R. Oellinger

Long-term outcome in kidney transplant recipients over 70 years in the Eurotransplant Senior Kidney Transplant Program: a single center experience.

Background. Kidney transplantation in the elderly is complicated by comorbidities and a higher incidence of death. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys from older donors to the increasing number of older recipients. In this retrospective, single center data analysis, we compare the outcome of recipients older than 70 years with younger recipients transplanted under the ESP protocol. Methods. Between 1999 and 2009, a total of 83 kidneys were transplanted under the ESP protocol in Innsbruck and 19 of the recipients were older than 70 years (mean, 72.7 years). Cold ischemia time was kept short in both groups by giving preference to regional donor organs. Results. Patient survival at 1 and 5 years were 95% and 67% in the 70+ group and 94.4% and 82.6% in the 70− group. Graft survival was 95% and 52% at 1 and 5 years in the 70+ group and 94.4% and 79.0% in the 70− group. When censored for death, graft survival at year 1 and 5 were 100% and 82% in the 70+ group and 98.1% and 92.7% in the 70− group. The delayed graft function rate was high in both groups (36.8% and 41.1%, respectively). Morbidities were largely related to hemodynamic, oncologic, and infectious events. Cardiac failure was the major cause of death. Conclusion. Relatively good results can be achieved with renal transplantation in patients older than 70 years under careful pretransplant evaluation and postoperative management of comorbidities.

Alemtuzumab in solid organ transplantation and in composite tissue allotransplantation

Alemtuzumab (Campath®, Genzyme Corporation, MA, USA) is a potent monoclonal antilymphocyte, anti-CD52 antibody. Since the 1980s, alemtuzumab has been used extensively in organ transplantation as an induction agent - also with the aim of avoiding or reducing maintenance immunosuppression. We herein review the literature on alemtuzumab in solid organ and composite tissue allotransplantation with an emphasis on clinical and mechanistic aspects of alemtuzumab. In summary, the use of alemtuzumab in solid organ and composite tissue allotransplantation shows excellent early results and holds potential for wider use in conjunction with immunosuppression minimization protocols.

Murine cervical heart transplantation model using a modified cuff technique

Mouse models are of special interest in research since a wide variety of monoclonal antibodies and commercially defined inbred and knockout strains are available to perform mechanistic in vivo studies. While heart transplantation models using a suture technique were first successfully developed in rats, the translation into an equally widespread used murine equivalent was never achieved due the technical complexity of the microsurgical procedure. In contrast, non-suture cuff techniques, also developed initially in rats, were successfully adapted for use in mice(1-3). This technique for revascularization involves two major steps I) everting the recipient vessel over a polyethylene cuff; II) pulling the donor vessel over the formerly everted recipient vessel and holding it in place with a circumferential tie. This ensures a continuity of the endothelial layer, short operating time and very high patency rates(4). Using this technique for vascular anastomosis we performed more than 1,000 cervical heart transplants with an overall success rate of 95%. For arterial inflow the common carotid artery and the proximal aortic arch were anastomosed resulting in a retrograde perfusion of the transplanted heart. For venous drainage the pulmonary artery of the graft was anastomosed with the external jugular vein of the recipient(5). Herein, we provide additional details of this technique to supplement the video.

The 28‐year incidence of de novo malignancies after liver transplantation: A single‐center analysis of risk factors and mortality in 1616 patients

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow‐up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow‐up. The median follow‐up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3‐81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A–treated compared with tacrolimus‐treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow‐up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404–1414 2017 AASLD.

Outcome analysis of laparoscopic incisional hernia repair and risk factors for hernia recurrence in liver transplant patients

Incisional hernia is a common complication after liver transplantation (LT). Immunosuppression, obesity, and use of steroids are known risk factors. The purpose of the retrospective study was to summarize and evaluate experiences and results of laparoscopic intraperitoneal onlay mesh (IPOM) hernia repair.

Novel Candidate Markers Characterizing Cellular Senescence in Aged Zero Hour Kidney Biopsies Predict Post Transplant Outcome.: Abstract# D2352

D2352 Novel Candidate Markers Characterizing Cellular Senescence in Aged Zero Hour Kidney Biopsies Predict Post Transplant Outcome. P. Hutter,1 J. Guenther,1 H. Schwelberger,1 M. Biebl,1 S. Schneeberger,1 R. Oellinger,1 D. Strauch,2 P. Neuhaus,2 J. Pratschke,1 K. Kotsch.1 1Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Tyrolia, Austria; 2Institut of Medical Immunology, Charite-Universitemedizin Berlin, Berlin, Germany. Advanced donor age adversely affects allograft outcome following renal transplantation.Candidate genes involved in cellcycle regulation and telomere shortening have been already described as markers for cellular senescence.There is still a lack of biomarkers for defi ning older and marginal organs in order to adopt immunosuppression for improved long-term outcome.To characterize senescence in the donor organ, we fi rst studied gene expression for selected candidate markers(CM) in a small sample cohort of 57 zero hour kidney biopsies derived from deceased donors.Among them 26 biopsies were derived from donors>55 yrs(mean66.5±7.4) and 31 specimens were derived from donors<55 yrs(mean 41.35±8.4).Compared with younger donors,elderly donors revealed a signifi cant de novo mRNA expression of CM including immunoproteasome subunits PSMB8,9,10;(p<0.001 respectively), MHC classII transcripts including HLA-DRB(p<0.01)or transcripts of the receptor NKG2D(p=0.0036).Next, we confi rmed gene expression of CM in an independent patient cohort consisting of 139 biopsy samples.Based on sample size,3 groups were defi ned according to donor age:0-30yrs(group I,21±4.9yrs,n=30),31-54yrs(group II, 46.5±6.6yrs,n=50)and>55 yrs(group III,64.07±7yrs,n=59).Whereas no differences were observed between group I and group II, aged kidneys(group III) revealed a significant gene expression of PSMB9(p=0.0405) and PSMB10(p=0.0223) compared with middle aged kidneys(group II).In addition,HLA-DRB(p=0.0215) and PSMB9(p=0.0129) were signifi cantly induced in group III in comparison with group I.Strikingly,transcripts of the activating NK cell receptor NKG2D revealed the highest gene induction in group III versus group II and group I(p<0.001,respectively) indicating enhanced infi ltration of NKG2D+ CD8+ T cells or NK cells in elderly kidneys. Linear restriction analysis revealed a strong correlation especially for pre-transplant NKG2D mRNA expression with serum creatinine levels at hospital discharge(p=0.0003), at 3months(p=0.004) and at 6months post transplantation(p=0.0031).Our results reveal novel candidate markers in aged renal allografts providing help in the assessment of organ quality and implicating the potential of pretreatment strategies. Abstract# D2353 Differential Molecular Profi les in Steatotic Allografts Early Post-Liver Transplantation. R. Gehrau, V. Mas, J. Suh, K. Brayman, D. Maluf. Surgery, UVA, Charlottesville, VA. Body: Severe graft steatosis has been associated with poor outcomes after liver transplantation (LT). The present study aimed to identify molecular mechanisms associated with ischemia reperfusion injury (IRI) in steatotic liver allografts. D2353 Differential Molecular Profi les in Steatotic Allografts Early Post-Liver Transplantation. R. Gehrau, V. Mas, J. Suh, K. Brayman, D. Maluf. Surgery, UVA, Charlottesville, VA. Body: Severe graft steatosis has been associated with poor outcomes after liver transplantation (LT). The present study aimed to identify molecular mechanisms associated with ischemia reperfusion injury (IRI) in steatotic liver allografts. Patients and Methods: Consecutive LT cases (n=46) were grouped by allograft steatosis as Non-Fatty (NF) (< 15%, n=22) and Fatty (F) (>15 %, n=24). Paired biopsy samples at pre (L1) and post-reperfusion (90 min, L2) were collected. Total RNA was isolated and used for gene expression microarrays hybridization. Probeset summaries were obtained using RMA algorithm. Pairwise comparisons between L1 vs. L2 were fi t using two-sample t-test. A p-value ≤ 0.001 was considered signifi cant. FDR was controlled at 10%. Affected cellular functions and molecular pathway analysis from the identifi ed gene expression profi les were conducted using IPA tool. Top signifi cant genes were confi rmed using RT-qPCR. Results: Demographics and clinical characteristics were similar between groups. Pairwise comparisons between L1 vs. L2 identifi ed 474 genes and 467 genes signifi cantly and differentially expressed for NF and F allografts, respectively. Both molecular profi les revealed 122 common genes encoding mostly for proinfl ammatory cytokines and chemokines involved in myeloid cells, neutrophils, and phagocytes mobilization. Pathway analyses were performed for each molecular profi le. Interestingly, a comparison analysis revealed marked T cell-mediated immune response activation in F allografts post-reperfusion. Deregulated F allograft cellular functions post-reperfusion demonstrated chemotaxis activation and increased proliferation of T lymphocytes, thymocytes, with increased T helper cells differentiation. However, NF allograft post-reperfusion molecular profi les showed T lymphocytes proliferation inhibition. Post-reperfusion F allograft molecular profi les also associated with activation of connective tissue cells and keratinocytes proliferation and increased fi broblasts mobilization may be in response to increased tissue damage. Conversely, the connective tissue cells proliferative activity was decreased in NF graft livers. Conclusions:Increased allograft steatosis may trigger exacerbation of IRI through a pro-infl ammatory processes by induction of a T cell-mediated immune response. Abstract# D2354 Urinary Cell mRNA Profi les Demonstrate Persistent BKV Replication and a Profibrotic Milieu Despite Clearance of BK Viremia/ Nephropathy. C. Snopkowski, J. Lee, T. Muthukumar, R. Ding, C. Li, J. Lee, S. Kapur, S. Seshan, M. Suthanthiran, D. Dadhania. Transplantation Medicine, Weill Cornell Medical Center, NY, NY. Background: BKV nephropathy is not only associated with increased risk of proximate graft loss but also a signifi cantly shortened graft survival compared to those who did not develop BKVN (KI 2005, vol 68 p1834). The basis for this progressive decline despite clearance of BKV viremia/nephropathy is not clear. We have previously reported that heightened expression of mRNAs associated with fi brosis at the time of BKVN predicts subsequent renal allograft loss. Herein we explored the changes in urinary cell mRNA profi les following clearance of BKVN and BK viremia. Methods: We prospectively studied 13 patients who developed BKVN and followed them until they had clearance of viremia and histology. Histological clearance was demonstrated by the absence of SV40 immunostaining of allograft biopsies. Urine specimens were collected at the time of BKVN diagnosis and at the time of BKVN clearance. Urine mRNA profi les at the time of BKVN diagnosis and following BKVN clearance were measured using real-time quantitative PCR. Results: BKVN clearance occurred at mean(SD) of 6±0.9 months. BKV copies in the blood decreased from 6.8x105±10x105 copies to 1x103 ± 9x102. Mean serum creatinine (mg/dL) levels at the time of BKVN diagnosis were not different from the levels obtained at the time of BKVN clearance (2.1±0.8 vs. 2.1±0.7). D2354 Urinary Cell mRNA Profi les Demonstrate Persistent BKV Replication and a Profibrotic Milieu Despite Clearance of BK Viremia/ Nephropathy. C. Snopkowski, J. Lee, T. Muthukumar, R. Ding, C. Li, J. Lee, S. Kapur, S. Seshan, M. Suthanthiran, D. Dadhania. Transplantation Medicine, Weill Cornell Medical Center, NY, NY. Background: BKV nephropathy is not only associated with increased risk of proximate graft loss but also a signifi cantly shortened graft survival compared to those who did not develop BKVN (KI 2005, vol 68 p1834). The basis for this progressive decline despite clearance of BKV viremia/nephropathy is not clear. We have previously reported that heightened expression of mRNAs associated with fi brosis at the time of BKVN predicts subsequent renal allograft loss. Herein we explored the changes in urinary cell mRNA profi les following clearance of BKVN and BK viremia. Methods: We prospectively studied 13 patients who developed BKVN and followed them until they had clearance of viremia and histology. Histological clearance was demonstrated by the absence of SV40 immunostaining of allograft biopsies. Urine specimens were collected at the time of BKVN diagnosis and at the time of BKVN clearance. Urine mRNA profi les at the time of BKVN diagnosis and following BKVN clearance were measured using real-time quantitative PCR. Results: BKVN clearance occurred at mean(SD) of 6±0.9 months. BKV copies in the blood decreased from 6.8x105±10x105 copies to 1x103 ± 9x102. Mean serum creatinine (mg/dL) levels at the time of BKVN diagnosis were not different from the levels obtained at the time of BKVN clearance (2.1±0.8 vs. 2.1±0.7). Conclusion: Lower level of BKV replication in the urine persists following histological clearance of BKVN. Despite signifi cant decrease in BKV replication, levels of TGFb1, PAI-1, vimentin, TIMP-1 and fi bronectin mRNA increased signifi cantly following clearance of BKVN. Our data generates the hypothesis that persistence of a profi brotic milieu following resolution of BKVN contributes to progressive decline in renal function. Abstract# D2355 Molecular Marker Strategies Supporting The Novartis US92 StudyA Metabolite Biomarker Discovery Study in Plasma From Renal Transplant Patients. J. Klepacki,1 J. Klawitter,1 J. Klawitter,1 G. Ingle,2 D. Patel,2 U. Christians.1 1iC42 Clinical Research and Development, University of Colorado, Aurora, CO; 2Novartis Pharmaceuticals, East Hanover, NJ. Purpose. Vascular endothelial dysfunction is a major risk factor after renal transplantation. We assessed endothelial function in the plasma of a subset of renal transplant patients enrolled in the Novarti

Liver Transplantation for Nonalcoholic Steatohepatitis. Organ Waste or Successful Treatment of the New Epidemic? A Single Center Experience.: Abstract# 1500

1500 Liver Transplantation for Nonalcoholic Steatohepatitis. Organ Waste or Successful Treatment of the New Epidemic? A Single Center Experience. B. Kern,1 R. Sucher,1 J. Fritz,2 B. Feurstein,1 C. Fabritius,1 C. Boesmueller,1 R. Oellinger,1 J. Pratschke,1 S. Schneeberger.1 1Visceral-, Transplant-, Thoracic Surgery, Medical University, Innsbruck, Austria; 2Statistics and Informatics, Medical University, Innsbruck, Austria. Background: Nonalcoholic steatohepatitis (NASH) may become the leading indication for orthotopic liver transplantation (OLT). The aim of this study was to describe the clinical outcome of NASH patients compared to patients with other common indications for OLT. Methods: This is a retrospective analysis of 515 patients who underwent deceased-donor OLT between 2002 and 2012. Results: The incidence of NASH was 14,4% (74/515). Study population included 116 (22,5%) women and 399 (77,5%) men. NASH cohort compared to the nonNASH cohort showed no signifi cance on patient survival (p=0,109). Patients with a malignancy displayed a shorter overall survival (p=0,009). Average MELD score was 21,0, average BMI 25,3. Patients with a lower MELD at time of transplantation were associated with a signifi cantly better overall survival (p=0,043). BMI greater than 30kg/m2 had no impact on survival rates. Diabetes was diagnosed in 124 patients, compared to the patients with no evidence of diabetes overall survival was signifi cantly shorter (p=0,006). NASH patients with diabetes had similar overall survival and complications when compared to NASH patients without diabetes (p=0,242; p=0.112 respectively). Donor data such as BMI over 30 kg/m2, sever steatosis, age over 55 years and cold ischemic time over 14 hours had no impact on patient survival. Infection rate was signifi cantly higher in the NASH cohort (p=0,04). NASH patients with HCC were associated with a signifi cantly shorter overall survival compared to HCC patients with no evidence of NASH (p=0,02; see fi gure 1). Conclusion: Metabolic comorbidities such as diabetes signifi cantly impact on patient survival. NASH predicts an inferior outcome in patients with HCC compared to other liver diseases. Accurate preoperative treatment of metabolic disorders and intensifi ed infection prophylaxis should be considered in patients with NASH undergoing OLT. Criteria for OLT in patients with HCC and NASH should be revisited. Abstract# 1501 The Negative Predictive Value of Preoperative Stress Testing for NonFatal Cardiac Events After Orthotopic Liver Transplantation in the Modern Era. F. Niyazi, R. Patel, Y. Nasr, J. Perez, S. Mawri, M. Njeim, A. Yoshida, D. Moonka, S. Jafri, J. Schairer, K. Abdul-Nour. Internal Medicine, Henry Ford Health System, Detroit, MI. Aim: Studies evaluating functional stress testing as the means of preoperative cardiac clearance in patients awaiting orthotopic liver transplantation (OLT) have shown signifi cant variability in the prediction of major adverse cardiovascular events (MACE). Given increased co-morbid cardiac risk factors in our current era of transplant we evaluated the negative predictive value (NPV) of stress echocardiography (SE) for post-OLT survival and MACE in the modern era. Methods: We performed a retrospective review on 384 consecutive patients who received an OLT between 2007 and 2011. Data was collected on demographic characteristics, pertinent pre-operative laboratory results, echocardiographic studies and post-operative events. Mortality was confi rmed by public documents available via the Social Security Death Index. MACE was defi ned as a combined outcome of cardiac death, new onset congestive heart failure, nonfatal myocardial infarction, stroke or need for coronary revascularization. The NPV of SE for cardiac mortality and MACE were calculated using the subgroup of patients that achieved an adequate level of cardiac stress while undergoing testing. A SE was considered abnormal if there were wall motion abnormalities or drop in ejection fraction greater than 5%. Results: 384 consecutive patients received an OLT between January 2007 and November 2011. Over a 3 year post-operative follow-up period there were 82 total deaths, 17 cardiac deaths, 12 nonfatal myocardial infarctions, 15 new onset heart failure and 5 coronary revascularizations. 276 (72%) patients were evaluated by SE. Within the stress testing cohort of patients, 189 (68%) reached target heart rate for optimal stress testing. Hypertension (34%) and diabetes mellitus (25%) were prevalent in this group. A normal SE had a 98.4% NPV for cardiac mortality at 3 years of postoperative follow-up and a 92.51% NPV for MACE. Survival rate at 3 years postoperatively was 78.6%. Conclusion: The overall survival rate of liver transplant patients in our highly morbid recent liver transplant population is comparable to the national survival rates. The unadjusted NPV of SE was very strong for prediction of cardiac events. Well-thought evidence based strategies that incorporate other clinical predictors in the modern transplant population are still needed. Abstract# 1502 Post Liver Transplant Biliary Complications in Deceased Donor Liver Grafts: Analysis of Preservation Solution. R. Mangus, R. Chihara, T. Borup, A. Marshall, J. Fridell, C. Kubal, A. Tector. Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. 1502 Post Liver Transplant Biliary Complications in Deceased Donor Liver Grafts: Analysis of Preservation Solution. R. Mangus, R. Chihara, T. Borup, A. Marshall, J. Fridell, C. Kubal, A. Tector. Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. Objective: Histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions are the two solutions used primarily in abdominal organ procurement in the U.S. Bile duct complications are common in the post liver transplant (LT) period and may be related to the arterial blood supply for the biliary system. Because HTK is much less viscous than UW, it has been hypothesized that this solution provides a better fl ush of the biliary microcirculation. Improved blood clearance from these small vessels may lower the risk for thrombus formation and improve post-transplant biliary perfusion leading to a lower risk of biliary complications. This study reviews the biliary complications in a large number of deceased donor LTs and compares outcomes for HTK and UW. Methods: Data were extracted using a retrospective review of all liver transplants between 2001 and 2013, with an extensive review of all endoscopic and percutaneous biliary imaging and post-transplant liver function enzymes. Our center uses doppler ultrasound and biliary imaging as fi rst evaluation for elevated liver enzymes, prior to biopsy, resulting in a large number of imaging studies. Primary outcomes included need for imaging, any leak, and stricture formation.