg/dL at 5 yr. CONCLUSION: Application of a nephrotoxicity- and atherogenicity-free, MMF-based i.s. induction/maintenance protocol in elderly recipient of kidneys from elderly cadaver donors leads to improved long-term outcomes which are comparable with data from young recipients who have received allografts from young cadaver donors.