A Pilot Study of Postoperative Animal Welfare as a Guidance Tool in the Development of a Kidney Autotransplantation Model With Extended Warm Ischemia Background. This pilot study aimed to maintain acceptable animal welfare in the development of a porcine autotransplantation model with severe and incremental renal ischemic injury, a model for usage in future intervention studies. Secondary aims were to develop and test methods to collect blood and urine without the need to restrain or use sedative and avoid transportation to optimize welfare of the pig. Methods. Kidneys from 7 female pigs were subjected to incremental durations of warm ischemia (WI) 30, 45, or 75 minutes by left renal artery and vein clamping. After static cold storage, contralateral nephrectomy was performed, and the injured graft was autotransplanted and animals observed for 14 days. Animal welfare was assessed and recorded using a structured scoring sheet before and 4 days after the kidney autotransplantation. Furthermore, blood samples were drawn daily the first week and every second day the following week using a semi-central venous catheter. An ostomy bag around the genitals was tested for urine collection. Measured glomerular filtration rate was calculated using renal clearance of chromium-51-labeled ethylenediamine tetraacetic acid on day 14. Results. None of the 7 animals died during the follow-up. The animal welfare was moderately affected when applying 75 minutes of WI (n = 2), and for that reason WI was not further increased. Pigs with lower WI had no observed welfare issues. With 75 minutes of WI peak, plasma creatinine was 1486 and 1317 µmol/L, reached on day 4. Lowest glomerular filtration rate levels were observed in the pigs with 75 minutes of WI. Conclusions. WI up to 75 minutes caused the intended severely impaired renal function without significantly compromising animal welfare. Blood and urine was collected postoperatively without sedation of the pigs or use of a metabolic cage. Published online 8 October, 2019. Received 21 February 2019. Revision received 18 July 2019. Accepted 12 August 2019. S.L., A.K.K., U.M., M.E., B.K.M., B.J., J.H., C.M., R.J.P., and C.C.B. performed the research design. S.L., A.K.K., and U.M. performed the research. S.L., A.K.K., U.M., M.E., B.K.M., B.J., J.H., C.M., R.J.P., and C.C.B. performed the analysis and interpretation of data. S.L. and A.K.K. drafted the manuscript. S.L., A.K.K., U.M., M.E., B.K.M., B.J., J.H., C.M., R.J.P., and C.C.B. performed the critical revision. The authors declare no conflicts of interest. This work was supported by The Lundbeck Foundation, grant number: R198-2015-184. The Lundbeck Foundation had no role in study design; in the collection, analysis or interpretation of data; in the writing of the report; or the decision to submit the article for publication. Correspondence: Stine Lohmann, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Blvd 99, 8200 Aarhus N, Denmark. (stiloh@clin.au.dk). 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.

Assessment of Restored Kidney Transplantation Including the Use of Wider Criteria for Accepting Renal Donors After Cancer Excision Background. The transplantation of kidneys after cancer excision (restored kidney transplantation, RKT) warrants further evaluation as a source of kidneys for transplantation. We determined whether larger cancers can be safely transplanted, the risks of adverse events from RKT, and whether RKT confers a survival advantage for patients waiting for transplantation. Methods. In a retrospective cohort study, 23 dialysis patients awaiting transplant underwent RKT at John Hunter Hospital, Australia between 2008 and 2015. Patients were >60 years old and accepted onto the National Organ Matching Service. This RKT Group was divided into donor renal cancers ≤30 mm and >30–≤50 mm. Adverse event profiles for RKT recipients were compared with 22 standard live donor recipients using logistic regression analyses. Recipient and transplant survivals for RKT were compared with 2050 controls from Australian New Zealand Dialysis Transplant Registry using Cox regression models. To increase statistical power for survival analyses, data from 25 RKT recipients from Princess Alexandra Hospital, Brisbane were added, thus creating 48 RKT recipients. Results. There were no significant differences in mortality, transplant failure nor AEs between the 2 cancer Groups. RKT increased the risks of Adverse event profiles (odds ratio: 6.48 [2.92–15.44]; P < 0.001). RKT reduced mortality risk by 30% (hazard ratio [HR]: 0.70 [0.36–1.07]; P = 0.299) compared with those continuing on the transplant list who may or may not be transplanted. RKT significantly reduced mortality risk for those remaining on dialysis (HR: 2.86 [1.43–5.72]; P = 0.003). Transplant survival for RKT was reduced compared with control deceased donor (HR: 0.42 [0.21–0.83]; P = 0.013) and live donor transplants (HR: 0.33 [0.02–0.86]; P =0.023). Conclusions. The use of larger carefully selected cancer-resected kidneys for transplantation appears safe and effective. RKT confers a possible survival advantage compared with waiting for transplantation, an increased survival compared with those remaining on dialysis but reduced transplant survival. Published online 8 October, 2019. Received 2 June 2019. Revision received 4 September 2019. Accepted 6 September 2019. P.S. generated data from NTU and performed study design and critically analyzed the article. A.D.H. performed study design, wrote paper except statistics, constructed the tables and critically analyzed the article. M.K.H. performed data collection and critically analyzed the article. P.R.T. performed study design and critically analyzed the article. D.A.C. peformed data analysis, graph preparation, and critically analyzed the article. D.W.J. supplied data from PAH and critically analyzed the article. C.O. performed study design and data analyses, wrote statistics section, and critically analyzed the article. S.C. performed data analyses and critically analyzed the article. J.R.A. performed study design and data analyses and critically analyzed the article. The authors declare no conflicts of interest. This work was supported by the Research Funds of the Newcastle Transplant Unit, Hunter New England Local Health District, NSW, Australia. The data reported here have been supplied by the Australia and New Zealand Dialysis and Transplant Registry. The interpretation and reporting of these data are the responsibility of the authors and should not be seen as an official policy or interpretation by the Australia and New Zealand Dialysis and Transplant Registry. Correspondence: Adrian D. Hibberd, MD, FRACS, FACS, Transplant Surgeon, Newcastle Transplant Unit, John Hunter Hospital, PO Box 1083, Newcastle, NSW 2300, Australia. (adrian.hibberd@health.nsw.gov.au). 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.

Cytokine Profiles in Children After Pediatric Kidney Transplantation With Acute Cellular Compared to Chronic Antibody-mediated Rejection and Stable Patients: A Pilot Study Background. Different patterns of plasma cytokines can be expected in the case of chronic active-antibody-mediated (cAMR) and acute cellular rejection (AR) after kidney transplantation (KTx). Methods. IL-2, 4, 6, 10, 17A, tumor necrosis factor alpha, and interferon gamma were measured in 51 pediatric KTx recipients at time of renal biopsy (17 AR, 14 cAMR, 20 normal). Patients were divided into a training (n = 30) and a validation (n = 21) set. Results. IL-6 was significantly higher in AR patients and significantly lower in the case of cAMR. In children with s-creatinine increase, IL-6 values were significantly different between AR and cAMR. IL-10 levels showed similar tendencies. For IL-2, 4, 17A, tumor necrosis factor alpha, and interferon gamma, no differences were found. In the independent validation cohort, the receiver operating characteristic area under the curve for IL-6 was 0.79 and 0.70 for AR and cAMR. In children with AR, an IL-6 <1141 fg/ml, and in those with cAMR, an IL-6 >721 fg/ml was associated with a specificity of 86%/76%, a sensitivity of 71%/80%, a positive predictive value of 56%/45%, and a negative predictive value of 92%/94%. Conclusions. In this pilot study, the plasma IL-6 level is a promising biomarker to identify pediatric kidney transplant recipients free from AR and cAMR and might help to distinguish between both entities, whereas there is only a nonsignificant trend toward the usability of IL-10. Validation in larger cohorts in combination with other biomarkers are warranted. Published online 8 October, 2019. Received 25 July 2019. Revision received 17 August 2019. Accepted 19 August 2019. T.A.-G. and L.P. participated in research design. N.B. performed the research and participated in data analysis. All three authors participated in the writing of the manuscript and approved the final version. M.V. performed the analysis of donor specific antibodies. The authors declare no funding or conflicts of interest. Correspondence: Lars Pape, MD, PhD, Department of Pediatric Nephrology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. (Pape.Lars@mh-hannover.de). 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.

Development and Validation of a Socioeconomic Kidney Transplant Derailers Index Background. Socioeconomic barriers can prevent successful kidney transplant (KT) but are difficult to measure efficiently in clinical settings. We created and validated an individual-level, single score Kidney Transplant Derailers Index (KTDI) and assessed its association with waitlisting and living donor KT (LDKT) rates. Methods. The dataset included 733 patients presenting for KT evaluation in a transplant center in California. Exploratory factor analysis was used to identify socioeconomic barriers to KT (derailers) to include in the index. Potential KT derailers included health insurance, employment, financial insecurity, educational attainment, perception of neighborhood safety, access to a vehicle, having a washer/dryer, and quality of social support. Validity was tested with associations between KTDI scores and the following: (1) the Area Deprivation Index (ADI) and (2) time to KT waitlisting and LDKT. Results. Nine derailers were retained, omitting only social support level from the original set. The KTDI was scored by summing the number of derailers endorsed (mean: 3.0; range: 0–9). Black patients had higher estimated KTDI scores than other patient groups (versus White patients, 3.8 versus 2.1; P < 0.001, effect size = 0.81). In addition, the KTDI was associated with the ADI (γ = 0.70, SE = 0.07; P < 0.001). Finally, in comparison to the lower tertile, patients in the upper and middle KTDI tertiles had lower hazard of waitlisting (upper tertile hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.25-0.45; middle tertile HR: 0.54, 95% CI: 0.40-0.72) and receiving an LDKT (upper tertile HR: 0.15, 95% CI: 0.08-0.30; middle tertile HR: 0.35, 95% CI: 0.20-0.62). These associations remained significant when adjusting for the ADI and other patient characteristics. Conclusions. The KTDI is a valid indicator of socioeconomic barriers to KT for individual patients that can be used to identify patients at risk for not receiving a KT. Published online 8 October, 2019. Received 16 May 2019. Revision received 22 June 2019. Accepted 26 June 2019. This work was supported by NIDDK R01DK088711-01A1 (awarded to A.D.W.), HRSA R39OT26843-01-02 (awarded to A.D.W.), and HRSA R39OT29879 (awarded to A.D.W.). The authors declare no conflicts of interest. J.D.P. conceived the study design, conducted statistical analyses, and led the article drafting. J.L.B. conducted statistical analyses and critically reviewed the article. Y.C. prepared the data and critically reviewed the article. A.D.W. conceived the study design, conducted data analyses, and critically reviewed the article. M.R., A.P., and C.A. provided input to the study design and performed critical review of the article. 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: John D. Peipert, MA, Northwestern University Feinberg School of Medicine, 625 N Michigan, Suite 2700, Chicago, IL 60611. (john.peipert@northwestern.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.

Comparison of Supraceliac and Infrarenal Aortic Conduits in Liver Transplantation: Is There a Difference in Patency and Postoperative Renal Dysfunction? Background. Aorto-hepatic conduits can provide arterial inflow for liver transplants in cases where the native hepatic artery is unsuitable for use. Methods. Clinical outcomes of all patients undergoing liver transplantation (LT) with an aorto-hepatic conduit between 2000 and 2016 were included. Recipients were divided into 2 groups: those with a supraceliac (SC) aortic conduit (N = 22) and those with an infrarenal (IR) aortic conduit (N = 82). Results. There was no difference in calculated model for end-stage liver disease score between the 2 groups. The SC group received grafts with a higher mean donor risk index (1.69 versus 1.48; P = 0.02). Early allograft dysfunction was 18.2% in the SC group and 29.3% in the IR group (P = 0.30). In the SC group, 10.5% of patients required initiation of postoperative continuous renal replacement therapy compared to 12.1% of patients in the IR group (P = 0.69). No difference in the rate of postoperative acute kidney injury was seen between the 2 groups (P = 0.54). No significant difference in median creatinine at 1 year was seen between the SC (1.2 mg/dL; IQR 1–1.3) and IR (1.2 mg/dL; IQR 0.9–1.5) groups (P = 0.85). At a median follow-up of 5.3 years, thrombosis of the aortic conduit occurred in 0% of patients in the SC group and 6.1% of patients in the IR group (P = 0.24). Graft survival was not significantly different between the 2 groups (P = 0.47). Conclusions. No difference in renal dysfunction as demonstrated by need for post-LT continuous renal replacement therapy, acute kidney injury, or creatinine at 1 year post-LT was seen between SC and IR aortic conduits. A slight trend of higher conduit thrombosis rate was seen with IR compared to SC aortic conduits; however, this did not reach statistical significance. Both SC and IR aortic conduits represent reasonable options when the native hepatic artery is unsuitable for use. Published online 8 October, 2019. Received 24 June 2019. Revision received 17 August 2019. Accepted 3 September 2019. The authors declare no funding or conflicts of interest. D.L., D.D.L., S.C., C.B.T., and K.P.C. participated in research design, performance of the research, and writing of the article. D.L., S.C., and K.P.C. participated in data analysis. Correspondence: Kristopher P. Croome, MD, Department of Transplant, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL 32224. (croome.kristopher@mayo.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.

Insulin-Independent Reversal of Type-1 Diabetes Following Transplantation of Adult Brown Adipose Tissue Supplemented With IGF-1 Background. As our previous publications show, it is feasible to reverse type 1 diabetes (T1D) without insulin in multiple mouse models, through transplantation of embryonic brown adipose tissue (BAT) in the subcutaneous space. Embryonic BAT transplants result in rapid and long-lasting euglycemia accompanied by decreased inflammation and regenerated healthy white adipose tissue, with no detectable increase in insulin. To translate this approach to human patients, it is necessary to establish practical alternatives for embryonic tissue. Adult adipose tissue transplants or BAT-derived stem cell lines alone fail to reverse T1D. A likely reason is transplant failure resulting from lack of growth factors abundant in embryonic tissue. Adding growth factors may enable transplants to survive and vascularize as well as stimulate adipogenesis and decrease inflammation in the surrounding host tissue. Previous data points to insulin like growth factor 1 (IGF-1) as the most likely candidate. Embryonic BAT abundantly expresses IGF-1, and embryonic BAT transplant recipients exhibit increased plasma levels of IGF-1. Therefore, we tested the ability of temporary administration of exogenous IGF-1 to enable adult BAT transplants to correct T1D. Methods. Fresh BAT from healthy adult CB7BL/6 donors were transplanted in the subcutaneous space of hyperglycemic nonobese diabetic recipients. Exogenous IGF-1 was administered daily for a week following transplant, at 100 µg/kg SC. Results. Adult BAT transplants with IGF-1 supplementation produced rapid long-lasting euglycemia at a 57% success rate, in contrast with no recovery in the control groups who received adult BAT alone, IGF-1 alone, or no treatment. Conclusions. Temporary supplementation with IGF-1 enables adult BAT transplants to correct T1D phenotypes independent of insulin, providing a possible route to translate this treatment to human patients. Published online 8 October, 2019. Received 25 June 2019. Revision received 24 August 2019. Accepted 30 August 2019. S.C.G. participated in the research design, performance of research, analysis and interpretation of data, and writing of the article. D.W.P. participated in the research design, interpretation of data, and writing of the article. The authors declare no conflicts of interest. This work was supported by grants from the Diabetes Research Connection (S.C.G.), Washington University Diabetes Center (DK-020579) (S.C.G.), Iacocca Family Foundation (D.W.P.), and Washington University School of Medicine (D.W.P.). Correspondence: Subhadra C. Gunawardana, PhD, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S Euclid Ave, Campus box 8228, St Louis, MO 63110. (subhadra.gunawardana@wustl.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.

Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys Background. . Normothermic machine perfusion (NMP) may allow resuscitation and improved assessment of kidneys before transplantation. Using discarded human kidneys, we investigated the mechanistic basis and translational potential of NMP compared with cold static storage (CS). Methods. Discarded deceased donor kidneys (n = 15) underwent 1-hour NMP following CS. Renal perfusion, biochemical, and histologic parameters were recorded. NMP was directly compared with CS in paired donor kidneys using simulated transplantation with allogeneic whole blood, followed by assessment of the aforementioned parameters, in addition to RNA sequencing. Results. Kidneys were successfully perfused, with improved renal blood flows and resistance over the course of perfusion, and evidence of urine output (median 21 mL), in all but one kidney. NMP completely resolved nonperfused regions in discarded donation after circulatory death kidneys. In paired kidneys (n = 4 pairs), transcriptomic analyses showed induction of stress and inflammatory pathways in NMP kidneys, with upregulation of pathways promoting cell survival and proliferation. Furthermore, the NMP pairs had significantly better renal perfusion (1.5–2 fold improvement) and functional parameters, and amelioration of cell death, oxidative stress, and complement activation. Conclusions. In this pilot preclinical study using simulated transplantation of paired kidneys, NMP of discarded marginal kidneys demonstrated some significant mechanistic benefits in comparison to CS alone. NMP may have potential to reduce organ discards and enhance early graft function in such kidneys. Published online 8 October, 2019. Received 8 August 2019. Accepted 24 August 2019. W.J.H., N.M.R., and H.C.P. are co-senior authors. This work was supported by Royal Australasian College of Surgeons—Sir John Loewenthal Project Grant. B.X. is an employee of Thermo Fisher Scientific. The other authors declare no conflicts of interest. A.M.H. designed and performed the experiments, collected and interpreted data, and wrote the manuscript; D.B.L., B.X., M.H., Y.V.C., K.K., and R.M. performed and/or advised on certain aspects of experiments and were involved in manuscript revision; E.P. and C.H.P. provided statistical and pathological analyses, respectively; R.G., C.Z., P.R., J.L., R.D., and L.Y. assisted in the performance and/or coordination of experiments or organ retrieval, and also assisted in manuscript writing; S.A., G.T., G.W., and G.O. advised on experimental design, data interpretation, and manuscript writing; and W.J.H., N.M.R., and H.C.P. designed experiments, provided advice and assistance in the performance of experiments and data analysis/interpretation, and wrote the manuscript. 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 (http://www.transplantationdirect.com). Correspondence: Henry C. Pleass, MD, Department of Surgery, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia. (henry.pleass@sydney.edu.au) or Natasha M. Rogers, PhD, Department of Renal Medicine, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia. (natasha.rogers@sydney.edu.au) or Wayne J. Hawthorne, PhD, Department of Surgery, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia. (wayne.hawthorne@sydney.edu.au). 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.

Incidentally Detected Malignancies in Lung Transplant Explants Background. Active malignancy diagnosed within 5 years is an absolute contraindication for lung transplantation. In this study, we evaluated the rate of incidental malignancies detected in explanted lungs at our institution and assessed the posttransplant survival in patients with nonsmall cell lung cancer (NSCLC). Methods. A retrospective chart review of lung transplant recipients at our institution from February 1999 to June 2017 was conducted. A literature review was performed to evaluate the prevalence and survival outcomes in patients with unexpected malignancies. Results. From 407 patients who underwent lung transplantation, 9 (2.2%) were discovered to have malignant neoplasms. There were 3 cases of adenocarcinoma, 3 cases of adenocarcinoma in situ, 2 cases of squamous cell carcinoma, and 1 case of metastatic renal cell carcinoma. An extensive literature review found 12 case reports or case series reporting malignancy discovered at the time of lung transplantation. The overall prevalence of incidental neoplasms among 6746 recipients is around 1.5% (n = 103). The most common neoplasms discovered included adenocarcinoma (n = 56, 54%) and squamous cell carcinoma (n = 29, 28%). The overall 3-year survival was 54.4% for patients with localized NSCLC compared to 5.7% for those with nonlocalized disease. Conclusions. Unidentified malignancies occur despite aggressive radiographic surveillance with poor posttransplant outcomes in patients with advanced malignancy. Malignancy-related radiographic findings may be missed pretransplant secondary to architectural distortion of lung parenchyma related to end-stage lung disease or because of the critical timing of surgery when donor lungs are available. Published online 8 October, 2019. Received 5 August 2019. Revision received 3 September 2019. Accepted 6 September 2019. The authors declare no funding or conflicts of interest. D.A. participated in research design, performance of research, data collection, data analysis, and writing of the article. W.H. participated in research design, data analysis, and writing of the article. D.N. participated by reviewing the article. S.V. participated in research design and reviewing the article. Correspondence: Dhruv A. Amratia, MD, Emory University School of Medicine, 615 Michael St, Suite 205, Atlanta, GA 30322. (damrati@emory.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.