Acute venous thrombosis of a renal transplant: early detection with color Doppler sonography.

The observation of a recent case of an acute venous thrombosis of a renal transplant is the opportunity to review and present the role of color Doppler sonography for the early detection of such a severe and uncommon complication.

Is there an increased incidence of surgically removed thyroid carcinoma in Belgium ten years after Chernobyl? A study of hospital discharge data.

In order to provide some answers to the much debated subject of the consequences of the Chernobyl accident, this study attempts to measure the incidence of surgically removed thyroid cancers in Belgium ten years following the explosion. The analysis was made from the hospital discharge data between 1993 and 1998. It offers the advantage of national coverage in spite of certain validity limits. The results show an increase in surgically removed thyroid cancers, which is not, however, evident in the more susceptible younger generation who were involved at the time of the accident. Furthermore, the geographic distribution of the incidence is more marked in the south of the country, unaffected by the radioactive iodine contamination of 1986, which was more prevalent in the east of the country. The study of the type of surgery involved shows a rise in the proportion of total thyroidectomies. These findings are in favour of the hypothesis of a causal effect linking the increased incidence of thyroid cancers to medical practice and surgery in particular and not to the consequence of the possible contamination.

The history of the EuroSPK - Study Group.

The EuroSPK Study group was created during the 4th Spitzingsee 1997 workshop in Kühtai, Austria. Thanks to W. Land for the incentive to gather European Centres--with Switzerland and Israel--and propose them to joint efforts and share data in the field of pancreas transplantation. Today, two prospective randomized studies have been already performed; a lot of data and results have been generated and worldwide spread. The spirit of the group will continue with a new interest in innate immunity and prevention of the ischemic reperfusion injury in pancreas transplantation.

Persistence of a chimerical phenotype after hepatocyte differentiation of human bone marrow mesenchymal stem cells.

OBJECTIVES: Recent studies have suggested the potential of mesenchymal stem cells (MSCs) to differentiate into a hepatocyte-like lineage. Here, we evaluate the efficacy of hepatocyte differentiation of MSCs by studying acquisition of hepatocyte-like features together with alteration of the native mesenchymal phenotype. MATERIAL AND METHODS: In vitro, we have investigated protein and mRNA level expression of hepatocyte and mesenchymal markers of mesenchymal-derived hepatocyte-like cells (MDHLCs) and we have evaluated their functionality using metabolic assays. In vivo, we investigated co-expression of hepatocyte (albumin, alpha-foetoprotein, cytokeratin 18) and mesenchymal (fibronectin, vimentin) markers after transplantation of MSCs or MDHLCs into severe combined immune deficiency mice. RESULTS: We observed that while in vitro these cells acquired some phenotypic and functional features of mature hepatocytes, they partially preserved their mesenchymal phenotype. After intrasplenic transplantation, engrafted MSCs with isolated expression of fibronectin and alpha-foetoprotein were observed. When these cells were injected into the liver, they expressed all analysed markers, confirming the chimaeric co-expression observed in vitro. Conversely, liver-engrafted MDHLCs conserved their hepatocyte-lineage markers but lost their chimaeric phenotype. CONCLUSIONS: Hepatocyte differentiation of MSCs predominantly allows the acquisition of phenotypic hallmarks and provides chimaeric cells that maintain expression of initial lineage markers. However, advanced maturation to the hepatocyte-like phenotype could be obtained in vivo by conditioning MSCs prior to transplantation or by infusing cells into the liver micro-environment.

Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond.

The Immunosuppression in Pancreas Transplantation was historically based on the fact that the pancreas is an extremely immunogenic organ. Quadruple drug therapy with polyclonal or monoclonal antibodies induction was the mainstay therapy since the introduction of Cyclosporine A. In the modern era of Immunosuppression, Mycophenolate Mofetil replaced Azathioprine while Tacrolimus-another potent calcineurin inhibitor-had-and still has-a difficult challenge to replaced Cyclosporine A, due to its potential diabetogenic effect. Thanks to the first two EuroSPK studies which prospectively tried to answer several questions in that field. But, the future challenge will be in understanding the impact of innate immunity and ischemic reperfusion injuries on the long-term graft function. Hopefully, new drugs will be available and tested to block unspecific deleterious reactions to attenuate the proinflammatory response. It will be the aim of the third Euro SPK Study.

Non-heart-beating donor, 10-year experience in a Belgian transplant center.

All over the world, transplant teams are looking for ways to increase and improve the donor pool. Non-heart-beating donation may increase the number of donors, even if some technical, logistical, and emotional problems are still encountered. The results obtained by our team should stimulate other centers to implement this kind of donation in their hospitals. Herein we have described our experience with non-heart-beating donation.

CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study.

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.

Cost of renal transplant in Belgium.

The objective of this study was to analyze 1-year direct medical costs of kidney transplantation in Belgium. The analysis included the last 150 patients who received a kidney transplant, were treated with cyclosporine, and had 1 year follow-up data. All patient were adults (>18 years) at the time of transplantation. Patient files were retrospectively analyzed. Key clinical events, such as primary hospitalization for transplantation; immunosuppressive drug use; patient survival; graft survival; acute rejection; CMV infection; adverse events and serious complications; treatment of adverse events; treatment of complications; repeat hospitalization; and follow-up hospital consultations were recorded. Total length of stay in the hospital was also recorded. For each patient, information up to 1 year following renal transplantation (or until death if death occurred before 1 year posttransplantation) was collected. Cost information was obtained from anonymous hospital bills that provided amounts paid by the health care payer and patient. Two perspectives are considered in this study: health care payer (INAMI/RIZIV) perspective and patient perspective. For the whole population (n = 143), 7 patients with graft failure were excluded. The mean direct medical costs from the health care payer's perspective, and patient's perspective were 37,792 Euro, and 2,034 Euro, respectively. During this 1-year period, patients were hospitalized for an average of 29 days. One-year direct medical costs of kidney transplantation are substantial. In Belgium, most of the direct medical costs are borne by the health care payer.

Non-heart-beating donor, renewal of an old procedure: a Belgian experience.

The shortage of donated organs has become a problem in transplantation throughout the world. Transplant teams are looking for other ways to increase and improve the donor pool. Non-heart-beating donation may be a source to increase the number of donors, even if some technical, logistical, and emotional problems are encountered. The results obtained by our team should stimulate other centers to implement this kind of donation in their hospitals. We describe our experience in the policy of non-heart-beating donation and encourage transplant centers to develop such a program.

Pancreas transplantation for treatment of generalized allergy to human insulin in type 1 diabetes.

We report the case of a 29-year-old man with a 14-year history of type 1 diabetes, normal renal function, and mild diabetic retinopathy. The patient progressively developed a generalized allergic reaction to two insulin excipients--protamine and metacresol--with systemic manifestations of tremor, tachycardia, vertigo, shortness of breath, and short episodes of unconsciousness causing him to be out of work. In June 2003, he received a vascularized cadaveric pancreas transplant using induction with polyclonal antibodies along with tacrolimus and sirolimus but without steroids. A hyperglycemic episode following corticosteroid therapy for rejection treatment required reintroduction of insulin therapy with prompt reappearance of allergic manifestations. Now, the patient is euglycemic without insulin or allergic manifestations and a glycated hemoglobin of 6.4%.

Tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: the EURO-SPK 3-year results.

UNLABELLED: This 3-year study compared tacrolimus versus cyclosporine (CsA) microemulsion (ME) in conjunction with rATG induction, mycophenolate mofetil (MMF) and short-term corticosteroids in primary simultaneous pancreas-kidney (SPK) transplantation. PATIENTS AND METHODS: This large, prospective, multicenter study was conducted in 10 European centers and one center in Israel. Of the 205 SPK transplants performed from 1998 to 2000, 103 patients were randomly assigned to tacrolimus and 102 to CsA ME. All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: In total, 36.9% patients receiving tacrolimus and 57.8% receiving CsA ME discontinued treatment (P = .003). Although 3-year patient and kidney graft survival rates were similar in both groups, pancreas survival was superior with tacrolimus (89.2% versus 72.4%; P = .002). Thrombosis resulted in pancreatic allograft loss in 10 patients receiving CsA ME and in 2 treated with tacrolimus (P = .02). The first episode of biopsy-proven rejection was moderate or severe in 1 of 31 tacrolimus-treated patients and 11 of 39 patients receiving CsA ME (P = .009). Overall adverse event frequency was similar in both groups, but surgical events were lower in the tacrolimus treated group. CONCLUSION: Tacrolimus was more effective than CsA-ME to prevent moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreatic graft survival and reduced the risk of pancreas thrombosis.

Immunosuppressive drugs after simultaneous pancreas-kidney transplantation.

INTRODUCTION: We report the early and late secondary effects of tacrolimus or cyclosporine-microemulsion (ME), in combination with mycophenolate mofetil (MMF), and rATG. PATIENTS AND METHODS: One hundred three patients were randomly assigned to tacrolimus (initial oral dose 0.2 mg/kg) and 102 to cyclosporine-ME (initial daily oral dose 7 mg/kg). All patients received 4 days of concomitant rATG induction therapy [ATG-Fresenius Biotech GmbH (ATG-F) daily dose of 4 mg/kg or Thymoglobulin-Genzyme/Sangstat (Thymo-S) 1.25 mg/kg], MMF (2 to 3 g per day), and short-term corticosteroids. RESULTS: Thymo-S was associated with a transiently lower white cell count in the first 3 months compared with ATG-F, while ATG-F caused a lower albeit transient early nadir in platelet count. Both polyclonal preparations were well tolerated; they did not differ with respect to clinically relevant side effects such as infections and malignancies. Higher cyclosporine-ME trough levels were associated with pancreas graft thrombosis. Study withdrawal was more frequent among patients on cyclosporine-ME therapy, because of toxicities, graft loss, and lack of efficacy, the last being the cause of subsequent switch to tacrolimus. Tacrolimus-treated patients were mainly withdrawn from the study due to MMF discontinuation. CONCLUSION: Short-term induction therapy in combined kidney-pancreas transplantation is effective and well tolerated. Tacrolimus causes fewer pancreas graft losses and fewer drug discontinuations due to side effects. When MMF is combined with tacrolimus, dose reductions and discontinuations are common.

Effect of HLA matching in simultaneous pancreas-kidney transplantation.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of HLA matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. PATIENTS AND METHODS: The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor-recipient HLA data were available. A group of 45 patients with 0 to 3 HLA mismatches (MM) was compared to 135 patients with 4 to 6 MM. RESULTS: There were no differences in 3-year kidney, pancreas, or patient survival rates between the 0 to 3 and 4 to 6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0 to 3 MM (66%) were rejection free at 3 years than those with 4 to 6 MM (41%; P = .003). The relative risk of acute rejection was 2.6 times higher among patients with 4 to 6 MM than among those with 0 to 3 MM. In conclusion, there was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA matches, which may impact long-term survival.

Corticosteroid withdrawal in simultaneous pancreas-kidney transplantation: a 3-year report.

UNLABELLED: Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patient health, requiring eventual discontinuation. Herein, we present an evaluation of the safety and feasibility of corticosteroid withdrawal based on the findings of the Euro-SPK001 study. PATIENTS AND METHODS: In this prospective, multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients were randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporine microemulsion (CsA-ME) and MMF (n = 102). All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: Corticosteroid withdrawal was successful in the majority of in-study patients: 66% tacrolimus and 73% cyclosporin-ME. In-study patients selected for corticosteroid withdrawal experienced fewer pancreatic or kidney graft losses and fewer episodes of acute rejection compared with out-of-study patients or those continuing corticosteroid therapy. Acute rejection episodes occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in both MMF and tacrolimus dosage. CONCLUSION: Corticosteroid withdrawal was successful in the majority of in-study patients. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate possible positive effects on glucose metabolism and hypertension.

Simultaneous pancreas-kidney transplantation: analysis of rejection.

UNLABELLED: The 3-year data concerning the occurrence of rejection episodes (RE) are reported herein. PATIENTS AND METHODS: Two hundred five simultaneous pancreas-kidney (SPK) transplantations were performed from May 1998 to September 2000, including 103 patients randomly assigned to tacrolimus (Tac) and 102 to cyclosporine microemulsion (CsA-ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. RESULTS: After a follow-up of 3 years, acute rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving CsA 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 (88% and 90%). Actuarial rejection-free graft survival was not significantly different between the two groups (54% and 44% at 3 years posttransplant). In a multivariate analysis, HLA compatibility (P = .003) and graft vessel extension (P = .0005) had a significant influence on rejection-free survival. Rejection influenced pancreatic graft survival (P = .01) and pancreatic graft loss owing to rejection influenced patient survival (P = .02). In the intent-to-treat analysis of early rejection, first moderate-to-severe episodes (1 of 40 versus 12 of 47; P = .004) and refractory episodes (2 of 40 versus 10 of 47; P = .03) were significantly lower with tacrolimus than with CsA ME. Pancreatic graft survival was worse among late rejectors (53%) than nonrejectors (86%; P = .002). In addition, serum creatinine was highest in late rejectors. In conclusion, Tac-based immunosuppressive therapy shows advantages over CsA ME in terms of the severity of acute rejection episodes among patients undergoing SPK transplantation.

Cytomegalovirus infection in simultaneous pancreas-kidney transplantation.

INTRODUCTION: In this open-label multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients between 1998 and 2000 were randomly assigned to tacrolimus or cyclosporine-microemulsion (ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil and short-term corticosteroids. We report the 3-year data related to the occurrence, severity and effect of cytomegalovirus (CMV) infections. The type of CMV prophylaxis and treatment was at the discretion of the investigator. RESULTS: The overall incidence of CMV infection was 34% with no difference in incidence between the tacrolimus and cyclosporine-ME treatment arms. Statistically significant fewer CMV infections occurred among patients who received ganciclovir (22%) than those who did not receive prophylaxis (42%; P = .0075) or were treated with acyclovir (43%; P = .0066). The CMV infection rate according to donor recipient CMV serological status was: D-/R- group 11%, which was lower than the D-/R+ group at 40% (P = .0035), the D+/R+ group at 37% (P = .0024), or the D+/R- group at 52% (P = .00001). Among the last three groups, the infection rate was lower in patients on ganciclovir than those with no prophylaxis or on acyclovir (22% vs 64%; P = .00001). The incidence of acute rejection episodes was higher among patients without ganciclovir prophylaxis. No difference was observed in actuarial patient, kidney, or pancreas survival rates between patients with versus without infection. CONCLUSIONS: Ganciclovir prophylaxis effectively prevented CMV infection in SPK transplant recipients, especially in higher risk groups. An effect of CMV prophylaxis on the incidence of rejection is possible.

Metabolic assessment after simultaneous pancreas-kidney transplantation.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has become a standard therapy for patients with type 1 diabetes and end-stage renal disease. We analyzed metabolic data in this clinical setting under tacrolimus- versus cyclosporine microemulsion (ME)-based immunosuppressive therapy. PATIENTS AND METHODS: We analyzed 205 patients enrolled in the Euro-SPK001 study for fasting blood glucose, fasting C peptide, glycated hemoglobin (HbA(1c)), blood lipids (total cholesterol and triglycerides), and pancreatic enzymes at regular intervals during the study. We compared blood pressure values with target levels for diabetic patients published by the European Society for Hypertension. RESULTS: Throughout the study, HbA(1c) and fasting C peptide levels were within the normal range in the two groups. Fasting blood glucose was higher during the first 2 months posttransplant in the tacrolimus group than in the cyclosporine-ME group, but no differences were seen thereafter. From month 2 posttransplant, mean levels of total cholesterol were significantly lower among patients receiving tacrolimus than those in the cyclosporine-ME group. In addition, patients receiving cyclosporine-ME showed serologic features of mild pancreatitis with elevated blood amylase and lipase levels during the first 6 months posttransplant. The two regimens were comparable with respect to hypertension, but target levels were reached in only 50% of the patients. CONCLUSION: Except for lipid profiles, no major differences in metabolic effects or blood pressure control were observed among SPK transplant patients receiving immunosuppression based on tacrolimus versus cyclosporine-ME. In view of the potential risk of hypertension, antihypertensive strategies should be implemented for all patients.

Simultaneous pancreas-kidney transplantation in a large multicenter study: surgical complications.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has evolved as an effective treatment modality for patients with end-stage nephropathy owing to type 1 diabetes mellitus. This kidney-pancreas transplant procedure includes a number of risks, one of them being surgical complications, which were analyzed in this large prospective multicenter study. PATIENTS AND METHODS: The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporine ME (n = 102) in the Euro-SPK001 study. Surgical complications were defined as any intervention in the postoperative course related to the transplant procedure. RESULTS: The number of patients undergoing relaparotomy was significantly lower among the tacrolimus group (26.2%) as compared to the cyclosporine ME group (43.1%, P = .0109). Relaparotomy was performed earlier in the cyclosporine ME group (day 14 +/- 17) compared to patients in the tacrolimus group (day 26 +/- 26, P = .0506). Graft vessel thrombosis, intra-abdominal hemorrhage, and enteric or ureteral leakage within the first 3 months occurred significantly more frequently in cyclosporine ME-treated patients. Donor age above 45 years showed a negative impact on surgical complications. Relaparotomy had no impact on patient survival but significantly affected pancreas and kidney graft survival in both groups. CONCLUSION: This prospective, randomized, multicenter trial in patients undergoing primary SPK demonstrated a benefit of tacrolimus over cyclosporine ME with regard to the incidence of surgical complications and, consecutively, to kidney and pancreas graft survival.