Jeroen Dubbeld

Similar liver transplantation survival with selected cardiac death donors and brain death donors

The outcome of orthotopic liver transplantation (OLT) with controlled graft donation after cardiac death (DCD) is usually inferior to that with graft donation after brain death (DBD). This study compared outcomes from OLT with DBD versus controlled DCD donors with predefined restrictive acceptance criteria.

Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal.

Background Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn. Methods This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 &mgr;g·hr/mL). Results The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated. Conclusion These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.

The price of donation after cardiac death in liver transplantation: a prospective cost-effectiveness study.

This study aims to perform a detailed prospective observational multicenter cost‐effectiveness study by comparing liver transplantations with Donation after Brain Death (DBD) and Donation after Cardiac Death (DCD) grafts. All liver transplantations in the three Dutch liver transplant centers between 2004 and 2009 were included with 1‐year follow‐up. Primary outcome parameter was cost per life year after transplantation. Secondary outcome parameters were 1‐year patient and graft survival, complications, and patient‐level costs. From 382 recipients that underwent 423 liver transplantations, 293 were primarily transplanted with DBD and 89 with DCD organs. Baseline characteristics were not different between both groups. The Donor Risk Index was significantly different as were cold and warm ischemic time. Ward stay was significantly longer in DCD transplantations. Patient and graft survival were not significantly different. Patients receiving DCD organs had more and more severe complications. The cost per life year for DBD was € 88 913 compared to € 112 376 for DCD. This difference was statistically significant. DCD livers have more and more severe complications, more reinterventions and consequently higher costs than DBD livers. However, patient and graft survival was not different in this study. Reimbursement should be differentiated to better accommodate DCD transplantations.

Matrix metalloproteinase 2 genotype is associated with nonanastomotic biliary strictures after orthotopic liver transplantation.

Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT.

A Novel Technique for Auxiliary Partial Liver Transplantation With Reno‐Portal Anastomosis and Avoidance of the Hepatoduodenal Ligament

Auxiliary liver transplantation (ALT) is a treatment for acute liver failure when regeneration of the native liver is possible or for metabolic disorders. In selected cases ALT and orthotopic liver transplantation (OLT) have similar survival when ALT is performed in the orthotopic position (auxiliary partial orthotopic liver transplantation, APOLT). Drawback of ALT with portal vein to portal vein anastomosis is the frequent occurrence of thrombosis, compromising both graft and native liver, and the necessity of a significant resection. To avoid division of portal flow we performed ALT with an end‐to‐end anastomosis between the graft portal vein and the left renal vein of the recipient (reno‐portal ALT, REPALT). The hepatic artery was anastomosed to the aorta using an iliac arterial graft conduit. The bile duct was anastomosed to the stomach. In the two cases presented here excellent immediate graft function occurred with rapid regeneration of the graft and without early vascular complications.

High peak alanine aminotransferase determines extra risk for nonanastomotic biliary strictures after liver transplantation with donation after circulatory death

Orthotopic liver transplantation (OLT) with donation after circulatory death (DCD) often leads to a higher first week peak alanine aminotransferase (ALT) and a higher rate of biliary nonanastomotic strictures (NAS) as compared to donation after brain death (DBD). This retrospective study was to evaluate whether an association exists between peak ALT and the development of NAS in OLT with livers from DBD (n = 399) or DCD (n = 97) from two transplantation centers. Optimal cutoff value of peak ALT for risk of development of NAS post‐DCD‐OLT was 1300 IU/l. The 4‐year cumulative incidence of NAS after DCD‐OLT was 49.5% in patients with a high ALT peak post‐OLT, compared with 11.3% in patients with a low ALT peak. (P < 0.001). No relation between peak ALT and NAS was observed after DBD‐OLT. Multivariate analysis revealed peak ALT ≥1300 IU/l [adjusted hazard ratio (aHR) = 3.71, confidence interval (CI) (1.26–10.91)] and donor age [aHR = 1.04, CI 1.00–1.07] to be independently associated with development of NAS post‐DCD‐OLT. A peak ALT of <1300 IU/l carries a risk for NAS similar to DBD‐OLT. Thus, in DCD‐OLT, but not in DBD‐OLT, peak ALT discriminates patients at high or low risk for NAS.

Reuse of Auxiliary Liver Grafts in Second Recipients With Chronic Liver Disease

We describe the first cases of reuse of auxiliary liver grafts for orthotopic transplantation in chronic liver disease. A reduced liver graft (segments 2, 3, half of 4) was first transplanted auxiliary for acute liver failure using a new technique. After regeneration of both native liver and graft, the auxiliary graft was removed and immunosuppression discontinued in the first recipients. After informed consent of donors and recipients, both auxiliary grafts were then orthotopically transplanted into second recipients. Both grafts function normally. Reuse of auxiliary grafts may help to reduce the shortage or liver grafts available for transplantation.

Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures

The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re‐)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End‐Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty‐three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi‐institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss. Liver Transplantation 22 420‐426 2016 AASLD

Glycemic Stability Through Islet-After-Kidney Transplantation Using an Alemtuzumab-Based Induction Regimen and Long-Term Triple-Maintenance Immunosuppression.

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long‐term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab‐based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One‐ and 2‐year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet‐after‐kidney transplantation in patients with type 1 diabetes using an alemtuzumab‐based induction regimen leads to considerable islet allograft function and improvement in glycemic control.

Report of the first five DCDD pancreas transplants within the Eurotransplant region; excellent results with prolonged first warm ischemia times

Dear Sirs, The success of pancreas transplantation has led to an increased number of pancreas transplantations, which again has led to an increased need for suitable pancreas allografts. This initiated a search for alternative ways to increase the number of pancreas donors. Donation-aftercirculatory-determination-of-death (DCDD) is such an alternative and is a recognized form of transplantation with regard to kidney, liver, and lung transplantation. However, there is limited experience with DCDD in pancreas transplantation [1–6]. A large study with Scientific Registry of Transplant Recipients (SRTR) data showed DCDD-status to have a marginally significant risk (HR 1.39; P = 0.10) compared with a donation-after-brain-death (DBD)-donor [1]. Nevertheless, similar patient survival and graft survival rates between DBD and DCDD-groups at 1-year, 5-years [2,3,6], and even 10-years follow-up [5] have been reported. Results describe higher rate of renal complications such as delayed graft function (DGF) or urinary tract infections [2,3] after DCDD transplantation, however, there were no higher rates in pancreas-related complications [2,5]. Interestingly, these reports are always with rather short 1st warm ischemia times (WITs), ranging from 14 min [4] to 21 min [5]. Within the Eurotransplant region DCDD is only performed in Austria, Belgium, and The Netherlands. In February 2011, the first DCDD pancreas transplantation within the Eurotransplant region was performed in our center. Since then four more DCDD pancreas transplantations were performed. All five allografts were procured from DCDD-donors in The Netherlands. Pancreas allografts were matched and offered via Eurotransplant. Donor, transplant, and recipient characteristics are shown in the Table 1. HTK perfusion-fluid was used in all procedures. All patients were treated with alemtuzumab (Campath) induction-therapy and maintained on duo therapy, consisting of tacrolimus and mycophenalate mofetil. At 1-year follow-up all recipients are alive with optimally functioning pancreas and kidney allografts. There were no perioperative complications. Three pancreas allografts were enteric-drained and two were initially bladder-drained and converted to enteric drainage afterward, according to a two-step protocol [7]. All patients had immediate pancreas function, measured as peroperative lowering of the blood glucose levels, and, except for the fourth recipient, all SPKpatients had immediate kidney function, measured as peroperative diuresis. There were a few long-term complications: the first patient developed moderate interstitial and vascular rejection after 3 months, which was treated with antirejection therapy consisting of methylprednisolone. The third recipient developed a hematoma near the pancreas allograft, for which he was reoperated twice. After 2 months this recipient developed acute kidney insufficiency because of a ureteral stricture caused by a renal BK-infection, for which he was reoperated and reinsertion of the ureter to the bladder was performed. After lowering the immunosuppressive therapy, this recipient developed an interstitial rejection episode of the kidney, which was treated with methylprednisolone. The fourth recipient had a DGF of the kidney, for which he was treated with dialysis on days 2, 3, 4, and 6 postoperatively. After 6 weeks, a CT-scan showed a distal, partial venous thrombosis in the splenic vein, for which anticoagulant therapy (coumarine) was started liberally. The fifth recipient showed acute respiratory insufficiency because of a rhinovirus-infection 2 days after the operation, for which he was shortly admitted to the intensive care unit (ICU). HbA1c-values at 3-months follow-up were normal (mean of 32.6 mmol/mol) and most recent values are still within the normal ranges for all patients. Most of the postoperative complications our recipients experienced are not necessarily directly related to DCDD-allografts. Only DGF of the kidney in the fourth recipient is seen more often after DCDD transplantation [2,3,5]. Although DCDD pancreas transplantation is not a new concept worldwide, only few reports of pancreas transplantation using allografts from DCDD-donors have been published [1–5]. Within Europe, UK-Transplant has the largest series of DCDD pancreas transplantation [8], with