Organ Transplantation

Nontuberculous mycobacteria in solid organ transplant Purpose of review Nontuberculous mycobacteria (NTM) are emerging pathogens of concern especially in solid organ transplant candidates and recipients. This review aims to address diagnostic challenges, new and emerging treatment options, and infection prevention. Recent findings The incidence of NTM infections in transplant candidates and recipients is rising. The infection prevalence of these environmental pathogens varies geographically by species with a coastal predominance. Although existing guidelines from the American Thoracic Society, Infectious Diseases Society of America, and British Thoracic Society provide recommendations for diagnosis and management, they do not fully address the subtle nuances and challenges faced in managing infections in immunocompromised transplant recipients. Evolving data on new therapeutic agents and their use in combination therapy will help individualize treatment regimens while limiting adverse effects and improving compliance. Use of combination β-lactams, avibactam, tedizolid, clofazimine, bedaquiline, liposomal amikacin, and ciprofloxacin for commonly isolated species such as Mycobacterium abscessus and Mycobacterium avium complex have proven effective. Summary Further studies are needed to determine the incidence of NTM infection in a prospective, multicentric manner and evaluate the most promising synergistic treatment combinations in transplant recipients. Correspondence to Shweta Anjan, MD, 1120 NW 14th Street Suite 863, Miami, FL 33136, USA. Tel: +1305 243 4598; fax: +1305 243 4037; e-mail: sxa835@med.miami.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The future of HIV Organ Policy Equity Act is now: the state of HIV positive to HIV+ kidney transplantation in the United States Purpose of review We report the current state of HIV-to-HIV kidney transplantation in the United States and remaining challenges in implementing this practice nationally. Recent findings The HIV Organ Policy Equity (HOPE) Act, which was the first step in unlocking the potential of HIV+ organ donors, mandates clinical research on HIV positive to HIV+ transplantation. As of March 2019, there have been 57 HOPE donors, including both true and false-positive HOPE donors resulting in more than 120 transplants. Summary The HOPE Act, signed in 2013, reversed the federal ban on the transplantation of organs from HIV D+ into HIV R+ . Ongoing national studies are exploring the safety, feasibility, and efficacy of both kidney and liver transplantation in this population. If successfully and fully implemented, HIV positive to HIV+ transplantation could attenuate the organ shortage for everyone waiting, resulting in a far-reaching public health impact. Correspondence to Christine M. Durand, MD, Medicine and Oncology, Johns Hopkins University School of Medicine, 725 North Wolfe Street/PCTB Room 228, Baltimore, MD 21205, USA. E-mail: christinedurand@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The true risk of living kidney donation Purpose of review The safety of living donor nephrectomy is essential to the continued success, growth, and sustainability of the clinical practice of living donor kidney transplantation. This review summarizes recent advances in our understanding of the perioperative and long-term risks faced by living kidney donors. Recent findings Although adverse perioperative complications are extremely rare, donors particularly men, Black, or obese, frequently experience minor complications that result in delayed return to normal duties at home and work. Similarly, although long-term complications such as end-stage renal disease (ESRD) are rare, recent studies suggest a relative increase in risk of ESRD that is attributable to donation. Several risk calculators have been developed to help donors and their care providers quantify the baseline and postdonation risk of ESRD based on demographic and health characteristics. Thresholds of risk may help define what is an acceptable level of risk to the donor and the transplant center. Summary Individualized risk calculators now allow care providers and potential donors to objectively and transparently participate in shared decision-making about the safety of living kidney donation. Correspondence to Macey Henderson, JD, PhD, Department of Surgery, Division of Transplantation, Johns Hopkins School of Medicine, 2000 E Monument Street Baltimore, MD 21205, USA. Tel: +1 443 287 6649; fax: +1 410 630 7217; e-mail: macey@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Novel therapeutic strategies for renal graft preservation and their potential impact on the future of clinical transplantation Purpose of review The current review aims to examine recent evidence about improvements, therapeutics and novel approaches for renal graft preservation along with presenting a pragmatic outlook on their potential for clinical translation. Recent findings Modifying established cold preservation methods (4 °C) with oxygenation, gene therapies and gasotransmitters such as hydrogen sulfide has been shown to improve renal graft outcomes with minimum modifications to current protocols. These strategies have also shown promise in the context of normothermic preservation (34–37 °C), which circumvents the damage caused by cold preservation. Although normothermic machine perfusion (NMP) is being evaluated in clinical trials, it is limited by high cost, the use of blood and the lack of standardized protocols. Recent studies confirmed that preservation at subnormothermic temperatures (∼20 °C) is effective with approved preservation solutions and, in conjunction with exogenous hydrogen sulfide therapy, this approach may expedite a static preservation alternative to NMP. Summary Progress has been made in investigating improvements and alternatives to cold preservation. Promising therapeutic strategies have also been studied in the context of cold, subnormothermic and normothermic preservation. Further research is needed to optimize clinical renal graft preservation. Correspondence to Alp Sener, MD, PhD, FRCSC, University Hospital, C4-208, London Health Sciences Centre, 339 Windermere Road, London, ON, Canada N6A 5A5. Tel: +1 519 685 8500x33352; e-mail: alp.sener@lhsc.on.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Community-acquired respiratory viruses in solid organ transplant Purpose of review Respiratory viruses are common in solid organ transplant (SOT) recipients and recognized as a significant cause of mortality and morbidity. This review examines the literature on influenza and noninfluenza viruses in the SOT recipient. Recent findings Advances in immunosuppression and antimicrobial prophylaxis have led to improved patient and graft survival, yet respiratory viruses continue to be a common cause of disease in this population. Influenza viruses have received top priority regarding prevention and treatment, whereas advances in molecular diagnostic tests detecting an array of other respiratory viruses have expanded our knowledge about the epidemiology and impact of these viruses in both the general population and SOT patients. Effective treatment and prevention for noninfluenza respiratory viruses are only emerging. Summary Respiratory viruses can contribute to a wide array of symptoms in SOT, particularly in lung transplant recipients. The clinical manifestations, diagnosis, and treatment options for influenza and noninfluenza viruses in SOT patients are reviewed. PCR and related molecular techniques represent the most sensitive diagnostic modalities for detection of respiratory viruses. Early therapy is associated with improved outcomes. Newer classes of antivirals and antibodies are under continuous development for many of these community acquired respiratory viruses. Correspondence to Michael G. Ison, MD, MS, Northwestern University Feinberg School of Medicine, 645 N Michigan Avenue Suite 900, Chicago, IL 60611, USA. Tel: +1 312 695 4186; fax: +1 312 695 5088; e-mail: mgison@northwestern.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Noninvasive biomarkers in monitoring kidney allograft health Purpose of review A key aspect of posttransplant management is to identify and treat graft injury before it becomes irreversible. The gold-standard for detection is histology, but biopsy is uncomfortable for the patient and carries a risk of complications. Detection of changes at a molecular level may preempt histological injury, and thereby identify injury earlier. Recent findings Indicators of immune system activation, such as candidate chemokines chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10, and by-products of neutrophil activity, have been related to acute rejection and early allograft function. Transcriptomic studies of multiple-gene panels have identified candidate combinations that have proven very promising in risk-stratification and prediction of acute rejection, as well as diagnosis of both T-cell-mediated and antibody-mediated rejection. Serum and urine cell-free DNA is also a promising area of investigation, particularly in antibody-mediated rejection. Summary Noninvasive, rapid, and accurate tests for risk-prediction and diagnosis in renal transplant allografts are urgently required. The ideal candidate is one that can be measured in either urine or blood, is cheap, and is both sensitive and specific for the condition of interest. Numerous strategies have been proposed, with varying degrees of clinical and preclinical success. A few that meet the essential criteria have been evaluated; a few have made it as far as clinical testing. Correspondence to John M. O'Callaghan, MBBS, BSc, DPhil, FRCS, Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Oxford OX3 7LE, UK. Tel: +4401865227131; e-mail: john.ocallaghan@ouh.nhs.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Antimicrobial stewardship in transplant patients Purpose of review To provide an update on the current landscape of antimicrobial stewardship in solid organ transplant (SOT) recipients. Recent findings Constructing personalized antimicrobial prescribing approaches to avoid untoward consequences of antimicrobials while improving outcomes is an emerging and critical aspect of transplant medicine. Stewardship activities encompassing the specialized interests of transplant patients and programs are evolving. New literature evaluating strategies to optimize antimicrobial agent selection, dosing, and duration have been published. Additionally, consensus guidance for certain infectious clinical syndromes is available and should inform institutional clinical practice guidelines. Novel metrics for stewardship-related outcomes in transplantation are desperately needed. Though exciting new molecular diagnostic technologies will likely be pivotal in the care of immunocompromised patients, optimal clinical adaptation and appropriate integration remains unclear. Important studies understanding the behaviors influencing antimicrobial prescribing in organizational transplant cultures are needed to optimize interventions. Summary Consequences of antimicrobial use, such as Clostridiodes difficile and infections with multidrug-resistant organisms disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Application of ASP interventions tailored to SOT recipients is recommended though further studies are needed to provide guidance for best practice. Correspondence to Jonathan Hand, MD, 1514 Jefferson Highway, New Orleans, LA 70121, USA. Tel: +1 504 842 1191; fax: +1 504 842 5254; e-mail: Jonathan.Hand@ochsner.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Caring for the patient with a failing allograft: challenges and opportunities Purpose of review The population of kidney transplant recipients with advanced chronic kidney disease is growing but their outcomes are poor and care is not standardized. There has been wide variety of research in recent years on different aspects of care in failing allografts, and these research findings may help the providers in optimizing care. The purpose of the review is to outline the challenges and opportunities in management of failing allograft, and provide tools for improvement. Recent findings This review summarizes the recent research in field of failing allograft including outcomes, immunosuppression, risk factor management, multidisciplinary CKD care, dialysis initiation, nephrectomy and re-transplantation. Summary Kidney allograft failure is a period of higher risk of mortality compared with other transition periods for patients with ESRD. Risk mitigation is a complex challenge for patients and their care teams. In addition to summarizing the recent literature, we propose a checklist approach to the various issues, medical, surgical, psychological and nutritional as patients approach kidney transplant failure while they consider initiation of dialysis and possible repeat transplantation. Once standard algorithms are instituted, studies can be conducted to identify those high-value interventions that actually reduce morbidity and mortality risk during this transition period. Correspondence to Nikhil Agrawal, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. Tel: +617 632 9700; e-mail: nagrawa2@bidmc.harvard.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

A diagnostic 'C' saw: the Ups and downs of C1q testing Purpose of review The present review will focus on recently published data of solid organ allograft recipients reporting that patients with de-novo donor-specific HLA antibodies (DSA) that fix complement in vitro have a significantly higher risk for antibody-mediated rejection (AMR) and/or graft loss compared to patients whose de-novo DSA do not fix complement or patients who present with preexisting complement fixing DSA. Recent findings HLA DSAs that fix complement in vitro appear to be a key indicator for rejection and failure of kidney, heart, and lung allografts from studies performed around the world. The majority of these studies are population based and retrospective in nature. Although these studies seemingly indicate that in-vitro complement activating DSAs represent a higher clinical risk than noncomplement fixing DSAs, the majority have not accounted for false-negative reactions attributable to the so-called prozone/interference phenomenon. In the limited number of published studies addressing that concern, high mean fluorescence intensity (MFI) value noncomplement fixing DSAs correlate as well as complement fixing DSAs with AMR and graft loss. Combined with the cost of additional testing, these observations bring into question whether there is sufficient clinical applicability to warrant routine testing for complement fixing antibodies. Summary Complement fixing DSAs are clearly associated with AMR and/or loss of transplanted allografts. However, under appropriate testing conditions, complement fixing capability typically correlates with MFI values of the DSAs. As such, the routine implementation of in-vitro assays to determine whether DSAs fix complement is of questionable value especially when considering additional issues such as cost of testing, logistics, and whether the test results factor into individualized patient care. Correspondence to Howard M. Gebel, PhD, Department of Pathology, Room HB53, 1364 Clifton Road NE, Atlanta, GA 30322, USA. Tel: +404 712 8199; fax: +404 712 4717; e-mail: hgebel@emory.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Epitope matching in kidney transplantation: recent advances and current limitations Purpose of review Evolution of human leukocyte antigen (HLA) molecular typing techniques has progressively enabled more accurate determination of the three-dimensional building blocks that form the antibody accessibility and binding sites of each HLA allele. These immunogenic HLA regions known as epitopes are composed of polymorphic sequences of amino acid residues termed eplets. This review provides a critical appraisal of the current understanding of epitope compatibility in kidney transplantation. Recent findings There is a tendency to suggest that epitope matching is likely to be superior to broad antigen HLA matching such that the allocation of donor kidneys to patients with a more favorable epitope compatibility profile may lead to better allograft outcomes. A growing body of work has highlighted the association between a greater number of eplet mismatches and adverse allograft outcomes, and approaches using eplet matching have been successfully implemented in organ allocation programs. However, our understanding of epitope compatibility remains in its infancy, requiring further and more in-depth evaluation. Critically, it remains unclear how best to translate findings derived at the population level to the care of individual patients. Questions that need to be answered include a lack of consensus in the definition and interpretation of epitope compatibility, are class I and II compatibility of similar clinical importance, how best to define predetermined mismatch thresholds for utilization in organ allocation, and whether other properties such as differences in electrostatic potential between donor and recipient HLA alleles are also important in determining immunological compatibility. Summary Epitope matching likely represents a valid progression in understanding donor–recipient HLA compatibility. However, more clinical data and a better understanding about differences in methods to determine epitope compatibility are required before the approach can be widely applied in clinical practice. Corresponding to Nicholas G. Larkins, MBBS (Hons), FRACP MMed (Clin Epi), PhD, Department of Nephrology, Perth Children's Hospital, 15 Hospital Ave., Nedlands, Perth, Western Australia 6009, Australia. Tel: +61 08 6456 0216; e-mail: nicholas.larkins@health.wa.gov.au 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 © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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