Organ Transplantation

Repeated kidney re-transplantation in times of organ shortage – a critical review Purpose of review Organ shortage forces those responsible to streamline allocation rules to provide a maximum of candidates with a graft and to optimize transplant outcome. Recently, repeated kidney re-transplantation was investigated in several studies with different analytic settings concerning the control group, the donors, parameters influencing outcome, and demographic characteristics. This review gives an overview on the candidates awaiting a repeated re-transplantation, summarizes the outcome, and comments on the relevance of these findings in the context of sustained organ shortage. Recent findings Repeated kidney re-transplantation is technically and immunologically feasible and the recipients' survival is better compared to candidates remaining on dialysis or on the waiting-list. However, the outcome is mainly reported to be worse as compared to first or second kidney transplantation. Kidneys from living donors seem to have a favorable impact on outcome in this setting. Summary The survival benefit of repeated re-transplantation recipients over patients on dialysis demands for continuation of this procedure. Comprehensive registries are essential to continuously optimize allocation. Governmental authorities are obliged to set the course to increase organ donation rather than forcing transplant decision makers to withhold a third or fourth graft from any candidate. Correspondence to Volker Assfalg, TransplanTUM, Munich Transplant Center, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Ismaningerstr. 22, D-81675 Munich, Germany. Tel: +49 (0) 89 4140 2121; fax: +49 (0) 89 4140 4870; e-mail: volker.assfalg@tum.de Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Developments in immunosuppression Purpose of review In this review, we discuss achievements in immunosuppression in kidney transplant recipients published at last 18 months. Recent findings Results of recent trials with everolimus in low-risk primary kidney transplant recipients suggest that lowTAC/EVR combination is noninferior and CMV and BKV viral infections are less frequent to standTAC/MPA. Iscalimab monoclonal antibody, which prevents CD40 to CD154 binding, has just recently entered phase II clinical studies in kidney transplantation. Eculizumab, anti-C5 monoclonal antobody was recently shown to improve outcomes in DSA+ living-donor kidney transplant recipients requiring pretransplant desensitization because of crossmatch positivity. Proximal complement C1 inhibition in patients with antibody-mediated rejection was studied in several phase I trials. Summary Recent knowledge creates a path towards future immunosuppression success in sensitized recipients and in those in high risk of viral infections or CNI nephrotoxicity. Correspondence to Ondrej Viklicky, MD, PhD, Professor of Medicine, Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic. Tel: + 420 23605 4110; fax: +420 23605 3168; e-mail: ondrej.viklicky@ikem.cz Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Kidney and pancreas transplant candidacy Purpose of review Kidney and/or pancreas transplantation candidacy criteria have evolved significantly over time reflecting improved pre and post-transplant management. With improvement in medical care, potential candidates for transplant not only are older but also have complex medical issues. This review focuses on the latest trends regarding candidacy for kidney and/or pancreas transplantation along with advances in pretransplant cardiac testing. Recent findings More candidates are now eligible for kidney and/or pancreas transplantation owing to less stringent candidacy criteria especially in regards to age, obesity, frailty and history of prior malignancy. Pretransplant cardiovascular assessment has also come a long way with a focus on less invasive strategies to assess for coronary artery disease. Summary Criteria for kidney and/or pancreas transplantation are expanding. Patients who in the past might have been declined because of numerous factors are now finding that transplant centers are more open minded to their candidacy, which could lead to better access to organ transplant wait list. Correspondence to Rafael Villicana, MD, Transplant Institute, Loma Linda University Health, 197 East, Caroline Street Suite 1400, San Bernardino, CA 92408, USA. Tel: +1 909 558 3144; e-mail: rvillicana@llu.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

New concepts in chronic antibody-mediated kidney allograft rejection: prevention and treatment Purpose of review Chronic antibody-mediated rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. Recent findings One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active rejection. Summary There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment. Correspondence to Georg A. Böhmig, MD, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel: +43 1 40400 43630; fax: +43 1 40400 39302; e-mail: georg.boehmig@meduniwien.ac.at Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Variations in DNA methylation and allograft rejection Purpose of review DNA methylation is involved in gene transcription and as such important for cellular function. Here, the literature on DNA methylation in relation to acute rejection is summarized with a focus on the potential clinical utility of DNA methylation for monitoring transplant rejection. Recent findings The tight transcriptional control of DNA methylation in immune cell function, e.g. demethylation in regulatory T-cell-specific genes for stable immunosuppressive capacities, suggests an important role for DNA methylation variations in the antidonor-directed immune response. Until today, differentially methylated DNA in immune cells, however, has not been described at the moment of allograft rejection. The ability to locus-specific modify DNA methylation could facilitate the generation of stable cells for cellular therapy purposes. The unique cell-specific characteristics of DNA methylation provide the opportunity to identify its cellular origin. Examining methylation of cell-free DNA in blood or urine may serve as a 'liquid biopsy' enabling minimally invasive detection of allograft rejection. Summary Actual research publications on DNA methylation in relation to allograft rejection are scarce, which makes it challenging to determine its potential clinical value. Extensive research is needed to investigate the value of DNA methylation in early recognition, diagnosis, and/or successful treatment of allograft rejection. Correspondence to Karin Boer, PhD, Erasmus MC, Room Na-520, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +3110 7035419; e-mail: karin.boer@erasmusmc.nl Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Cardiac evaluation of the kidney or liver transplant candidate Purpose of review As the field of transplant has advanced, cardiac events have become the leading cause of morbidity and mortality after liver and kidney transplantation ahead of graft failure and infection. This trend has been bolstered by the transplantation of older and sicker patients who have a higher burden of cardiovascular risk factors, accentuating the need to determine which patients should undergo more extensive cardiac evaluation prior to transplantation. Recent findings Computed tomography coronary angiography with or without coronary artery calcium scoring is now preferred over stress imaging in most transplant candidates for assessment of coronary artery disease. Assessment of cardiac structure and function using transthoracic echocardiography with tissue doppler imaging and strain imaging is recommended, particularly in liver transplant candidates who are at high risk of cirrhotic cardiomyopathy, for which new diagnostic criteria were recently published in 2019. Summary Cardiac evaluation of liver and kidney transplant candidates requires a global assessment for both short and long-term risk for cardiac events. Imaging of cardiac structure and function using transthoracic echocardiography with tissue doppler imaging and strain imaging is recommended. Risk stratification should consider both the anatomic and functional consequences of coronary artery disease in transplant candidates. Video abstract http://links.lww.com/MOT/A27 Correspondence to Lisa B. VanWagner, MD, MSc, FAST, FAHA, Department of Medicine, Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, 676 N. St Clair St - Suite 1400, Chicago, IL 60611, USA. Tel: +1 630 695 1632; fax: +1 312 695 3999; e-mail: lvw@northwestern.edu Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.co-transplantation.com). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Epigenetic modifications and the development of kidney graft fibrosis Purpose of review To outline recent discoveries in epigenetic regulatory mechanisms that have potential implications in the development of renal fibrosis following kidney transplantation. Recent findings The characterization of renal fibrosis following kidney transplantation has shown TGFβ/Smad signaling to play a major role in the progression to chronic allograft dysfunction. The onset of unregulated proinflammatory pathways are only exacerbated by the decline in regulatory mechanisms lost with progressive patient age and comorbidities such as hypertension and diabetes. However, significant developments in the recognition of epigenetic regulatory markers upstream of aberrant TGFβ-signaling has significant clinical potential to provide therapeutic targets for the treatment of renal fibrosis. In addition, discoveries in extracellular vesicles and the characterization of their cargo has laid new framework for the potential to evaluate patient outcomes independent of invasive biopsies. Summary The current review summarizes the main findings in epigenetic machinery specific to the development of renal fibrosis and highlights therapeutic options that have significant potential to translate into clinical practice. Correspondence to Valeria R. Mas, MS, PhD, FAST, Professor of Surgery, Chief, Surgical Sciences Division, Department of Surgery, School of Medicine, University of Maryland, HSF3 Building, W Baltimore Street, 7th Floor, Room 71, Baltimore, MD 21201, USA. Tel: +1 901 448 3071; fax: +1 901 448 3071; e-mail: vmas@som.umaryland.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Technical advancements in epigenomics and applications in transplantation Purpose of review To summarize recently developed next generation sequencing-based methods to study epigenomics and epitranscriptomics. To elucidate the potential applications of these recently developed methods in transplantation research. Recent findings There are several methods established with the collaborative efforts from different consortiums, such as ENCODE, Human Cell Atlas, and exRNA consortium to study role of epigenetics in human health. Rapid development in the sequencing technology also enabled the establishment of these genome-wide studies. This review specifically focuses on these techniques, such as EM-seq to study DNA methylation, CUT&RUN, and CUT&Tag to study histone/transcription factor--DNA interactions, ATAC-seq to study chromatin accessibility, Hi-C to explore 3D genome architecture and several methods to study epigenetics at single-cell level. In addition, we briefly mentioned recent efforts to study lncRNAs and extracellular miRNAs. Summary Technical advancements in genomics, particularly epigenomics, shed light on the role of epigenetics and recently epitranscriptomics in different fields. Application of those techniques to transplantation research is still very limited because of technical limitations. On the other hand, there are a lot of promising studies showing that these new techniques can be adapted to study the molecular biology of transplant-related problems. Correspondence to Canan Kuscu, PhD, Transplant Research Institute, University of Tennessee Health Science Center, 71S Manassas Street, TSRB Rm 421, Memphis, TN 38103, USA. Tel: +1 901 448 3162; e-mail: ckuscu@uthsc.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Systems biology approaches in solid organ transplantation Purpose of review Organ transplantation research has led to the discovery of several interesting individual mechanistic pathways, molecules and potential drug targets but there are still no comprehensive studies that have addressed how these varied mechanisms work in unison to regulate the posttransplant immune response that drives kidney rejection and dysfunction. Recent findings Systems biology is a rapidly expanding field that aims to integrate existing knowledge of molecular concepts and large-scale genomic and clinical datasets into networks that can be used in cutting edge computational models to define disease mechanisms in a holistic manner. Systems biology approaches have brought a paradigm shift from a reductionist view of biology to a wider agnostic assessment of disease from several lines of evidence. Although the complex nature of the posttransplant immune response makes it difficult to pinpoint mechanisms, systems biology is enabling discovery of unknown biological interactions using the cumulative power of genomic data sets, clinical data and endpoints, and improved computational methods for the systematic deconvolution of this response. Summary An integrative systems biology approach that leverages genomic data from varied technologies, such as DNA sequencing, copy number variation, RNA sequencing, and methylation profiles along with long-term clinical follow-up data has the potential to define a framework that can be mined to provide novel insights for developing therapeutic interventions in organ transplantation. Correspondence to Sunil M. Kurian, PhD, Research Scientist, Scripps Clinic Bio-Repository & Bio-Informatics Core, Scripps Center for Organ & Cell Transplantation Research, 10666 N. Torrey Pines Road, 200N, La Jolla, CA 92037, USA. Tel: +1 858 554 4371; e-mail: Kurian.Sunil@scrippshealth.org Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Dissecting the human kidney allograft transcriptome: single-cell RNA sequencing Purpose of review Single-cell RNA sequencing (scRNA-seq) has provided opportunities to interrogate kidney allografts at a hitherto unavailable molecular level of resolution. Understanding of this technology is essential to better appreciate the relevant biomedical literature. Recent findings Sequencing is a technique to determine the order of nucleotides in a segment of RNA or DNA. RNA-seq of kidney allograft tissues has revealed novel mechanistic insights but does not provide information on individual cell types and cell states. scRNA-seq enables to study the transcriptome of individual cells and assess the transcriptional differences and similarities within a population of cells. Initial studies on rejecting kidney allograft tissues in humans have identified the transcriptional profile of the active players of the innate and adaptive immune system. Application of scRNA-seq in a preclinical model of kidney transplantation has revealed that allograft-infiltrating myeloid cells follow a trajectory of differentiation from monocytes to proinflammatory macrophages and exhibit distinct interactions with kidney allograft parenchymal cells; myeloid cell expression of Axl played a major role in promoting intragraft myeloid cell and T-cell differentiation. Summary The current review discusses the technical aspects of scRNA-seq and summarizes the application of this technology to dissect the human kidney allograft transcriptome. Correspondence to Thangamani Muthukumar, MD, Division of Nephrology, Hypertension, and Transplantation Medicine, Weill Cornell Medicine, 525 E 68 Street, Box 3, New York, NY 10065, USA. Tel: +1 212 746 4430; fax: +1 212 746 6894; e-mail: mut9002@med.cornell.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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