Organ transplantation from “increased infectious risk donors”: the experience of the Nord Italia Transplant program — A retrospective study

The purpose of this study was to assess the safety and the clinical outcome associated with organ transplantation from increased infectious risk donors (IRD). We retrospectively identified all adult deceased IRD referred to the Nord Italia Transplant program coordinating center from November 2006 to November 2011. All potential donors were screened for social risk factors that may increase the risk of donor‐derived infection with human immunodeficiency (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). All recipients were followed monthly for the first 6 months post‐transplant. A total of 86 potential IRD were identified during the study period. Three hundred and seventy‐nine organs from IRD were offered to the transplant centers, but only 185 (48.8%) were used for transplantation. Organs from IRD were transplanted into 174 recipients. The complete follow‐up data were available for 152 of 174 (87.3%) recipients. During a mean follow‐up of 11.7 months (median 12; range 2.4–12), no transmission of HIV, HBV, or syphilis was documented by serology and nucleic acid testing (NAT) testing. Two patients transplanted with organs from HCV‐RNA‐positive donors, as expected, developed post‐transplant HCV infection. In conclusion, the use of organs from IRD was associated with a safe increase in the transplant procedures in our country.     

Accepting hepatitis C virus–infected donor hearts for transplantation: Multistep consent,unrealized opportunity,and the Stanford experience

The current mismatch between supply and demand of organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Advancements of direct‐acting antiviral agent (DAA) therapy for hepatitis C virus (HCV) have allowed entertaining the use of viremic donor organs in nonviremic recipients. In this report, we describe the evolution of HCV treatment, ethics and informed consent, cost‐effectiveness of HCV medications in treating acute HCV post‐transplantation, and the Stanford experience with two HCV‐viremic donor heart transplantations. We describe excellent short‐term outcomes post–heart transplantation with HCV NAT‐positive organs. The availability of this therapy may expand the donor pool. While we await larger‐scale clinical data on the effectiveness and safety of DAA therapy in patients after heart transplantation, many transplant centers have already started accepting organs from HCV‐infected donors, balancing the unknown long‐term risks versus the benefits of shorter wait times and expansion of the donor pool. Protocols and multidisciplinary teams are needed to effectively communicate risk to potential recipients, to ensure timely DAA access, and to implement appropriate clinical follow‐up in order to achieve excellent clinical outcomes and to maximize the donor pool by utilizing HCV‐infected organs for heart transplantation.     

Donor screening algorithm for exclusion of thrombophilia during evaluation of living donor liver transplantation

Ogawa H, Fujimoto Y, Yamamoto K, Hata T, Nagai S, Kamei H, Arikawa T, Nakamura T, Kiuchi T. Donor screening algorithm for exclusion of thrombophilia during evaluation of living donor liver transplantation.
Clin Transplant 2011: 25: 277–282. © 2010 John Wiley & Sons A/S. Abstract: Living donor liver transplantation (LDLT) has evolved based on the premise that donor safety is most important. In 2005, we encountered a donor who developed a pulmonary embolism during the early post‐operative period. As it is important for donors to be healthy, most risk factors related to perioperative thrombosis, such as obesity, age, and malignancy are used as exclusion criteria during the evaluation process. We speculated that thrombophilia not detected by conventional laboratory examinations may cause post‐operative thrombotic complications and should be investigated by application of additional parameters, including protein S, protein C, antithrombin III, anti‐β2‐glycoprotein I antibodies (anti‐β2GPI), and lupus anticoagulant. From July 2005 to June 2007, we evaluated 44 donor candidates for LDLT using our novel algorithm for screening of thrombophilia, which revealed two suspected candidates (one with low protein S, one with low protein C, and positive anti‐β2GPI findings), who were subsequently excluded from the donor pool. Thereafter, all donor hepatectomies, which included two borderline donors given anticoagulants perioperatively, were performed without complications. Four donors (two suspected, two borderline) would not have been recognized without additional screening. In conclusion, we were able to detect thrombophilia and avoid donor thrombosis using additional screening criteria and our novel algorithm.     

Expanding access to transplantation with hepatitis C‐positive donors: A new perspective on an old issue

With the need for organs far exceeding supply, donors previously exposed to hepatitis B (HBV) and hepatitis C (HCV) viral infections should be considered for transplantation. Although many centers have protocols for transplanting organs from HBV core antibody‐positive (HBcAb+) donors into select recipients, in the era of direct‐acting antivirals (DAAs), a new focus should be placed on HCV‐positive donors. The transmission rate from HCV antibody‐positive (HCVAb+) nucleic acid testing negative (HCV NAT‐) donors is expected to be very low, and we encourage use of such organs in HCV recipients provided a normal biopsy, appropriate counseling, and careful post‐transplant monitoring. While transmission of HCV from HCV NAT+ donors is universal, the success of DAA in obtaining a sustained viral response in post‐transplant recipients should make the use of these organs more appealing. We herein provide information to help guide the use of organs from HCV donors.     

Evidence‐based development of liver allocation: a review

Liver transplantation has undergone a rapid evolution from a high‐risk experimental procedure to a mainstream therapy for thousands of patients with a wide range of hepatic diseases. Its increasing success has been accompanied by progressive imbalance between organ donor supply and the patients who might benefit. Where demand outstrips supply in transplantation, a system of organ allocation is inevitably required to make the wisest use of the available, but scarce, organs. Early attempts to rationally allocate donor livers were particularly hampered by lack of available and suitable data, leading to imperfect solutions that created or exacerbated inequities in the system. The advent and maturation of evidence‐based predictors of waiting list mortality risk led to more objective criteria for liver allocation, aided by the increasing availability of data on large numbers of patients. Until now, the vast majority of allocation systems for liver transplantation have relied on estimation of waiting list mortality. Evidence‐based allocation systems that incorporate measures of post‐transplant outcomes are conceptually attractive and these transplant benefit‐based allocation systems have been developed, modeled, and subjected to computer simulation. Future implementations of benefit‐based liver allocation await continued refinement and additional debate in the transplant community.     

Guidelines for the Psychosocial Evaluation of Living Unrelated Kidney Donors in the United States

Under the auspices of the United Network for Organ Sharing, the American Society of Transplant Surgeons and the American Society of Transplantation, a meeting was convened on May 25, 2006, in Washington, DC, to develop guidelines for the psychosocial evaluation of prospective living kidney donors who have neither a biologic nor longstanding emotional relationship with the transplant candidate. These 'unrelated' donors are increasingly often identified by transplant candidates via the Internet, print media and other public appeals. The expansion of living donor kidney transplantation to include significant numbers of donors with little to no preexisting relationship to the candidate has caused concern in the medical community regarding such psychosocial factors as donor psychological status, motivation, knowledge about donation and the potential for undue pressure to donate under some circumstances. Therefore, experts in mental health; psychosocial, behavioral and transplant medicine; and medical ethics met to specify (a) characteristics of unrelated donors that increase their risk for, or serve as protective factors against, poor donor psychosocial outcomes, (b) basic principles underlying informed consent and evaluation processes pertinent to these donors and (c) the process and content of the donor psychosocial evaluation. The meeting deliberations resulted in the recommendations made in this report.     

Increasing access to kidney transplantation in countries with limited resources: The Indian experience with Kidney Paired Donation

According to the Indian chronic kidney disease registry, in 2010 only 2% of end stage kidney disease patients were managed with kidney transplantation, 37% were managed with dialysis and 61% were treated conservatively without renal replacement therapy. In countries like India, where a well‐organized deceased donor kidney transplantation program is not available, living donor kidney transplantation is the major source of organs for kidney transplantation. The most common reason to decline a donor for directed living donation is ABO incompatibility, which eliminates up to one third of the potential living donor pool. Because access to transplantation with human leukocyte antigen (HLA)‐desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end stage kidney disease patients. KPD is a rapidly growing and cost‐effective living donor kidney transplantation strategy for patients who are incompatible with their healthy, willing living donor. In principle, KPD is feasible for any centre that performs living donor kidney transplantation. In transplant centres with a large living donor kidney transplantation program KPD does not require extra infrastructure, decreases waiting time, avoids transplant tourism and prevents commercial trafficking. Although KPD is still underutilized in India, it has been performed more frequently in recent times. To substantially increase donor pool and transplant rates, transplant centres should work together towards a national KPD program and frame a uniform acceptable allocation policy.     

Tissue and blood protozoa including toxoplasmosis,Chagas disease,leishmaniasis, Babesia,Acanthamoeba, Balamuthia,and Naegleria in solid organ transplant recipients— Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of tissue and blood protozoal infections in the pre‐ and post‐transplant period. Significant new developments in the field have made it necessary to divide the previous single guideline published in 2013 into two sections, with the intestinal parasites separated from this guideline devoted to tissue and blood protozoa. The current update reflects the increased focus on donor screening and risk‐based recipient monitoring for parasitic infections. Increased donor testing has led to new recommendations for recipient management of Toxoplasma gondii and Trypanosoma cruzi. Molecular diagnostics have impacted the field, with access to rapid diagnostic testing for malaria and polymerase chain reaction testing for Leishmania. Changes in Babesia treatment regimens in the immunocompromised host are outlined. The risk of donor transmission of free‐living amebae infection is reviewed. Changing immigration patterns and the expansion of transplant medicine in developing countries has contributed to the recognition of parasitic infections as an important threat to transplant outcomes. Medications such as benznidazole and miltefosine are now available to US prescribers as access to treatment of tissue and blood protozoa is increasingly prioritized.     

Successful Heart Transplantation From a Donor With Ullrich Congenital Muscular Dystrophy

Heart transplantation is the most effective therapy for children with end‐stage heart disease; however, its use is limited by the number of donor organs available. This shortage may be further compounded by concerns about organ quality, leading to refusal of potential donor organ offers. We report on the successful transplantation and 5‐year follow‐up of a heart from a donor with Ullrich congenital muscular dystrophy (UCMD). The candidate was critically ill at the time of the transplant and the donor organ was declined repeatedly on the match run list due to concerns about organ quality, despite having normal cardiac function by echocardiography on minimal inotropic support. We believe the diagnosis of “muscular dystrophy” in the donor combined with a lack of understanding about the specifics of the diagnosis of UCMD enabled our candidate to receive a primary offer for this organ. We are unaware of any previous reports of the use of a heart from a donor with UCMD for orthotopic heart transplantation in adults or children.     

Impact of the OPTN transmissible diseases policy and US PHS increased risk donor guidelines on living donor candidates

Donor‐derived human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) transmissions in transplantation have led to policies mandating assessment of donor behavioral history, and disclosure of donor increased risk (IR) status to recipients. Organ Procurement Transplantation Network (OPTN) policy safeguards were promulgated in the context of deceased donation, with its narrow time window for organ utilization and uncertainty about donor history. These policies have been applied to living donation without substantive data on risk of disease transmission in living donor transplantation. Unlike for deceased donors, the OPTN does not collect data on living donor IR status. Given the feasibility of thorough living donor evaluation via already‐mandated lab tests and clinical assessments, living donor IR assessment and associated disclosures may have limited benefit in improving recipient informed consent. Applying the current IR policy to living donors may also introduce unintended consequences to donors and recipients, causing donors psychological harm, delays in donation to avoid IR status disclosure, and potential withdrawal from donation. We suggest strategies that reduce risk of harm to donor candidates while maintaining policy compliance, and review additional approaches for evaluating risk of disease transmission in living donor candidates. Data on the risk of disease transmission by living donors are needed to inform policy modification.     

Durability of the hepatitis B vaccination in pediatric renal transplant recipients

Since hepatitis B virus (HBV) vaccine implementation, HBV infection has significantly decreased. However, adult renal transplant recipients show a higher rate of seroreversion compared to the general population, leading to HBV infection risk. Data are limited in pediatric renal transplant recipients. Retrospective data were collected to determine the seroprotection and durability of HBV vaccination in pediatric renal transplant patients from 2004 to 2014. One hundred subjects were categorized based on pre‐ and post‐transplant hepatitis B surface antibody (HBsAb). Pretransplant, 85 recipients (85%) had a positive HBsAb compared to 15 (15%) with negative HBsAb. In univariable analyses, other than age (P < .05) no significant differences existed pretransplant by demographics, pretransplantation dialysis, or number of vaccinations. Of the 85 pretransplantation responders, 53 (62%) remained HBsAb positive post‐transplantation, 28 (32%) seroreverted, and 4 developed indeterminate titers. All seroreversions occurred within 5 years post‐transplant. Receipt of a living donor organ had higher risk of reversion (P = .005). No significant differences were found in demographics, pretransplantation dialysis, vaccination number, or acute rejection. Despite vaccination, 15% of pediatric renal transplant candidates were seronegative, and an additional 32% lost seroprotection within 5 years post‐transplantation leaving nearly half of transplant recipients at risk for HBV infection.     

Intestinal parasites including Cryptosporidium,Cyclospora, Giardia,and Microsporidia,Entamoeba histolytica,Strongyloides, Schistosomiasis,and Echinococcus: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of intestinal parasites in the pre‐ and post‐transplant period. Intestinal parasites are prevalent in the developing regions of the world. With increasing travel to and from endemic regions, changing immigration patterns, and the expansion of transplant medicine in developing countries, they are increasingly recognized as a source of morbidity and mortality in solid‐organ transplant recipients. Parasitic infections may be acquired from the donor allograft, from reactivation, or from de novo acquisition post‐transplantation. Gastrointestinal multiplex assays have been developed; some of the panels include testing for Cryptosporidium, Cyclospora, Entamoeba histolytica, and Giardia, and the performance is comparable to conventional methods. A polymerase chain reaction test, not yet widely available, has also been developed to detect Strongyloides in stool samples. New recommendations have been developed to minimize the risk of Strongyloides donor‐derived events. Deceased donors with epidemiological risk factors should be screened for Strongyloides and recipients treated if positive as soon as the results are available. New therapeutic agents and studies addressing the optimal treatment regimen for solid‐organ transplant recipients are unmet needs.     

Donor‐Derived Fungal Infections in Organ Transplant Recipients: Guidelines of the American Society of Transplantation,Infectious Diseases Community of Practice†

Donor‐derived fungal infections can be associated with serious complications in transplant recipients. Most cases of donor‐derived candidiasis have occurred in kidney transplant recipients in whom contaminated preservation fluid is a commonly proposed source. Donors with cryptococcal disease, including those with unrecognized cryptococcal meningoencephalitis may transmit the infection with the allograft. Active histoplasmosis or undiagnosed and presumably asymptomatic infection in the donor that had not resolved by the time of death can result in donor‐derived histoplasmosis in the recipient. Potential donors from an endemic area with either active or occult infection can also transmit coccidioidomycosis. Rare instances of aspergillosis and other mycoses, including agents of mucormycosis may also be transmitted from infected donors. Appropriate diagnostic evaluation and prompt initiation of appropriate antifungal therapy are warranted if donor‐derived fungal infections are a consideration. This document discusses the characteristics, evaluation and approach to the management of donor‐derived fungal infections in organ transplant recipients.     

Transplantation of high‐risk donor organs: a survey of US solid organ transplant center practices as reported by transplant infectious diseases physicians

Abstract: Public Health Service (PHS) guidelines developed in 1994 provide guidance to minimize the risk of HIV transmission and to monitor recipients following the transplantation of “high‐risk” organs. There are no data on current practices or opinions of these policies by transplant infectious diseases (TID) physicians. An electronic survey was sent to all US solid organ transplatation centers with identified TID expertise as self‐reported to the American Society of Transplantation and Infectious Diseases Society of America. A total of 108 surveys were sent in December 2007 and 32 responses were received (30%). Thirty‐three percent of centers obtain only verbal, 52% verbal and written, and 14% do not obtain any special consent from recipients of organs from high‐risk donors (ROHRD). Post‐solid organ transplantation serologies for HIV, hepatitis B (HBV), and hepatitis C virus (HCV) are obtained at 40% of centers in ROHRD only, 20% in all recipients, and not performed in 40%; post‐solid organ transplantation nucleic acid testing (NAT) testing is carried out in 36–45% of centers in ROHRD, 11% in all recipients, and not performed in approximately 50% of centers. Only 22.7% of respondents believed current guidelines accurately represent what they consider to be high‐risk donors. There is significant variability in the acceptance and management of ROHRD in the US. Most TID experts do not feel that the current PHS guidelines accurately define high‐risk donors.     

MicroRNA‐21 (miR‐21) expression in hypothermic machine perfusate may be predictive of early outcomes in kidney transplantation

Hypothermic machine perfusion is effective in improving outcome following kidney transplantation. Molecular analyses of hypothermic machine perfusate (HMP) have the potential to identify biomarkers of organ viability prior to transplantation, offering significant advantages to the transplant surgeon, and leading to a potential increase in the organ donor pool. MicroRNAs are emerging as important biomarkers in the context of kidney injury and transplantation. Recent data demonstrate increased microRNA‐21 (miR‐21) expression in the kidney following acute kidney injury. This study investigated the potential of miR‐21 detected in HMP to act as a sentinel for early kidney transplant outcomes. MiR‐21 was found to be readily detectable in HMP by RT‐qPCR. Eleven ECD kidneys were maintained on a hypothermic machine perfusion system for a median 627 (range 117–1027) minutes, and evaluation of flow and resistance characteristics suggested stability on the machine from 60 min post‐perfusion. MiR‐21 quantification at 60 min post‐perfusion correlated with eGFR at 6 and 12 months post‐transplantation. These data suggest that miR‐21 expression in HMP may be predictive of early outcomes following kidney transplantation. In the era of ECD kidneys, a reliable measure of organ quality is urgently needed, and this study suggests miR‐21 may be such a marker.     

Cryptococcosis in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of cryptococcosis in the pre‐ and post‐transplant period. The current update now includes a discussion of cryptococcosis, which is the third most common invasive fungal infection in SOT recipients. Infection often occurs a year after transplantation; however, early infections occur and donor‐derived infections have been described within 3 months after transplant. There are two main species that cause infection, Cryptococcus neoformans and C gattii. Clinical onset may be insidious, but headaches, fevers, and mental status changes should warrant diagnostic testing. The lateral flow cryptococcal antigen assay is now the preferred test from serum and cerebrospinal fluid due to its rapidity, accuracy, and cost. A lumbar puncture with measurement of opening pressure is recommended for patients with suspected or proven cryptococcosis. Lipid amphotericin B plus 5‐flucytosine is used as initial treatment of meningitis, disseminated infection, and moderate‐to‐severe pulmonary infection, followed by fluconazole as consolidation therapy. Fluconazole is effective for mild‐to‐moderate pulmonary infection. Immunosuppression reduction as part of management may lead to immune reconstitution syndrome that may resemble active disease.     

The Risk of End‐Stage Renal Disease Among Living Donor Liver Transplant Recipients in the United States

Since initiation of model for end‐stage liver disease (MELD)‐based allocation for liver transplantation, the risk of posttransplant end‐stage renal disease (ESRD) has increased. Recent US data have demonstrated comparable, if not superior survival, among recipients of living donor liver transplants (LDLT) when compared to deceased donor liver transplant (DDLT) recipients. However, little is known about the incidence of ESRD post‐LDLT. We analyzed linked Scientific Registry of Transplant Recipients (SRTR) and US Renal Data System (USRDS) data of first‐time liver‐alone transplant recipients from February 27, 2002 to March 1, 2011, and restricted the cohort to recipients with a laboratory MELD score ≤25 not on dialysis prior to transplantation, in order to evaluate the incidence of ESRD post‐LDLT, and to compare the incidence among LDLT versus DDLT recipients. There were 28 707 DDLT and 1917 LDLT recipients included in the analyses. The 1‐, 3‐ and 5‐year unadjusted risk of ESRD was 1.7%, 2.9% and 3.4% in LDLT recipients, compared with 1.5%, 3.0% and 4.8% in DDLT recipients (p > 0.05), respectively. In multivariable competing risk Cox regression models, there was no association between receiving an LDLT and risk of ESRD (sub‐hazard ratio: 0.99, 95% CI: 0.77–1.26, p = 0.92). In conclusion, the incidence of ESRD post‐LDLT in the United States is low, and there are no significant differences among LDLT and DDLT recipients with MELD scores ≤25 at transplantation.     

Four years of experience with the Australian kidney paired donation programme

New approaches to increase kidney transplantation rates through expansion of live donor kidney transplantation have become necessary due to ongoing shortage of deceased donor organs. These strategies include desensitization in antibody‐incompatible transplants to overcome the barrier of blood group incompatibility or human leucocyte antigen antibodies between recipient and donor and kidney paired donation (KPD) programmes. In KPD, a kidney transplant candidate with an incompatible live donor joins a registry of other incompatible pairs in order to find potentially compatible transplant solutions. To match the largest possible number of donor–recipient pairs while minimizing immunologic risk, KPD programmes use sophisticated algorithms to identify suitable matches with simultaneous two‐way or more complex multi‐way exchanges as well as including non‐directed anonymous donors to start a chain of compatible transplantations. Because of the significant immunologic barriers when fewer donor options are available, the optimal solution for difficult‐to‐match, highly sensitized patients is access to more potential donors using large multi‐centre or national KPD registries. This review focuses on the first 4 years of experience with the Australian multi‐centre KPD programme that was established in October 2010.     

Functional analysis of CD4+ CD25bright T cells in kidney transplant patients: improving suppression of donor-directed responses after transplantation

Abstract: Background: The role of CD4⁺ CD25^bright regulatory T cells (Treg) in controlling alloreactivity is established, but little is known whether antigen‐specific Treg are induced in fully immunosuppressed kidney transplant patients. Methods: The frequency and function of CD25^bright T cells of nine stable kidney transplant patients before and 0.5–2 yr after transplantation were measured. Patients received triple therapy consisting of cyclosporine, mycophenolate mofetil and prednisone. To investigate the influence of transplantation and immunosuppression on Treg function, we compared their suppressive capacities pre‐ and post‐transplantation using mixed lymphocyte reactions and kept the CD25^?/dim effector T‐cell (Teff) population constant. Results: After transplantation, the percentage of CD4⁺ CD25^bright T cells significantly decreased from 8.5% pre‐transplant to 6.9% post‐transplant (median, p = 0.05). However, the lower percentage of post‐transplant CD4⁺ CD25^bright T cells was not associated with reduced, but rather improved suppressor function of these cells. The proliferative response of pre‐transplant Teff to donor‐antigens was more profoundly suppressed by post‐transplant Treg than by pre‐transplant Treg (pre‐transplant 18% vs. post‐transplant 55% median, p = 0.03) and was comparable against third party antigens at a CD25^bright:CD25^?/dim ratio of 1:20. Conclusions: In immunosuppressed kidney transplant patients, the donor‐directed suppressive capacity of CD4⁺ CD25^bright regulatory T cells improved, which may contribute to the development of donor‐specific hyporesponsiveness against the graft.     

Leishmaniasis in solid organ and hematopoietic stem cell transplant recipients

Leishmaniasis occurs in <1% of solid organ and hematopoietic stem cell transplant recipients in endemic countries in which transplants are performed. Visceral leishmaniasis (VL) makes up the bulk of reported cases. The onset generally occurs months after transplantation and the mode of acquisition is often impossible to determine, but de novo vector‐borne infection and reactivation of inapparent infection are thought to be the principal means. The potential role of clinically inapparent donor infection is uncertain and screening is not currently recommended, nor is it recommended for recipients from endemic areas, some of whom may have detectable circulating protozoan nucleic acid. While transplant recipients with VL often present with the non‐specific findings of fever and cytopenia, the additional presence of hepatosplenomegaly in patients from endemic areas should lead to a directed diagnostic evaluation with bone marrow examination and PCR testing of marrow and peripheral blood having a high yield. Management may often be complicated by the presence of concomitant infections. A lipid formulation of amphotericin B is the preferred treatment, especially for VL, but the relapse rate in transplant recipients is approximately 25%. PCR monitoring of blood for either secondary prophylaxis or preemptive therapy requires further study.