Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study.

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

The prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys.

Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been prospectively validated. Prospectively collected RR values of 302 machine-perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1-year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 38.1 [1.56-934]; p = 0.026) [corrected] but the predictive value of RR was low, reflected by a c-statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1-year graft failure (hazard ratio 12.33 [1.11-136.85]; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand-alone quality assessment tool cannot be used to predict outcome with sufficient precision.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC(0-24) of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC(0-24) and C(min) for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Liver transplant donation after cardiac death: experience at the University of Liege.

OBJECTIVE: Donation after cardiac death (DCD) has been proposed to overcome in part the organ donor shortage. In liver transplantation, the additional warm ischemia time associated with DCD procurement may promote higher rates of primary nonfunction and ischemic biliary lesions. We reviewed the results of liver transplantation from DCD. PATIENTS AND METHODS: From 2003 to 2007, we consecutively performed 13 controlled DCD liver transplantations. The medical records of all donors and recipients were retrospectively reviewed, evaluating in particular the outcome and occurrence of biliary complications. Mean follow-up was 25 months. RESULTS: Mean donor age was 51 years, and mean intensive care unit stay was 5.4 days. Mean time between ventilation arrest and cardiac arrest was 9.3 minutes. Mean time between cardiac arrest and arterial flushing was 7.7 minutes. No-touch period was 2 to 5 minutes. Mean graft cold ischemia time was 295 minutes, and mean suture warm ischemia time was 38 minutes. Postoperatively, there was no primary nonfunction. Mean peak transaminase level was 2546 UI/mL. Patient and graft survival was 100% at 1 year. Two of 13 patients (15%) developed main bile duct stenosis and underwent endoscopic management of the graft. No patient developed symptomatic intrahepatic bile duct strictures or needed a second transplantation. CONCLUSIONS: Our experience confirms that controlled DCD donors may be a valuable source of transplantable liver grafts in cases of short warm ischemia at procurement and minimal cold ischemia time.

Organ procurement after euthanasia: Belgian experience.

Euthanasia was legalized in Belgium in 2002 for adults under strict conditions. The patient must be in a medically futile condition and of constant and unbearable physical or mental suffering that cannot be alleviated, resulting from a serious and incurable disorder caused by illness or accident. Between 2005 and 2007, 4 patients (3 in Antwerp and 1 in Liège) expressed their will for organ donation after their request for euthanasia was granted. Patients were aged 43 to 50 years and had a debilitating neurologic disease, either after severe cerebrovascular accident or primary progressive multiple sclerosis. Ethical boards requested complete written scenario with informed consent of donor and relatives, clear separation between euthanasia and organ procurement procedure, and all procedures to be performed by senior staff members and nursing staff on a voluntary basis. The euthanasia procedure was performed by three independent physicians in the operating room. After clinical diagnosis of cardiac death, organ procurement was performed by femoral vessel cannulation or quick laparotomy. In 2 patients, the liver, both kidneys, and pancreatic islets (one case) were procured and transplanted; in the other 2 patients, there was additional lung procurement and transplantation. Transplant centers were informed of the nature of the case and the elements of organ procurement. There was primary function of all organs. The involved physicians and transplant teams had the well-discussed opinion that this strong request for organ donation after euthanasia could not be waived. A clear separation between the euthanasia request, the euthanasia procedure, and the organ procurement procedure is necessary.

The history of pancreas transplantation: past, present and future.

The first attempt to cure type 1 diabetes by pancreas transplantation was done at the University of Minnesota, in Minneapolis, on December 17, 1966, followed by a series of whole pancreas transplantation. Due to the lack of potent immunosuppressive drugs, rejections and infections, it was concluded that pancreas was less antigenic than the kidney which was less antigenic than the duodenum. It opened the door to a period, between the mid 70's to mid 80's where only segmental pancreatic grafts were used in the recipient. Numerous techniques for diverting or dealing with the pancreas juice secretion were described, none of them being satisfactory. In the late 70's - early 80's, three major events happened and boosted the development of pancreas transplantation: firstly the introduction of Cyclosporine A in the clinical field, secondly the organization on March 1980, of the first international meeting on Pancreas Transplantation with the first report of the International Pancreas Transplantation Registry (IPTR) and finally in 1982, the organization of the first informal so-called Spitzingsee meetings where pancreas transplantation successes but mainly failures were discussed which precluded the onset of IPITA (International Pancreas and Islet Transplantation Association), EuroSPK (European Study Group for simultaneous Pancreas and Kidney Transplantation) and EPITA (European Pancreas and Islet Transplantation Association). During one of the Spitzingsee meetings, participants had the idea to renew the urinary drainage technique of the exocrine secretion of the pancreatic graft with segmental graft and eventually with whole pancreaticoduodenal transplant. That was clinically achieved during the mid 80's and remained the mainstay technique during the next decade. In parallel, the Swedish group developed the whole pancreas transplantation technique with enteric diversion. It was the onset of the whole pancreas reign. The enthusiasm for the technique was rather moderated in its early phase due to the rapid development of liver transplantation and the need for sharing vascular structures between both organs, liver and pancreas. During the modern era of immunosuppression, the whole pancreas transplantation technique with enteric diversion became the gold standard for simultaneous pancreas and kidney transplantation (SPK), with portal drainage of the venous effluent of the pancreas, even for pancreas after kidney (PAK) or pancreas transplantation alone (PTA). Today, there remains room for improvement: safety of using the duodeno-duodenal anastomosis technique must be confirmed by prospective analysis while preventing ischemic reperfusion injuries, using specific drugs; that must be assessed in new trials.

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.

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.

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.

Intravenous Immunoglobulins in the Prevention of Rejection of a Second or Third Kidney Graft.

BACKGROUND: Intravenous immunoglobulin (IVIg) reduces acute rejection episodes in kidney transplantation, but adverse events (AEs) are common. The aim of this study was to assess whether human IVIg enhances immunosuppressive effects without increasing AEs in the prevention of acute kidney graft rejection. METHODS: Patients receiving a second or third kidney graft were treated with standard immunosuppressant therapy with (n = 18) or without (n = 10) IVIg. The primary efficacy endpoint was biopsy-proven acute rejection (BPAR) rate at 3 months, and secondary endpoints included acute rejection rate at 12 months, intensity of rejection, and patient survival. RESULTS: Patients in the experimental arm received 3 infusions of IVIg. The BPAR rate decreased with IVIg versus standard immunosuppression alone over 12 months of follow-up. Experimental versus control rates of survival without BPAR were 94% versus 63% and 82% versus 63% at 3 and 12 months. The intensity of the acute rejection episodes (BANFF 97 grade) was similar between groups. One patient from each group died during the 12-month follow-up period. Treatment-emergent AEs were reported in 100% and 94.4% of the control and experimental arms. Most AEs were considered unrelated or unlikely to be related to treatment. CONCLUSIONS: This study supports the efficacy and safety of IVIg in highly sensitized transplant patients for improving transplant rates and reducing graft rejection episodes.

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.

[What's new in immunosuppression for renal transplantation?]. / Actualités sur les agents immunosuppresseurs utilisés en transplantation rénale.

The goal of immunosuppression in transplantation is to prevent acute rejection and, more recently, chronic renal graft rejection related in part to side-effects of immunosuppressive therapy (hypertension, diabetes, dyslipidaemia,..). The development of new drugs in renal transplantation has improved graft survival, but also the patient's quality of life. A better understanding of the side-effects of immunosuppressive therapy and the observation of optimal drug associations to reduce these side-effects have often led to propose modifications of the immunosuppressive regimen, mainly at the end of the first trimester after renal transplantation. The aim of this overview is to describe the available oral immunosuppressive agents, especially the new ones, their advantages, but also the danger when different drugs are added in acute illness.

[Ultrasonic scalpel in thyroid surgery]. / Bistouri ultracision en chirurgie thyroïdienne.

The thyroid gland is highly vascularized and, in all Thyroid surgery, a special attention must be paid to haemos. tasis and coagulation. Any carelessness in the control of thyroid vessels can indeed entail serious consequences. In this respect, the ultrasonic scalpel represents a significant progress. In this paper, the ultrasonic dissector will first be presented. Then a prospective, randomized trial comparing the results obtained with this apparatus to those obtained with the conventional method of hemostasis in a series of 34 patients submitted to total thyroidectomy for multinodular goiter will be summarized. Without increasing the costs, the ultrasonic dissector allows a saving of operative time as well as a reduction of peroperative bleeding and of postoperative use of antalgics. Finally, the results of 1696 total thyroidectomies performed with the use of the ultrasonic dissector will be briefly outlined.

Pregnancy after combined pancreas-kidney transplantation.

Four successful cases of pregnancy after combined pancreas-kidney transplantation at four different centers are summarized. The techniques used for the pancreas transplantations were duct obstruction in one patient and enteric exocrine diversion in two patients; in all three patients the insulin delivery was to the systemic circulation. In one patient exocrine diversion was to the stomach and the vascular anastomosis to the splenic vessels, thus accomplishing portal insulin delivery. Immunosuppression consisted of cyclosporin and prednisolone in two patients; cyclosporin alone in one patient; and cyclosporin, azathioprine, and prednisolone in one patient. In all a cesarean section was performed, due to deteriorating renal function in two patients, a fall in fetal growth in one patient, and fear of inducing pancreas-graft pancreatitis during normal delivery in one patient. In all four women, perfect metabolic control was retained throughout the pregnancy, and despite the proximity of the pancreas graft to the growing uterus in three of the women, the pancreas grafts did not suffer any damage during the pregnancy. However, in one patient the pancreas graft was lost in acute rejection after delivery. This pancreas had functioned normally for 3 yr before this occasion. Of the offspring, one was completely normal, one had a bilateral cataract, and two were small for date. The latter two subsequently showed normal growth development. At follow-up at 3, 5, 7, and 28 mo, all kidney grafts and three of the pancreas grafts remained functional. We conclude that after combined pancreas-kidney transplantation, successful conception and pregnancy can be obtained. Despite reduced islet mass (segmental grafts), normal metabolic control can be retained throughout the pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporin A for immunosuppression: observations in rat heart, pancreas, and islet allograft models and in human renal and pancreas transplantation.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

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.

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.

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.

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%.