Gabriela Berlakovich

American Journal of TransplantationVolume 14, Issue 9 p. 1992-2000 Meeting ReportFree Access Proceedings From an International Consensus Meeting on Posttransplantation Diabetes Mellitus: Recommendations and Future Directions A. Sharif, Corresponding Author A. Sharif Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Birmingham, UKCorresponding author: Adnan Sharif, adnan.sharif@uhb.nhs.ukSearch for more papers by this authorM. Hecking, M. Hecking Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorA. P. J. de Vries, A. P. J. de Vries Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorE. Porrini, E. Porrini Center for Biomedical Research of the Canary Islands, CIBICAN, University of La Laguna, Tenerife, SpainSearch for more papers by this authorM. Hornum, M. Hornum Department of Nephrology, Copenhagen University Hospital Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorS. Rasoul-Rockenschaub, S. Rasoul-Rockenschaub Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorG. Berlakovich, G. Berlakovich Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Krebs, M. Krebs Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorA. Kautzky-Willer, A. Kautzky-Willer Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorG. Schernthaner, G. Schernthaner Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorP. Marchetti, P. Marchetti Department of Endocrinology and Metabolism, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Pacini, G. Pacini Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, ItalySearch for more papers by this authorA. Ojo, A. Ojo Division of Nephrology, University of Michigan Health System, Ann Arbor, MISearch for more papers by this authorS. Takahara, S. Takahara Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, JapanSearch for more papers by this authorJ. L. Larsen, J. L. Larsen Department of Internal Medicine, Nebraska Medical Center, Omaha, NESearch for more papers by this authorK. Budde, K. Budde Department of Nephrology, Charité University, Berlin, GermanySearch for more papers by this authorK. Eller, K. Eller Clinical Division of Nephrology, Medical University of Graz, Graz, AustriaSearch for more papers by this authorJ. Pascual, J. Pascual Servicio de Nefrología, Hospital del Mar, Parc de Salut Mar, Barcelona, SpainSearch for more papers by this authorA. Jardine, A. Jardine Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UKSearch for more papers by this authorS. J. L. Bakker, S. J. L. Bakker Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorT. G. Valderhaug, T. G. Valderhaug Department of Endocrinology, Akershus University Hospital, Lorenskog, NorwaySearch for more papers by this authorT. G. Jenssen, T. G. Jenssen Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this authorS. Cohney, S. Cohney Department of Nephrology, Royal Melbourne and Western Hospitals, Melbourne, AustraliaSearch for more papers by this authorM. D. Säemann, M. D. Säemann Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this author A. Sharif, Corresponding Author A. Sharif Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Birmingham, UKCorresponding author: Adnan Sharif, adnan.sharif@uhb.nhs.ukSearch for more papers by this authorM. Hecking, M. Hecking Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorA. P. J. de Vries, A. P. J. de Vries Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorE. Porrini, E. Porrini Center for Biomedical Research of the Canary Islands, CIBICAN, University of La Laguna, Tenerife, SpainSearch for more papers by this authorM. Hornum, M. Hornum Department of Nephrology, Copenhagen University Hospital Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorS. Rasoul-Rockenschaub, S. Rasoul-Rockenschaub Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorG. Berlakovich, G. Berlakovich Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Krebs, M. Krebs Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorA. Kautzky-Willer, A. Kautzky-Willer Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorG. Schernthaner, G. Schernthaner Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorP. Marchetti, P. Marchetti Department of Endocrinology and Metabolism, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Pacini, G. Pacini Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, ItalySearch for more papers by this authorA. Ojo, A. Ojo Division of Nephrology, University of Michigan Health System, Ann Arbor, MISearch for more papers by this authorS. Takahara, S. Takahara Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, JapanSearch for more papers by this authorJ. L. Larsen, J. L. Larsen Department of Internal Medicine, Nebraska Medical Center, Omaha, NESearch for more papers by this authorK. Budde, K. Budde Department of Nephrology, Charité University, Berlin, GermanySearch for more papers by this authorK. Eller, K. Eller Clinical Division of Nephrology, Medical University of Graz, Graz, AustriaSearch for more papers by this authorJ. Pascual, J. Pascual Servicio de Nefrología, Hospital del Mar, Parc de Salut Mar, Barcelona, SpainSearch for more papers by this authorA. Jardine, A. Jardine Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UKSearch for more papers by this authorS. J. L. Bakker, S. J. L. Bakker Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorT. G. Valderhaug, T. G. Valderhaug Department of Endocrinology, Akershus University Hospital, Lorenskog, NorwaySearch for more papers by this authorT. G. Jenssen, T. G. Jenssen Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this authorS. Cohney, S. Cohney Department of Nephrology, Royal Melbourne and Western Hospitals, Melbourne, AustraliaSearch for more papers by this authorM. D. Säemann, M. D. Säemann Department of Internal Medicine, Medical University of Vienna, Vienna, AustriaSearch for more papers by this author First published: 06 August 2014 https://doi.org/10.1111/ajt.12850Citations: 293AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM. Abbreviations AGM afternoon glucose monitoring CNI calcineurin inhibitor GRADE Grading of Recommendations Assessment, Development and Evaluation NODAT new-onset diabetes after transplantation OGTT oral glucose tolerance test PTDM posttransplantation diabetes mellitus Introduction Previously published consensus guidelines on the diagnosis and management of diabetes mellitus after transplantation acknowledged the importance of posttransplant diabetes in all forms of solid organ transplantation and the need for pro-active, multi-disciplinary management 1, 2. As these were based on conferences held a decade ago, an International Expert Panel of clinicians/researchers was recently convened (Vienna, Austria, September 8–9, 2013) with two objectives: (1) update previous consensus statements and (2) debate current gaps in our clinical evidence base. The panel comprised 24 transplant clinicians, diabetologists and scientists with an active interest in the field. Invitations were based upon a meeting prerequisite to systematically review existing literature for presentation at an open scientific session, encouraging debate and discussion 3. This session contributed to the proceedings of the subsequent closed meeting of the International Expert Panel the following day. While the focus was on kidney transplantation, reflecting the published literature, the principles are likely relevant to all forms of solid organ transplantation. This Meeting Report summarizes our major recommendations from the consensus meeting, with quality of evidence graded in line with GRADE (Grading of Recommendations Assessment, Development and Evaluation) definitions 4. GRADE provides a systematic approach to grade quality of evidence and strength of recommendations. Consensus opinion was to provide the following recommendations: high (Recommendation 4), moderate (Recommendations 2, 3, 5 and 6) and none possible (Recommendation 1 and 7). Readers requiring comprehensive literature reviews as background information are recommended recent publications in this area 5, 6. It is anticipated these opinion-based recommendations will form the template for a planned comprehensive update to existing guidelines. Recommendation 1: Change Terminology From New-Onset Diabetes After Transplantation Back to Posttransplantation Diabetes Mellitus (PTDM) The term new-onset diabetes after transplantation (NODAT) was adopted to acknowledge the pathophysiological consequences of transplantation on glycemic metabolism. However, the term may be misleading, as diabetes is often unrecognized 7, 8. The term NODAT implies exclusion of diabetes prior to transplantation, but effective pretransplant screening is impractical for many centers. The term posttransplantation diabetes mellitus (PTDM) addresses these shortcomings by simply describing newly diagnosed diabetes mellitus in the posttransplantation setting (irrespective of timing or whether it was present but undetected prior to transplantation or not). The term PTDM should be utilized for clinically stable patients who have developed persistent posttransplantation hyperglycemia (see Table 1). The term prediabetes should be utilized for patients with posttransplantation hyperglycemia not reaching diagnostic thresholds for PTDM (impaired fasting glucose and/or impaired glucose tolerance) (Table 1). Fasting glucose has a low sensitivity for diagnosing PTDM, as kidney allograft recipients have relatively preserved fasting glucose concentrations after an oral glucose tolerance test (OGTT) 9-11. Consequently, lowering the threshold for impaired fasting glucose in the screening for PTDM seems appropriate and the American Diabetes Association cutoff (5.6 mmol/L [100 mg/dL]) was preferred over the World Health Organization cutoff (6.1 mmol/L [110 mg/dL]). These updated terms are utilized for the rest of this report. Table 1. Diagnostic criteria for diabetes mellitus and prediabetes by the American Diabetes Association (ADA) ADA11 A confirmatory laboratory test based on measurements of venous plasma glucose must be done on any subsequent day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. Symptoms of diabetes include polyuria, polydipsia and unexplained weight loss. Random plasma glucose is defined as any time of day without regard to time since last meal. Fasting is defined as no caloric intake for at least 8 h. The oral glucose tolerance test should be performed using a glucose load of 75 g anhydrous glucose dissolved in water. Diabetes mellitus Symptoms of diabetes plus RPG ≥ 200 mg/dL (11.1 mmol/L) OR FPG ≥ 126 mg/dL (7.0 mmol/L) OR 2HPG ≥ 200 mg/dL (11.1 mmol/L) during an OGTT OR HbA1c ≥ 6.5% Prediabetes Impaired fasting glucose FPG 100–126 mg/dL (5.6–6.9 mmol/L) Impaired glucose tolerance FPG < 7.0 mmol/L AND 2HPG 7.8–11.0 mmol/L Increased risk of diabetes HbA1c 5.7–6.4% Normal glucose tolerance FPG < 110 mg/dL (5.6 mmol/L) AND 2HPG < 140 mg/dL (7.8 mmol/L) AND HbA1c < 5.7% RPG, random plasma glucose; FPG, fasting plasma glucose; 2HPG, 2-h plasma glucose after an oral glucose. 1 A confirmatory laboratory test based on measurements of venous plasma glucose must be done on any subsequent day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. Symptoms of diabetes include polyuria, polydipsia and unexplained weight loss. Random plasma glucose is defined as any time of day without regard to time since last meal. Fasting is defined as no caloric intake for at least 8 h. The oral glucose tolerance test should be performed using a glucose load of 75 g anhydrous glucose dissolved in water. Recommendation 2: Exclude Transient Posttransplantation Hyperglycemia From PTDM Diagnosis Hyperglycemia is exceptionally common in the early posttransplant period, detectable in approximately 90% of kidney allograft recipients in the early few weeks 12, 13. Hyperglycemia can also occur as a consequence of rejection therapy, infections and other critical conditions. While identifying transient posttransplantation hyperglycemia is important, being an important risk factor for subsequent PTDM 14, ubiquitously labeling the majority of kidney allograft recipients with PTDM in the immediate posttransplant setting is not helpful. A formal diagnosis of PTDM is best made when patients are stable on their likely maintenance immunosuppression, with stable kidney allograft function and in the absence of acute infections. Recommendation 3: Expand Screening Tests for PTDM Using Postprandial Glucose Monitoring and HbA1c to Raise Suspicion, While Oral Glucose Tolerance Tests Remain the Most Important The transplant community lacks data linking glycemic parameters with long-term macrovascular (e.g. myocardial infarct, stroke) and microvascular (e.g. retinopathy, nephropathy) complications, remaining dependent on outcome studies from the nontransplant population 15. As no glycemic indicator posttransplantation has demonstrated superiority with regard to long-term outcomes, the optimal measure remains unclear. At present, the OGTT is considered the gold standard for diagnosing PTDM. OGTTs identify more patients with diabetes posttransplantation than fasting glucose measurement alone 9-11, a similar observation to the general population, but detection is higher due to different pathophysiology between PTDM and type 2 diabetes 6, 16. An OGTT also allows diagnosis of impaired glucose tolerance to be made, which is an independent risk factor for long-term development of PTDM, cardiovascular disease and mortality when tested either before 17 or after transplantation 18, 19. However, OGTTs are not widely used as they are time consuming and impractical in a large transplant program. HbA1c-based diagnosis is endorsed for diagnosis of diabetes mellitus in the general population 20 and we recommend elevated HbA1c be used to recognize PTDM (see Table 1). Caution must be exercised with its use early posttransplantation, as a normal HbA1c will not exclude diagnosis in the presence of posttransplantation anemia and/or dynamic renal allograft function 21. However, HbA1c 5.7–6.4% or higher in this early period would indicate the need to follow up with a recognized diagnostic test, although HbA1c greater than 6.5% is unlikely to be a false positive. Shabir et al 22 suggest optimum HbA1c cut-off values for predicting PTDM at 3 and 12 months of 44 mmol/mol (6.2%) and 48 mmol/mol (6.5%), respectively (latter equivalent to general population), but this analysis was based on a small cohort of 71 kidney allograft recipients and requires further validation. Yates et al 23 recently reported afternoon glucose monitoring (AGM) in kidney allograft recipients, using capillary blood glucose, was more sensitive to both OGTT and HbA1c for detecting hyperglycemia in the initial 6-week posttransplant period in patients on corticosteroid containing regimens. However, this approach has not been validated for diagnosis of PTDM. Thus, testing for AGM in the early postoperative period may better identify individuals who should receive an OGTT or other recognized diagnostic testing. The use of screening strategies should help to streamline diagnosis of PTDM, through identification of a subset of high-risk patients who should undergo further testing. One study demonstrated the benefit of a screening algorithm based upon fasting glucose and/or HbA1c, thereby reducing overall number of OGTTs required 9. The superiority of this streamlined approach over more widespread OGTT testing for PTDM remains to be determined. Surveillance for glycemic abnormalities pretransplantation, including OGTT when possible, will help identify patients who have undiagnosed diabetes 8 or prediabetes 17. Studies have shown the utility of glucose-based diagnostic criteria pretransplantation 8, but using HbA1c is fraught with difficulty in patients with severe renal impairment or end-stage kidney disease. Kidney transplant candidates should have an annual check of glycemic status, either in the form of fasting glucose or risk-stratified OGTT (based upon center-specific screening algorithm). However, evidence is insufficient to recommend OGTTs for all kidney transplant candidates unless it forms part of a risk-stratified algorithm 8. Recommendation 4: Identify Patients at Risk for PTDM Risk factors for PTDM are well established 24, encompassing both general (e.g. age, family history of diabetes, prior history of glucose intolerance 25) and transplant-specific (e.g. immunosuppression) factors, with accruing risk factors associated with greater PTDM risk. Novel targets continue to be identified, incorporating an improved understanding of metabolic syndrome and identification of select genetic polymorphisms as PTDM risk factors. Israni et al 26 found posttransplant metabolic syndrome independently associated with subsequent risk of PTDM. When occurring pretransplantation, the metabolic syndrome 27 and its components such as pretransplant hypertriglyceridemia and BMI 28, as well as prediabetes 17 have predicted increased risk for PTDM. Specifically pretransplantation insulin resistance, putatively the underlying pathophysiology of metabolic syndrome, was found to be a risk factor for PTDM 7. Pancreatic beta cell dysfunction (reflected by high fasting proinsulin concentrations) has been shown to be a risk factor for PTDM 29 and these data are supported by genetic polymorphism studies. Kim et al 30 identified an association between single nucleotide polymorphisms within 10 genes of interleukins or their receptors as predictors of PTDM. Similarly, Tavira et al 31 demonstrated an association between KNNJ11 polymorphisms, hypothesized to impair insulin release from pancreatic beta cells, and PTDM. Screening for posttransplant glucose abnormalities (Recommendation 3) is even more important in those patients identified to be at a higher risk of PTDM. In a prospective cohort of over 600 patients undergoing serial OGTTs, the vast majority of late PTDM were prediabetic at 3 months 32. Trials are needed to determine whether modifying established or novel risk factors can attenuate progression to PTDM. Recommendation 5: Choose and Use Immunosuppression Regimens Shown to Have the Best Outcome for Patient and Graft Survival, Irrespective of PTDM Risk Immunosuppression is the major modifiable risk factor for development of PTDM but risk versus benefit analysis is required to balance risk of developing PTDM versus rejection. Cole et al 33 demonstrated adverse graft survival after development of either rejection or PTDM, with development of both resulting in the worst outcomes. Therefore, no specific recommendation is made to advocate a definitive immunosuppressant strategy for allograft recipients based upon PTDM risk alone. Based on the current lack of evidence we also recommend caution in immunosuppressant adjustments in the event that PTDM develops, with a need to account for patient-specific risk factors such as immunological risk. The DIRECT study confirmed the increased diabetogenicity of tacrolimus compared to cyclosporine postkidney transplantation in a randomized controlled trial, with no difference in adverse events 34. However, this was a 6-month trial and glycemic benefits need to be weighed against risk for long-term graft attrition. In addition, target tacrolimus levels were higher than the contemporary approach of reduced calcineurin inhibitor (CNI) exposure. A recent meta-analysis of 56 randomized controlled trials demonstrated less PTDM and better overall graft survival with CNI-minimization or avoidance strategies using new agents such as belatacept or tofacitinib 35. Results are awaited from groups evaluating alternative strategies such as selecting CNI (tacrolimus vs. cyclosporine) based on pretransplant PTDM risk (clinicaltrials.org: NCT01002339). There is limited evidence supporting conversion from tacrolimus to cyclosporine in established PTDM, both from previous literature 36 and a preliminary report of randomized trial data 37, but the benefits must be weighed against any risks associated with conversion. Late changes in immunosuppressive regimens may reverse PTDM without jeopardizing graft outcomes, but this requires further evaluation to ensure glycemic benefits outweigh allograft risks. Johnston et al, analyzing data from the United States Renal Data System, found sirolimus were independently associated with increased risk for PTDM 38. Fewer reports have conflictingly found glycemic benefits after conversion from CNIs to sirolimus 39. There is no evidence to suggest any glycemic effects of anti-proliferative agents such as mycophenolate mofetil or azathioprine. Steroid minimization is a common strategy to attenuate risk of PTDM. However, a beneficial effect of corticosteroid sparing strategies has not been demonstrated 40. A recent meta-analysis of corticosteroid withdrawal between 3 and 6 months after transplantation found no meaningful effect on PTDM incidence 41. Early corticosteroid withdrawal after a few days has shown decreased PTDM incidence, but this was only significant when the CNI used was cyclosporine compared to tacrolimus 42. Moreover, a mild increase in the incidence of acute rejection with corticosteroid sparing strategies might counterbalance the metabolic beneficial effect 41. The degree of glycemic burden from low-dose corticosteroid maintenance therapy is unclear and therefore steroid avoidance/withdrawal strategies require careful risk/benefit assessment in the context of long-term outcomes. The impact of steroid avoidance/withdrawal is all the more uncertain given the current use of lower CNI target levels and rapid weaning of corticosteroids. Split corticosteroid dosing may also reduce glycemic variability and peak hyperglycemia 43. Data in relation to the impact of induction therapy are limited and no firm conclusions can be drawn. In a recent meta-analysis of five studies (n = 492 patients), the mAb alemtuzumab was found to be associated with a borderline lower risk of developing PTDM than IL-2 receptor antagonists 44. This could be due to CNI- and steroid-sparing strategies employed with alemtuzumab use or a diabetogenic effect of IL-2 receptor antagonists. Supporting the latter is a single-center retrospective study of 264 renal transplant recipients, where induction with basiliximab was associated with a significantly greater risk of developing PTDM compared to no induction (51.5% vs. 36.9%, p = 0.017) at 10 weeks posttransplantation 45. Recommendation 6: Use Strategies for Prevention and Treatment Beyond Modification of Immunosuppressive Regimens Prevention is ideal and guidance should be given to all potential transplant recipients regarding their risk of developing PTDM. Intervention when necessary can be in the form of nonpharmacological and/or pharmacological therapy. Sharif et al 46 demonstrated the potential for benefit from lifestyle modification in kidney allograft recipients with impaired glucose tolerance (13/25 patients reverted to normal glucose tolerance after median of 9 months, with only 1 progressing to PTDM). Thus, as observed in the general population 47, exercise and lifestyle modification may reduce the risk of patients with prediabetes developing PTDM. However, there remains a need for well-powered clinical trials to evaluate the feasibility and efficacy of these interventions to prevent PTDM in a larger renal transplant population. Werzowa et al 48 reported a randomized controlled trial comparing safety and efficacy of vildagliptin (dipeptidylpeptidase-4 inhibitor) with pioglitazone (thiazolidinedione) or placebo in kidney allograft recipients with impaired glucose tolerance. Adverse events were equivalent in all three arms and both pioglitazone and vildagliptin produced comparable reduction in 2-h postprandial glucose levels. Metformin may be an attractive anti-hyperglycemic agent to reduce the likelihood of PTDM in high-risk individuals 49 but the benefits of metformin need to be weighed against the risks associated with metformin in the context of impaired renal function (e.g. lactic acidosis). However, this association has been the subject of critical analysis 50 and well-designed clinical trials are necessary to shed light on the benefit versus risk ratio in relation to metformin. Lifestyle modification > oral anti-diabetic therapy > insulin is an appropriate stepwise approach for management of late-PTDM, but with immediate posttransplant hyperglycemia we recommend the reverse as the most appropriate management. Insulin is the only safe and effective agent in the context of high glucocorticoid doses and acute illness early posttransplant, but early and aggressive use of insulin may also have long-term benefits. In a randomized controlled trial, Hecking et al 12 demonstrated the benefit of early basal insulin therapy following detection of early posttransplant hyperglycemia (<3 weeks) at reducing subsequent odds of developing PTDM within the first year posttransplantation by 73%. A larger randomized controlled clinical trial (ITP-NODAT, clinicaltrials.org: NCT01683331) is currently evaluating whether these findings are reproducible in five centers recruiting over 300 patients. In addition, this study will determine whether early insulin therapy is feasible in patients who are hospitalized for a much shorter period than utilized in the original study. Treatment of posttransplantation hyperglycemia is in line with postoperative glucose management and, although representing a major shift from previous practice, consensus opinion was that this approach should be recommended but a glucose threshold for starting insulin was not specified (Figure 1). Although a relatively high glucose threshold of 200 mg/dL (evening or fasting) has been previously suggested, it may be reasonable to lower this threshold but further research is warranted before firm guidance can be issued. Figure 1Open in figure viewerPowerPoint Flowchart highlighting updated diagnostic and management framework for posttransplantation diabetes mellitus. The armamentarium of anti-diabetic therapy is increasing and individual pharmacological risk/benefit profiles must be evaluated in the context of transplantation 5, 6, 20. Dose adjustments or

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

All oral direct acting antivirals (DAA) have been shown to improve the liver function of patients with decompensated cirrhosis but it is presently unknown whether this clinical improvement may lead to the delisting of some patients. The aim of this study was to assess if and which patients can be first inactivated due to clinically improvement and subsequently delisted in a real life setting.103 consecutive listed patients without hepatocellular carcinoma were treated with different DAA combinations in 11 European centres between February 2014 and February 2015.The cumulative incidence of inactivated and delisted patients by competing risk analysis was 15.5% and 0% at 24weeks, 27.6% and 10.3% at 48weeks, 33.3% and 19.2% at 60weeks. The 34 patients who were inactivated showed a median improvement of 3.4 points for MELD (delta MELD, p<0.0001) and 2 points for Child-Pugh (CP) (delta-CP, p<0.0001). Three variables emerged from the most parsimonious multivariate competing risk model as predictors of inactivation for clinical improvement, namely, baseline MELD classes (MELD 16-20: HR=0.120; p=0.0005, MELD >20:HR=0.042; p<0.0001), delta MELD (HR=1.349; p<0.0001) and delta albumin (HR=0.307; p=0.0069) both assessed after 12weeks of DAA therapy.This study showed that all oral DAAs were able to reverse liver dysfunction and favoured the inactivation and delisting of about one patient out-of-three and one patient out-of-five in 60weeks, respectively. Patients with lower MELD scores had higher chances to be delisted. The longer term benefits of therapy need to be ascertained.The excellent efficacy and safety profile of the new drugs against Hepatitis C virus, "direct acting antivirals" or DAAs, have made antiviral therapy possible also for patients with advanced liver disease and for those on the waiting list for liver transplantation (LT). This study shows for the first time that the DAAs may lead to a remarkable clinical improvement allowing the delisting of one patient out of 5.

•An increasing proportion of patients are being transplanted for non-alcoholic steatohepatitis (NASH) in Europe.•Hepatocellular carcinoma was more common in patients transplanted with NASH.•Survival in recipients with NASH is comparable to that of other disease indications.•Age, BMI, and advanced liver disease predicted poorer outcomes in NASH recipients. Background & AimsLittle is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors.MethodsWe analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival.ResultsAmong 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH – an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61–65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors.ConclusionsThe number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications.Lay summaryThe prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis. Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH – an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61–65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications.

Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear.In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints.Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015).HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events.This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.

Many transplant centers are reluctant to accept alcoholic patients for OLT because of their supposed potential for alcoholic recidivism and poor compliance with the required immunosuppressive regimen, both of which result in graft failure. Only inconclusive data related to these arguments are available. From May 1982 to January 1993, 58 patients received OLT at our institution for end-stage cirrhosis, where alcohol was the only toxic component. The indication for OLT in these patients was considered with particular attention to recidivism and compliance. Overall survival in this group was 71% and 63% at 1 and 5 years, respectively, with an average survival time of 78 months. Actuarial survival of patients transplanted since January 1989 (n = 37) was 86% and 83% at 1 and 2 years (average survival 42 months). Nonfatal clinical endpoints were analyzed in those patients surviving at least 3 months (n = 44). Return to alcohol abuse has been documented in 14 persons at routine short-term outpatient checkups. The estimated risk for alcoholic recidivism amounts to 31%, with a median follow-up of 33 months. Compliance with immunosuppressive regimen was expressed as a dependent value of acute rejection episodes (0.3 per patient, median follow-up 33 months), chronic rejection (occurred in none of the patients), and measurements of CsA HPLC blood trough level (92.2% within the target range). The preversus postoperative improvement of employment, marital, and social status after OLT showed a statistically significant difference. Unwillingness to offer OLT to individuals with alcoholic liver disease because of failure to demonstrate 100% long-term abstinence appears difficult to defend in the face of good results in survival, compliance, and social rehabilitation.

Objective Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. Design Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. Results From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10–30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15–19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44–102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31–170). Conclusions Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n = 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n = 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n = 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

Alcoholic liver disease (ALD) is now the commonest indication for liver transplantation and has accounted for 5716 transplants in Europe between January 1988 and June 2000 [1]; however, it remains controversial. The proportion of patients grafted for ALD in Europe is overall 17%; however, both the proportion of patients grafted for alcohol-related liver disease and the absolute number of patients grafted has risen; there is great variation between countries (from 0% (in Poland) to 30% (in Spain)) (Fig. 1). Survival after transplantation for ALD is possible (5 and 10-year survival rates are 67 and 55% (graft survival) and 71 and 59% (patient survival)) [1] which is similar to those for other indications although this does not necessarily imply that the outcome is as good in the two groups since there may be considerable differences in case-mix. There is no doubt that a small proportion of patients return to a damaging pattern of drinking but the number of grafts lost through a return to drinking is, at least according to published reports, small [2].

To determine whether long-term oral anticoagulant treatment was effective in improving graft performance and preventing major amputation following vein bypass surgery for femoropopliteal atherosclerosis, a clinical trial was conducted in one single center and continued during 10 years. After 130 patients had electively received a femoropopliteal vein graft, they were randomly assigned to a therapy group (treatment with phenprocoumon [n = 66]) or to a control group (n = 64) that remained without any anticoagulant treatment. Primary end points of the study were graft reocclusion and limb loss. The median durations of primary patency and limb salvage were significantly longer for treated patients than that for controls. In addition, survival in the therapy group was longer. Following autologous vein bypass surgery in the treated group, the results were superior in terms of graft patency, limb salvage, and survival.

The appropriate time point for starting immunosuppressive treatment with calcineurin inhibitors after orthotopic liver transplantation (OLT) has been a subject of debate. The aim of the study was to analyze the effects of anti-thymocyte globulin (ATG) induction therapy on rejection, renal function, infection, tumor rate, and survival. We retrospectively analyzed 391 patients after OLT who had either received calcineurin inhibitors immediately after OLT (n = 129) or after an initial short-term Thymoglobulin induction therapy (n = 262). The 1-year acute rejection rate was 14.5% vs. 31.8% in favor of ATG (P = 0.0008). Rejection grades and the need for treatment also differed significantly (7.3% vs. 23.3%; P = 0.001). Serum creatinine at transplantation was similar in both groups (1.14 mg/dL vs.1.18 mg/dL; P = NS). Postoperative hemofiltration was less frequently seen after induction therapy (P < 0.05). Reduced renal function at 1 year was commonly observed, but serum creatinine (1.26 mg/dL vs. 1.37mg/dL; P = 0.015) and glomerular filtration rate (81 mL/min vs. 75 mL/min; P = 0.02) were far better in the ATG group. Undesired side effects occurred at a similar rate in both groups. Five-year patient survival was also similar in the 2 groups (70.1% and 74.3%; P > 0.05). Short-term ATG induction therapy with delayed administration of calcineurin inhibitors led to a more favorable rejection rate and an improved clinical course in case of a rejection episode. It has beneficial effects on renal function immediately after OLT as well as later, and no additional harmful effects.

Background. The purpose of this study was to analyze the impact of extended donor criteria (EDC) and of changes in the Model for End-Stage Liver Disease (MELD) score while waiting for liver-transplantation (Δ-MELD) on patient survival and initial graft function. Methods. We included 386 consecutive patients with end-stage liver disease who underwent orthotopic liver transplantation at the Medical University Vienna between 1997 and 2003. Primary outcome was patient survival and secondary outcome was initial graft function. EDC included: age >60 years, >4 days intensive medical care, cold ischemia time >10 hr, need for noradrenalin >0.2 μg/kg/min or doputamin >6 μg/kg/min, a donor peak serum sodium >155 mEq/L, a donor serum creatinine >1.2 mg/100 mL, and a body mass index >30. Results. Δ-MELD was significantly higher in the nonsurvivor population (P=0.01) and EDC showed a significant influence on initial graft function (P=0.01). Worsening in either Δ-MELD or the presence of at least two EDC was not associated with an increased risk of primary graft dysfunction and death. Worsening in Δ-MELD and the presence of at least two EDC was significantly associated with primary graft dysfunction (P=0.01) and death (P=0.008). Conclusion. The combination of a liver recipient with worsening Δ-MELD and a potential donor with at least two EDC should be avoided.

Hemodynamic monitoring using transesophageal echocardiography (TEE) in patients with signs of portal hypertension undergoing orthotopic liver transplantation (OLT) carries potential risk of esophageal and gastric variceal hemorrhage. The aim of our retrospective analysis was to evaluate the safety of intraoperative TEE monitoring during OLT in patients with esophagogastric varices.A retrospective analysis of 396 liver transplant recipients was performed at the Medical University of Vienna monitored by TEE during OLT between 2003 and 2010.Varices were documented by esophagogastroduodenoscopy in 287 (72.5%) of 396 analyzed patients: 130 (32.8%) varices grade I (<5 mm under insufflation) and 157 (39.6%) varices grade II (>5 mm under insufflation). Red spot signs were identified in 40 patients (10.1%). Most varices (82.2%) were documented in the esophagus, 4.2% in the stomach, and 13.6% in both (esophagus and stomach). Only one major bleeding occurred, and it was only in a case of one patient with an esophageal varix, which was treated with a balloon tamponade during OLT. Although patients with varices demonstrated a significantly longer prothrombin time and lower platelet count, there was no significant difference in the requirement for blood products among patients with and without varices.TEE is a relatively safe method for monitoring cardiac performance with a low incidence of major hemorrhagic complications in patients with documented esophagogastric varices undergoing OLT.

Liver transplantation has emerged as an established and well-accepted therapeutic option for patients with acute and chronic liver failure and hepatocellular carcinoma. The disproportion between recipients and donors is still an ongoing problem that has only been solved partially over the last centuries. For several patients no life-saving organs can be distributed. Therefore, objective and internationally established recommendations regarding indication and organ allocation are imperative. The aim of this article is to establish evidence-based recommendations regarding the evaluation and assessment of adult candidates for liver transplantation. This publication is the first Austrian consensus paper issued and approved by the Austrian Society of Gastroenterology and Hepatology in cooperation with the Austrian Society of Transplantation, Infusion and Genetics.

Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4-18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9-9.1) and patient survival (HR 2.3; 95% CI 1.5-3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7-4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival.

Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.

Plasma disappearance rate of indocyanine green (PDRICG) has been proposed for assessment of liver function in liver transplants donors and recipients, in patients with chronic liver failure, and as a prognostic factor in critically ill patients. The assessment of PDRICG using a newly developed noninvasive digital pulse densitometry method was simultaneously compared to invasive aortic fiber-optic method in patients undergoing orthotopic liver transplantation (OLT). Fourteen consecutive liver transplant candidates (11 male, 3 female) were prospectively enrolled into the study. A 4F aortic catheter with an integrated fiber-optic device and a thermistor was inserted via a femoral artery sheath for invasive aortic (INV) PDRICG assessment in all patients. The fiber-optic device was connected to a computer system (COLD-Z021, PULSION Medical Systems, Munich, Germany). A finger-piece sensor was used for non-invasive (NINV) pulse-densitometric PDRICG assessment. For the PDRICG assessment.5 mg/kg of ICG in cooled saline (10-15 mL) was injected through a central venous catheter. The assessments of PDRICG were performed after induction of anesthesia, after clamping of the hepatic artery, after clamping of the inferior vena cava, after reperfusion of the graft, and on the first postoperative day. During the PDRICG measurements, the investigators were blinded for the results of the noninvasive monitoring. Seventy-one pairs of measurements were performed successfully. PDRICG ranged from 0%/min to 43.8 %/min (11.6%/min +/- 9.6 %/min, mean +/- SD) for invasive and from 2.6%/min to 36.1 %/min (10%/min +/- 7.6 %/min, mean +/- SD) for noninvasive assessment method. The linear regression analysis yielded the equation: PDRICG(NINV) = 1.493 +/- 0.735 x PDRICG(INV), with a correlation coefficient of r = 0.93 (P <.0001). The analysis according to Bland and Altman showed a good agreement between the PDRICG(NINV) and PDRICG(INV) with a mean bias 1.5 +/- 3.8 for all measurements. In conclusion, according to these results, the noninvasive transcutaneous pulse-densitometric method correlates well with the invasive aortic fiber-optic method and thus can be used in patients undergoing liver transplantation.

Donor criteria for liver grafts have been expanded because of organ shortage. Currently, no exact definitions for extended donor grafts have been established. The aim of this study was to analyze the impact of donor-specific risk factors, independent of recipient characteristics. In collaboration with Eurotransplant and European Liver Transplant Register, solely donor-specific parameters were correlated with 1-year survival following liver transplantation. Analyses of 4701 donors between 2000 and 2005 resulted in the development of a nomogram to estimate graft survival for available grafts. Predictions by nomogram were compared to those by Donor Risk Index (DRI). In the multivariate analysis, cold ischemic time (CIT), highest sodium, cause of donor death, γ-glutamyl transferase (γ-GT), and donor sex (female) were statistically significant factors for 3 months; CIT, γ-GT, and cause of donor death for 12-month survival. The median DRI of this study population was 1.45 (Q1: 1.17; Q3: 1.67). The agreement between the nomogram and DRI was weak (kappa = 0.23). Several donor-specific risk factors were identified for early survival after liver transplantation. The provided nomogram will support quick organ quality assessment. Nevertheless, this study showed the difficulties of determining an exact definition of extended criteria donors.

In Brief Background Endothelial glycocalyx participates in the maintenance of vascular integrity, and its perturbations cause capillary leakage, loss of vascular responsiveness, and enhanced adhesion of leukocytes and platelets. We hypothesized that marked shedding of the glycocalyx core protein, syndecan-1, occurs in end-stage liver disease (ESLD) and that it increases during orthotopic liver transplantation (OLT). We further evaluated the effects of general anesthesia on glycocalyx shedding and its association with acute kidney injury (AKI) after OLT. Patients and Methods Thirty consecutive liver transplant recipients were enrolled in this prospective study. Ten healthy volunteers served as a control. Acute kidney injury was defined by Acute Kidney Injury Network criteria. Results Plasma syndecan-1 was significantly higher in ESLD patients than in healthy volunteers (74.3 ± 59.9 vs 10.7 ± 9.4 ng/mL), and it further increased significantly after reperfusion (74.3 ± 59.9 vs 312.6 ± 114.8 ng/mL). The type of general anesthesia had no significant effect on syndecan-1. Syndecan-1 was significantly higher during the entire study in patients with posttransplant AKI stage 2 or 3 compared to patients with AKI stage 0 or 1. The area under the curve of the receiver operating characteristics curve of syndecane-1 to predict AKI stage 2 or 3 within 48 hours after reperfusion was 0.76 (95% confidence interval, 0.57–0.89, P = 0.005). Conclusions Patients with ESLD suffer from glycocalyx alterations, and ischemia-reperfusion injury during OLT further exacerbates its damage. Despite a higher incidence of AKI in patients with elevated syndecan-1, it is not helpful to predict de novo AKI. Volatile anesthetics did not attenuate glycocalyx shedding in human OLT. Shedding of the glycocalyx core protein, syndecan-1, occurs in ESLD, increases during liver transplantation with ischemia perfusion injury, is unaffected by the type of general anesthesia used, and is not helpful to predict acute kidney injury.

Kidney paired donation (KPD) is an efficient strategy to circumvent major immunological barriers in patients who have a willing and medically able, but incompatible living donor. In recent years, several countries have developed successful KPD programs, including highly active multicenter alliances in the United States, and even international cross-border kidney shipment has been documented (1-3). In Europe, several countries are running independent KPD programs, with the Dutch program being the most prominent (4). This article is protected by copyright. All rights reserved.

Objective The aim of this study was to evaluate the prognostic potential of a 3-parameter visual scoring (qualitative score [QS]) system for hepatobiliary phase gadoxetic acid–enhanced magnetic resonance imaging (MRI) in orthotopic liver transplant grafts. Materials and Methods This retrospective study of 128 patients was approved by our institutional review board. Two readers independently assigned 3 QSs to T1-weighted MRI scans, 20 minutes after the administration of gadoxetic acid (hepatobiliary phase), based upon the following: (1) liver parenchymal enhancement (EnQS, 0–2); (2) biliary contrast excretion (ExQS, 0–2); and (3) signal intensity of the portal vein relative to the liver parenchyma, that is, the portal vein sign (PVsQS, 0–2). The functional liver imaging score (FLIS) was calculated as the sum score of these 3 parameters. The relative liver enhancement (RLE) was measured as well. Demographic, clinical, laboratory parameters, and imaging findings were included in univariate and multivariate statistical analyses. The primary end point was graft failure, that is, retransplantation or death from liver failure. The probability of graft survival was calculated by Kaplan-Meier estimates and Cox proportional hazards regression. Results In the univariate analysis, EnQS, ExQS, PVsQS, and FLIS scores, as well as RLE, were significantly associated with the 1- to 3-year probability of graft survival ( P &lt; 0.001). For a FLIS of (0), the 3-year probability of graft survival was 6.5%, whereas it was 51.3% for a FLIS of (1–3) and 100% for a FLIS of (4–6) ( P &lt; 0.001). In the multivariate survival models, EnQS, ExQS, and PVsQS, each independently outperformed the majority of clinical and laboratory parameters, and the FLIS did even better regarding the prediction of 1- to 3-year graft survival. Conclusions In liver transplant recipients, gadoxetic acid–enhanced MRI-derived QSs (ie, EnQS, ExQS, and PVsQS), as well as the FLIS and RLE, can predict graft survival probability.

Background and Aims The Model for End‐Stage Liver Disease (MELD) is used for clinical decision‐making and organ allocation for orthotopic liver transplantation (OLT) and was previously upgraded through inclusion of serum sodium (Na) concentrations (MELD‐Na). However, MELD‐Na may underestimate complications arising from portal hypertension or infection. The von Willebrand factor (vWF) antigen (vWF‐Ag) correlates with portal pressure and seems capable of predicting complications in patients with cirrhosis. Accordingly, this study aimed to evaluate vWF‐Ag as an adjunct surrogate marker for risk stratification on the waiting list for OLT. Approach and Results Hence, WF‐Ag at time of listing was assessed in patients listed for OLT. Clinical characteristics, MELD‐Na, and mortality on the waiting list were recorded. Prediction of 3‐month waiting‐list survival was assessed by receiver operating characteristics and net reclassification improvement. Interestingly, patients dying within 3 months on the waiting list displayed elevated levels of vWF‐Ag ( P &lt; 0.001). MELD‐Na and vWF‐Ag were comparable and independent in their predictive potential for 3‐month mortality on the waiting list (area under the curve [AUC], vWF‐Ag = 0.739; MELD‐Na = 0.764). Importantly, a vWF‐Ag cutoff at 413% identified patients at risk for death within 3 months of listing with a higher odds ratio (OR) than the previously published cutoff at a MELD‐Na of 20 points (vWF‐Ag, OR = 10.873, 95% confidence interval [CI], 3.160, 36.084; MELD‐Na, OR = 7.594, 95% CI, 2.578, 22.372; P &lt; 0.001, respectively). Ultimately, inclusion of vWF‐Ag into the MELD‐Na equation significantly improved prediction of 3‐month waiting‐list mortality (AUC, MELD‐Na–vWF = 0.804). Conclusions A single measurement of vWF‐Ag at listing for OLT predicts early mortality. Combining vWF‐Ag levels with MELD‐Na improves risk stratification and may help to prioritize organ allocation to decrease waiting‐list mortality.

Model for end-stage liver disease (MELD) score has emerged as a useful tool in predicting mortality in patients awaiting liver transplantation. There is still, however, discussion as to whether further parameters could improve the sensitivity and specificity of the MELD score. From 1997 to 2003, 621 adult patients with end-stage liver disease were listed for orthotopic liver transplantation (OLT). Patients suffering from hepatoma were excluded from analysis (113 patients). The MELD score was investigated at the time of listing (MELD ON) and of coming off the list (MELD OFF). Patients who died while on the waiting list showed a significant increase in their MELD score during the waiting time (MELD ON: 21 +/- 7 vs. MELD OFF: 28 +/- 9) as well as a significantly higher MELD ON compared with patients who were transplanted (MELD ON: 16 +/- 5 vs. MELD OFF: 17 +/- 7) or removed from the waiting list (MELD ON: 16 +/- 6 vs. MELD OFF: 12 +/- 3). Multivariate analysis identified MELD ON, ascites and recurrent infection as independent risk factors for death on the waiting list (P < 0.01). MELD score was not identified as a predictor for the post-transplant survival rate. MELD score is a strong predictor for death on the waiting list, but refractory ascites and recurrent infection are independent risk factors, too.

A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 +/- 0.19 g/cm2 vs. CON: 0.73 +/- 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.

The predictive value of MELD score for post-transplant survival has been under constant debate since its implementation in 2001. Aim of this study was to assess the impact of alterations in MELD score throughout waiting time (WT) on post-transplant survival. A single-centre retrospective analysis of 1125 consecutive patients listed for liver transplantation between 1997 and 2009 was performed. The impact of MELD score and dynamic changes in MELD score (DeltaMELD), as well as age, sex, year of listing and WT were evaluated on waiting list mortality and post-transplant survival. In this cohort, 539 (60%) patients were transplanted, 223 (25%) died on list and 142 (15%) were removed from the waiting list during WT. One-, three- and five-year survival after liver transplantation were 83%, 78% and 76% respectively. DeltaMELD as a continuous variable proved to be the only significant risk factor for overall survival after liver transplantation (hazard ratio (HR): 1.06, 95% confidence interval (CI) 1.02-1.1, P = 0.013). The highest risk of post-transplant death could be defined for patients with a DeltaMELD > 10 (HR: 4.87, 95% CI 2.09-11.35, P < 0.0001). In addition, DeltaMELD as well as MELD at listing showed a significant impact on waiting list mortality. DeltaMELD may provide an easy evaluation tool to identify patients on the liver transplant waiting list with a high mortality risk after transplantation in the current setting. Temporarily withholding and re-evaluating these patients might improve overall outcome after liver transplantation.

Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist's assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient's pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key factor determining the outcome of transplantation for alcoholic cirrhosis is intensive lifelong medical and psychological care. Post-transplant surveillance might be much more important than pre-transplant selection.

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post-LT long-term observation is challenging, and biomarkers as carbohydrate-deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow-up was 73 months (0-213). One- and five-year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post-transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single-center analysis showed good post-transplant long-term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post-LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.

Serum C-reactive protein (CRP) is a prognostic factor for overall survival (OS) and recurrence of hepatocellular carcinoma (HCC) in patients treated with resection or non-surgical treatment. Here, we investigated the association of elevated CRP (≥1 vs. <1 mg/dL) with (i) recurrence of HCC and (ii) OS after liver transplantation (LT).Adult HCC patients undergoing orthotopic deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed.Among 216 patients included, 132 (61.1%) were transplanted within the Milan criteria and forty-two patients (19.4%) had microvascular invasion on explant histology. Seventy patients (32.4%) showed elevated CRP (≥ 1 mg/dL). On multivariate analysis, a CRP ≥ 1 mg/dL was an independent risk factor for HCC recurrence with a 5-year recurrence rate of 27.4% vs. 16.4% (HR 2.33; 95% CI 1.13-4.83; p = 0.022). OS was similar in patients with normal vs. elevated CRP levels.Elevated serum CRP is associated with HCC recurrence after LT and may be a marker for more aggressive tumor biology. Future studies should evaluate whether patients with elevated pre-transplant CRP levels benefit from closer monitoring for HCC recurrence.

Rationale: Kidney homeostasis is critically determined by the coordinated activity of the renin-angiotensin system (RAS), including the balanced synthesis of its main effector peptides Ang (angiotensin) II and Ang (1–7). The condition of enzymatic overproduction of Ang II relative to Ang (1–7) is termed RAS dysregulation and leads to cellular signals, which promote hypertension and organ damage, and ultimately progressive kidney failure. ACE2 (angiotensin-converting enzyme 2) and NEP (neprilysin) induce the alternative, and potentially reno-protective axis by enhancing Ang (1–7) production. However, their individual contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD) has not yet been elucidated. Objective: To examine whether NEP-mediated Ang (1–7) generation exceeds Ang II formation in the healthy kidney compared with diseased kidney. Methods and Results: In this exploratory study, we used liquid chromatography-tandem mass spectrometry to measure Ang II and Ang (1–7) synthesis rates of ACE, chymase and NEP, ACE2, PEP (prolyl-endopeptidase), PCP (prolyl-carboxypeptidase) in kidney biopsy homogenates in 11 healthy living kidney donors, and 12 patients with CKD. The spatial expression of RAS enzymes was determined by immunohistochemistry. Healthy kidneys showed higher NEP-mediated Ang (1–7) synthesis than Ang II formation, thus displaying a strong preference towards the reno-protective alternative RAS axis. In contrast, in CKD kidneys higher levels of Ang II were recorded, which originated from mast cell chymase activity. Conclusions: Ang (1–7) is the dominant RAS peptide in healthy human kidneys with NEP rather than ACE2 being essential for its generation. Severe RAS dysregulation is present in CKD dictated by high chymase-mediated Ang II formation. Kidney RAS enzyme analysis might lead to novel therapeutic approaches for CKD.

Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes.We determined whether addition of vWF-Ag and CRP to the Model for End-Stage Liver Disease-Sodium (MELD-Na) score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na, 0.764; MELD-Na + CRP, 0.790; MELD-Na + vWF, 0.803; MELD-Na + CRP + vWF-Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD-Na, 0.677; MELD-Na + CRP + vWF-Ag, 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation.The addition of vWF-Ag and CRP-reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT-to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Early diagnosis and monitoring of an alcohol relapse in patients after orthotopic liver transplantation for alcoholic cirrhosis is of importance for the long-term outcome. A prospective study of 97 patients who underwent orthotopic liver transplant for alcoholic cirrhosis has been performed. All of the recipients considered for analysis survived for at least 3 months and were under the care of one specialist psychologist. Mean follow-up amounted to 48.5 ± 1.4 months. The rates of alcohol relapse at 1 and 3 years after orthotopic liver transplant were 6 and 9%, respectively. Carbohydrate-deficient transferrin is a biological marker for alcohol abuse independently of liver disease and has been used for the first time ever in liver graft recipients. A total of 830 values were included prospectively in the study population. Detection of alcohol relapse had a sensitivity of 92% and a specificity of 98%. Changes in carbohydrate-deficient transferrin levels indicated clandestine and sporadic drinking after transplantation. Furthermore, clinical events were not found to influence carbohydrate-deficient transferrin, either in patients with or without alcoholic relapse. In our opinion, carbohydrate-deficient transferrin is a useful screening marker for alcohol relapse in patients after orthotopic liver transplant for alcoholic cirrhosis, to select those patients who need special attention from the psychologist.

Abstract Background: Ingestion of Amanita phalloides is the most common cause of lethal mushroom poisoning. The relative late onset of symptoms is a distinct diagnostic feature of Amanita intoxication and also the main reason of failure for extracorporeal removal of Amanita ‐specific toxins from the gut and circulation. Patients and methods: Extracorporeal albumin dialysis (ECAD) has been used on six consecutive patients admitted after A. phalloides poisoning with acute liver failure (ALF). Results: Six patients, with mean age of 46 years (range: 9–70 years), underwent one to three ECAD treatments. The mean time from mushroom ingestion until the first ECAD treatment was 76 h. Two patients regenerated spontaneously under ECAD treatment and orthotopic liver transplantation (OLT) could be avoided. Two patients were successfully bridged to OLT and one patient died because of cerebral herniation. One patient was treated with ECAD immediately after OLT because of the graft dysfunction and survived without re‐transplantation. Conclusion: ECAD appeared to be a successful treatment perspective in supporting liver regeneration or in sufficient bridging to OLT and also in treatment of graft dysfunction after OLT in patients with A. phalloides poisoning.

Recipients of live donor transplant kidneys (LIV) exhibit a significantly longer allograft half-life compared with cadaveric donor organs (CADs). The reasons are incompletely understood. Therefore this study sought to elucidate the genome-wide gene expression profiles in microdissected transplant kidney biopsies obtained from five cadaveric and five matched live donors before transplantation. cDNA microarrays were used to determine the transcripts in isolated glomeruli (G) and the tubulointerstitial (TI) compartment. Data were subjected to hierarchical clustering, maxT adjustment and a jackknife procedure to ensure robustness of reported findings; validation was performed by independent analysis of split biopsies and TaqMan-PCR. One hundred and thirteen sequences representing 62 unique genes (17 redundant features), and 34 ESTs separated G from TI. No difference in gene expression was found in G between LIV and CAD kidneys, but nine genes (two represented twice) and three ESTs were abundantly expressed in the CAD TI compared with LIV. The main biological function of these genes is counter regulation of oxidative stress. Promoter analysis of significant features suggested coregulated gene groups. These data suggest that CAD kidneys exhibit a distinctly different set of transcripts in the TI compartment but not in the G compartment when compared with LIV kidneys.

It remains unclear which liver graft reperfusion technique leads to the best outcome following transplantation. An online survey was sent to all transplant centres (n = 37) within Eurotransplant (ET) to collect information on their technique used for reperfusion of liver grafts. Furthermore, a systematic review of all literature was performed and a meta-analysis was conducted based on patients' mortality, number of retransplantations and incidence of biliary complications, depending on the technique used. Of the 28 evaluated centres, 11 (39%) reported performing simultaneous reperfusion (SIMR), 13 (46%) perform initial portal vein reperfusion (IPR), 1 (4%) performs an initial hepatic artery reperfusion (IAR) and 3 (11%) perform retrograde reperfusion (RETR). In 21 centres (75%), one reperfusion technique is used as a standard, but in only one centre is this decision based on available literature. Twenty centres (71%) said they would agree to participate in randomized controlled trials (RCT) if required. For meta-analysis, IAR vs. IPR, SIMR vs. IPR and RETR vs. IPR were compared. There was no difference between any of the techniques compared. There is no consensus on a preferable reperfusion technique. Available evidence does not help in the decision-making process. There is thus an urgent need for multicentric RCTs.

Late allocation of organs for transplant impairs post–liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow‐up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child‐Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child‐Pugh C, was an independent predictor of reduced transplant‐free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post‐LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post‐LT mortality. Liver Transplantation 24 15–25 2018 AASLD.

Transjugular intrahepatic portosystemic shunt (TIPS) implantation is used for treatment of several complications in patients with liver cirrhosis. Recent studies have identified a survival benefit for patients on the waiting list after TIPS implantation, but the optimal time point for TIPS implantation prior to orthotopic liver transplantation (OLT) has not been established.This study retrospectively assessed patients undergoing TIPS implantation before or after listing for OLT at the Medical University of Vienna. n = 98 patients with TIPS on the waiting list between January 1993 and December 2013 were identified (n = 73 (74.5%) pre-listing TIPS, n = 25 (25.5%) post-listing TIPS). A matched control group at the time of OLT without TIPS (n = 60) was included.More patients with post-listing TIPS (28.0%, 7/25) showed clinical improvement and went off-list than patients with pre-listing TIPS (8.2%, 6/73, p = .0119). A similar proportion of patients with pre-listing TIPS (19.2%, 14/73) and post-listing TIPS (20.0%, 5/25) died on the OLT waiting list. Transplant surgery time was similar in patients with and without TIPS: 348(±13) vs. 337(±10) minutes (p = .5139). Estimated 1-year post-transplant survival was similar across all groups (pre-listing TIPS: 76.2%, post-listing TIPS: 86.0%, no TIPS: 91.2%, log-rank p = .1506).TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT.

The quantification of donor-derived cell-free DNA (ddcfDNA) in recipient's plasma is a novel, but technically challenging noninvasive method to assist the diagnosis of acute rejection (AR). A quantitative real-time PCR (qPCR) approach targeting insertion/deletion polymorphisms (INDEL) was adapted to measure ddcfNA in plasma samples from 29 kidney transplant recipients obtained at time of clinically indicated biopsies (eight patients with a histologically verified AR, nine with borderline rejection and 12 without evidence of rejection). Measured ddcfDNA levels of smaller INDEL amplicon targets differed significantly (P = 0.016, Kruskal–Wallis H test) between recipients with biopsy-proven AR (median 5.24%; range 1.00–9.03), patients without (1.50%; 0.41–6.50) and patients with borderline AR (1.91%; 0.58–5.38). Similarly, pairwise testing by Mann–Whitney U-tests revealed significant differences between recipients with AR and without AR (P = 0.012) as well as patients with AR and borderline histology (P = 0.015). Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve for discriminating AR and non-AR biopsies of 0.84 (95% CI: 0.66–1.00). The determined cutoff value of 2.7% ddcfDNA showed a sensitivity of 0.88 (95% CI: 0.63–1.00) and specificity of 0.81 (95% CI: 0.64–0.98). INDEL qPCR represents a novel method to quantify ddcfDNA on standard qPCR instruments within 6–8 h with high sensitivity and specificity to detect AR.

Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease that affects up to 30% of patients with cirrhosis [1]. Intrapulmonary vascular dilatations and shunts result in gas exchange abnormalities, ranging from elevated alveolar–arterial oxygen gradients with no hypoxaemia to very severe hypoxaemia [1, 2]. Currently, liver transplantation (LT) is the only treatment option [3]. The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing liver disease severity that has been validated to predict the 3-month waiting list mortality and is used by Eurotransplant for prioritising allocation of liver transplants [4]. However, this score poorly predicts overall and post-transplant survival, and does not take into account complications that affect outcomes independent of liver disease severity [5]. Equal overall survival among liver transplantation candidates supports current prioritisation policy for severe hepatopulmonary syndrome <http://ow.ly/4SQS30mwOtK> The authors thank Roos Colman (Dept of Public Health, Biostatistics Unit, Ghent University, Ghent, Belgium) for her assistance in the statistical analysis of the data, the Eurotransplant representatives for supporting the organisation of this work and all Eurotransplant liver transplantation centres for providing data to the Eurotransplant registry.

Background. Destruction of the endothelial glycocalyx has been observed within lung and kidney grafts during ischemic organ preservation. We aimed to quantify glycocalyx damage within human liver grafts after organ preservation and correlate the results with graft injury and postoperative graft function in patients undergoing orthotopic liver transplantation (OLT). Methods. Syndecan-1 (Sdc-1) was measured as indicator of glycocalyx degradation in effluents of 38 liver grafts and serum of patients undergoing OLT. Effluent Sdc-1 concentrations were correlated with hepatic injury markers from the effluent. Furthermore, we assessed the association of Sdc-1 with early allograft dysfunction (EAD), 1-year graft survival, and 1-year patient survival. Results. Effluent Sdc-1 concentrations correlated with effluent concentrations of hepatocellular injury markers, including alkaline phosphatase ( R = 0.543, P = 0.003), aspartate aminotransferase ( R = 0.420, P = 0.029), and lactate ( R = 0.574, P = 0.002). Sdc-1 effluent concentrations were greater in patients who developed EAD compared with those without EAD (4720 [4374–5133] vs 3838 [3202–4240] ng/mL, P = 0.015). Furthermore, receiver operating characteristics analyses revealed that effluent Sdc-1 concentrations (AUC = 0.82, P = 0.017) and serum Sdc-1 concentrations (AUC = 0.84, P = 0.006) were associated with the development of EAD. These results were confirmed by regression analyses. No association was found between Sdc-1 and 1-year graft survival or 1-year patient survival. Conclusions. Our data suggest that the glycocalyx is damaged within human liver grafts during preservation and the extent of glycocalyx damage correlates with the severity of hepatocellular injury. Recipients of livers grafts with greater glycocalyx damage might be at higher risk for development of EAD after OLT.

Equality, diversity, and inclusion (EDI) are fundamental principles. Little is known about the pattern of practice and perceptions of EDI among liver transplant (LT) providers. International Liver Transplant Society (ILTS) EDI Committee survey around topics related to discrimination, mentorship, and gender. Answers were collected and analyzed anonymously. Worldwide female leadership was also queried via publicly available data. The survey was e-mailed to 1312 ILTS members, 199 responses (40.7% female) were collected from 38 countries (15.2% response rate). Almost half were surgeons (45.7%), 27.6% hepatologists and 26.6% anesthetists. Among 856 LT programs worldwide, 8.2% of leadership positions were held by females, and 22% of division chiefs were female across all specialties. Sixty-eight of respondents (34.7%) reported some form of discrimination during training or at their current position, presumably related to gender/sexual orientation (20.6%), race/country of origin (25.2%) and others (7.1%). Less than half (43.7%) received mentorship when discrimination occurred. An association between female responses and discrimination, differences in compensation, and job promotion was observed. This survey reveals alarmingly high rate of experience with racial and gender disparity, lack of mentorship, and very low rates of female leadership in the LT field and calls to action to equity and inclusion.

Despite major advances in immunopharmacology, virtually all patients receive the same center-specific immunosuppressive regimen following orthotopic liver transplantation (OLT). The present analysis was performed on the hypothesis that the original disease representing the indication for OLT leads to a different initial immunological situation of the patient. The type of original disease might therefore be a predisposing factor for acute rejection episodes and influence graft and patient survival. From January 1988 to July 1994, 34 patients received OLT at our institution for end-stage primary biliary cirrhosis (group 1) and 66 patients for end-stage alcoholic cirrhosis (group 2). Overall survivals at 1 and 5 years in group 1 versus group 2 were 67% versus 80% and 50% versus 68%, respectively(P<0.04). Retransplantation was performed in 21% of patients from group 1 and in 6% from group 2. The estimated risk for freedom from acute rejection amounts to 38% in group 1 compared with 59% in group 2(P<0.02). Multivariate regression analysis of potential risk factors identified only the underlying disease as independent predictor. Analysis of cumulative rates of clinically relevant rejection episodes stratified by group revealed 0.29 and 0.05 episodes per patient at one month and 0.80 and 0.06 at six months (P<0.009) respectively. In our clinical experience it was possible to confirm the hypothesis that the underlying disease is the reason for a significantly different incidence of acute rejection episodes and that it subsequently influences graft and patient survival. This approach to an individually adapted immunosuppressive therapy should be taken into consideration and other appropriate parameters investigated.

To determine the real value of liver imaging in cirrhosis by macro- and histomorphologic examination of the entire organ after orthotopic liver transplantation for hepatocellular carcinoma (HCC).In comparative studies, a virtual sensitivity of up to 94% is described for helical computed tomography in HCC staging. The tumor detection rate of intraoperative ultrasonography (IOUS) is reported to be almost 100%.This prospective observational study comprised 23 patients with HCC in cirrhosis admitted for orthotopic liver transplantation. Results of preoperative triphasic helical computed tomography (HCT) and IOUS were correlated with histopathologic results after 3-mm-slicing of the explanted liver.Overall, 179 liver segments were examined by HCT, IOUS, and MHM. Fifty-two malignant lesions and 10 dysplastic nodules were revealed by MHM. Using HCT, 13 HCCs could not be identified in 8 patients and 15 results were falsely positive in 10 patients. The detection rate of dysplastic nodes was 40% for HCT and 60% for IOUS. IOUS missed four HCCs in four patients and had six false-positive results in six patients. In a segment-based analysis, the overall accuracy of IOUS was significantly higher for IOUS (95.5%) versus HCT (89.9%). In the lesion-by-lesion analysis, the sensitivity was 92.3% for IOUS and 75.0% for HCT, with a significant difference.Correlation of explanted liver pathologic results offers precise evaluation of imaging modalities. The data of this histopathologically based study confirm that IOUS is significantly superior in staging HCC in cirrhosis versus CT, even after technical refinements through enhanced multiphasic high-velocity helical scanning.

Early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT) causes marked morbidity and mortality. We conducted a prospective pilot study to assess the safety and efficacy of molecular adsorbent recirculating system (MARS) in treatment of EAD after OLT. Twelve consecutive adult liver allograft recipients with a median age of 48 years, 9 of whom were male, were prospectively included and supported with MARS. EAD was defined as the presence of at least 2 of the following: serum bilirubin >10 mg/dL, prothrombin time <40%, aspartate aminotransferase or alanine transferase >1,000 U/L, and plasma disappearance rate of indocyanine green (PDR(ICG)) <10% per minute within 72 hours after reperfusion. One-year patient and graft survival was 66%. There was a significant decrease in serum bilirubin (P = 0.002), serum creatinine (P = 0.006), and aspartate aminotransferase (P = 0.005) and a significant increase in PDR(ICG) (P = 0.007) after MARS treatment. Prothrombin time, albumin level, and platelet count remained stable. Sustained improvement of renal and neurological function and of mean arterial pressure were observed. No MARS-related adverse effects occurred. MARS treatment provides a safe approach to the treatment of EAD after OLT. On the basis of this pilot study, a multicenter randomized clinical trial that uses MARS treatment in EAD after OLT has been initiated.

Background. Liver transplantation for nonresectable liver metastases from colorectal cancer was abandoned in 1994 on account of high recurrence rates. The aim of this study was to investigate whether the genetic detection of micrometastases in histologically negative lymph nodes of the primary colon cancer could be applied to select patients for liver transplantation. Methods. We analyzed 21 patients with colorectal cancer who had undergone liver transplantation between 1983 and 1994 for liver metastases. Eleven patients were histologically lymph node negative at the time of surgery; ten patients with lymph node metastases served as control group. DNA sequencing was used to screen tumor material for p53 and K-ras mutations. Mutant allele-specific amplification (MASA) was then used to search for micrometastases in DNA from regional lymph nodes of the primary colorectal cancer. Results. p53 and K-ras mutations were detected in 12 (57%) and 3 (14%) of 21 patients in the colorectal cancer, respectively. The mutations were confirmed in the corresponding liver metastases. Of 11 patients with histologically negative lymph nodes, nine were eligible for MASA due to presence of p53 or K-ras mutation. MASA revealed six of nine patients to be genetically positive for micrometastases. Three patients were both genetically and histologically negative. These three patients showed a significantly longer overall survival (P=0.011) of 4, 5, and 20 years, respectively. Conclusions. We conclude that the genetic detection of micrometastases by MASA could be a powerful prognostic indicator for selecting patients with colorectal liver metastases who could benefit from liver transplantation.

It is current practice that patients with hepatocellular carcinoma (HCC) listed for liver transplantation should receive locoregional treatment if the suspected waiting time for transplantation is longer than 6 months, even in the absence of prospective randomized data. Aim of this study was the comparison of single versus multimodality locoregional treatment strategies on outcomes after liver transplantation. This is a retrospective analysis of 150 HCC patients listed for liver transplantation at our center between 2004 and 2011. Outcomes were analyzed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) in relation to intention-to-treat and overall survival after liver transplantation. Overall, 92 patients (63%) were transplanted in this cohort. The intention-to-treat 1‑, 3‑, 5‑year waiting list survival was 80, 59, and 50% respectively. In RFA-(radiofrequency ablative) and TACE-(transarterial chemoembolisation)-based regimens, rates of transplanted patients were comparable (69 vs. 58%, p = ns). No difference was seen in overall survival after liver transplantation when comparing TACE- and RFA-based regimens. Patients receiving multimodality locoregional therapy had lower overall survival after transplantation (p = 0.05) TACE- and RFA-based regimens showed equal outcomes in terms of transplantation rate, tumor response, and post-transplant survival. Patients in need of more than one treatment modality might identify a cohort with poorer post-transplant survival. Direct comparison of TACE and RFA in a multimodality setting, analysis according to mRECIST.

Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL.Concentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI.Forty-five patients (mean age 55±8 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.55-0.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.62-0.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.53-0.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.64-0.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not.In the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI.

With restricted numbers of available organs, futility in liver transplantation has to be avoided. The concept of dynamic changes in MELD score (DeltaMELD) has previously been shown to be a simple tool to identify patients with the greatest risk of death after transplantation. Aim was to validate this concept with the Eurotransplant (ET) database.A retrospective registry analysis was performed on all patients listed for liver transplantation within ET between 2006 and 2011. Patients <18 years of age, acute liver failure, malignancy and patients listed for retransplantation were excluded. Influence of MELD at listing (MELDon), MELD at transplantation (MELDoff), DeltaMELD, age, sex, underlying disease and time on the waiting list on overall survival after liver transplantation were evaluated.A total of 16 821 patients were listed for liver transplantation, 8096 met the inclusion criteria. Age, MELD on and DeltaMELD showed significant influence on survival on the waiting list. Age and DeltaMELD showed influence on survival after liver transplantation, with DeltaMELD>10 showing a 1.6-fold increased risk of death.The concept of DeltaMELD was validated in a large, prospective data set. It provides a simple tool to identify patients with increased risk of death after liver transplantation and might help improve long-term results.

Transplant InternationalVolume 11, Issue 4 p. 277-280 Free Access Management of lymphoceles after kidney transplantation Georg Bischof, Georg Bischof Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorSusanne Rockenschaub, Susanne Rockenschaub Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorGabriela Berlakovich, Gabriela Berlakovich Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorFritz Längle, Fritz Längle Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorFerdinand Mühlbacher, Ferdinand Mühlbacher Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorReinhold Függer, Reinhold Függer Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorRudolf Steininger, Rudolf Steininger Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this author Georg Bischof, Georg Bischof Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorSusanne Rockenschaub, Susanne Rockenschaub Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorGabriela Berlakovich, Gabriela Berlakovich Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorFritz Längle, Fritz Längle Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorFerdinand Mühlbacher, Ferdinand Mühlbacher Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorReinhold Függer, Reinhold Függer Departments of General Surgery, University Clinic of Surgery Wahringer Gurtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this authorRudolf Steininger, Rudolf Steininger Department of Transplant Surgery, University Clinic of Surgery, Währinger Gürtel 18–20, A-1090 Vienna, AustriaSearch for more papers by this author First published: 28 June 2008 https://doi.org/10.1111/j.1432-2277.1998.tb00970.xCitations: 42AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Abstract Post-transplant lymphoceles (LC) may lead to impaired graft function. Treatment modalities include fine-needle aspiration, percutaneous drainage, and surgical internal drainage. Recently, laparoscopic fenestration has been performed with good results, but experience is still limited. Between January 1991 and August 1996, 919 kidney transplantations were performed in 876 patients at our department. There were 745 first, 133 second, 30 third, 9 fourth, and 2 fifth operations. Sixty-three symptomatic LCs were detected in 62 patients (6.8 %) after 39 ± 31 days. In 44 % of the cases, graft function was impaired; in 29 % hydronephrosis was documented and in 6 % infection of the LC. Forty-five of the 62 patients with LC (73 %) had histologically proven rejection. Thirty-five of the 63 LCs were drained percutaneously, 20 LCs were internally drained by open surgery, and 8 LCs were drained by laparoscopy. In 14 of the 47 patients (30%) with primary percutaneous drainage, LC recurred; infection occurred in 17%. Twelve of these patients underwent surgery. One surgical redrainage was necessary after open fenestration. No conversion or complication was noted in the laparoscopy group. We conclude that surgery for post-transplant lymphoceles is safe and effective. We favor the laparoscopic technique in selected patients. Citing Literature Volume11, Issue4July 1998Pages 277-280 ReferencesRelatedInformation

Transplant InternationalVolume 17, Issue 10 p. 617-621 Free to Read Pretransplant screening of sobriety with carbohydrate-deficient transferrin in patients suffering from alcoholic cirrhosis Gabriela A. Berlakovich, Corresponding Author Gabriela A. Berlakovich Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaE-mail: gabriela.berlakovich@meduniwien.ac.at Tel.: +43-1-404004000 Fax: +43-1-404006872Search for more papers by this authorThomas Soliman, Thomas Soliman Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorEdith Freundorfer, Edith Freundorfer Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorThomas Windhager, Thomas Windhager Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorMartin Bodingbauer, Martin Bodingbauer Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorPeter Wamser, Peter Wamser Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorHubert Hetz, Hubert Hetz Department of Anesthesiology and ICM, University of Vienna, Vienna, AustriaSearch for more papers by this authorMarkus Peck-Radosavljevic, Markus Peck-Radosavljevic Department of Gastroenterology and Hepatology, University of Vienna, Vienna, AustriaSearch for more papers by this authorFerdinand Muehlbacher, Ferdinand Muehlbacher Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this author Gabriela A. Berlakovich, Corresponding Author Gabriela A. Berlakovich Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaE-mail: gabriela.berlakovich@meduniwien.ac.at Tel.: +43-1-404004000 Fax: +43-1-404006872Search for more papers by this authorThomas Soliman, Thomas Soliman Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorEdith Freundorfer, Edith Freundorfer Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorThomas Windhager, Thomas Windhager Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorMartin Bodingbauer, Martin Bodingbauer Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorPeter Wamser, Peter Wamser Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this authorHubert Hetz, Hubert Hetz Department of Anesthesiology and ICM, University of Vienna, Vienna, AustriaSearch for more papers by this authorMarkus Peck-Radosavljevic, Markus Peck-Radosavljevic Department of Gastroenterology and Hepatology, University of Vienna, Vienna, AustriaSearch for more papers by this authorFerdinand Muehlbacher, Ferdinand Muehlbacher Department of Transplant Surgery, University of Vienna, Waehringer-Guertel 18–20, 1090 Vienna, AustriaSearch for more papers by this author First published: 11 March 2005 https://doi.org/10.1111/j.1432-2277.2004.tb00395.xCitations: 31AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Abstract Sufficient assessment of potential candidates for orthotopic liver transplantation (OLT) is the most important factor for a low alcohol relapse rate after transplantation in patients suffering from alcoholic cirrhosis. In the current study the efficiency of pretransplant screening with carbohydrate-deficient transferrin (CDT) was analysed in patients on the waiting list for OLT. A prospective study was performed in 44 patients who had undergone OLT for alcoholic cirrhosis. All patients had had pretransplant assessment by a specialist psychologist and were found to have no problems with alcohol. Pre- and post-transplant CDT monitoring was performed. Overall, 790 CDT values were measured in the study population. The median observation period was 2.1 months before and 41.2 months after transplantation, respectively. In 35 patients (80%) pretransplant CDT values were found to be above the reference value, but only one patient suffered an alcohol relapse after transplantation. Of the nine patients (20%) who demonstrated normal CDT before transplantation, two suffered an alcohol relapse after transplantation. CDT is a very useful marker for the monitoring of an alcohol relapse in patients following OLT for alcoholic cirrhosis, as has been previously indicated. However, CDT does not appear to be useful as a pretransplant screening marker for selection of potential transplant candidates suffering from alcoholic cirrhosis. Citing Literature Volume17, Issue10November 2004Pages 617-621 RelatedInformation

Orthotopic liver transplantation (OLT) represents a curative treatment option for end‐stage liver disease (ESLD). Although epidemiology of ESLD has recently changed due to the rising prevalence of nonalcoholic fatty liver disease and the decreased burden of hepatitis C virus infections due to highly effective antiviral regimens, the management of portal hypertension (PHT) remains a clinical challenge in the pre‐ and post‐OLT setting. The measurement of the hepatic venous pressure gradient represents the most reliable but invasive tool for assessment of the severity of PHT. Although novel liver ultrasound and magnetic resonance–based elastography methods have been developed, their value to screen for liver fibrosis and PHT in transplanted patients remains to be established. Nonselective beta‐blockers represent the cornerstone of medical treatment of PHT, but more studies on their effects on clinical endpoints after OLT are needed. Statins are widely used to treat hyperlipidemia, which is a common condition after OLT. Although a growing body of evidence suggests that statins decrease portal pressure and PHT‐related complications in ESLD, studies on potential benefits of statins after OLT are lacking. Finally, transjugular intrahepatic portosystemic shunts (TIPS) are effective in decreasing PHT and seem to decrease mortality on the OLT waiting list. Moreover, TIPS does not have an impact on liver function nor complicate the transplant surgical procedures. TIPS may also be used after OLT, but the evidence is limited. In conclusion, whereas the management of PHT in patients with ESLD is based on strong evidence, further data on the value of noninvasive monitoring tools as well as on medical and invasive treatment options in the post‐OLT setting are needed to improve management strategies in patients with recurrent PHT after liver transplantation. Liver Transplantation 24 112–121 2018 AASLD.

To determine whether there is a difference in the outcome of renal transplantation (RT) in patients with posterior urethral valves (PUV) and children with non-uropathy related end stage renal disease.Data were acquired retrospectively. We analyzed possible factors that influence the function of renal allografts and graft survival. Between 1995 and 2016 there were 149 RT. Out of them, there were 27 boys with PUV, who received 29 kidneys. Thirty patients, who received a total of 31 renal grafts due to a non-uropathic (NU) diagnosis, served as control group. Mean follow-up was 7.4 to 10.2 years.There was no difference in estimated graft survival between patients with PUV and NU patients. Graft failure occurred in 23.1% of PUV patients and 34.5% patients of the NU group. There was no statistically significant disparity in graft function between the two groups. Age at transplantation and donor age were the only factors that had a significant impact on renal function. There was a higher incidence of UTI in the PUV group (96%) than in the NU group (67%). Vesicostomy was the favourable intervention in regards of graft function.RT in PUV patients is successful with the same outcome as in NU patients. Bladder dysfunction may not have a major impact on graft function and graft survival. It seems that the type of pre-transplant surgical procedures may influence outcome. Therefore, these interventions -if necessary- should be limited to a minimum.Retrospective Comparative Study LEVEL OF EVIDENCE: Level III.

About 15% of liver transplantations (LTs) in Eurotransplant are currently performed in patients with a high-urgency (HU) status. Patients who have acute liver failure (ALF) or require an acute retransplantation can apply for this status. This study aims to evaluate the efficacy of this prioritization.Patients who were listed for LT with HU status from January 1, 2007, up to December 31, 2015, were included. Waiting list and posttransplantation outcomes were evaluated and compared with a reference group of patients with laboratory Model for End-Stage Liver Disease (MELD) score (labMELD) scores ≥40 (MELD 40+).In the study period, 2299 HU patients were listed for LT. Ten days after listing, 72% of all HU patients were transplanted and 14% of patients deceased. Patients with HU status for primary ALF showed better patient survival at 3 years (69%) when compared with patients in the MELD 40+ group (57%). HU patients with labMELD ≥45 and patients with HU status for acute retransplantation and labMELD ≥35 have significantly inferior survival at 3-year follow-up of 46% and 42%, respectively.Current prioritization for patients with ALF is highly effective in preventing mortality on the waiting list. Although patients with HU status for ALF have good outcomes, survival is significantly inferior for patients with a high MELD score or for retransplantations. With the current scarcity of livers in mind, we should discuss whether potential recipients for a second or even third retransplantation should still receive absolute priority, with HU status, over other recipients with an expected, substantially better prognosis after transplantation.

Anaemia is common in patients with end-stage liver disease. Pre-operative anaemia is associated with greater mortality after major surgery. We analysed the association of pre-operative anaemia (World Health Organization classification) with survival and complications after orthotopic liver transplantation using Cox and logistic regression models. We included patients undergoing their first orthotopic liver transplantation between 2004 and 2016. Out of 599 included patients, 455 (76%) were anaemic before transplantation. Pre-operative anaemia was not associated with the survival of 485/599 (81%) patients to 1 year after liver transplantation, OR (95%CI) 1.04 (0.64-1.68), p = 0.88. Pre-operative anaemia was associated with higher rates of intra-operative blood transfusions and acute postoperative kidney injury on multivariable analysis, OR (95%CI) 1.70 (0.82-2.59) and 1.72 (1.11-2.67), respectively, p < 0.001 for both. Postoperative renal replacement therapy was associated with pre-operative anaemia on univariate analysis, OR (95%CI) 1.87 (1.11-3.15), p = 0.018.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.

Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient. Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients. Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients. Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR &amp;lt;35 mL/min/1.73 m 2 ], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation. Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning. Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.

Background and Aims: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplantant (post-LT) outcomes in Europe. Approach and Results: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients &lt; 16 years with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p &lt; 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02–1.06) and MELD score (aHR:1.04,95%CI:1.01–1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41–0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00–1.03) and GS (aHR:1.02,95%CI:1.01–1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16–0.54) and GS (aHR:0.48,95%CI:0.29–0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). Conclusions: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

<h2>Abstract</h2><h3>Background</h3> Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the relation between the type of calcineurin inhibitor (CNI) and long-term outcomes following LT in patients with PBC. <h3>Methods</h3> Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the dataset of the European Liver Transplant Registry. Patients who received a donation after brain death (DBD) graft between 1990 and 2021 with at least one year of event-free follow-up were included. <h3>Results</h3> In total, 3175 PBC patients were followed for a median duration of 11.4 years (IQR 5.9 – 17.9) after LT. Tacrolimus (Tac) was registered in 2056 (64.8%) patients and cyclosporin (CsA) in 819 (25.8%). Adjusted for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (aHR 1.07, 95%CI 0.92-1.25, <i>p</i>=0.402) or death (aHR 1.06, 95%CI 0.90-1.24, p=0.473) over CsA. In this model maintenance mycophenolate was associated with a lower risk of graft loss (aHR 0.72, 95%CI 0.60-0.87, <i>p</i><0.001) or death (aHR 0.72, 95%CI 0.59-0.87, p<0.001), while these risks were higher with use of steroids (aHR 1.31, 95%CI 1.13-1.52, p<0.001, and aHR 1.34, 95%CI 1.15-1.56, p<0.001, respectively). <h3>Conclusions</h3> In this large LT registry, type of CNI was not associated with long-term graft or recipient survival, reassuring us to continue the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that threshold for combination treatment with Tac and MMF should be low. <h3>Impact And Implications</h3> This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following DBD liver transplantation (LT). While tacrolimus has been previously related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patient transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings reassure physicians on the continued use of Tac after LT in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.

Platelets were shown to be relevant for liver regeneration. In particular, platelet-stored serotonin (5-HT) proved to be a pro-regenerative factor in this process. The present study aimed to investigate the perioperative course of 5-HT and evaluate associations with patient and graft outcomes after othotopic liver transplantation (OLT).

T-cell depletion is an essential aspect of clinical immunosuppression. The aim of the present study was to compare the efficacy of two dosage regimens in this setting. We retrospectively compared 246 patients (group 1) who received a 10-day antithymocyte globulin (ATG) induction protocol with 226 patients (group 2) who received a 3-day protocol. The 6-month rejection rate was 22.3% in group 1 and 12.7% in group 2 (P = 0.03). The sub-analysis showed a higher rejection rate in patients with cholestatic disease (P = 0.01), who were more numerous in group 1. This resulted in an overall difference between the groups. Rates of de novo malignancies and recurrent hepatocellular carcinoma were identical. Viral infection rates were 16% and 18%, respectively (P > 0.5). The rates of bacterial and fungal infection were also similar (37% vs. 42%, P > 0.1). However, infection and ATG administration are independent risk factors for survival. A lower rate of fatal infection was observed in group 2 (P = 0.01), while the 10-day ATG regimen had a detrimental effect on patients who had infection (P < 0.0001). Our results strongly support the application of 3-day ATG induction therapy regimen after orthotopic liver transplantation, as it is associated with the same rejection rate as long-term ATG induction therapy, without the negative survival effect of the latter due to lethal infection.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72-99) in the tolerant cohort and 118 μmol/l (IQR 99-143) in the control group. Mixed linear-model showed around 29% lower average creatinine levels throughout follow-up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long-term immunosuppression for many years, suggesting permanent donor-specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Abstract Background The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy. Methods Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres. Results Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention. Conclusion A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.

In recent years, significant progress has been made in the field of liver machine perfusion. Many large transplant centers have implemented machine perfusion strategies in their clinical routine. Normothermic machine perfusion (NMP) is primarily used to determine the quality of extended criteria donor (ECD) organs and for logistical reasons. The vast majority of studies, which assessed the viability of perfused grafts, focused on hepatocellular injury. However, biliary complications are still a leading cause of post-transplant morbidity and the need for re-transplantation. To evaluate the extent of biliary injury during NMP, reliable criteria that consider cholangiocellular damage are needed. In this review, different approaches to assess damage to the biliary tree and the current literature on the possible effects of NMP on the biliary system and biliary injury have been summarized. Additionally, it provides an overview of novel biomarkers and therapeutic strategies that are currently being investigated. Although expectations of NMP to adequately assess biliary injury are high, scant literature is available. There are several biomarkers that can be measured in bile that have been associated with outcomes after transplantation, mainly including pH and electrolytes. However, proper validation of those and other novel markers and investigation of the pathophysiological effect of NMP on the biliary tree is still warranted.

Background. The aim of the present analysis was to define the role of simultaneous heart and kidney transplantation (HNTX) using organs from the same donor by evaluation of clinical strategy and achieved outcome compared with a reference group of concurrently single heart transplant (HTX) and kidney transplant (NTX) recipients. Compared with other organ combinations(pancreas-kidney, heart-lung), HNTX has been performed infrequently and is reported mainly as case records in the literature. Because of expansion of recipient selection criteria for HTX and NTX, the number of patients requiring simultaneous replacement of both organs is increasing. Methods. Six HNTX recipients, three of them suffering from long-standing type I diabetes, received transplants between September 1990 and March 1996 and were analyzed in terms of clinical and immunological demographics and outcome. They were compared with 379 HTX and 769 NTX recipients operated upon within this period. Results. Survival for HNTX is 100% with a mean follow-up of 32.7±21.1 months. Cold ischemic time of the kidney was significantly shorter for HNTX than for NTX (6.5±1.0 hr vs. 22.1±6.8 hr,P<0.005). Although HNTX patients received HLA-unmatched grafts, no rejection of the kidney has been observed to date. There was no difference for rejection of the heart in HNTX compared to HTX recipients. Conclusions. Satisfying results are obtained by HNTX and justify the use of two organs for one recipient. The favorable immunological behavior of the kidney despite use of HLA-unmatched grafts is most probably explained by higher immunosuppression and short cold ischemic time, although a combination effect cannot be excluded.

Abstract Belatacept was recently evaluated in liver transplantation (LT) in a phase II multicenter trial, which was terminated prematurely. Patients were more than two yr post‐LT at the time. As high rates of spontaneous tolerance after LT have been reported and as belatacept has marked immunomodulatory effects, we decided to maintain the belatacept patients enrolled at our center (n = 4) on MMF monotherapy. All belatacept patients on MMF monotherapy developed graft dysfunction consistent with acute rejection after a mean period of 10.3 (7–14) wk. Patients were therefore switched to triple therapy with CNI, MMF, and corticosteroids. Graft dysfunction resolved within 1–3 wk after switch. At the time of belatacept discontinuation, mean eGFR was 105.1 mL/min/1.73 m² (92.1–118.9) in belatacept patients compared to 58 mL/min/1.73 m² (36.1–98.2) in controls (p = 0.022). One yr after the switch to CNI therapy, eGFR had declined by 27.4 mL (19.2–39.3; p = 0.008). Thus, LT patients treated with belatacept show superior kidney function that declines upon institution of CNIs. MMF monotherapy following withdrawal of belatacept is associated with a high incidence of graft dysfunction. Belatacept has no obvious immunomodulatory effects in LT recipients that would be sufficient to allow drug withdrawal with a high rate of success.

While belatacept has shown favorable short- and midterm results in kidney transplant recipients, only projections exist regarding its potential impact on long-term outcome. Therefore, we performed a retrospective case-match analysis of the 14 belatacept patients originally enrolled in the phase II multicenter trial at our center. Fifty six cyclosporine (CyA)-treated patients were matched according to age at transplantation, first/retransplant, and donor type. Ten years after kidney transplantation, kidney function remained superior in belatacept-treated patients compared with the CyA control group. Moreover, none of the belatacept-treated patients had donor-specific antibodies ≥10 years post-transplantation compared with 38.5% of tested CyA-treated subject (0/10 vs. 5/13; P = 0.045). Notably, however, patient and graft survival was virtually identical in both groups (71.4% vs. 71.3%; P = 0.976). In the present single-center study population, patients treated with belatacept demonstrated a patient and graft survival at 10 years post-transplant which was comparable to that of similarly selected CNI-treated patients. Larger studies with sufficient statistical power are necessary to definitively determine long-term graft survival with belatacept.

This study investigated the impact of Model of end-stage liver disease (MELD)-score introduction (MELDi) on waitlist mortality and post-liver transplant (LT) survival in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).LT candidates with PSC or PBC listed between January 1983 and March 2016 were included and followed until December 2016. After MELDi in 2004, PBC patients were listed according to labMELD, PSC patients according to the highest MELD during active cholangitis (chMELD).In total, 100 PBC and 76 PSC patients were included. Waitlist mortality in PBC was significantly higher than in PSC (16% vs. 5.3%, p = 0.031), whereas PSC patients were significantly more often withdrawn from the waitlist due to improved condition (3.0% vs. 13.2%, p = 0.017). Competing risks analysis identified MELDi (HR = 4.12) and PBC (HR = 2.95) as significant predictors of waitlist mortality. Yet, overall 10 y-patient survival increased after MELDi by 18.8% leading to a 1 y-, 5 y-, and 10 y-patient survival of 98.2%, 70.6% and 70.6% in PBC, and 83.3%, 83.3%, and 80.6% in PSC, respectively.PSC patients showed significantly lower waitlist mortality irrespective of MELDi, whereas in PBC waitlist mortality further increased after MELDi. Utility of MELD and chMELD did not impair post LT outcome.

Steroid pretreatment of deceased donors reduces inflammation in allografts and is recommended by organ procurement guidelines. The impact on long-term graft outcome, however, remains elusive. In this multicenter randomized controlled trial, 306 deceased donors providing organs for 455 renal transplant recipients were randomized to 1000 mg of methylprednisolone or placebo prior to organ procurement (ISRCTN78828338). The incidence of biopsy-confirmed rejection (Banff>1) at 3 months was 23 (10%) in the steroid group and 26 (12%) in the placebo group (P = .468). Five-year functional graft survival was 84% and 82% for the steroid group and placebo group, respectively (P-value = .941). The hazard ratio of functional graft loss was 0.90 (95% confidence interval 0.57-1.42, P = .638) for steroid vs placebo in a multivariate Cox model. We did not observe effect modification by any of the predictors of graft survival and treatment modality. A robust sandwich estimate was used to account for paired grafts of some donors. The mean estimated GFR at 5 years was 47 mL/min per 1.73 m2 in the steroid group and 48 mL/min per 1.73 m2 in the placebo group (P = .756). We conclude that steroid pretreatment does not impact on long-term graft survival. In a donor population with higher risk of delayed graft function, however, repetitive and higher doses of steroid treatment may result in different findings.

ObjectiveWe aimed to compare routine preoperative color-coded duplex ultrasound (DUS) to clinical examination (CE) alone in surgery for arteriovenous fistula (AVF) with special emphasis on long-term outcomes and cost effectiveness.MethodsAll patients undergoing an AVF formation or revision between January 1, 2011, and December 31, 2016, at our tertiary referral center were subject to analysis. Routine DUS was performed in 114 patients and CE alone in 217 patients. Primary and secondary patency, the need for revision or reintervention to obtain patency, and individual as well as overall costs were analyzed.ResultsPrimary patency rate was higher in AVF after DUS compared with CE alone at 62% vs 26% (P < .05), respectively. Patients receiving DUS had significantly lower rates of revision and revisions per patient when compared with CE (25.4% vs 59.4% [P < .0001]; 0.36 ± 0.71 vs 1.06 ± 1.55 [P < .0001], respectively). Costs per patient were significantly lower in the DUS group compared with CE at 4074€ vs 6078€ (P < .0001).ConclusionsWe were able to show that patients receiving preoperative DUS showed higher patency rates and needed fewer revisions. Standard preoperative ultrasound examination is an easy tool to improve outcomes and cost effectiveness in AVF surgery.

Oral ingestion of potassium dichromate produces a complex spectrum of complications. It has an extremely poor prognosis and usually leads to rapid death.We report the case of a 16-year-old male patient who was admitted to hospital after oral ingestion of potassium dichromate with suicidal intention.The patient's condition deteriorated, and he became comatose within 5 days in spite of immediate attempts at detoxification. Because of irreversible liver failure, which occurred within 2 days after admission, and because of cerebral edema, the decision to perform a liver transplantation was made. On day 6 after admission, a compatible donor liver was transplanted. The course of liver transplantation and the patient's subsequent recovery were uneventful.The rationale for the delayed transplantation was to avoid damage of the new organ because of high serum chromium levels. Despite severe organ damage, the chromium content of the liver was increased. To the authors' knowledge, this is the first case report of acute toxic liver failure, caused by potassium dichromate poisoning, treated successfully by means of liver transplantation.

Background. Monitoring immunosuppression with cyclosporine microemulsion formulation (CsA-MEF) by using 2-hour CsA blood levels (C2) has been strongly recommended after kidney transplantation. The aim of our study was to evaluate the impact of C2 monitoring on the clinical outcome early after transplantation in a single-center setting. Methods. Nonsensitized, consecutive, de novo cadaveric kidney-transplant recipients were treated with CsA-MEF, mycophenolate mofetil, and steroids. Patients receiving transplants after January 2002 (n=89) were prospectively monitored by C2 levels (target: 1,500±200 ng/mL [fluorescence-polarization immunoassay]). They were retrospectively compared with the patients receiving transplants during 2001 (n=88) who had been monitored by C0 levels (target: 250±50 ng/mL). Results. In the intention-to-treat analysis, 40 (45.4%) patients in the C0 group and 25 (28.1%) patients in the C2 group received treatment for rejection (P=0.017). The incidence of histologically verified rejection of Banff grade I or higher was 20.45% in the C0 group and 13.48% in the C2 group (P=0.235). In the per-protocol analysis, incidence of treated rejection was 24.7%, and incidence of histologically verified rejection of Banff grade I or higher was 12.35% in the C2 group (P=0.004 and 0.160, respectively, vs. C0). Mean CsA-MEF doses were 1.7 to 2 times higher in the C2 group than in the C0 group throughout follow-up (P=0.019). In the C2 group, target C2 levels were achieved on average 4 days after transplantation, and there was no significant difference in C2 levels between patients who rejected and patients who did not reject. Conclusion. Kidney-transplant recipients monitored by C2 levels receive significantly higher doses of CsA-MEF and have a lower incidence of early acute allograft rejection than patients monitored by C0 levels. In C2 monitored patients, C2 levels are not predictive for the incidence of early allograft rejection.

Abstract: Background: In January 1999 a new kidney allocation program was launched by the Eurotransplant Foundation, the ‘Eurotransplant Senior Program’ (ESP). Cadaveric donors above the age of 65 yr are allocated to kidney transplant recipients of the same age group. Methods: Using a single‐center database, 91 patients who underwent first renal transplantation at the age of 65 yr and older in the years 1999–2002 were identified. Fifty‐six patients were transplanted through ESP allocation (study group) and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS) procedure. Results: Age, sex and comorbid conditions did not differ by group. The rate of acute rejection episodes, primary non‐function, delayed graft function, perioperative mortality did not differ by group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p = 0.015) from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group, cumulative patient survival according to the Kaplan–Meier estimation was not statistically different at five yr. Conclusions: We did not find a relevant difference in the outcome between young and old kidney transplants in old recipients after this long observation period.

Background Nonalcoholic fatty liver disease (NAFLD) can be considered the hepatic manifestation of the metabolic syndrome with nonalcoholic steatohepatitis (NASH) as its progressive form. With increasing prevalence of the metabolic syndrome, NASH cirrhosis is becoming a leading cause for liver transplantation. Some cases of orthotopic liver transplantation (OLT) due to cryptogenic cirrhosis (CC) might show typical features of NASH cirrhosis. Therefore, our aim was to assess recurrence of liver fibrosis in patients transplanted for NASH versus CC after OLT. Patients and methods Patients transplanted for CC or NASH between 1 January 2004 and 30 September 2015 were included. The histological NAFLD activity score and the NAFLD fibrosis score (NFS) were assessed. Results In total, 15 and 12 patients underwent OLT because of NASH and CC, respectively. The case load for OLT because of NASH was constantly increasing ( n =2 in 2004–2007 vs. n =9 in 2012–2015) whereas decreasing for CC ( n =6 in 2004–2007 vs. n =2 in 2012–2015). Patient characteristics at OLT were similar, except for an older age and a higher BMI in NASH patients (59.1±2.2 vs. 51.8±2.9 years, P =0.05; 27.7±1.2 vs. 24.3±0.8 kg/m 2 , P =0.035). Although post-OLT plasma lipid levels and incidence of de-novo hypertension, diabetes, and hyperlipidemia were similar between groups, the post-transplant NFS re-increased in the NASH group (but not in the CC: −0.1317 vs. −1.3645 at 12 months post-OLT, P =0.0400). Post-transplant survival was similar in NASH and CC patients. Conclusion According to the NFS, some NASH patients show recurrence of fibrosis as early as 6–12 months after OLT.

Kidney transplantation represents the treatment of choice for end-stage renal disease (ESRD). However, nephrectomy bears certain short- as well as long-term risks for the healthy, voluntary donor. As obesity is increasing and is a known risk factor for surgical complications, we wanted to assess the impact of BMI on perioperative complication rates and renal function. We retrospectively assessed patients undergoing living donor kidney nephrectomy at our institution. We identified 289 donors that underwent unilateral nephrectomy between January 2006 and December 2015. Donors were categorized according to their BMI (BMI <25 kg/m2, BMI ≥25/<30 kg/m2, BMI ≥30 kg/m2). Where indicated, analysis of variance (ANOVA) was used to compare groups, a stepwise linear regression model was used to assess impact of BMI on the change of eGFR. 126 donors (43.6%) had a BMI <25 while 120 (41.5%) had a BMI ≥25/<30 and 43 (14.9%) were obese with a BMI ≥30. BMI had no statistically significant influence on the percentage of laparoscopic approach (86.5% vs. 83.3% vs. 88.4%, p = 0.6564), on conversion rates (0% vs. 2.0% vs. 2.6%, p = 0.2879) or postoperative complication rates defined as Clavien Dindo ≥ II (8.7% vs. 13.3% vs. 14.0%, respectively; p = 0.4474). Notably, there were no Grade III or higher complications in any group. There was no difference in pre-operative kidney function, postoperative surgical site infection or systemic infection. BMI and male sex had a statistically significant influence on short-term decline of eGFR. Obese donors do not suffer from an increased risk of intraoperative or perioperative complication rates. However, male sex and high BMI are associated with a more pronounced short-term decline in renal function. The impact of BMI on long-term consequences for kidney donors needs to be defined in larger prospective cohorts.

Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to donor-specific tolerance. Patients reported in the literature that underwent kidney transplantation (KT) after a previous HSCT from the same haploidentical donor typically received short-term immunosuppression, mainly for safety reasons and concerns of triggering graft-versus-host disease.We describe the case of a 22-year-old patient who developed chronic kidney failure after receiving haploidentical HSCT from his father for the treatment of metastatic rhabdomyosarcoma. Five years after HSCT, he received a preemptive kidney transplant from his father. Steroid treatment, which had been prescribed for the underlying kidney disease, was withdrawn within 2 months posttransplant, and no de novo immunosuppression was given. Donor-specific tolerance was assessed with mixed lymphocyte reaction and INF-γ ELISPOT before (D0) and after KT (D9). Furthermore, the exact level of donor-derived T cells was measured with real-time polymerase chain reaction before and 1 year after KT.In vitro assays (mixed lymphocyte reaction and ELISPOT) revealed donor-specific tolerance before and after transplantation, respectively. The number of recipient-derived T cells was low before KT and virtually did not change over time (0.0139% ± 0.0039 and 0.0120% ± 0.0067; P = NS). Graft function was excellent throughout the follow-up (36 months post KT: serum creatinine, 1.18 mg/dL). Protocol biopsies performed 1 and 12 months after transplantation confirmed the absence of rejection.This is one of the first cases of kidney transplantation from the same donor after previous haploidentical HSCT with a corticosteroid taper alone. Our results suggest that immunosuppression can be avoided in such cases.

Ultrasound is routinely performed at our transplant unit within the first 48 h of kidney transplantation (KTX). The objective of this study was to evaluate the association of ultrasound results and, in particular, elevated resistance indices (RIs) with the occurrence of surgical complications and allograft outcomes.The study included all kidney allograft recipients undergoing transplantation at our center between January 2010 and December 2011 (N = 329). Ultrasound examination was performed on 315 recipients (95.7%).Delayed graft function was more common in subjects with a high RI (≥0.7) than in patients with an RI < 0.7 (47.2 vs. 28.2%; p = 0.032). A lack of arterial signal was detected in eight patients (2.5%), of whom five had a vascular complication that required surgical therapy. In 12 patients (3.8%), RI was 1 without any other signs of vascular impairment. Even though such values can be a sign of venous thrombosis, no case was observed in any of these patients.The results of our study suggest that ultrasound evaluation of the transplanted kidney shortly after transplantation is a valuable tool not only for detecting vascular complications but also as a predictor of graft outcome regarding delayed graft function.

Changes in recipient and donor characteristics are redefining the role of induction in liver transplant recipients. Older recipients are more common, with greater concomitant comorbidity. Moderate or severe renal dysfunction is now estimated to affect 40% of liver transplant recipients. Donors are also becoming older, and other factors such as more frequent non-alcoholic fatty liver disease (NAFLD) compromise the quality of some grafts. Rejection rates are now relatively low (~10%) but some patients have a markedly increased risk such as younger recipients and those undergoing re-transplantation. Induction immunosuppression is associated with a significant reduction in rejection risk but due to various factors universal induction is not justified. Steroid-free therapy without induction increases the risk of biopsy-proven acute rejection (BPAR) but randomized trials have shown that induction with an interleukin-2 antagonist receptor (IL-2RA) agent or with rabbit antithymocyte globulin (rATG) maintains immunosuppressive efficacy in steroid-free regimens. Delayed calcineurin inhibitor (CNI) initiation (e.g. to days 4-5 post-transplant) can prevent deterioration of renal function during the first year post-transplant, but requires induction with an IL-2RA agent or rATG to maintain early immunosuppressive efficacy. IL-2RA induction may be inadequate to ensure a low risk of rejection in a steroid-free regimen combined with delayed tacrolimus. Randomized trials of CNI withdrawal at month 1 post-transplant have only achieved an acceptable rate of BPAR when induction is administered. In terms of safety, an increased rate of infection does not seem to be a concern. The most recent large-scale analyses have not indicated any evidence for an increased risk of malignancy, or specifically post-transplant lymphoproliferative disease. In summary, the place of induction in the management of liver transplant patients is becoming established. Selective use in high-risk individuals to avoid graft rejection is still relevant, but the key rationale for induction is to facilitate steroid-sparing and CNI-sparing regimens to reduce long-term complications.

After liver transplantation, the endoscopic approach has become the standard treatment modality for biliary complications. Aim of this study was to compare primary endoscopic with primary surgical management.A retrospective review on 1188 consecutive liver transplant patients between 1989 and 2009 was performed. Management strategies (endoscopic, surgical or combined approach) were evaluated for treatment success as well as patient survival.Biliary complications after liver transplantation were diagnosed in 211 (18%) patients. Initial endoscopic approach (N=162, 77%) was successful in 97 of 162 (60%) patients. In 80% of patients, success was achieved within a median of four ERCPs. Sixty-one patients (38%) were referred to surgery after non-successful ERCP. Initial surgical approach was performed in 49/211 patients (23%) with successful management in 38/49 (78%) of patients. Patients presenting with intraluminal objects needed a significantly higher number of ERCPs to reach treatment success (median 3 versus 2 interventions, p=0.001) but had an equal endoscopic success rate (p=0.427). Patients with successful endoscopic treatment showed lower mortality compared to patients with primary surgical treatment (p=0.029).Endoscopic management should be considered as the primary approach for biliary complications after liver transplantation.

Background. Simultaneous double-organ transplants comprising various organ combinations have become frequent. The purpose of this article is to report on a single center's experience of simultaneous heart and kidney transplantation (HNTX) with particular emphasis on selection criteria and patient outcome. Methods. From September 1990 to January 1997, nine patients underwent HNTX, receiving both grafts from a single donor selected on ABO blood group compatibility and a negative lymphocytotoxic crossmatch, but without regard to HLA-antigen matching. Results. One patient died of acute humoral rejection of the cardiac graft shortly after surgery. Eight patients are alive and well and have normal cardiac and renal function at a mean follow-up of 44±28 months. Conclusion. HNTX offers a compelling therapeutic solution in the treatment of advanced cardiac and renal failure in carefully selected patients. Because the heart and kidney rejection episodes were independent of each other, rejection surveillance should be carried out separately for each transplanted organ.

To evaluate the outcomes of patients with achalasia who had undergone myotomy and an antireflux operation because dilatations had not yielded satisfactory results.Retrospective analysis.University-based tertiary care center.Of 39 patients who met inclusion criteria, 18 female patients and 18 male patients (age range; 17-85 years; median age, 54 years; range of time elapsed since operation, 1-22 years; median time, 6 years) could be studied. Antireflux operations included 360 degrees fundoplications in 27 patients, anterior hemifundoplications in 5 and other procedures in 4.Dysphagia for solid foods and liquids, regurgitation, heartburn, retrosternal pain and body weight.Excellent, good, and fair results of myotomy and antireflux operation were encountered in 14, 3, and 6 patients, respectively, and poor or absent results in the remaining 13 patients. The resting pressure of the lower esophageal sphincter was significantly lower at follow-up than preoperatively, and this was associated with reduced dysphagia for solid foods in 14 patients and for liquids in 16 of 17 patients.Myotomy and antireflux operation yielded excellent to fair results in 23 patients in whom dilatations had not facilitated swallowing. Poor results in the remaining 13 patients seemed to be attributable to the 360 degrees fundoplication performed in 12 of them. In these patients, a further surgical intervention seemed to be indicated.

Abstract: Background: Strictures and concrements are the most common biliary complications following liver transplantation. Endoscopic treatment might not lead to a definitive cure in all patients, especially in strictures involving the biliary bifurcation. The aim of this study was to determine the efficacy and the long‐term outcome of hepaticojejunostomy (HJS) for post‐transplant biliary tract obstruction. Material and methods: Thirty‐seven patients were retrospectively studied for resolving of cholestasis and the incidence of recurring biliary obstruction. Results: Surgery was performed because of anastomotic strictures in 11, ischemic strictures at the donor common bile duct in seven, strictures involving the bile duct bifurcation in 10, hepatolithiasis without strictures in one and biliary cast formation diagnosed by endoscopic retrograde cholangiography or T‐tube cholangiography in eight patients. Cholestasis instantly improved in 82% of the patients. After a long‐term follow‐up of median 33 months (range 3–149), 28 of the patients (76%) required no further intervention for recurring biliary obstruction following HJS. Anastomotic strictures were observed in six (16%), recurring biliary concrements in two patients (5%). Conclusion: HJS did prevent recurrent biliary obstruction in the majority of the patients. We therefore recommend early HJS for complicated post‐transplant biliary tract obstruction not treatable by a limited number of endoscopic interventions.

Background Liver transplantation (LT) in elderly recipients is controversially discussed in the literature with only little data on long-term outcome available. We aimed to evaluate the safety and efficiency of LT in elderly recipients (>65 years). Methods Between 1989–2016, 139 patients >65 years-old were listed for liver transplantation, and 76 (55%) were transplanted. Patient outcome and characteristics were evaluated separately for the time period before (1989–2004) and after (2005–2016) MELD-implementation. Post-transplant outcome was compared between the elderly cohort and LT-recipients aged 18–65 years (n = 1395). Results Overall survival of patients >65 years was better in the MELD-era compared to the earlier period (1- and 5-year-survival: 73%, 60% vs. 69%, 37%, respectively; p = 0.055). The main differences between the two groups included higher recipient age (p = 0.001) and BMI (p = 0.001), higher donor age (p < 0.001), less need of intraoperative red blood cells (p = 0.008) and a lower number of postoperative rejections (p = 0.03) after 2004. Comparing the overall survival of patients transplanted in the MELD-era aged 18–65 years vs. >65 years displayed comparable 1- and 5 year-survival rates (81%, 68% vs. 73% and 60%, respectively, p = 0.558). Conclusion In the modern era, outcome of patients receiving LT with >65 years is comparable to <65 year-old patients. After careful evaluation, patients >65 years old should be considered for LT.

Graft rinse prior reperfusion in liver transplantation (LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant (ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in LT. The most commonly used rinse solution was albumin. Nineteen centers stated interest in participating in a multicenter RCT in the field. The published literature does not provide concluding appraisal of the benefit of graft rinse in LT. Graft rinse protocols are not standardized and are based on personal experience. Appropriately designed clinical trials addressing the topic are demanded. The online survey appears to be a helpful tool for the evaluation of clinical practice and future research topics in the transplant community.

Alcohol use disorder (AUD) is one of the most important risk factors for the development of alcohol-related liver cirrhosis (ALC). Importantly, psychiatrists are an integral part of the interdisciplinary care for patients with AUD and ALC. The aim of the current study was to investigate whether sex influences the outcome within this group of patients. For this purpose, data of all registrations for liver transplantations due to ALC within the Eurotransplant region from 2010 to 2019 were analyzed for sex disparities using competing risk models and in-between group comparisons. Relevant sex differences in registration numbers (24.8% female) and investigated outcomes were revealed. Risk ratios for a positive outcome, i.e., transplantation (0.74), and those of adverse outcomes, i.e., removal from waiting list (1.44) and death on waiting list (1.10), indicated a relative disadvantage for female patients with ALC. Further, women listed for liver transplantations were significantly younger than their male counterparts. Notably, sex disparities found in registration and outcome parameters were independent of differences found in the prevalence of AUD and liver transplantations. Further research is necessary to identify the underlying mechanisms and establish strategies to ensure equity and utility in liver transplantations due to ALC.

The International Liver Transplantation Society (ILTS) has placed a strong focus on achieving gender equality and equity in liver transplant (LT). We aimed to understand gender distribution in leadership positions among LT physicians around the world and within ILTS.In 2019, the ILTS Equality, Diversity, and Inclusion Committee distributed a survey to obtain granular data on gender and characteristics of transplant physicians as well as those in leadership positions in each center. Additionally, data were collected on the gender composition of the ILTS membership, council, chairpersons, and committees and from the United Network for Organ Sharing.Data were collected from 243 transplant centers. Thirty-two (13.2%) had at least 1 woman as the director of LT, chief of transplant surgery, or chief of transplant hepatology. Of the 243 centers, 133 reported the age and gender of the leadership personnel. Women physicians comprised 152 of the 833 transplant surgeons (18.2%) and 298 of the 935 hepatologists (31.9%). Among the 1331 ILTS physician members, 588 (44.2%) provided gender information in their member profiles, and 155 (26.3%) identified themselves as women. Of the 26 ILTS leadership positions, 7 (26.9%) were held by women.This analysis of worldwide gender distribution in the LT physician workforce showed notable gender disparity in LT leadership around the globe and within the ILTS. These data provide a launching point for promoting and achieving gender equality and equity in LT.

Background: Available tacrolimus formulations exhibit substantial inter- and intra-individual variability in absorption and metabolism. The present non-interventional cohort study aimed to assess the tolerability and effectiveness of the once-daily tacrolimus formulation, LCPT, in hepatic allograft recipients in real life. Materials and methods: This study was conducted in Austria and the Czech Republic between July 2016 and August 2019. Patients aged ≥ 18 years old received LCPT per the approved label and local clinical routine. All the participants provided informed consent. Patients newly treated with tacrolimus (de novo) directly after transplantation were observed for six months. The relevant clinical variables were tacrolimus trough level (TL), total daily dose (TDD), number of dose adjustments, kidney and liver function, and tolerability. Results: Of the 70 analyzed patients, 72.9% were male and 85.7% were aged &lt; 65 years old. The mean (SD) time to achieve tacrolimus target TL was 6.4 (4.6) days after 4.4 (4.0) dose adjustments; thereafter, TL remained stable throughout observation at approximately 8 ng/mL. The LCPT TDD at initiation was 8 mg and decreased by a median of 41.4% to 5 mg at 6 months. Liver function continuously improved, and kidney function remained stable. LCPT was well tolerated with 24 adverse events in eight patients (17 related to immunosuppression, mostly mild renal insufficiency, and hematological adverse events); two serious unrelated adverse events were reported (atrial flutter and liver dysfunction). Conclusions: TL was rapidly attained with few dose adaptations after LCPT initiation in de novo liver transplant patients. Liver function rapidly improved, whereas kidney function remained normal. LCPT was well-tolerated in this population.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

Background. During the perioperative period of living donor liver transplantation, anesthesiologists and intensivists may encounter patients in receipt of small grafts that puts them at risk of developing small for size syndrome (SFSS). Methods. A scientific committee (106 members from 21 countries) performed an extensive literature review on aspects of SFSS with proposed recommendations. Recommendations underwent a blinded review by an independent expert panel and discussion/voting on the recommendations occurred at a consensus conference organized by the International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplantation Society of India. Results. It was determined that centers with experience in living donor liver transplantation should utilize potential small for size grafts. Higher risk recipients with sarcopenia, cardiopulmonary, and renal dysfunction should receive small for size grafts with caution. In the intraoperative phase, a restrictive fluid strategy should be considered along with routine use of cardiac output monitoring, as well as use of pharmacologic portal flow modulation when appropriate. Postoperatively, these patients can be considered for enhanced recovery and should receive proactive monitoring for SFSS, nutrition optimization, infection prevention, and consideration for early renal replacement therapy for avoidance of graft congestion. Conclusions. Our recommendations provide a framework for the optimal anesthetic and critical care management in the perioperative period for patients with grafts that put them at risk of developing SFSS. There is a significant limitation in the level of evidence for most recommendations. This statement aims to provide guidance for future research in the perioperative management of SFSS.

Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide.

A 35-year period of clinical development resulted in orthotopic liver transplantation (OLT) becoming a standardized surgical procedure. Despite this progress, the rate of technical complications is still high. Although the main problem in most analyses is vascular or bile duct failure, we observed a remarkable number of parenchymal liver injuries that led to intraoperative problems. Our aim, therefore, is to present an overall report on the incidence, treatment, and clinical course of parenchymal liver injuries in OLT.Five hundred seventy-two consecutive OLT procedures performed between 1988 and 1998 were analyzed in a retrospective study. Parenchymal liver injury was diagnosed by means of examination of the surgical reports. Donor- and recipient-related data followed the medical report. The lesions were classified according to the Organ Injury Scale.Parenchymal liver injury was diagnosed in 23 patients (4%). The lesions were classified as grade Ia (13.1%), grade Ib (13.1%), grade IIb (52.1%), grade IIIa (17.1%), and grade IIIb (4.3%). In 19 patients (82.6%), the lesion was detected during OLT, and in four patients (17.4%), during relaparotomy. The latter group showed significantly higher-grade injuries. Treatment was suture or fibringlue alone, 17.4%; fibringlue and hemostyptics, 26.1%, mesh wrapping 30.4%, and mesh packing 26.1%. Seven patients (30.4%) underwent relaparotomy. Further active bleeding was not found in any of them. Statistical analysis found a correlation between injury grade and relaparotomy rate. No patients died as a result of parenchymal liver injury.Parenchymal liver injuries can be treated well, with no adverse effect on patient or graft survival. An early decision concerning the surgical procedure for controlling hemorrhage is required. A basically aggressive therapeutic approach might avoid further complications relating to reperfusion edema.

The choice of material for above-knee femoropopliteal bypass grafting is a matter of continuing controversy for various reasons. The most important argument in favor of alloplastic grafts is to preserve the autologous saphenous vein for a below-knee bypass, which might become indicated at a later date.A consecutive series of above-knee reconstructions were analyzed with regard to long-term behavior. Early graft occlusions were not included, and the median follow-up was 83 months.A university hospital with a particular interest in vascular surgery.Four hundred forty-two patients received either autologous saphenous vein (n = 310) or alloplastic graft (n = 132) material, and were analyzed in a univariate (Kaplan-Meier) and multivariate (Cox) manner.Analysis as to whether alloplastic graft material provides equal or less favorable results as compared with autologous saphenous vein material, in terms of primary and secondary patency, secondary below-knee bypass grafting, limb salvage, and survival.Although univariate analysis demonstrated a significantly better primary patency rate for autologous saphenous vein material, multivariate analysis did not show any effect of the material in terms of patency, limb salvage, and survival. The frequency of secondary below-knee repair was 7% (31 patients); 56% were performed in the first 2 years postoperatively. This amounted to an estimated probability of 4.4% and 12.3% at 18 years, respectively.The small probability of secondary below-knee repair in our series does not support the policy to use alloplastic grafts routinely for a primary above-knee bypass, to spare the saphenous vein. Therefore, patients should be offered the best material for the first operation even at the above-knee level.

Indocyanine green dye (ICG) has been used in tests for a global measure of liver perfusion and excretory function for more than three decades [1] and has shown good correlation with the severity of hepatic disease as well as with outcome in liver transplant recipients [2-5]. We report a case of the early detection of graft nonfunction after orthotopic liver transplantation (OLT) using a bedside monitoring device for fiberoptic assessment of ICG plasma disappearance rate (ICG (PDR)) (normal value 20%-30%) [2] in a 43-yr-old woman who underwent OLT because of cholangiocellular carcinoma. Retransplantation was performed, and the patient was dismissed from the hospital 3 wk after the first OLT. Case Report A 43-yr-old, 59-kg female patient was postoperatively admitted to the intensive care unit (ICU) after she had undergone uncomplicated elective OLT for the treatment of malignancy. On admission, the patient was endotracheally intubated, and the lungs were mechanically ventilated. She was hemodynamically stable. Arterial blood gas analysis revealed no metabolic disorders. Laboratory samples showed reduced synthesis of clotting factors and an increase of serum transaminases. Measurement of gastric intramucosal PCO2 and calculation of intramucosal pH revealed no abnormalities. Postreperfusion ICGPDR (24.8%) and ICGPDR on admission (20.3%) indicated good functioning of the graft initially. The ICGPDR was evaluated after a single bolus injection, via a central venous line into the right atrium, of ICG (0.3 mg/kg body-weight), diluted in 10 mL of dextrose 5%. Exponential decay time for the dye indicator over a period of 240 s was recorded using a 3F fiberoptic thermistor-tipped catheter advanced via the right femoral artery into the descending aorta, and ICG (PDR) was calculated using the COLD-Z021[trade mark sign] system (Pulsion Medical Systems, Munich, Germany). ICGPDR performed routinely three times daily demonstrated a decrease to 5% approximately 8 h after admission and a value of 0% 2 h later. Doppler ultrasound examination was conducted by an experienced investigator. The results, however, were inconclusive, mainly because of anatomic difficulties/bowel movement and intestinal gas. The patient was immediately scheduled for angiography, which showed a complete stop of blood flow in the hepatic artery, as well as in the portal vein. Because no anatomical abnormalities of the anastomoses had been reported during transplantation and clotting times were still prolonged, a thrombosis was extremely unlikely. All other diagnostic tests or clinical signs were inconclusive, not abnormal, or within the range of impairment expected in a patients who had undergone uncomplicated OLT. The time course of all variables is shown in Figure 1 and Table 1.Figure 1: Time course of indocyanine green dye plasma disappearance rate (ICGPDR), gastric intramucosal pH (pHi), and gastric intramucosal PCO2 (PrCO2) in the immediate postoperative period. adm. = admission, p.o. = postoperative.Table 1: Laboratory FindingsThe patient was scheduled for a high-urgency retransplantation. Forty-six hours after OLT, she underwent uncomplicated retransplantation with immediate excellent graft function (ICGPDR 26.4%). Her recovery from the procedure was uneventful, and ICGPDR of the new graft remained stable on follow-up (ICGPDR 19.8% on admission, 21% on Day 4 postoperatively). On Day 21, the patient was discharged. Histological analysis of the primary graft revealed complete ischemic necrosis, despite the fact that no thrombus could be detected during relaparatomy. Anamnesis of donor risk factors revealed short-term noradrenaline support at the end of her 3-day ICU stay due to brain injury. However, the functioning of other organs harvested and transplanted was excellent. Discussion Assessment of graft function and differential diagnosis of graft dysfunction in the immediate postoperative course after OLT remains especially difficult because of etiological complexity. Differential diagnosis includes primary nonfunction of the graft, rejection, infection, drug toxicity, and thrombosis of the hepatic blood vessels. Routine laboratory investigations, including bilirubin, serum transaminases and, clotting tests, are of little diagnostic value because the results are difficult to interpret and are often nonspecific in the early postoperative period [6,7]. Furthermore, invasive techniques increase the risk of serious complications. Early detection of graft dysfunction or nonfunction depends largely on the experience of the intensivist and the correct interpretation of laboratory tests or other more conclusive investigations. In our patient, there were no findings suggesting early graft nonfunction, with the exception of the bedside ICGPDR assessment. In particular, there were neither clinical signs nor alterations in the laboratory tests except those expected. In contrast to previous reports, gastric intramucosal PCO2 and intramucosal pH could not be verified as sensitive markers of liver dysfunction after OLT in this case [8,9]. Those variables reflect gastric mucosal hemodynamics and determine total splanchnic perfusion. Because systemic hemodynamics were stable in our patient, we hypothesize that splanchnic perfusion was also stable and that the problem was solely hepatic. Hepatic dysfunction might not be detected by this method if it does not result from compromised splanchnic hemodynamics or if it does not lead to changes in the acid-base balance [10]. Even Doppler ultrasound examination failed to detect hepatic ischemia. Besides the difficulties in examination because of anatomic causes, this investigation might be flawed by great interindividual variation in the interpretation of the results, depending on the expertise of the investigator. Because of the total stop in hepatic blood flow, the patient presented with functional anhepacy within a few hours. She did not develop hemodynamic instability and metabolic derangement. This might have been a prerequisite for successful retransplantation and outcome, together with the fact that the patient was otherwise healthy, with the exception of the underlying cholangiocellular carcinoma. Routine monitoring with dynamic liver function tests, e.g., ICGPDR or monoethylglycinexylidide, has rarely been reported because the tests used to require specialized laboratories. Investigations of this nature have also been time consuming. The ICGPDR, as assessed using a bedside monitoring device Pulsion COLD-System[trade mark sign], is based on the principle of a once-applied ICG dye indicator bolus. Consecutive measurement of the exponential decay time of the dye via a fiberoptic catheter provides quick and reliable information concerning the global performance of the graft [5]. We do not rely on certain cutoff points of ICGPDR as a prognostic value of outcome. Nevertheless, changes observed in ICGPDR after OLT indicate the necessity to follow-up with more invasive techniques and should influence treatment decisions.

Indocyanine green dye (ICG) has been used in tests for a global measure of liver perfusion and excretory function for more than three decades [1] and has shown good correlation with the severity of hepatic disease as well as with outcome in liver transplant recipients [2-5]. We report a case of the early detection of graft nonfunction after orthotopic liver transplantation (OLT) using a bedside monitoring device for fiberoptic assessment of ICG plasma disappearance rate (ICG (PDR)) (normal value 20%-30%) [2] in a 43-yr-old woman who underwent OLT because of cholangiocellular carcinoma. Retransplantation was performed, and the patient was dismissed from the hospital 3 wk after the first OLT. Case Report A 43-yr-old, 59-kg female patient was postoperatively admitted to the intensive care unit (ICU) after she had undergone uncomplicated elective OLT for the treatment of malignancy. On admission, the patient was endotracheally intubated, and the lungs were mechanically ventilated. She was hemodynamically stable. Arterial blood gas analysis revealed no metabolic disorders. Laboratory samples showed reduced synthesis of clotting factors and an increase of serum transaminases. Measurement of gastric intramucosal PCO2 and calculation of intramucosal pH revealed no abnormalities. Postreperfusion ICGPDR (24.8%) and ICGPDR on admission (20.3%) indicated good functioning of the graft initially. The ICGPDR was evaluated after a single bolus injection, via a central venous line into the right atrium, of ICG (0.3 mg/kg body-weight), diluted in 10 mL of dextrose 5%. Exponential decay time for the dye indicator over a period of 240 s was recorded using a 3F fiberoptic thermistor-tipped catheter advanced via the right femoral artery into the descending aorta, and ICG (PDR) was calculated using the COLD-Z021[trade mark sign] system (Pulsion Medical Systems, Munich, Germany). ICGPDR performed routinely three times daily demonstrated a decrease to 5% approximately 8 h after admission and a value of 0% 2 h later. Doppler ultrasound examination was conducted by an experienced investigator. The results, however, were inconclusive, mainly because of anatomic difficulties/bowel movement and intestinal gas. The patient was immediately scheduled for angiography, which showed a complete stop of blood flow in the hepatic artery, as well as in the portal vein. Because no anatomical abnormalities of the anastomoses had been reported during transplantation and clotting times were still prolonged, a thrombosis was extremely unlikely. All other diagnostic tests or clinical signs were inconclusive, not abnormal, or within the range of impairment expected in a patients who had undergone uncomplicated OLT. The time course of all variables is shown in Figure 1 and Table 1.Figure 1: Time course of indocyanine green dye plasma disappearance rate (ICGPDR), gastric intramucosal pH (pHi), and gastric intramucosal PCO2 (PrCO2) in the immediate postoperative period. adm. = admission, p.o. = postoperative.Table 1: Laboratory FindingsThe patient was scheduled for a high-urgency retransplantation. Forty-six hours after OLT, she underwent uncomplicated retransplantation with immediate excellent graft function (ICGPDR 26.4%). Her recovery from the procedure was uneventful, and ICGPDR of the new graft remained stable on follow-up (ICGPDR 19.8% on admission, 21% on Day 4 postoperatively). On Day 21, the patient was discharged. Histological analysis of the primary graft revealed complete ischemic necrosis, despite the fact that no thrombus could be detected during relaparatomy. Anamnesis of donor risk factors revealed short-term noradrenaline support at the end of her 3-day ICU stay due to brain injury. However, the functioning of other organs harvested and transplanted was excellent. Discussion Assessment of graft function and differential diagnosis of graft dysfunction in the immediate postoperative course after OLT remains especially difficult because of etiological complexity. Differential diagnosis includes primary nonfunction of the graft, rejection, infection, drug toxicity, and thrombosis of the hepatic blood vessels. Routine laboratory investigations, including bilirubin, serum transaminases and, clotting tests, are of little diagnostic value because the results are difficult to interpret and are often nonspecific in the early postoperative period [6,7]. Furthermore, invasive techniques increase the risk of serious complications. Early detection of graft dysfunction or nonfunction depends largely on the experience of the intensivist and the correct interpretation of laboratory tests or other more conclusive investigations. In our patient, there were no findings suggesting early graft nonfunction, with the exception of the bedside ICGPDR assessment. In particular, there were neither clinical signs nor alterations in the laboratory tests except those expected. In contrast to previous reports, gastric intramucosal PCO2 and intramucosal pH could not be verified as sensitive markers of liver dysfunction after OLT in this case [8,9]. Those variables reflect gastric mucosal hemodynamics and determine total splanchnic perfusion. Because systemic hemodynamics were stable in our patient, we hypothesize that splanchnic perfusion was also stable and that the problem was solely hepatic. Hepatic dysfunction might not be detected by this method if it does not result from compromised splanchnic hemodynamics or if it does not lead to changes in the acid-base balance [10]. Even Doppler ultrasound examination failed to detect hepatic ischemia. Besides the difficulties in examination because of anatomic causes, this investigation might be flawed by great interindividual variation in the interpretation of the results, depending on the expertise of the investigator. Because of the total stop in hepatic blood flow, the patient presented with functional anhepacy within a few hours. She did not develop hemodynamic instability and metabolic derangement. This might have been a prerequisite for successful retransplantation and outcome, together with the fact that the patient was otherwise healthy, with the exception of the underlying cholangiocellular carcinoma. Routine monitoring with dynamic liver function tests, e.g., ICGPDR or monoethylglycinexylidide, has rarely been reported because the tests used to require specialized laboratories. Investigations of this nature have also been time consuming. The ICGPDR, as assessed using a bedside monitoring device Pulsion COLD-System[trade mark sign], is based on the principle of a once-applied ICG dye indicator bolus. Consecutive measurement of the exponential decay time of the dye via a fiberoptic catheter provides quick and reliable information concerning the global performance of the graft [5]. We do not rely on certain cutoff points of ICGPDR as a prognostic value of outcome. Nevertheless, changes observed in ICGPDR after OLT indicate the necessity to follow-up with more invasive techniques and should influence treatment decisions.

Post-transplant lymphoceles (LC) may lead to impaired graft function. Treatment modalities include fine-needle aspiration, percutaneous drainage, and surgical internal drainage. Recently, laparoscopic fenestration has been performed with good results, but experience is still limited. Between January 1991 and August 1996, 919 kidney transplantations were performed in 876 patients at our department. There were 745 first, 133 second, 30 third, 9 fourth, and 2 fifth operations. Sixty-three symptomatic LCs were detected in 62 patients (6.8%) after 39 +/- 31 days. In 44% of the cases, graft function was impaired; in 29% hydronephrosis was documented and in 6% infection of the LC. Forty-five of the 62 patients with LC (73%) had histologically proven rejection. Thirty-five of the 63 LCs were drained percutaneously, 20 LCs were internally drained by open surgery, and 8 LCs were drained by laparoscopy. In 14 of the 47 patients (30%) with primary percutaneous drainage, LC recurred; infection occurred in 17%. Twelve of these patients underwent surgery. One surgical redrainage was necessary after open fenestration. No conversion or complication was noted in the laparoscopy group. We conclude that surgery for post-transplant lymphoceles is safe and effective. We favor the laparoscopic technique in selected patients.

Acute liver failure (ALF) is a rare clinical syndrome associated with a mortality of up to 80% and its management remains an interdisciplinary challenge. Despite recent improvements in intensive care management, the mortality of patients with ALF remains high and is related to complications such as cerebral edema, sepsis and multiple organ failure. Emergency orthotopic liver transplantation (OLT) is currently the only effective treatment for those patients who are unlikely to recover spontaneously. Nevertheless, OLT is not always possible because of the shortage of the organs and/or complications related to ALF. Newly introduced liver-assist devices can temporarily support the patient's liver until native liver recovers or can serve as a bridging device until a liver graft is available. The support devices use both cell-based and non-cell-based techniques. One of the latest non-cell-based extracorporeal hepatic support devices, the molecular adsorbent recycling system (MARS), is based on the concept of albumin dialysis. MARS utilises selective hemodiafiltration with countercurrent albumin dialysis aiming to selectively remove both water-soluble and albumin-bound toxins of the low and middle molecular-weight range. We report on a young patient who presented with clinical symptoms of ischemic hepatitis and multi-organ failure (APACHE II score 38-->predicted postoperative mortality 87%) due to prolonged hemorrhagic shock. OLT was contraindicated because of history of pancreas cancer with metastases. It was necessary to use aggressive conservative therapy and an extracorporeal liver-assist device until liver regeneration began and hemodynamic conditions were stable. The patient underwent five treatments with MARS. During the treatment, there were improvements of hemodynamics, respiratory function, acid-base disturbances and laboratory parameters. The plasma disappearance rate of indocyanine green, a parameter of dynamic liver function, improved during MARS treatment. Although repeated neurological examination predicted diffuse brain damage (brain oedema, decreased cerebral blood flow), the patient recovered without any neurological deficits. The patient survived and was discharged from the hospital in good condition. In this case MARS treatment was successful in supporting the patient through the most critical period of ALF.

The product of the concentrations of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 (urinary [TIMP-2] × [IGFBP-7]) has been suggested as biomarker for early detection of acute kidney injury (AKI) in various clinical settings. However, the performance of urinary [TIMP-2] × [IGFBP-7] to predict AKI has never been assessed in patients undergoing orthotopic liver transplantation (OLT). Thus, the aim of this study was to assess the early predictive value of urinary [TIMP-2] × [IGFBP-7] for the development of AKI after OLT. In this observational study, urinary [TIMP-2] × [IGFBP-7] was measured in samples from adult OLT patients. AKI was diagnosed and classified according to KDIGO criteria. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of urinary [TIMP-2] × [IGFBP-7] for the development of AKI. Forty patients (mean age 55 ± 8 years) were included. Twenty-eight patients (70%) developed AKI stage 1, 2, or 3 within 48 h after OLT. Urinary [TIMP-2] × [IGFBP-7] was not predictive for AKI at the end of OLT (AUC: 0.54, CI [0.32–0.75], P = 0.72), at day 1 (AUC: 0.60, CI [0.41–0.79], P = 0.31), or day 2 after OLT (AUC: 0.63, CI [0.46–0.8], P = 0.18). Based on our results, routine clinical use of urinary [TIMP-2] × [IGFBP-7] cannot be recommended for risk assessment of AKI in patients undergoing OLT.

Sparse data are available about the effect of therapy methods on antibody levels in patients with liver failure. The aim of this study was to determine serum immunoglobulin concentrations in patients with chronic hepatic failure (CHF), acute- (ALF), or acute-on-chronic liver failure (ACLF) and to evaluate the impact of MARS treatment or liver transplantation (LT) on antibody levels.We followed ten patients with ALF, twelve with ACLF and 18 with CHF. Eight patients with ALF and seven with ACLF underwent MARS therapy, whereas the rest received LT. 13 healthy volunteers served as controls. Serum antibody concentrations were measured using ELISA-technique.Median serum levels of IgA, IgG and IgM were significantly increased in patients with CHF compared to ALF or controls (P<0.02, P<0.01, and P<0.01). IgM and IgG concentrations were also significantly elevated in patients with CHF compared to ACLF (IgM, 3.7 vs. 1 g/L, P<0.001; IgG, 8.7 vs. 3.1 g/L, P=0.004). Immediately after LT a significant decrease of IgA (6.9 vs. 3.1 g/L, P=0.004), IgG (8.7 vs. 5.1 g/L, P=0.02) and IgM (3.7 vs. 1.8 g/L, P=0.001) was detected in patients with CHF and antibody levels further decreased the days after LT reaching levels comparable to healthy individuals. MARS treatment had no apparent effect on the immunoglobulin profile in patients with ALF or ACLF.We provide evidence that LT reverses hypergammaglobulinemia in patients suffering from CHF within one day, which could be explained to a reconstituted hepatic antibody clearance, whereas MARS treatment has no immediate effect on immunoglobulin levels.

Since most of studies investigating cytokine levels during human orthotopic liver transplantation used venovenous bypass (VVB), it may be difficult to distinguish between the increase in proinflammatory mediators induced by VVB, by ischemia-reperfusion injury or by splanchnic venous congestion in the anhepatic phase. The goal of this investigation was to assess the levels of interleukin-6 (IL-6) and soluble interleukin-2 receptors (sIL-2r) during OLT procedures routinely performed without VVB.Twenty-one consecutive patients underwent OLT with cross clamping of the inferior caval vein without VVB. Soluble IL-2r concentrations were measured by means of luminescence enzyme immunometric assay and IL-6 by means of a sequential immunometric assay. Time points (TP) of sampling were before induction of anesthesia (TP1), after cross-clamping of the inferior vena cava (TP2), 15 minutes after reperfusion (TP3), and 24 hours after the transplant procedure (TP4).Soluble IL-2r increased significantly 24 hours after transplantation (P =.02) compared to TP1, TP2, and TP3. IL-6 increased significantly during the anhepatic period (TP2 vs TP1, P =.003) and again in the reperfusion period (TP2 vs TP3, P =.002). Twenty-four hours after surgery IL-6 declined significantly (TP3 vs TP4, P =.001), but remained significantly higher (P = 0.04) compared to TP1. Furthermore, we examined the relative changes (DeltaTP %) in perioperative levels of cytokines compared with those previously published in studies using VVB. We observed higher values of DeltaTP % of IL-6 in TP2 and TP4 among our group of patient without VVB. The data on sIL-2r were similar, suggesting no major effects of the operative technique on sIL-2r levels.The two interleukins showed different perioperative trends. Our data suggest that cross clamping contributes more to cell activation, namely, increased release of IL-6 in the anhepatic phase than the use of VVB. However, no major differences were observed during the reperfusion period. The extent of clinical effect on graft function of higher IL-6 levels in the anhepatic period among recipients not supported with VVB remains to be clarified.

We assessed whether standardized application of an absorbable polysaccharide hemostatic powder (HaemoCer™) has an effect on lymphocele rate after kidney transplantation. For this nonrandomized prospective trial, we first aimed to know our center-specific lymphocele rate diagnosed by ultrasound imaging. We retrospectively assessed all patient records of the elapsed year resulting in a center-specific rate of 20%, this was consistent with literature. The power analysis showed that 108 patients were required to detect a 50% reduction in lymphocele rate. During the prospective study period, 155 patients undergoing kidney transplantation were recruited to receive HaemoCer™ intraoperatively. In two patients, the product accidentally was not used. Six patients were excluded from analysis because of failure to complete follow-up (one early death and five early graft failures). Of the remaining 147 patients, 15 developed lymphoceles, which represents a rate of 10.2%; (95% CI: 6.3–16.2%). Compared to the expected occurrence, this was significantly lower (P = 0.003). Lymphoceles appeared to be associated with preoperative donor-specific antibody, retransplantation and immunoadsorption in HLA or ABO incompatible donors. At our institution, the frequency of lymphoceles after kidney transplantation appeared to be significantly reduced when HaemoCer™ was applied routinely. The magnitude of the effect warrants randomized evaluation.