Joris J. Blok

The Eurotransplant Donor Risk Index in Liver Transplantation: ET-DRI

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan–Meier and Cox regression models. From 5723 patients follow‐up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET‐DRI). Concordance‐index calculation shows this ET‐DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET‐DRI for risk indication and possibly for allocation purposes within the Eurotrans‐plant region.

Validation of the donor risk index in orthotopic liver transplantation within the Eurotransplant region

In Eurotransplant, more than 50% of liver allografts come from extended criteria donors (ECDs). However, not every ECD is the same. The limits of their use are being explored. A continuous scoring system for analyzing donor risk has been developed within the Organ Procurement and Transplantation Network (OPTN), the Donor Risk Index (DRI). The objective of this study was the validation of this donor risk index (DRI) in Eurotransplant. The study was a database analysis of all 5939 liver transplants involving deceased donors and adult recipients from January 1, 2003 to December 31, 2007 in Eurotransplant. Data were analyzed with Kaplan‐Meier and Cox regression models. Follow‐up data were available for 5723 patients with a median follow up of 2.5 years. The mean DRI was remarkably higher in the Eurotransplant region versus OPTN (1.71 versus 1.45), and this indicated different donor populations. Nevertheless, we were able to validate the DRI for the Eurotransplant region. Kaplan‐Meier curves per DRI category showed a significant correlation between the DRI and outcomes (P < 0.001). A multivariate analysis demonstrated that the DRI was the most significant factor influencing outcomes (P < 0.001). Among all donor, transplant, and recipient variables, the DRI was the strongest predictor of outcomes. Liver Transpl 18:113–120, 2012.

Longterm results of liver transplantation from donation after circulatory death

Donation after circulatory death (DCD) liver transplantation (LT) may imply a risk for decreased graft survival, caused by posttransplantation complications such as primary nonfunction or ischemic‐type biliary lesions. However, similar survival rates for DCD and donation after brain death (DBD) LT have been reported. The objective of this study is to determine the longterm outcome of DCD LT in the Eurotransplant region corrected for the Eurotransplant donor risk index (ET‐DRI). Transplants performed in Belgium and the Netherlands (January 1, 2003 to December 31, 2007) in adult recipients were included. Graft failure was defined as either the date of recipient death or retransplantation whichever occurred first (death‐uncensored graft survival). Mean follow‐up was 7.2 years. In total, 126 DCD and 1264 DBD LTs were performed. Kaplan‐Meier survival analyses showed different graft survival for DBD and DCD at 1 year (77.7% versus 74.8%, respectively; P = 0.71), 5 years (65.6% versus 54.4%, respectively; P = 0.02), and 10 years (47.3% versus 44.2%, respectively; P = 0.55; log‐rank P = 0.038). Although there was an overall significant difference, the survival curves almost reach each other after 10 years, which is most likely caused by other risk factors being less in DCD livers. Patient survival was not significantly different (P = 0.59). Multivariate Cox regression analysis showed a hazard ratio of 1.7 (P < 0.001) for DCD (corrected for ET‐DRI and recipient factors). First warm ischemia time (WIT), which is the time from the end of circulation until aortic cold perfusion, over 25 minutes was associated with a lower graft survival in univariate analysis of all DCD transplants (P = 0.002). In conclusion, DCD LT has an increased risk for diminished graft survival compared to DBD. There was no significant difference in patient survival. DCD allografts with a first WIT > 25 minutes have an increased risk for a decrease in graft survival. Liver Transplantation 22 1107–1114 2016 AASLD

Combined effect of donor and recipient risk on outcome after liver transplantation: Research of the Eurotransplant database

Recently the Eurotransplant donor risk index (ET‐DRI) was published, a model based on data from the Eurotransplant database that can be used for risk indication of liver donors within the Eurotransplant region. Because outcome after liver transplantation (LT) depends both on donor and recipient risk factors, a combined donor‐recipient model (DRM) would give a more complete picture of the overall risk involved. All liver transplants in adult recipients from January 1, 2008 to December 31, 2010 in the Eurotransplant region were included. Risk factors in donors and recipients for failure‐free (retransplant free) survival were analyzed in univariate and multivariate analyses. A simplified recipient risk index (sRRI) was constructed using all available recipient factors. A total of 4466 liver transplants were analyzed. Median donor risk index and ET‐DRI were 1.78 and 1.91, respectively. The ET‐DRI was validated in this new cohort (P < 0.001; concordance index [c‐index], 0.59). After construction of a simplified recipient risk index of significant recipient factors, Cox regression analysis showed that the combination ET‐DRI and sRRI into a new DRM gave the highest predictive value (P < 0.001; c‐index, 0.62). The combined model of ET‐DRI and sRRI gave a significant prediction of outcome after orthotopic LT in the Eurotransplant region, better than the ET‐DRI alone. This DRM has potential in comparing data in the literature and correcting for sickness/physical condition of transplant recipients. It is a first step toward benchmarking of graft survival in the Eurotransplant region. Liver Transpl 21:1486‐1493, 2015.

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

Incorporation of Donor Risk Into Liver Allocation Algorithms

WewouldliketothankAvolioetal.(1)forthecommentsonour article on the Eurotransplant Donor Risk Index (ET-DRI)(2). The Authors address an important issue: the practicalincorporation of donor risk into liver allocation algorithms.ItissuggestedthattheET-DRIshouldfirstbecomparedtoexisting donor-to-recipient-matching (D2Rm)-models, suchas D-MELD (3), BAR (4) or SOFT (5), for applicability andaccuracy before using it in liver allocation.We fully agree that transplantation outcome depends ondonor,transplantandrecipientriskfactors.Ofcourse,com-bining all these factors would lead to the best assess-ment of pretransplant risk and therefore best estimationof posttransplant results (note that all risk models arefrom observational studies, and have never been testedprospectively to confirm predictive value). The first stepis to look into donor and transplant factors, as did Fenget al. (6) for the UNOS region. In our current study wedescribe all significant donor- and transplant risk factorswithin the Eurotransplant-region, and combine these intoone number/score—the ET-DRI. The scores mentioned byAvolio et al. only include some of these factors or fac-tors that were not significant in our study; D-MELD onlyincludes donor age, BAR includes donor age and cold is-chemia time (CIT), and SOFT includes donor age, cause ofdeath, creatinine, allocation and CIT. The interesting thingabout the ET-DRI (and DRI) is that it is the strongest risk in-dicator when looking at donor and transplant factors, and itisacontinuousandvalidatedscore.Itprovidesonenumberthat represents the hazard ratio (HR) of that specific liverallograft, including the transplant factors allocation and CIT.Step 2 will be to investigate significant risk factor in recip-ients. Ultimately, research will be needed to see how tobest integrate both (donor/transplant and recipient) scoresto develop a D2R model, as stated by Avolio et al.Scores like D-MELD, BAR and SOFT do not take thestrongest donor factors into account: split-liver (HR1.67)and donation after cardiac death (DCD) (HR1.71). Althoughsuch allografts are scarce for the total Eurotransplant re-gion (6.5%), they account for almost 25% in, for example,the Netherlands, and in our opinion should therefore beincorporated in donor risk stratification.Clearly, further research is needed, especially for recipientrisk factors. The ET-DRI (DRI) gives a validated specific HRfor every single allograft, which is necessary to correct forinsuchresearch.Currentlytheonlyfactorusedinallocationistheextendedcriteriadonor(ECD).Weshowedthesupe-riorityofET-DRIoverECDforusewithintheEurotransplantregion.Furtherstepstobetakenaredevelopmentofa(val-idated) recipient risk index and the incorporation of donorand recipient risk scores into a risk stratifying model.Finally we agree that scores may be helpful for alloca-tion, but cannot replace individual assessment and deci-sion making of the transplantation team. In addition, thesocioethical choice of weighting utility versus equity re-mains a major factor of impact of how allocation will besteered in different countries. ET-DRI is a tool, rather thana means, which can be used to do this.

Liver transplantation with geriatric liver allografts: The current situation in Eurotransplant

In light of the donor organ shortage and the high number of liver transplantation (LT) candidates on the waiting list, the number of extended criteria donors (ECD) increased over time. Among the criteria defining an ECD, donor age is stretched most, so that the use of septuagenarian, octogenarian and even nonagenarian donors increasingly became common practice (1,2). This article is protected by copyright. All rights reserved.

Auxiliary or orthotopic liver transplantation for acute fatty liver of pregnancy: case series and review of the literature.

for acute fatty liver of pregnancy: case series and review of the literature J Ringers, KWM Bloemenkamp, N Francisco, JJ Blok, MS Arbous, B van Hoek a Department of Transplant Surgery, Leiden University Medical Centre, Leiden, the Netherlands b Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands c Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands d Department of Intensive Care, Leiden University Medical Centre, Leiden, the Netherlands Correspondence: Prof Dr B van Hoek, Department of Gastroenterology and Hepatology, C4-P, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands. Email b.van_hoek@lumc.nl

Why the donor risk index and Eurotransplant donor risk index can also be applied in France; reply to Winter et al. and statistical perspective

Dear Sirs: With interest we read the recent publication by Winter et al.1 In their publication, the authors describe the inability to validate the donor risk index (DRI)2 and Eurotransplant donor risk index (ETDRI)3 with data from the French liver transplant (LT) registry. The intention of the authors to validate the DRI/ETDRI for use as an indicator of donor risk and subsequently to improve matching between liver donors and LT recipients is relevant and important. In contrast to the presented results, we validated the DRI for the Eurotransplant region in 2011,4 regardless of differences in donor characteristics between the United Network for Organ Sharing (UNOS) and Eurotransplant. In this study, the authors found a comparable Harrell Cindex of 0.60 for the DRI and 0.62 for the ETDRI and concluded that they were not able to validate the discriminative ability. Apart from only six factors, all other factors were found to vary significantly between Eurotransplant and France (Table 2). This resulted in a significantly lower DRI in France (1.65 vs 1.71, P<.001). In addition, the French data are from 2009 to 2013, whereas the ETDRI and DRI are based on data from 2003 to 2007 and from 1998 to 2002 respectively. The authors base their external validation process on the technique described by Royston and Altman.5 Unfortunately, they did not follow their suggestions sufficiently closely, leading to uninterpretable results. The proposal of Royston5 to test for better or poorer discrimination in the French data, compared to the original data on which the index was developed, is indeed to test for βDRI = 1 in a model like the model (1) used in Winter et al. 1

Old‐to‐old pancreas transplantation, what is old in the USA may be young in Europe

Dear Sirs, With interest we read the recent article by Kayler et al. [1] in your Journal. The authors report the results of old-toold simultaneous pancreas kidney transplantation (SPKT) with the data of the Scientific Registry of Transplant Recipients (SRTRs). Their study shows that patient and deathcensored pancreas graft survival of old-to-old SPKT are inferior as compared to young-to-old SPKT: at 3-years follow-up, respectively, 84% vs. 90% (P = 0.03) and 65% vs. 73% (P = 0.54). Multivariate analyses gave adjusted hazard ratios (HR) for old-to-old compared with youngto-old of 1.91 (patient survival) and 2.24 (death-censured pancreas graft survival). We hereby presume that the endpoint taken by the authors is the restart of insulin therapy. In our own center, 37% of the pancreas donors were ≥40 years old (median 36 years) and 59% of our recipients are ≥40 years (median 42 years), leading to an old-to-old group of 25% in our dataset (unpublished; n = 301, 1984– 2011) as compared to 16% in the Organ Procurement and Transplantation Network (OPTN) area. A Kaplan–Meier analysis of (death-censured) pancreas allograft survival in our center (based on the definition by the Pancreas Transplant Committee [2] e.g. combination of insulin re-start and HbA1c) comparing the four groups (young-to-young, young-to-old, old-to-young, and old-toold) did not show significant differences (P = 0.19), with a 74% 3-year graft survival (vs. 65% in the OPTN area) in the old-to-old group. These results, which are at least comparable with the OPTN, demonstrate the difference in outcome between the USA (OPTN) and one European pancreas transplantation center. Furthermore, there is a difference in donor and recipient characteristics between the two areas, something that was shown earlier for the liver donor population [3]. The fact that the authors chose 40 years (for donor and recipient) as a cutoff in the analysis to define ‘older’ age groups was due to a preliminary Cox-regression analysis; however, within Europe (or the Netherlands), a donor of ≥40 would not be categorized as an ‘old’ pancreas donor. Within the Netherlands, the age limit for pancreas donation is currently set at 60 years [4]. Obviously, a pancreas donor would ideally be <40 years of age, but in Europe and specifically the Netherlands, this is unfortunately not the case. The authors mention that their findings suggest that older candidates can be safely transplanted, particularly when transplanted with younger organs. The preliminary results of our own dataset suggest that old recipients can also be safely transplanted with an ‘older’ organ (especially if old is defined as ≥40). One of the conclusion of the authors, wait-listed candidates does not receive a survival benefit from accepting old-donor SPK organs over remaining on the waiting list for organs from a young donor, would not be applicable in the Netherlands, as the chance for a young donor is very low and would probably lead to an even longer wait-time. We congratulate the authors with the results of their study and hope that these results will be the first step toward a survival benefit model for pancreas transplant candidates. Unfortunately, the results are most likely not applicable for most European pancreas transplantation centers.