LATE GRAFT LOSS AFTER KIDNEY TRANSPLANTATION: IS “DEATH WITH FUNCTION” REALLY DEATH WITH A FUNCTIONING ALLOGRAFT? BACKGROUND: About half of late kidney allograft losses are attributed to death with function (DWF), a poorly-characterized outcome. An ongoing question is whether “DWF” is a consequence of chronic allograft dysfunction. Using the prospective DeKAF database, we sought to better define the impact, phenotype, and clinical course of DWF in the current era. METHODS: 3587 kidney recipients with functional grafts at 90 days posttransplant were followed prospectively for a median of 5.4 years. RESULTS: Characteristics at transplantation in those with DWF (N=350, 9.8%) differed from those who otherwise lost their grafts (DC-GF, N=295, 8.2%) or maintained function (MF, N=2942, 82.0%); DWF patients were older, sicker, had been on dialysis longer, with more preexisting cardiovascular disease. While DC-GF patients experienced more early rejection, more acute rejection after 90 days, and a clinically-significant decrease in kidney function prior to graft failure. In contrast, the clinical course after transplantation in DWF patients did not differ prior to death from those who maintained function throughout. CONCLUSIONS: DWF and DC-GF in kidney transplant recipients represent differing clinical phenotypes occurring in distinct patient populations. Reducing the impact of DWF requires better definition of causes and clinical course and then trials of therapies to improve outcomes. Composite endpoints in clinical trials that group DWF and DC-GF together may obscure important clinical findings. Clinical Trial Notation: A Study of Factors That Affect Long-Term Kidney Transplant Function (DeKAF) NCT00270712 Disclosure:“The authors declare no conflicts of interest.” Funding: This work was supported between 2005 and 2012 via a grant from the National Institutes of Health (5U01A1058013), and since 2013 by unrestricted grants from Astellas, Bristol-Myers Squibb, Novartis, Pfizer, and Sanofi-Aventis. Corresponding author: Robert S. Gaston, M.D. Division of Nephrology, University of Alabama at Birmingham 1900 University Boulevard, 625 THT, Birmingham, Alabama 35294, Phone: 205-934-7220, Email: Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Urine injury biomarkers are not associated with kidney transplant failure Background: Kidneys transplanted from deceased-donors with serum creatinine-defined acute kidney injury (AKI) have similar allograft survival as non-AKI kidneys but are discarded at a higher rate. Urine injury biomarkers are sensitive markers of structural kidney damage and may more accurately predict graft outcomes. Materials and Methods: In the 2010-2013 multicenter Deceased Donor Study of 2430 kidney transplant recipients from 1298 donors, we assessed the association of donor urine injury biomarkers microalbumin, NGAL, KIM-1, IL-18, and L-FABP with graft failure (GF) and death-censored GF (dcGF) using Cox proportional hazard models (median follow-up 4 years). We examined if serum creatinine-defined donor AKI modified this association to assess the relationship between subclinical donor AKI (elevated biomarkers without creatinine-defined AKI) and graft failure. Through chart review of a sub-cohort (1137 recipients), we determined associations between donor injury biomarkers and a 3-year composite outcome of GF, mortality, or eGFR <=20mL/min/1.73m2. Results: Risk of GF, dcGF, and 3-year composite outcome did not vary with donor injury biomarker concentrations after adjusting for donor, transplant, and recipient characteristics (adjusted HR ranged from 0.96 to 1.01 per log-2 increase in biomarker). Subclinical injury in transplanted kidneys without AKI was not associated with GF. Conclusions: AKI measured using injury biomarkers was not associated with posttransplant graft outcomes (at median 4 years posttransplant). When assessing posttransplant graft viability, clinicians can prioritize other donor and recipient factors over donor kidney injury, measured by either serum creatinine or urine injury biomarkers. Corresponding author: Chirag R. Parikh, MD, PhD, Director, Division of Nephrology, Ronald Peterson Professor of Medicine, 1830 E. Monument St., 4th Floor, Suite 416, Baltimore, MD 21287, Phone: 410-955-5268 | Fax: 410-367-2258, Email: Chirag.Parikh@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

A Multicenter Japanese Survey Assessing the Long-Term Outcomes of Liver Retransplantation using Living Donor Grafts Background: Liver transplantation is the most suitable treatment option available for end-stage liver disease. However, some patients require retransplantation, despite medical advances that have led to improved survival. We aimed to compile a definitive, nationwide resource of liver retransplantation data in Japan, seeking to identify the predictors of patient survival post transplantation. Methods: Questionnaires were sent to 32 institutions that had conducted 281 retransplantations before 2015. Results: Among the 265 patients included in this study (142 pediatric cases), the average age at primary transplantation was 23 years, and retransplantation was performed after an average of 1,468 days. The main indication for retransplantation was graft rejection (95 patients). Living-donor liver transplantation accounted for 94.7% of primary transplantations and 73.2% of retransplantations. Patient survival at 1, 3, or 5 years did not differ by type of transplantation, but was better for pediatric (70.8%, 68.3%, 60.1%, respectively) than for adult (57.2%, 50.4%, 45.2%, respectively) recipients (p = 0.0003). Small-for-size syndrome, retransplantation within 365 days, and inpatient status at retransplantation were significant predictors of poor survival in pediatric cases. Retransplantation within 365 days and conditions warranting re- transplantation were significant predictors of poor survival in adult patients. Conclusions: In Japan, where more than 70% of retransplantations are performed using living donors, the indications and timing are different from those in previous reports from other countries, while maintaining comparable survival rates. Considering technical challenges, graft failure within 365 days should be thoroughly restricted to justify the use of living donor. Disclosure: The authors declare no conflicts of interest. Funding: The authors disclose no funding received for this work. Corresponding author: Kaori Kuramitsu, MD, PhD, Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe City, Hyogo, Japan. Phone: 81-78-382-6302, Fax: 81-78-382-6307,. E-mail: kkuramit@med.kobe-u.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Re: Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers No abstract available

Racial and Ethnic Disparities in Kidney Transplant Access within a Theoretical Context of Medical Eligibility Background: Non-Hispanic black (NHB) and Hispanic patients have lower access to kidney transplantation compared to non-Hispanic whites (NHWs). We examined whether differences in the prevalence of co-morbidities that affect eligibility for transplant contribute to disparities in receipt of transplantation. Methods: We performed a retrospective study of 986,019 adults who started dialysis between 2005-2014 according to the US Renal Data System. We compared prevalence of co-morbidities that could influence transplant eligibility by race/ethnicity. We examined time to first transplant by race/ethnicity in this overall cohort and in a “very healthy” sub-cohort without conditions that could be contraindications to transplantation. Results: During 2.3 years of mean follow-up, 64,892 transplants occurred. NHBs and Hispanics had a lower prevalence of medical barriers to transplantation at the time of dialysis initiation than NHWs, including age >70 years (26% in NHB vs. 47% in NHW) and malignancy (4% in Hispanics vs. 10% in NHWs). Access to transplant was 65% lower (95% CI 0.33-0.37) in NHBs and 43% lower (95% CI 0.54-0.62) in Hispanics (versus NHWs) in the first year after ESRD, but by Year 4, access to transplantation was not statistically significantly different between Hispanics or NHBs (versus NHWs). In our very healthy cohort, racial and ethnic disparities in access to transplantation persisted up to Year 5 in NHBs and Year 4 in Hispanics after ESRD onset. Conclusions: Differences in medical eligibility do not appear to explain racial/ethnic disparities in receipt of kidney transplantation and may mask the actual magnitude of the inequities that are present. * These authors contributed equally to this manuscript Disclosures: none. Funding: Dr. Ku was funded by National Institutes of Health K23 HL131023 and Dr. Johansen by K24 DK85153. Dr. Ku and Dr. Johansen were also funded by R01 DK115629. Corresponding Author: Elaine Ku, MD, Address for reprint requests: Division of Nephrology, University of California, San Francisco, 521 Parnassus Avenue, C443, Box 0532, San Francisco, CA 94143-0532, USA.Telephone: 415-476-2423, Fax:415-476-9976, E-mail: elaine.ku@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Anti-Thymocyte Globulin versus Interleukin-2 Receptor Antagonist in Kidney Transplant Recipients with Hepatitis C Virus Background: Hepatitis C virus-positive (HCV+) kidney transplant (KT) recipients are at increased risks of rejection and graft failure. The optimal induction agent for this population remains controversial, particularly regarding concerns that anti-thymocyte globulin (ATG) might increase HCV-related complications. Methods: Using SRTR and Medicare claims data, we studied 6780 HCV+ and 139,681 HCV- KT recipients in 1999-2016 who received ATG or interleukin-2 receptor antagonist (IL2RA) for induction. We first examined the association of recipient HCV status with receiving ATG (vs. IL2RA) using multilevel logistic regression. Then, we studied the association of ATG (vs. IL2RA) with KT outcomes (rejection, graft failure, and death) and hepatic complications (liver transplant registration and cirrhosis) among HCV+ recipients using logistic and Cox regression. Results: HCV+ recipients were less likely to receive ATG than HCV- recipients (living donor, aOR=0.640.770.91; deceased donor, aOR=0.710.810.92). In contrast, HCV+ recipients who received ATG were at lower risk of acute rejection compared to those who received IL2RA (1-year crude incidence=11.6% vs. 12.6%; aOR=0.680.820.99). There was no significant difference in the risks of graft failure (aHR=0.861.001.17), death (aHR=0.850.951.07), liver transplant registration (aHR=0.580.971.61), and cirrhosis (aHR=0.730.921.16). Conclusions: Our findings suggest that ATG, as compared to IL2RA, may lower the risk of acute rejection without increasing hepatic complications in HCV+ KT recipients. Given the higher rates of acute rejection in this population, ATG appears to be safe and reasonable for HCV+ recipients. DISCLOSURE:JMG receives speaking honoraria from Novartis. DLS receives speaking honoraria from Sanofi and Novartis. All other authors have no conflicts of interest. FUNDING:This work was supported by ASN Foundation for Kidney Research (Bae) and the National Institute of Health, U01AI134591 (Durand), K23CA177321-01A1 (Durand), K23DK115908 (Garonzik-Wang), F30DK095545 (Kucirka), R01DK120518 (McAdams-DeMarco), and K24DK101828 (Segev). * These authors contributed equally to this study. Contact Information: Dorry Segev, MD, PhD, Professor of Surgery and Epidemiology , Associate Vice Chair, Department of Surgery, Director, Epidemiology Research Group in Organ Transplantation, Johns Hopkins University, 2000 E Monument St, Baltimore, MD 21205, 410-502-6115 (tel); 410-614-2079 (fax); dorry@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

More than 25 years of pancreas graft survival after simultaneous pancreas and kidney transplantation: experience from the world’s largest series of long-term survivors Background: The first simultaneous pancreas and kidney (SPK) transplant was performed in 1966. Early procedures were associated with significant morbidity and mortality and were performed in very low numbers in select patients. Methods: This study includes all recipients of an SPK at the University of Wisconsin-Madison between 1986 and 1993 who were actively followed and had a functional pancreas allograft for more than 25 years as of 10/31/2018. Results: A total of 291 SPK were performed during the study period; of these, 39 patients still had a functional graft at last follow up and nine (18.8%) pancreas grafts were lost due to patient death or graft failure after more than 25 years. At last follow up, all 39 patients with functional pancreas graft had at least one co-morbidity, such as hypertension, hyperlipidemia, or coronary artery disease. Twenty-seven required enteric conversion; 11 patients experienced renal allograft failure (10 underwent a repeat kidney transplant); and 6 required amputation of part of the lower extremity. In the Cox regression analysis, bladder drained pancreas was associated with lower probability of prolonged pancreas graft survival (HR: 0.52; CI: 0.32 to 0.85; p=0.01). Conclusion: With careful and detailed follow-up and attention to complications, some recipients of pancreas grafts have outstanding outcomes. As the number of pancreas recipients with prolonged graft survival may be rising, healthcare providers should be aware of the management of complications associated with this unique group of patients. Acknowledgments: The authors are grateful to Ms. Dana Clark, MA for her editorial assistance, and to Dr. Brad Astor for statistical analysis. Disclosure: The authors declare no conflicts of interest The authors disclose no financial disclosure The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Corresponding author’s address, phone, and email: Sandesh Parajuli, MBBS, UW Medical Foundation Centennial Building 4175, 1685 Highland Avenue, Madison, WI 53705, Tel: 608-265-0152, Email: sparajuli@medicine.wisc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The tRNA(Ile) variant m.4309G>A may not cause Kearns Sayre syndrome No abstract available

EXPERIENCE WITH EARLY SORAFENIB TREATMENT WITH mTOR INHIBITORS IN HEPATOCELLULAR CARCINOMA RECURRING AFTER LIVER TRANSPLANTATION Background: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. Methods: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (01/2008-06/2018). Baseline and on-treatment data were collected. Results: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor (mTORi), 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% Confidence Interval [CI] 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95%CI 8-27); 5-year OS was 18% (95%CI 4-32%). Baseline predictors of OS were SOR+mTORi (HR 0.4, 95%CI 0.2-0.9, p=0.04), previous curative treatments (HR 0.3, 95%CI 0.2-0.7, p=0.003) and alpha-fetoprotein>100ng/ml (HR 2.5, 95%CI 1.1-5.0, p=0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR 0.4, 95%CI 0.2-1.0, p=0.04). Conclusions: Early and combined treatment with sorafenib and mTORi resulted in a favourable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS. Disclosures: Invernizzi F, speaker bureau for Abbvie; Iavarone M, speaker bureau for Bayer, Gilead Science, Janssen, BTG, Abbvie, MSD, consultant for BTG and Bayer; Donato MF, speaker bureau for BMS, Abbvie, MSD; Lampertico P, advisor and speaker bureau for Gilead, Roche, BMS, GSK, MSD, Arrowhead, Alnylam. The other authors have nothing to disclose. Funding: no financial support to be reported. Corresponding author: Massimo Iavarone, MD PhD, 1CRC “A. M. and A. Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F. Sforza 28, 20122 Milan, Italy. Tel 39-0255035432, Fax 39-0250320410, E-mail massimo.iavarone@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clinical relevance of arteriolar C4d staining in patients with chronic-active antibody-mediated rejection: A pilot study Introduction: C4d staining in peritubular capillaries (PTCs) is a well-established feature of antibody-mediated rejection (AMR). The relevance of C4d staining outside PTCs is not well understood. We investigated the significance of arteriolar C4d staining in c-aAMR. Methods: All for-cause renal allograft biopsies performed in 2007-2014 at the Erasmus MC and meeting the criteria for suspicious/diagnostic c-aAMR using the Banff Classification 2015, were included. For comparison, renal allograft biopsies from a matched control group and native renal biopsies were analyzed. Arteriolar C4d staining was semi-quantitatively scored as negative (0), small deposits in 1 arteriole (1+), small/large deposits in >1 arterioles (2+) or at least extensive deposits in most arterioles (3+). Results: Thirty-four of 40 (85%) patients with c-aAMR showed arteriolar C4d staining. A significant difference in arteriolar C4d score was observed between cases and matched controls (p=0.01) and a trend toward significance difference between cases and native renal biopsies (p=0.05). In the cases, arteriolar C4d staining was significantly associated with severity of arteriolar hyalinosis (ah) (p=0.004) and ≥2 arteriolar C4d staining was independently associated with better graft outcome in a multivariate Cox regression analysis (hazard ratio 0.260, 95%-Cl: 0.104-0.650, p=0.004). Conclusion: This pilot study shows that arteriolar C4d staining is more common in biopsies with c-aAMR compared to those without and that it is associated with ah. ≥2 arteriolar C4d staining is associated with superior graft outcome. However, larger studies are needed to examine these findings in more detail to asses if arteriolar C4d staining is truly related to antibody-mediated injury. Conflicts of interest: D.A. Hesselink has received lecture and consulting fees from Astellas Pharma and Chiesi Farmaceutici S.p.A., as well as grant support from Astellas Pharma, Bristol Myers-Squibb and Chiesi Farmaceutici S.p.A. (paid to the Erasmus MC). M.C. Clahsen-van Groningen received grant support from from Astellas Pharma (paid to the Erasmus MC). The other authors declare no conflicts of interest. Corresponding author: Malou L. H. Snijders, M.D., Dept. of Pathology, Room Be-230a, Erasmus MC, P.O. Box 2040, 3000 CA. Rotterdam, The Netherlands. Email: m.snijders@erasmusmc.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.