Antithymocyte Globulin Antibody Titer Congruent With Kidney Transplantation: Analysis of Incidence, Outcomes, Cost, and Alternative Targets Background. Rabbit antithymocyte globulin (rATG) use for immunosuppression induction is widespread but is contraindicated by the presence of anti-rATG antibodies. This study reports the incidence of positive anti-rATG antibody titers in patients before and after renal transplant and evaluates associated outcomes and costs. In addition, it will correlate CD40L and interleukin (IL)-21 with anti-rATG antibody titers. Methods. Clinical and billing records from the Indiana University Transplant Laboratory were reviewed for positive versus negative anti-rATG antibody titers, graft survival, and 7-day readmission costs between 2004 and 2018. Serum from patients with positive and negative rATG antibody titers were quantitated for CD40L and IL-21 by enzyme-linked immunosorbent assay. Results. On average, between 2004 and May 2018, 163 kidney transplants per year were performed. Anti-rATG antibody titers were ordered for 17 patients/year, of which 18.2% were positive at 1:100 titer either pre- or post-transplant. Time to graft loss correlated with a positive rATG titer at time of readmission. Moreover, second kidney transplant increased the anti-rATG positive rate. A weak correlation was observed between anti-rATG titer and recipient age. Seven-day readmission treatment costs were significantly lower in patients with positive anti-rATG titer. IL-21 and CD40L were significantly greater in patients with positive anti-rATG titers after transplant when compared with negative anti rATG patients. Conclusions. Positive anti-rATG antibody titer is associated with a significant negative impact on outcomes. Monitoring of anti-rATG antibody titer is recommended to optimize treatment options in patients, especially in the setting of second transplants. Elucidation of the mechanisms associated with positive anti-rATG antibody is required. IL-21 and CD40L are potential targets for future study. Published online 27 September, 2019. Received 4 June 2019. Revision received 10 July 2019. Accepted 19 July 2019 The authors declare no funding. S.L. participated in the performance of the research and writing of the article. N.J.S. participated in research design, writing of the article, performance of the research, and participated in data analysis. M.A.M. participated in research design and writing of the article. H.E. participated in data analysis. E.D. participated in the performance of the research and writing of the article. A.S. participated in the writing of the article. W.C.G., Director of kidney transplant program at IUH, performed majority of kidney transplants and participated in the writing of the article. M.A.M. was supported by Indiana University Health program development. The other authors declare no conflicts of interest. Correspondence: Nicholas J. Skill, PhD, Division of Transplant, Department of Surgery, Indiana University School of Medicine, 635 Barnhill Dr MS2016, Indianapolis, IN 46202. (nskill@iupui.edu). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.

Bortezomib: A New Promising Therapy for Early Antibody-Mediated Rejection After Liver Transplantation? No abstract available

Outcomes of Liver Transplantation in Patients on Renal Replacement Therapy: Considerations for Simultaneous Liver Kidney Transplantation Versus Safety Net Background. As the liver transplant (LT) waiting list continues to outpace organ availability, many patients require renal replacement therapy (RRT) before LT. It is unclear which patients will benefit from simultaneous liver kidney (SLK) transplant as opposed to awaiting a Safety Net kidney transplant (KT) post-LT. Methods. In this study, a retrospective analysis of the United Network for Organ Sharing dataset was performed to identify risk factors associated with poor outcome for patients on RRT before LT who were listed for SLK and received either SLK vs LT alone (LTA). Results. Between January 2003 and December 2016, 8971 adult LT recipients were on RRT at the time of LT. 5359 were listed for and received LTA (Group 1). Of 3612 patients listed for SLK, 3414 (38.1%) received SLK (Group 2) and 198 (2.2%) received LTA (Group 3). Overall, Group 3 had lower graft and patient survival post-LT when compared with Groups 1 and 2 (P < 0.001). Serum creatinine at 1 year post-LT and cumulative incidence for KT at 3 years post-LT were higher for Group 3 (P < 0.001). On multivariate analysis, pre-LT diabetes (P = 0.002), Model of End-Stage Liver Disease score (P = 0.01), and donor kidney donor profile index (P = 0.025) were significant in Group 2. Recipient age >60 (P < 0.001) and RRT pre-LT (>90 days; P = 0.001) were associated with lower patient survival in Group 3. Conclusions. Among LT recipients on RRT before LT who were listed for SLK, RRT >90 days, and age >60 were associated with poor outcome following LTA. This suggests that programs should carefully weigh the decision to proceed with LTA vs waiting for SLK in this patient population. Future access to Safety Net KT will be an important consideration for these patients moving forward. Published online 19 September, 2019. Received 29 July 2019. Accepted 4 August 2019. A.P., A.S., N.K., and L.S. participated in the conception or design of the work. M.L., N.K., and L.S. participated in data acquisition and statistical analysis. J.E., N.K., L.S., A.P., B.N., M.L., V.T., and M.N. participated in analysis and interpretation of data. A.S., A.P., M.L., L.S., N.K., J.E., B.N., and V.T. participated in drafted the article. J.E., M.N., Y.G., and L.S. participated in critically revised the article. A.P., A.S., N.K., J.E., V.T., M.N., Y.G., L.S., M.L., and B.N. finally approved the version to be published. The authors declare no funding or conflicts of interest. Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantationdirect.com). Correspondence: Juliet Emamaullee, MD, PhD, FRCSC, Keck School of Medicine of the University of Southern California, 1510 San Pablo St, Suite 412, Los Angeles, CA 90033. (Juliet.emamaullee@med.usc.edu). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.

Blood Pressure and Living Kidney Donors: A Clinical Perspective Elevated blood pressure (BP), or “hypertension,” has been one of the main exclusion criteria for living kidney donation, as it is a risk factor for renal and cardiovascular disease. The effect of elevated BP in living kidney donors is not well studied or understood. The most current living kidney donation guidelines state that donors with a BP >140/90 mm Hg with 1–2 antihypertensive medications or evidence of end-organ damage should be excluded from living kidney donation. Yet, the definitions of “hypertension” have changed with the release of the American Heart Association (AHA)/American College of Cardiology (ACC) clinical practice guidelines suggesting that 120–129 mm Hg is elevated BP and Stage 1 hypertension is 130 mm Hg. However, the kidney function (in terms of estimated GFR) of “hypertensive” living kidney donors does not fare significantly worse postdonation compared with that of “normotensive” donors. In addition, even though living kidney donation itself is not considered to be a risk factor for developing hypertension, there exist certain risk factors (African American or Hispanic descent, obesity, age) that may increase the risk of living kidney donors developing elevated BP postdonation. The choice of BP targets and medications needs to be carefully individualized. In general, a BP <130/80 mm Hg is needed, along with lifestyle modifications. Published online 19 September, 2019. Received 17 July 2019. Revision received 5 August 2019. Accepted 9 August 2019. All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in Transplantation. A.R. and M.R.W. performed the conception and design of study, acquisition of data, analysis and/or interpretation of data, and drafting the manusript. A.R., S.Y., F.A., L.S., K.S., M.K., N.N., J.S.B., and M.R.W revised the manuscript critically for important intellectual content and approved of the version of the manuscript to be published. The authors declare no funding or conflicts of interest. Correspondence: Matthew R. Weir, MD, Division of Nephrology, University of Maryland School of Medicine, 22 S. Greene St., Room N3W143, Baltimore, MD 21201. (mweir@som.umaryland.edu). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.

The Evolution of Monoclonal Gammopathy of Undetermined Significance in Kidney Transplant Recipients Background. It is unclear if immunosuppression increases the likelihood of malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and whether adverse renal outcomes in kidney transplant recipients with MGUS are more frequent. Methods. We performed a retrospective cohort study of kidney transplant recipients at the Centre Hospitalier de l’Université de Montréal between 2000 and 2016. Results. Among 755 study participants, 13 (1.7%) were found to have MGUS before transplant. Two evolved to smoldering multiple myeloma and 2 presented paraprotein-induced allograft injury from light chain deposition disease. Forty-six patients developed posttransplant MGUS (2.5% 5-y cumulative incidence) of which 1 progressed to multiple myeloma and 1 experienced kidney allograft loss from light chain deposition disease. None of the patients with a malignant transformation or paraprotein-induced renal disease after transplantation had had a systematic workup before transplantation to exclude hematologic malignancies and paraprotein-related kidney injury. Nine posttransplant MGUS (21%) were transient. Multivariable analysis revealed that age at transplant (hazard ratio 1.05 per 1-y increase, 95% confidence intervals, 1.02-1.08) and prior cytomegalovirus infection (hazard ratio 2.22, 95% confidence intervals, 1.07-4.58) were associated with the development of MGUS after transplantation. Of 7 posttransplant lymphoproliferative disorders, none were preceded by MGUS. Conclusions. Our results suggest that the identification of MGUS in a transplant candidate should lead to further investigations to exclude a plasma cell neoplasm and monoclonal gammopathy of renal significance before transplantation. MGUS arising after transplantation appears to carry a favorable evolution. Published online 19 September, 2019. Received 17 July 2019. Accepted 4 August 2019. M-F.G. collected the data and participated in research design, in the writing of the paper, in the performance of the research and in data analysis. H.C., J-P.E., and B.L. participated in research design, in the writing of the paper, in the performance of the research, and in data analysis. M.L. participated in pathologic review of cases and and provided histology figures for the manuscript. The authors declare no funding or conflicts of interest. Correspondence: Marie-France Gagnon, MD, Division of Hematology-Oncology, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, 1051 Sanguinet StStreet, Montreal, Quebec, Canada, H2X 3E4. (marie-france.gagnon@umontreal.ca). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.

Bortezomib Against Refractory Antibody-Mediated Rejection After ABO-Incompatible Living-Donor Liver Transplantation: Dramatic Effect in Acute-Phase? Antibody-mediated rejection (AMR) is a refractory rejection after donor-specific antibody-positive or ABO blood-type incompatible (ABOi) organ transplantation. Rituximab dramatically improved the outcome of ABOi living-donor liver transplantation (LDLT); however, an effective treatment for posttransplant AMR, once occurred, is yet to be established. A 44-year-old woman with biliary cirrhosis underwent ABOi-LDLT from her sister (AB-to-A). Pretransplant rituximab diminished CD19/20-positive B lymphocytes to 0.6%/0.0%; however, AMR occurred on posttransplant day-6 with marked increase in both CD19/20 cells (17.1%/5.8%) and anti-B IgM/G-titers (1024/512). Despite rituximab readministration, steroid-pulse, intravenous immunoglobulin, and plasmapheresis, AMR was uncontrollable, with further increasing CD19/20 cells (23.0%/0.0%) and antibody-titers (2048/512). Bortezomib (1.0 mg/m2) was thus administered on posttransplant day-9, immediately ameliorating CD19/20 cells (1.3%/0.0%) and antibody-titers (<256/128). Complete remission of refractory AMR was obtained by just 2 doses of bortezomib. Her liver function has been stable thereafter for over 3 years. This case highlighted the efficacy of bortezomib against refractory AMR after ABOi-LDLT. Unlike previous reports, the efficacy was very dramatic, presumably due to the administration timing near the peak of acute-phase AMR. Published online 19 September, 2019. Received 18 March 2019. Revision received 25 April 2019. Accepted 4 May 2019. T.T. and K.H. participated in research design and the writing of the article. K.H., H.O., M.N., K.Y., J.K., A.Y., K.F., T.A., H.T., J.D., S.W., and A.T.-K. contributed in patient management, operation, and reviewing the article. S.U. supervised patient management, operation, and edited the article. A.T.-K. has received honoraria from Janssen Pharmaceutical K.K. This work was supported by Grants-in-Aid for Scientific Research B (No. 17H04271) to K.H. and S.U. from the Japan Society for the Promotion of Science, Tokyo, Japan. Correspondence: Koichiro Hata, MD, PhD, Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kawahara-cho 54, Shogoin, Sakyo-ku, Kyoto city, Kyoto 606–8507, Japan. (khata@kuhp.kyoto-u.ac.jp). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.

Milan-out Criteria and Worse Intention-to-Treat Outcome Postliver Transplantation Background. Milan criteria are widely used for liver transplantation selection in hepatocellular carcinoma but have been recognized to be too restrictive. Milan-out criteria are increasingly being adopted. Our aim was to analyze if liver transplantation waitlisted Milan-out hepatocellular carcinoma patients have different outcome than Milan patients. Methods. Retrospective study including all consecutive patients with hepatocellular carcinoma admitted in the waiting list for liver transplantation between January 2012 and January 2015. We included 177 patients, 146 of which eventually transplanted. Downstaging was achieved in the Milan-out cases (n = 29) before waitlisting. Results. From diagnosis to last follow-up, 29% patients died. Survival at 1 and 5 years from diagnosis was 93% and 75%, respectively in the within Milan group compared with 91% and 61% in the Milan-out group (P = 0.03). Treatment failure occurred in 20% of cases due to tumor progression in the waiting list (44%), death on the waiting list (20%), and hepatocellular carcinoma recurrence postliver transplantation (9%). Milan-out criteria was the only variable predictive of treatment failure remaining in the multivariate analysis with a hazard ratio (HR) of 1.7 (HR, 1.7; 95% confidence interval, 1.34-4.55; P = 0.010) and HR of 1.43 (1.23-6.5) in the hepatocellular carcinoma recurrence. Conclusions. Milan-out criteria are associated with a higher intention-to-treat liver transplantation failure from time of inclusion in the waiting list. However, survival rates are still >50% at 5 years of follow-up. Published online 19 September, 2019. Received 25 June 2019. Revision received 19 July 2019. Accepted 23 July 2019. M.B. and A.R. involved in study concept and design. J.H. and F.S.J. involved in acquisition of data. J.H., T.D.M., and M.B. involved in statistical analysis. J.H., T.D.M., and M.B. involved in analysis and interpretation of data. M.B. and J.H. involved in drafting of the manuscript. T.D.M., G.S., C.V., F.S.J., A.R., and M.B. involved in critical revision of the manuscript. This work was supported by a grant from Ciberehd (Instituto de Salud Carlos III, Madrid, Spain). The authors declare no conflicts of interest. Correspondence: Marina Berenguer, MD, PhD, Hospital Universitario y Politécnico La Fe, Avda. Fernando Abril Martorell 106, 46026 Valencia Spain. (marina.berenguer@uv.es). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Authors. Published by Wolters Kluwer Health, Inc.