The 50 most-cited articles in Transplantation, 2017

The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors is intended to assist medical professionals who evaluate living kidney donor candidates and provide care before, during and after donation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach and guideline recommendations are based on systematic reviews of relevant studies that included critical appraisal of the quality of the evidence and the strength of recommendations. However, many recommendations, for which there was no evidence or no systematic search for evidence was undertaken by the Evidence Review Team, were issued as ungraded expert opinion recommendations. The guideline work group concluded that a comprehensive approach to risk assessment should replace decisions based on assessments of single risk factors in isolation. Original data analyses were undertaken to produce a "proof-in-concept" risk-prediction model for kidney failure to support a framework for…

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and…

In Brief Kidney Disease: Improving Global Outcomes (KDIGO) engaged an evidence review team and convened a work group to produce a guideline to evaluate and manage candidates for living kidney donation. The evidence for most guideline recommendations is sparse and many “ungraded” expert consensus recommendations were made to guide the donor candidate evaluation and care before, during, and after donation. The guideline advocates for replacing decisions based on assessments of single risk factors in isolation with a comprehensive approach to risk assessment using the best available evidence. The approach to simultaneous consideration of each candidate’s profile of demographic and health characteristics advances a new framework for assessing donor candidate risk and for defensible shared decision making. One of the most important tasks we have to undertake is to evaluate and then care for living donors. This paper provides a summary of the KDIGO Guidelines and encapsulates what you will find in the guidelines themselves, which are published in full in a separate supplement. Care of our…

BACKGROUND: Antipig antibodies are a barrier to clinical xenotransplantation. We evaluated antibody binding of waitlisted renal transplant patients to 3 glycan knockout (KO) pig cells and class I swine leukocyte antigens (SLA). METHODS: Peripheral blood mononuclear cells from SLA identical wild type (WT), α1, 3-galactosyltransferase (GGTA1) KO, GGTA1/ cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) KO, and GGTA1/ CMAH /b1,4 N-acetylgalactosaminyl transferase (B4GalNT2) KO pigs were screened for human antibody binding using flow cytometric crossmatch (FCXM). Sera from 820 patients were screened on GGTA1/CMAH/B4GalNT2 KO cells and a subset with elevated binding was evaluated further. FCXM was performed on SLA intact cells and GGTA1/SLA class I KO cells after depletion with WT pig RBCs to remove cell surface reactive antibodies, but leave SLA antibodies. Lastly, human and pig reactive antibodies were eluted and tested for cross-species binding and reactivity to single-antigen HLA beads. RESULTS: Sequential glycan KO modifications significantly reduce antibody binding…

BACKGROUND: A program of normothermic ex situ liver perfusion (NESLiP) was developed to facilitate better assessment and use of marginal livers, while minimizing cold ischemia. METHODS: Declined marginal livers and those offered for research were evaluated. Normothermic ex situ liver perfusion was performed using an erythrocyte-based perfusate. Viability was assessed with reference to biochemical changes in the perfusate. RESULTS: Twelve livers (9 donation after circulatory death [DCD] and 3 from brain-dead donors), median Donor Risk Index 2.15, were subjected to NESLiP for a median 284 minutes (range, 122-530 minutes) after an initial cold storage period of 427 minutes (range, 222-877 minutes). The first 6 livers were perfused at high perfusate oxygen tensions, and the subsequent 6 at near-physiologic oxygen tensions. After transplantation, 5 of the first 6 recipients developed postreperfusion syndrome and 4 had sustained vasoplegia; 1 recipient experienced primary nonfunction in conjunction with a difficult explant. The subsequent 6 liver transplants, with livers perfused at lower…

BACKGROUND: Treatment decisions in kidney transplantation requires patients and clinicians to weigh the benefits and harms of a broad range of medical and surgical interventions, but the heterogeneity and lack of patient-relevant outcomes across trials in transplantation makes these trade-offs uncertain, thus, the need for a core outcome set that reflects stakeholder priorities. METHODS: We convened 2 international Standardized Outcomes in Nephrology-Kidney Transplantation stakeholder consensus workshops in Boston (17 patients/caregivers; 52 health professionals) and Hong Kong (10 patients/caregivers; 45 health professionals). In facilitated breakout groups, participants discussed the development and implementation of core outcome domains for trials in kidney transplantation. RESULTS: Seven themes were identified. Reinforcing the paramount importance of graft outcomes encompassed the prevailing dread of dialysis, distilling the meaning of graft function, and acknowledging the terrifying and ambiguous terminology of rejection. Reflecting critical trade-offs between graft health and…

BACKGROUND: Nonalcoholic steatohepatitis (NASH), a clinically aggressive variant of nonalcoholic fatty liver disease (NAFLD), is becoming an increasingly common indication for liver transplantation (LT); however, relatively little is known regarding its clinical course post-LT. The aim of the current study is to describe disease recurrence and clinical course after LT. METHODS: All surviving patients transplanted for NASH at the authors' institution had transient elastography (TE) to evaluate hepatic steatosis and fibrosis. The charts of deceased patients were reviewed for liver biopsy to evaluate for disease recurrence. Finally, causes of mortality in these patients were evaluated. RESULTS: Of the 103 patients who met criteria, 56 had TE, whereas 34 had a liver biopsy. Steatosis was detected in 49 (87.5%) of the patients who had a TE and were defined to have recurrent NAFLD. Most patients had liver stiffness measurements consistent with no fibrosis (42.9%) or F1-F2 fibrosis (30.4%). Advanced fibrosis was noted in 26.8%, whereas 5.4% had cirrhosis but were clinically compensated. In…

Uterus transplantation (UTx) has been successfully introduced as a treatment option for women with absolute uterine factor infertility (AUFI). AUFI representing approximately 3% to 5% of the female general population is linked to either congenital uterine agenesis (Mayer-Rokitansky-Küster-Hauser syndrome), major congenital uterine malformation (hypoplastic uterus, fraction of bicornuate/unicornuate uterus), a surgically absent uterus, or an acquired condition (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defect placentation. The world's first clinical uterus transplant was performed in 2000. However, a hysterectomy became necessary shortly after the surgery due to uterine necrosis. In 2011, a group in Turkey reported on a surgically successful deceased donor transplant; however, this procedure has, to date, not resulted in a healthy live birth, the ultimate goal of UTx. Building on an extensive experimental background in various animal models, including primates, the Gothenburg group led by Brännström reported on the first…

BACKGROUND: Health-related quality of life (HRQOL) reflects a patient's disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT. METHODS: We ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models. RESULTS: Mean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney…

In Brief Antibiotic prophylaxis in the perioperative period is the standard of care for nearly all surgical procedures and routinely prescribed during solid organ transplantation (SOT). The primary goal of perioperative antibiotic prophylaxis is to minimize postoperative surgical site infections (SSIs). SSIs are a significant issue in SOT. Depending on the organ transplanted, SSIs occur in 3% to 53% of patients, with the highest rates observed in small bowel/multivisceral, liver, and pancreas transplant recipients. SOT recipients are also at increased risk of developing SSIs with antimicrobial-resistant organisms. In this article, we describe the epidemiology and risk factors for SSIs in SOT and examine the available literature to guide the use of different regimens for perioperative antibiotic prophylaxis for each organ. We have further addressed specific situations that are unique to each organ transplant type, such as the use of extracorporeal membrane oxygenation in thoracic organ transplantation, as well as an approach to perioperative antibiotic prophylaxis in the setting of…

BACKGROUND: Only a limited number of centers have performed laparoscopic living donor hepatectomy to date. In particular, laparoscopic right hepatectomy is rarely performed because the procedure can only be performed by surgeons with significant experience in both laparoscopic liver surgery and liver transplantation with living donor liver grafts. METHODS: Between November 2014 and February 2015, in a pure laparoscopic approach program for living right lobe donors at Asan Medical Center, 92 living donors underwent right hepatectomy for adult living donor liver transplantation. Among these, 3 pure laparoscopic living donor right hepatectomies were performed in 3 young female donors. RESULTS: The intraoperative and postoperative courses for all 3 donors and recipients were uneventful without any complications. Laparoscopic living donor hepatectomy has definite advantages over conventional open surgery, including decreased wound morbidity and faster recovery. CONCLUSIONS: According to the data of the present report, pure laparoscopic living donor right hepatectomy in properly selected…

Liver allocation in Eurotransplant is complex because allocation rules need to follow not only the guidelines of the European Commission but also the specific regulations of each of the 7 Eurotransplant countries with active liver transplant programs. Thirty-eight liver transplant centers served a population of about 135 million in 2015. Around 1600 deceased donor livers are transplanted annually. The number of deceased organ donors remains stable but donor age is increasing. Nevertheless, liver utilization rates are unchanged at around 80%. Donation after circulatory determination of death (DCD) increased fourfold in the past decade. In Belgium and the Netherlands, DCDs were responsible for 30% of deceased donor liver transplant activity in 2015; Austria only occasionally transplants a DCD liver; other Eurotransplant countries do not have active DCD programs. The most frequent indications for liver transplantation are alcoholic liver disease, hepatocellular carcinoma, and viral hepatitis. Livers are allocated first internationally to high urgency status patients or those with an…

Because of the lack of adequate organs, the number of patients with end-stage liver diseases, acute liver failure or hepatic malignancies waiting for liver transplantation is constantly increasing. Accepting aged liver grafts is one of the strategies expanding the donor pool to ease the discrepancy between the growing demand and the limited supply of donor organs. However, recipients of organs from old donors may show an increased posttransplantation morbidity and mortality due to enhanced ischemia-reperfusion injury. Energy metabolism, inflammatory response, and autophagy are 3 critical processes which are involved in the aging progress as well as in hepatic ischemia-reperfusion injury. Compared with young liver grafts, impairment of energy metabolism in aged liver grafts leads to lower adenosine triphosphate production and an enhanced generation of free radicals, both aggravating the inflammatory response. The aggravated inflammatory response determines the extent of hepatic ischemia-reperfusion injury and augments the liver damage. Autophagy protects cells by removal of damaged…

BACKGROUND: Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L. METHODS: Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury. RESULTS: The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro…

Inhibitors of the mechanistic target of rapamycin (mTOR) have unique antiatherosclerotic effects, such as depletion of plaque macrophages, induction of autophagy, and activation of cholesterol efflux. However, a common side effect of their use is dyslipidemia, a well-known risk factor for atherosclerosis. Indeed, mTOR inhibitors prevent lipid storage, increase low-density lipoprotein cholesterol levels, and activate lipolysis. Although the net effect of mTOR inhibition seems favorable, the use of cholesterol lowering drugs to manage dyslipidemia remains the most recommended strategy.

BACKGROUND: Cardiovascular events represent a major source of morbidity and mortality after liver transplantation and will likely increase given the aging population and nonalcoholic fatty liver disease as a leading indication for transplant. The optimal cardiovascular risk stratification approach in this evolving patient population remains unclear. The aims of this systematic review are to: (1) refine the definition, (2) characterize the incidence, and (3) identify risk factors for cardiovascular events post-liver transplantation. Additionally, we evaluated performance characteristics of different cardiac testing modalities. METHODS: MEDLINE via PubMed, EMBASE, Web of Science, and Scopus were searched for studies published between 2002 and 2016 (model of end-stage liver disease era). Two authors independently reviewed articles to select eligible studies and performed data abstraction. RESULTS: Twenty-nine studies representing 57 493 patients from 26 unique cohorts were included. Definitions of cardiovascular outcomes were highly inconsistent. Incidence rates were widely variable:…

Despite the rapidly increasing prevalence of obesity in the transplant population, the optimal management of obese liver transplant candidates remains undefined. Setting strict body mass index cutoffs for transplant candidacy remains controversial, with limited data to guide this practice. Body mass index is an imperfect measure of surgical risk in this population, partly due to volume overload and variable visceral adiposity. Weight loss before transplantation may be beneficial, but it remains important to avoid protein calorie malnutrition and sarcopenia. Intensive lifestyle modifications appear to be successful in achieving weight loss, though the durability of these interventions is not known. Pretransplant and intraoperative bariatric surgeries have been performed, but large randomized controlled trials are lacking. Traditional cardiovascular comorbidities are more prevalent in obese individuals and remain the basis for pretransplant cardiovascular evaluation and risk stratification. The recent US liver transplant experience demonstrates comparable patient and graft survival…

BACKGROUND: Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. METHODS: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents' scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. RESULTS: One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups…

In Brief Background Over 130 000 patients in the United States alone need a lifesaving organ transplant. Genetically modified porcine organs could resolve the donor organ shortage, but human xenoreactive antibodies destroy pig cells and are the major barrier to clinical application of xenotransplantation. The objective of this study was to determine whether waitlisted patients possess preformed antibodies to swine leukocyte antigen (SLA) class II, homologs of the class II HLA. Methods Sera from people currently awaiting solid organ transplant were tested for IgG binding to class II SLA proteins when expressed on mammalian cells. Pig fibroblasts were made positive by transfection with the class II transactivator. As a second expression system, transgenes encoding the alpha and beta chains of class II SLA were transfected into human embryonic kidney cells. Results Human sera containing IgG specific for class II HLA molecules exhibited greater binding to class II SLA positive cells than to SLA negative cells. Sera lacking antibodies against class II HLA showed no change in binding…

In Brief An expert panel from ILTS reviews the approach to management of HCV in the transplant recipient in the era of direct-acting anti-virals. Considerations range from preemption of recurrence to the treatment of fibrosing cholestatic hepatitis.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication in organ transplant recipients and is most often associated with the Epstein Barr virus (EBV). EBV is a common gammaherpes virus with tropism for B lymphocytes and infection in immunocompetent individuals is typically asymptomatic and benign. However, infection in immunocompromised or immunosuppressed individuals can result in malignant B cell lymphoproliferations, such as PTLD. EBV+ PTLD can arise after primary EBV infection, or because of reactivation of a prior infection, and represents a leading malignancy in the transplant population. The incidence of EBV+ PTLD is variable depending on the organ transplanted and whether the recipient has preexisting immunity to EBV but can be as high as 20%. It is generally accepted that impaired immune function due to immunosuppression is a primary cause of EBV+ PTLD. In this overview, we review the EBV life cycle and discuss our current understanding of the immune response to EBV in healthy, immunocompetent individuals, in transplant recipients, and in PTLD patients.…

BACKGROUND: It has been postulated that short wait time before liver transplant (LT) for hepatocellular carcinoma (HCC) results in the inclusion of tumors with aggressive biology, but prolonged wait time could result in a shift to more aggressive tumor behavior. We therefore test the hypothesis that a wait time "sweet spot" exists with a lower risk for HCC recurrence compared with the other 2 extremes. METHODS: This multicenter study included 911 patients from 3 LT centers with short, medium, and long wait times (median of 4, 7, and 13 months, respectively) who received Model for End Stage Liver Disease exception listing for HCC from 2002 to 2012. RESULTS: Wait time, defined as time from initial HCC diagnosis to LT, was less than 6 months in 32.4%, 6 to 18 months in 53.7%, and greater than 18 months in 13.9%. Waitlist dropout was observed in 18.4% at a median of 11.3 months. Probability of HCC recurrence at 1 and 5 years were 6.4% and 15.5% with wait time of less than 6 or greater than 18 months (n = 343) versus 4.5% and 9.8% with wait time of 6 to 18 months (n = 397), respectively…

BACKGROUND: The Public Health Service "Increased Risk" (PHS IR) designation identifies donors at increased risk of transmitting hepatitis B, C, and human immunodeficiency virus. Although the risk remains very low in the era of nucleic acid testing, we hypothesized that this label may result in decreased organ utilization. METHODS: Organ Procurement and Transplantation Network data were used to compare utilization rates between PHS-IR and non-PHS-IR donors, as well as to compare export rates and variation in utilization. RESULTS: Among adult standard criteria donors between 2010 and 2013 with a known PHS-IR status, covariate-adjusted utilization rates were lower among PHS-IR donors than non-PHS-IR donors for all organs. For example, 4073 (76.7%) of 5314 PHS-IR kidneys were used, compared with 25 490 (83.7%) of 30 456 non-PHS-IR kidneys-an absolute difference of 7%. Furthermore, all PHS-IR organs had higher export rates than non-PHS-IR organs. For example, 28.7% of PHS-IR kidneys were exported versus 19.7% of non-PHS-IR kidneys. Finally, the utilization rate of PHS-IR organs varied by…

BACKGROUND: There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. METHODS: Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. RESULTS: The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421…

Immunoglobulin G (IgG) is the dominant immunoglobulin and can be divided into 4 distinct subclasses. The evolution of IgG subclass switches is regulated by interaction with T cells and follows a 1-way direction (IgG3 → IgG1 → IgG2 → IgG4). Based on their structure, the 4 IgG subclasses can initiate different effector function such as complement activation, recruitment of various cells by Fc receptors, and agonistic signaling. Using current assays for HLA antibody detection as a template and replacing the generic reporter antibody with IgG subclass-specific reporter antibodies, it is possible to investigate the IgG subclasses of HLA antibodies. There are 15 different IgG subclass compositions possible. Based on the capability to activate the complement system and the class switch direction, 3 arbitrary patterns can be defined (ie, only complement-binding subclasses [IgG3 and/or IgG1], expansion to noncomplement-binding subclasses [IgG3 and/or IgG1 plus IgG2 and/or IgG4], and switch to noncomplement-binding subclasses [IgG2 and/or IgG4]). The latter group accounts for less than 5%,…

The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many developed countries over the last decade, predominantly due to infection with genotype 3 (G3) HEV. Infection with HEV G3 is important in transplant recipients because it can persist in immunosuppressed individuals, leading, if untreated, to the development of chronic hepatitis and significant liver fibrosis. The British Transplantation Society (BTS) has developed Guidelines for "Hepatitis E and Solid Organ Transplantation" to inform clinical teams and patients about hepatitis E, to help increase the recognition of persistent hepatitis E infection, and to provide clear guidance on its management. This guideline was published on the BTS website in June 2017 and aims to review the evidence relating to the diagnosis and management of persistent hepatitis E in solid organ transplant recipients and the methods of prevention of HEV infection. In line with previous guidelines published by the BTS, the guideline has used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE)…

BACKGROUND: The human regulatory macrophage (Mreg) has emerged as a promising cell type for use as a cell-based adjunct immunosuppressive therapy in solid organ transplant recipients. In this brief report, dehydrogenase/reductase 9 (DHRS9) is identified as a robust marker of human Mregs. METHODS: The cognate antigen of a mouse monoclonal antibody raised against human Mregs was identified as DHRS9 by immunoprecipitation and MALDI-MS sequencing. Expression of DHRS9 within a panel of monocyte-derived macrophages was investigated by quantitative PCR, immunoblotting and flow cytometry. RESULTS: DHRS9 expression discriminated human Mregs from a panel of in vitro derived macrophages in other polarisation states. Likewise, DHRS9 expression distinguished Mregs from a variety of human monocyte-derived tolerogenic antigen-presenting cells in current development as cell-based immunotherapies, including Tol-DC, Rapa-DC, DC-10, and PGE2-induced myeloid-derived suppressor cells. A subpopulation of DHRS9-expressing human splenic macrophages was identified by immunohistochemistry. Expression of…

BACKGROUND: Families are often asked to consent to the donation of their deceased relative's organs or tissues. These end-of-life conversations are important because they affect consent rates as well as the psychological impact of the decision for families. This scoping review of the literature on requesting family consent was prepared to support of the development of leading practice recommendations for end-of-life conversations with families of potential donors. A scoping review maps research activity in a field across a range of commentary and empirical study designs but does not attempt meta-synthesis of empirical data or quality assessment. METHODS: We performed a scoping review of the peer-reviewed literature from January 2000 to February 2015 on the questions of what constitutes an "effective" request and the factors that affect consent rates and family satisfaction with their decision and the process. This review includes a final set of 168 articles addressing (a) whether, when, and how to ask families for consent to donation or (b) characteristics of families or decedents…

BACKGROUND: Mycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium, and it is widely used after organ transplantation. In women, taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by men exposed to MPA. METHODS: We compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. A nationwide population-based retrospective cohort study was performed. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway. RESULTS: During the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significant increased risks of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts of children. The average dose (±SD) of…

The old-for-old allocation policy used for kidney transplantation (KT) has confirmed the survival benefit compared to remaining listed on dialysis. Shortage of standard donors has stimulated the development of strategies aimed to expand acceptance criteria, particularly of kidneys from elderly donors. We have systematically reviewed the literature on those different strategies. In addition to the review of outcomes of expanded criteria donor or advanced age kidneys, we assessed the value of the Kidney Donor Profile Index policy, preimplantation biopsy, dual KT, machine perfusion and special immunosuppressive protocols. Survival and functional outcomes achieved with expanded criteria donor, high Kidney Donor Profile Index or advanced age kidneys are poorer than those with standard ones. Outcomes using advanced age brain-dead or cardiac-dead donor kidneys are similar. Preimplantation biopsies and related scores have been useful to predict function, but their applicability to transplant or refuse a kidney graft has probably been overestimated. Machine perfusion techniques have…

BACKGROUND: The current Organ Procurement Transplantation Network policy grants Model for End-Stage Liver Disease (MELD) exception points to patients with portopulmonary hypertension (POPH), but potentially important factors, such as severity of liver disease and pulmonary hypertension, are not included in the exception score, and may affect survival. The purpose of this study was to identify significant predictors of waitlist mortality in patients with POPH. METHODS: We performed a retrospective cohort study of patients in the Organ Procurement and Transplantation Network database with hemodynamics consistent with POPH (defined as mean pulmonary arterial pressure >25 mm Hg and pulmonary vascular resistance [PVR] ≥240 dynes·s·cm) who were approved for a POPH MELD exception between 2006 and 2014. Using a Cox proportional hazards model, we identified predictors of waitlist mortality (or removal for clinical deterioration). RESULTS: One hundred ninety adults were included. Age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.00-1.08; P = 0.0499), initial native MELD score (HR,…

In Brief Background Coronary artery disease (CAD) is a significant problem during evaluation for liver transplantation (LT). We aim to assess survival in LT recipients based on presence, severity, extent of CAD, and cardiac events within 90 days of LT. Methods Eighty-seven LT recipients with history of pre-LT angiogram (December 2005 to December 2012) were compared with 2 control groups without prior angiogram, 72 LT recipients matched for cardiovascular risk factors (control group I), and 119 consecutive LT recipients without any CV risk factors (control group II). CAD was assessed by (1) vessel score (≥50% reduction in luminal diameter), and (2) Extent score (Reardon scoring system). Results Of the 87 LT recipients (study group), 58 (66.7%) had none or less than 50% stenosis, 29 (33.3%) had obstructive CAD (≥50% stenosis), 7 (8%) with single-vessel disease, and 22 (25.3%) with multivessel disease. In the study group, irrespective of prerevascularization severity of CAD (P = 0.357), number of segments involved (0, 1-2, > 2 segments, P = 0.304) and extent of CAD based on Reardon…

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease with a high rate of recurrence after kidney transplantation. Several factors, such as white race, rapid progression, and previous allograft failure due to recurrence, were found to be risks of recurrence. Data are limited on the benefits of rituximab and/or therapeutic plasma exchange (TPE) in preventing recurrence. In this study, we sought to assess the efficacy of rituximab and TPE for the prevention and treatment of recurrent FSGS after kidney transplantation. METHODS: We enrolled 66 patients with FSGS in this prospective observational study and followed their outcomes. Patients with high risk for recurrence received preventative therapy with TPE and/or rituximab. RESULTS: Twenty-three (62%) of the 37 patients who received preventative therapy developed recurrence compared with 14 (51%) recurrences of the 27 patients who did not receive any therapy (P = 0.21). There was a trend for less relapse when rituximab was used as a therapy for recurrent FSGS (6/22 vs 9/18, P = 0.066). We…

BACKGROUND: Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated. METHODS: Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes. RESULTS: The rejection incidence was higher in belatacept-treated…

BACKGROUND: Intensive Care to facilitate Organ Donation (ICOD) may help to increase the donor pool. We describe the Spanish experience with ICOD. METHODS: Achieving Comprehensive Coordination in Organ Donation (ACCORD)-Spain consisted of an audit of the donation pathway from patients who died as a result of a devastating brain injury (possible donors) in 68 hospitals during November 1, 2014, to April 30, 2015. We focused on possible donors whose families were interviewed to discuss organ donation once intensive care with a therapeutic purpose was deemed futile and brain death (BD) was a likely outcome. RESULTS: Of the 1970 possible donors in ACCORD-Spain, in 257, the family was interviewed once the decision had been made not to intubate/ventilate (n = 105), with the patient under intubation/ventilation outside of the intensive care unit (n = 59), or with the patient intubated/ventilated within the intensive care unit (n = 93).Consent to ICOD was obtained in 174 cases. Consent was higher when the donor coordinator participated in the interview (odds ratio, 2.32; 95% confidence…

BACKGROUND: The Model of Early Allograft Function (MEAF) grades the severity of liver graft dysfunction. Unlike the categorical early allograft dysfunction (EAD) classification, MEAF is a continuous score, based on bilirubin, international normalized ratio, and alanine aminotransferase within 3 days posttransplant. METHODS: Multivariable regression models were used to validate the MEAF score in 660 liver-only transplants performed between 2000 and 2014. MEAF performance for prediction of transplant survival was compared with that of EAD in univariable and multivariable models by means of Harrell's c-indices, integrated discrimination improvement, and net reclassification improvement. RESULTS: Median donor and recipient age was 52 years (interquartile range [IQR], 41-62 years) and 58 years (IQR, 50-64 years), respectively. Model for End-Stage Liver Disease score was 15 (IQR, 11-21); cold ischemia time, 8.0 hours (IQR, 6.4-9.7 hours); MEAF, 4 (IQR, 3-6). EAD occurred in 182 (27.6%) cases. Transplant survival was 93%, 90%, and 88% at 3, 6, and 12 months. Both MEAF and EAD were…

HLA antibodies, and specifically donor-specific-HLA antibodies, play a key role in transplant-related diagnostics and decision-making. It is now clear that the simple differentiation between absence and presence of HLA donor-specific antibodies does not provide sufficient granularity in all clinical circumstances. It addition, knowledge of HLA antibody strength has potential utility at different stages of recipient evaluation along the transplant timeline from initial pretransplant evaluation, evaluation of a specific potential donor, and posttransplant monitoring for de novo donor-specific antibodies. Here we compare data evaluating HLA antibody strength using the conventional IgG-mean fluorescence intensity approach with serial dilution studies (titration) and of C1q binding (C1q-mean fluorescence intensity). The added value of titration studies along the 3 milestones of the transplant cycle is emphasized.

In Brief Background As more patients survive into adulthood with repaired congenital heart disease (CHD), transplant centers now have patients presenting with both end-stage cardiac and hepatic failure. An understanding of the contemporary outcomes with combined heart liver transplantation (CHLT) in patients with CHD is needed. Methods A retrospective review of the outcomes of CHLT in CHD was conducted from October 1, 1987, to June 30, 2015, from the United Network of Organ Sharing (UNOS) database. Propensity score matched cohorts were formed for the assessment of posttransplant outcome: CHLT with CHD, CHLT without CHD, and isolated heart transplant for CHD (HT-CHD). Cohorts were matched based on age, body mass index, inotrope use, and ventilator support at the time of transplant. We assessed 30-day, 1-, 5-, and 10-year posttransplant survivals. Results There were 61 437 heart transplants during the study period, of which 190 (0.3%) were CHLT. Among CHLT, 41(22%) patients had CHD. In 26 (63%) of these, the indication for CHLT was hepatic congestion/cirrhosis of cardiac origin. In…

In Brief Background In a statement from the second International Consensus Conference for Laparoscopic Liver Resection, adult-to-adult laparoscopic donor surgery was the earliest phase of development. It was recommended that the procedure be performed under institutional ethical approval and a reporting registry. Method At our institute, we started laparoscopy-assisted donor hepatectomy (LADH) in 2007 and changed to pure laparoscopic donor hepatectomy (PLDH) in 2012. This study included 40 living donors who underwent LADH and 14 live donors who underwent PLDH. We describe the technical aspects and outcomes of our donor hepatectomy from assist to pure and examine the liver allograft outcomes of the recipients after LADH and PLDH. Results There was significantly less blood loss in the PLDH group (81.07 ± 52.78 g) than that in the LADH group (238.50 ± 177.05 g), although the operative time was significantly longer in the PLDH group (454.93 ± 85.60 minutes) than in the LADH group (380.40 ± 44.08 minutes). And there were no significant differences in postoperative complication rate in…

BACKGROUND: Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to…

BACKGROUND: Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure. METHODS: Single-center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, chronic lung allograft dysfunction (CLAD) progression, death, change in mean arterial pressure, and estimated glomerular filtration rate. RESULTS: Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic…

BACKGROUND: Alcoholic liver disease is a common indication for orthotopic liver transplantation (OLT). Although OLT has been shown to confer survival benefit to patients with acute alcoholic hepatitis (AAH), historically most programs require a 6-month abstinence period before OLT which excludes patients with AAH. Marijuana has become legal in more than half the states in the United States. This survey of liver transplant programs was conducted to evaluate current policies regarding alcohol, marijuana and methadone use. METHODS: A questionnaire was distributed to 100 United Network for Organ Sharing-approved liver transplant programs in North America that have performed at least 30 liver transplants/year in the last 5 years. RESULTS: Forty-nine programs responded. Only 43% of the programs required a specific period of abstinence before transplant for alcoholic liver disease and only 26% enforced 6-month abstinence policy. For patients with AAH, 71% programs waived the 6-month abstinence requirement and considered psychosocial factors, such as family support, patient's motivation, or…

BACKGROUND: Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. METHODS: Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. RESULTS: One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 ± 19.8 % vs 34.8 ± 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented…

In Brief Background The waiting list for kidney transplantation is long. The creation of “vouchers” for future kidney transplants enables living donation to occur when optimal for the donor and transplantation to occur later, when and if needed by the recipient. Methods The donation of a kidney at a time that is optimal for the donor generates a “voucher” that only a specified recipient may redeem later when needed. The voucher provides the recipient with priority in being matched with a living donor from the end of a future transplantation chain. Besides its use in persons of advancing age with a limited window for donation, vouchers remove a disincentive to kidney donation, namely, a reluctance to donate now lest one’s family member should need a transplant in the future. Results We describe the first three voucher cases, in which advancing age might otherwise have deprived the donors the opportunity to provide a kidney to a family member. These 3 voucher donations functioned in a nondirected fashion and triggered 25 transplants through kidney paired donation across the United…

In Brief The continual critical shortage of organs and cells from deceased human donors has stimulated research in the field of cross-species transplantation (xenotransplantation), with the pig selected as the most suitable potential source of organs. Since the US Food and Drug Administration concluded a comprehensive review of xenotransplantation in 2003, considerable progress has been made in the experimental laboratory to improve cell and organ xenograft survival in several pig-to-nonhuman primate systems that offer the best available models to predict clinical outcomes. Survival of heart, kidney, and islet grafts in nonhuman primates is now being measured in months or even years. The potential risks associated with xenotransplantation, for example, the transfer of an infectious microorganism, that were highlighted in the 2003 Food and Drug Administration guidance and subsequent World Health Organization consensus documents have been carefully studied and shown to be either less likely than previously thought or readily manageable by donor selection or recipient management…

BACKGROUND: The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients. METHODS: Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+). RESULTS: The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients…

BACKGROUND: Weight gain early after transplant is a risk factor for posttransplant metabolic syndrome (PTMS), cardiovascular events, and renal insufficiency. The impact of mammalian target of rapamycin inhibition on posttransplant weight gain and the development of PTMS components postliver transplantation were examined in a randomized, controlled study. METHODS: After a run-in period, patients (N = 719) were randomized at 30 ± 5 days posttransplant in a 1:1:1 ratio to 3 treatment groups: (i) everolimus (EVR) + reduced tacrolimus (TAC) (n = 245); (ii) TAC control (n = 243) or (iii) TAC elimination (n = 231). In this post hoc analysis, weight change at 12 and 24 months was compared between groups. Vital signs, lipids, and laboratory parameters at 12 and 24 months and rates of PTMS were assessed. RESULTS: Mean increase in weight from baseline was higher at month 12 in the TAC control arm (8.15 ± 9.27 kg) than in the EVR + reduced TAC (5.88 ± 12.60 kg, P = 0.056) and the TAC elimination arms (4.76 ± 9.94 kg, P = 0.007). At month 24, the TAC control arm displayed a significantly greater…

The Canadian public and healthcare professionals strongly support organ and tissue donation.1,2 However, Canada’s deceased donation rate is less than half of the best-performing countries, with variable family consent rates across the country.3 It is recognized that presenting the opportunity for donation to families who are in a stressful, traumatic situation is difficult and must be done with sensitivity to their unique situations, values, and beliefs. At the same time, international, national, and local leaders in this area have demonstrated that conversations with families can be done in a way that leads to improved and well-informed decision making and support and can have a positive impact on donation rates. In February 2014, Canadian Blood Services sponsored an invitational forum in Montreal for the development of leading practices related to effective requesting in deceased donation. This event focused on adult and pediatric neurological determination of death (NDD) and donation after circulatory death (DCD) organ donors (who could also be tissue donors) and had the…

BACKGROUND: Kidney transplantation in recipients with a previous malignancy is often deferred 2 to 5 years after cancer treatment due to fear of cancer recurrence. In Norway, the required waiting period has been 1 year. METHODS: We compared patient and graft survival of recipients with pretransplant cancer to the outcomes of matched recipients without such cancer (comparators) using Cox regression. RESULTS: From 1963 to 2010, 377 (6.4%) of 5867 recipients had a pretransplant cancer. During a median follow-up of 6.8 years, 256 recipients died, 35 (13.7%) from recurrent cancer and 27 (10.5%) from de novo cancer. Uncensored and death-censored graft loss occurred in 263 and 46 recipients, respectively. All-cause mortality was similar as in comparators (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.93-1.20]; P = 0.40), death-censored graft loss was lower (HR, 0.63; 95% CI, 0.47-0.84; P = 0.002), and uncensored graft loss was similar (HR, 0.99; 95% CI, 0.87-1.12; P = 0.87). Cancer mortality was higher than in comparators (HR, 1.97; 95% CI, 1.51-2.56; P < 0.001), particularly…

In Brief Improvement of long-term outcome of kidney transplantation has reached its limits due to consequences of efficient, but nonspecific immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been proposed as an alternative strategy for more refined therapy. The interest in MSCs comes from their anti-inflammatory properties on the one hand and their propensity to ameliorate tissue damage and mediate repair on the other hand. First clinical trials have demonstrated that administration of MSCs in kidney transplant recipients is safe and feasible, and follow-up studies have been initiated with the desired clinical efficacy to reduce ischemia-reperfusion injury, to prevent/reverse acute transplant rejection, and to improve long-term transplant survival with minimization of immunosuppression. To further promote wider application of MSC in renal transplantation, it is of importance to determine efficacy, to increase the understanding of the mechanism of action, and to develop tools to identify eligible patients. In addition, we should overcome challenges particularly at the…