Rescue Allocation Modes in Eurotransplant Kidney Transplantation: Recipient Oriented Extended Allocation Versus Competitive Rescue Allocation-A Retrospective Multicenter Outcome Analysis.

BACKGROUND: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. METHODS: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. RESULTS: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. CONCLUSIONS: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.

A possible role of microRNAs as predictive markers for the recurrence of hepatocellular carcinoma after liver transplantation.

With favourable 5-year survival rates up to 75%, liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). Nonetheless, tumour recurrence after LT remains a challenge. The aim of this retrospective study was to develop a predictive score for tumour recurrence after LT by combining clinical parameters with HCC biomarkers (microRNA). A microRNA (miRNA) microarray analysis was used to compare miRNA expression patterns in tissue samples of 40 patients with and without HCC recurrence after LT. In a screening cohort (n = 18), the miRNA analysis identified significant differences in the expression of 13 miRNAs in patients with tumour recurrence. Using the most significant miRNAs in this screening cohort, we could develop a predictive score, which combined the expression levels of miR-214, miR-3187 and the Milan criteria, and we could define low- and high-risk groups for tumour recurrence and death. The above score was evaluated in a second and independent cohort (n = 22). In contrast to the Milan criteria alone, this score was significantly associated with tumour recurrence. Our analysis indicated that the use of a specific miRNA expression pattern in combination with a limited tumour burden as defined by the Milan criteria may lead to a more accurate prediction of tumour recurrence.

Long-term follow-up of endoscopic therapy for stenosis of the biliobiliary anastomosis associated with orthotopic liver transplantation.

Endoscopic treatment for stenosis of an anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but the long-term outcomes and the risk factors for recurrence are unknown. All 374 patients who underwent OLT at Frankfurt University Hospital were screened for the occurrence of ABSs. ABSs were treated via the endoscopic insertion of a plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of the two (57.4%). The mean follow-up time was 151 weeks, and the mean survival time was 3.4 years. ABSs were observed in 47 patients (12.6%). The mean time from OLT to an ABS was 16.25 months (median = 3.25 months). The cumulative incidence rates for ABSs were 0.09 after 12 months, 0.10/24 m. and 0.11/36 m. In 12 cases (25.5%), ABSs were observed more than 12 months after OLT. ABSs recurred in 16 of the 47 patients (34%). The occurrence of an ABS 6 weeks or more after OLT was a significant predictor of ABS recurrence [P = 0.04, hazard ratio (HR) = 0.235]. There was a trend of hepatitis C virus (HCV) infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non-HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non-HCV etiology, P > 0.05). The severity of the initial stricture predicted ABS recurrence (P = 0.046, HR = 2.78), but it did not influence overall survival. The long-term resolution of ABSs was observed in 45 of the 47 patients (95.7%), and ABS recurrence was treated with another attempt (n = 16 or 34%) or 2 more attempts (n = 1) at endoscopic treatment. In conclusion, the long-term success of the endoscopic treatment of ABSs is highly probable if recurrent strictures are again treated endoscopically. ABSs might occur late (>36 months) after OLT, and lifelong follow-up is essential for identifying OLT patients with ABSs.

Long-term follow-up of endoscopic therapy in stenosis of the bilio-biliary anastomosis associated with orthotopic liver transplantation.

BACKGROUND: Endoscopic treatment of stenosis of the anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but long term outcome and risk factors for recurrence are unknown. METHODS: All 374 patients who underwent OLT at Frankfurt University hospital were screened for occurrence of ABS. ABS was treated by endoscopic insertion of plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of both (57.4%). Long-term outcome and risk factors for occurrence and recurrence of ABS was determined through competing risk analysis. Mean follow-up time was 151 weeks and mean survival was 3.4 years. RESULTS: ABS was observed in 47 patients (12.6%). Mean (median) time from OLT to ABS was 16.3 months (3.3 months). Cumulative incidence rates of ABS were 0.09 after 12 months, 0.10 after 24 months and 0.11 after 36 months. In 12 cases (25.5%), ABS was observed later than 12 months after OLT. ABS recurred in 14 of 47 (29%). Ocurrence of ABS more than six weeks after OLT was a significant predictor of ABS recurrence (p=0.04, H.R. 0.235). There was a trend of HCV infection to be predominant in patients with recurrence of ABS (30% HCV vs. 4% non-HCV) in comparison to patients with non-recurrence (HCV 36%, non-HCV 30%); p > 0.05. Severity of initial stricture predicted recurrence of ABS (p = 0.046, HR=2.78), but did not influence overall survival. Long-term resolution of ABS was observed in 45 of 47 patients (95.7%), recurrence of ABS was treated with a second (n= 16, 34%), or a third endoscopic treatment attempt (1). CONCLUSION: Long-term success of endoscopic treatment of ABS is highly probable if recurrent strictures are again treated endoscopically. ABS might occur late (>36 months) after OLT and life-long follow-up is essential in OLT patients to identify patients with ABS. © 2013 American Association for the Study of Liver Diseases.

Effects of mycophenolate mofetil introduction in liver transplant patients: results from an observational, non-interventional, multicenter study (LOBSTER).

The benefits of calcineurin inhibitor (CNI)-sparing regimens on renal function following liver transplantation (LT) have been demonstrated in clinical studies. This observational study assessed the real-life effects of mycophenolate mofetil (MMF) introduction in LT patients. Four hundred and ninety-seven patients in whom MMF was introduced according to local standards or clinical considerations were entered. Patients were grouped by time between transplantation and start of MMF (start of study): Group A (n = 263): ≤6 d; Group B (n = 64): >6 d to ≤1 month; Group C (n = 74): >1 month to ≤1 yr; and Group D (n = 96): >1 yr. CNI sparing occurred in all groups, particularly in Groups C and D. Mean MMF doses at 12 months were 1202.7, 1363.5, 1504.7, and 1578.1 mg/d, respectively, in Groups A-D. At introduction of MMF, median glomerular filtration rate was 73.3, 81.7, 62.7, and 53.7 mL/min/1.73 m(2) in Groups A-D. At 12 months, this decreased to 66 mL/min/1.73 m(2) in Groups A and B, remained stable in Group C, and increased in Group D (64.8 mL/min/1.73 m(2) ). Serious adverse drug reactions were lowest in Group D. In conclusion, MMF with a subsequent decrease in CNI was well tolerated and improved renal function even years after transplantation. A more forceful MMF dosing strategy with greater CNI sparing may further improve renal function.

Partial spleen resection with a radiofrequency needle device--a pilot study.

INTRODUCTION: Total splenectomy leads to an immunocompromised state, with an increased lifetime risk of infection. The lifetime risk of developing overwhelming postsplenectomy infection is 5 %, with a mortality rate of approximately 50 %. In addition to vaccination and antibiotic prophylaxis, partial splenectomy is believed to improve patient safety. METHODS: We performed partial splenectomy in seven patients using a radiofrequency (RF) technique with Habib® needles. In seven patients, an open access partial splenectomy was performed. In three patients, a partial splenectomy was performed simultaneously with intraabdominal tumour resection. In two patients, the upper pole of the spleen was removed due to tumours of the spleen. In one patient, a large symptomatic splenic cyst was resected and in another patient, a partial splenectomy was performed due to trauma. RF was applied using Habib® needles (AngioDynamics, Manchester, GA, 31816, USA). RESULTS: The partial splenectomy procedures were easy and safe in all seven patients. The RF application with the Habib® needles led to primary haemostasis. The blood loss was less than 50 ml in all cases. After a minimum follow-up of 1 year, there were no cases of infections or other adverse events related to the previous partial splenectomy. CONCLUSION: In our experience, partial splenectomy with Habib® needles is easy to perform and safe for the patient. Thus, radiofrequency resection is a good alternative to total splenectomy in many patients and reduces the risk of postsplenectomy infections.

Automated low flow pump system for the treatment of refractory ascites: a multi-center safety and efficacy study.

BACKGROUND & AIMS: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. METHODS: Forty patients at 9 centers (February 2010-June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. RESULTS: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1-6) vs. 0.2 (range 0-4); p <0.01]. Cirrhosis-related adverse events decreased along follow-up. CONCLUSIONS: The automated pump seems an efficacious tool to move out ascites from the peritoneal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results.

Early echocardiographic detection of a massive intracardiac thrombus in a patient scheduled for orthotopic liver transplantation.

Transesophageal echocardiography (TEE) in cases of orthotopic liver transplantation is gaining acceptance for intraoperative hemodynamic monitoring. The timepoint of TEE probe insertion varies and is based on the fear of bleeding complications in the setting of portal hypertension with esophageal varices. In this case, early insertion of the TEE probe and examination resulted in the early detection of a large intracardiac thrombus, and thus the cancellation of the planned procedure. This case highlights the potential value of early TEE examination in orthotopic liver transplantation.

Posthepatectomy liver failure.

BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the most serious complications after liver resection and is still reported in up to 8% after liver resection. AIMS: To provide an overview about the current status of risk analysis and definition of PHLF. Prevention and treatment is also discussed. METHODS: A literature review was carried out on PubMed using the terms 'liver failure', 'posthepatectomy' and 'liver surgery' to search relevant papers. DISCUSSION: PHLF remains a serious problem in patients undergoing major liver resection. Adequate preoperative risk assessment and an optimal postoperative treatment are essential for PHLF prevention.

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.

BACKGROUND & AIMS: Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. METHODS: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. RESULTS: Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). CONCLUSIONS: We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.

Comparison of the collagen haemostat Sangustop® versus a carrier-bound fibrin sealant during liver resection; ESSCALIVER-Study.

BACKGROUND: Haemostasis in liver surgery remains a challenge despite improved resection techniques. Oozing from blood vessels too small to be ligated necessitate a treatment with haemostats in order to prevent complications attributed to bleeding. There is good evidence from randomised trials for the efficacy of fibrin sealants, on their own or in combination with a carrier material. A new haemostatic device is Sangustop®. It is a collagen based material without any coagulation factors. Pre-clinical data for Sangustop® showed superior haemostatic effect. This present study aims to show that in the clinical situation Sangustop® is not inferior to a carrier-bound fibrin sealant (Tachosil®) as a haemostatic treatment in hepatic resection. METHODS/DESIGN: This is a multi-centre, patient-blinded, intra-operatively randomised controlled trial. A total of 126 patients planned for an elective liver resection will be enrolled in eight surgical centres. The primary objective of this study is to show the non-inferiority of Sangustop® versus a carrier-bound fibrin sealant (Tachosil®) in achieving haemostasis after hepatic resection. The surgical intervention is standardised with regard to devices and techniques used for resection and primary haemostasis. Patients will be followed-up for three months for complications and adverse events. DISCUSSION: This randomised controlled trial (ESSCALIVER) aims to compare the new collagen haemostat Sangustop® with a carrier-bound fibrin sealant which can be seen as a "gold standard" in hepatic and other visceral organ surgery. If non-inferiority is shown other criteria than the haemostatic efficacy (e.g. costs, adverse events rate) may be considered for the choice of the most appropriate treatment. TRIAL REGISTRATION: NCT00918619.

Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir.

OBJECTIVES: The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS: We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS: Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS: Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Chemokine receptor 5Delta32 mutation reduces the risk of acute rejection in liver transplantation.

BACKGROUND: Chemokine receptor 5 (CCR-5) plays a central role in allograft rejection. CCR-5Delta32 mutation results in a non-functioning receptor. Homozygous CCR-5Delta32 patients show a significantly improved kidney graft survival rate compared to CCR-5 wild-type patients. Similar correlations between the CCR-5Delta32 genotype and acute rejection or graft survival rate were shown for heart, lung and islet cell transplantation. MATERIAL/METHODS: The aim of this study was to examine CCR-5Delta32 and acute rejection after liver transplantation (OLT). 158 OLT patients were genotyped. Data of grafts and patients were collected prospectively into a transplant database. RESULTS: There were no significant differences between groups regarding patient, donor or graft variables. CCR-5 wild-type patients had explicitly more acute rejection episodes (p=0.086) than patients with the heterozygous or homozygous Delta32-mutation. Homozygous Delta32 patients had no acute rejection episodes. 12.5% of heterozygous patients had one acute rejection episode as opposed to 30.6% of wild-type patients. Only wild-type patients experienced more than one rejection episode. CONCLUSIONS: Patients with the Delta32-mutation might be candidates for a minimized immunosuppressive therapy. CCR-5 could be relevant as a target for a new therapeutic approach.

Chemokine Receptor-5Delta32 Mutation is No Risk Factor for Ischemic-Type Biliary Lesion in Liver Transplantation.

It has been shown that certain chemokine receptor polymorphisms may correspond to certain complications after organ transplantation. Ischemic-type biliary lesion (ITBL) encounters for major morbidity and mortality in liver transplant recipients. So far, the exact cause for ITBL remains unclear. Certain risk factors for the development of ITBL like donor age and cold ischemic time are well described. In a previous study, a 32-nucleotide deletion of the chemokine receptor-5Delta32 (CCR-5Delta32) was strongly associated with the incidence of ITBL in adult liver transplantation. This study re-evaluates the association of CCR-5Delta32 gene polymorphism and the incidence of ITBL. 169 patients were included into this retrospective analysis. 134 patients were homozygous for wild-type CCR-5, 33 patients heterozygous, and 2 patients were homozygous for CCR-5Delta32 mutation. There were no major differences in donor or recipients demographics. No association was found between CCR-5Delta32 mutation and the development of ITBL. We conclude that CCR-5Delta32 is no risk factor for the development of ITBL in our patient cohort.

Comparison of cyclosporine microemulsion and tacrolimus in 39 recipients of living donor liver transplantation.

New immunosuppressive agents and regimens should be evaluated specifically in living donor liver transplant patients due to potential clinical and pharmacokinetic differences between deceased donor and living donor transplant recipients. The analysis presented here is the first direct comparison of clinical outcomes using cyclosporine microemulsion (CsA-ME) with monitoring of blood concentration at 2 hours postdose (C2) and tacrolimus-based immunosuppression in living donor liver transplantation. The analysis was conducted on the data provided by the 39 recipients of a living donor transplant out of the 495 patients enrolled in a 6-month, randomized, prospective, multicenter, open-label study (LIS2T). Patients were randomized to CsA-ME (C2 monitoring) or tacrolimus (monitoring of predose trough drug blood level [C0)]) and were administered corticosteroids with or without azathioprine. Twenty-three living-donor patients received CsA-ME and 16 received tacrolimus. By month 6, 9% of patients receiving CsA-ME and 19% of those receiving tacrolimus had lost their graft or died (not significant [NS]). Nine episodes of biopsy-proven acute rejection were reported: 4 in the CsA-ME group (17%) and 5 in the tacrolimus cohort (31%, NS). There were no significant differences in any safety parameter between groups. The most frequently reported serious adverse events were infections, which occurred in 14 patients in the CsA-ME group (61%) and 13 patients in the tacrolimus arm (81%, NS). Twelve patients in the CsA-ME arm (52%) and 5 in the tacrolimus arm (31%, NS) discontinued the study prematurely. In conclusion, CsA-ME C2 monitoring or tacrolimus both offer effective protection against rejection in living donor liver transplants while maintaining a good safety profile.

CC chemokine receptor 5delta32 polymorphism-a risk factor for ischemic-type biliary lesions following orthotopic liver transplantation.

Ischemic-type biliary lesions are a major complication following orthotopic liver transplantation. They occur in up to 26% of liver transplant recipients. Among other factors, unknown immunologic factors have always been assumed to be partly responsible for these lesions. CC-chemokines and their receptors play a key role in postoperative immunomodulation after liver transplantation. The non-function CC-chemokine receptor 5delta32 polymorphism (CCR5delta32) has been shown to lead to a lower rate of acute rejection after kidney transplantation; in liver transplantation the role of CCR5delta32 is unclear. We investigated the influence of the CCR5delta32 after liver transplantation with special regard to ischemic-type biliary lesions. The CC-chemokine receptor-5 (CCR5) of 146 recipients was analyzed by polymerase chain reaction to detect CCR5delta32 in blood samples of patients after liver transplantation. One hundred twenty patients with wild-type CCR5 and 26 patients with CCR5delta32 (1 homozygote, 25 heterozygote) were identified. Ischemic-type biliary lesions occurred in 14 of 120 patients with wild-type CCR5 and in 8 of 26 patients with CCR5delta32 polymorphism (P = = 0.01). 5 year patient survival with CCR5delta32 and CCR5 was 70% and 85%, respectively (P =.0067). Our results show that the CCR5delta32 is a significant risk factor for the development of ischemic-type biliary lesions after liver transplantation and leads to a reduction in 5-year survival. In conclusion, the CCR5 status should be screened prospectively before liver transplantation.

Prevention of ischemic-type biliary lesions by arterial back-table pressure perfusion.

Ischemic-type biliary lesions (ITBLs) lead to considerable morbidity after orthotopic liver transplantation (OLT). The exact pathogenesis is unknown. We tested the hypothesis that insufficient perfusion of biliary arterial vessels might be responsible for ITBLs. This could be prevented by improved perfusion techniques. Since February 2000, we performed a controlled study using arterial back-table pressure perfusion (AP) to achieve reliable perfusion of the biliary-tract capillary system, which may be impaired by the high viscosity of University of Wisconsin solution. We retrospectively analyzed 190 OLTs performed between September 1997 and July 2002 with regard to ITBLs. One hundred thirty-one grafts were preserved by in situ standard perfusion (SP), including portal perfusion, whereas in 59 cases, additional AP was performed. Donor-related factors, recipient age, indication for OLT, OLT technique, immunosuppression, and ischemia time were similar in both groups. In the SP group, 21 of 131 patients (16%) developed ITBLs. Only 1 of 59 patients with grafts receiving AP developed ITBLs. This difference was highly significant (P =.004). Peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels within the first 3 days were significantly lower in the AP group (AST, P =.016; ALT, P =.007). Multivariate analysis showed a significant influence of AP (P =.010) and donor age (P =.003) on the development of ITBLs. AP is an easy and reliable method to prevent ITBLs in OLT. It therefore should be used as the standard technique in liver procurement.