American Society Of Transplantation Research Articles

Strategies for managing cytomegalovirus in transplant recipients

Importance of the field: Cytomegalovirus (CMV) is the most important pathogen that affects transplant recipients, by directly causing clinical disease and by indirectly reducing patient and allograft survival.Areas covered in this review: This review provides a brief overview of the direct and indirect effects of CMV disease and the traditional and newly described factors that increase the risk of disease after transplantation. Newly acquired data in the diagnostics, prevention and treatment of CMV infection are discussed, with emphasis on guidelines for management as recently endorsed by the American Society of Transplantation and the Transplantation Society.What the reader will gain: The reader will gain up-to-date insights into the contemporary management of CMV after solid organ transplantation. Practical aspects of its diagnosis, prevention and treatment are discussed. Emerging concerns of late-onset CMV disease and antiviral resistance are also highlighted to emphasize the need to optimize CMV-prevention strategies.Take home message: Prevention of CMV disease is an important goal in the management of solid organ transplant recipients. The efficacy of CMV prevention should be measured not only by the significant reduction in CMV incidence but, as importantly, by the improvement in long-term allograft and patient survival.

Drug Coverage for Transplantation Turns into Political Football

As Congress took on the issue of health care last year, they had a golden opportunity finally to extend Medicare coverage for immunosuppressive medications for kidney transplant recipients from the current 36 months to lifetime. This is an issue that the American Society of Transplantation (AST) and other members of the transplant community has long advocated, but this opportunity was squandered when the interests of big business triumphed over the needs of patients, and the provision was dropped from the Affordable Health Care for Americans Act. Although lifetime coverage almost became a reality, the dialysis industry and those whom they support have proved that money ultimately wins in politics. Currently, Medicare covers 80% of the cost of immunosuppressive medications for 36 months after transplantation (for those whose Medicare entitlement is based on ESRD). In 1999, Congress authorized an extension of Medicare coverage for immunosuppressive medication to lifetime, but only for a minority of patients: Those who were Medicare eligible as a result of age or disability. Medicare coverage for dialysis, a more expensive and far less effective therapy for ESRD, has been and continues to be for the lifetime of the patient. Many studies, going back well over a decade, including those conducted by the government itself, take issue with the policy. Kasiske et al. 1, in 1999, presented …

Guidance on Novel Influenza A/H1N1 in Solid Organ Transplant Recipients

Novel influenza A/H1N1 virus has caused significant illness worldwide. In response to this global crisis, the American Society of Transplantation (AST) Infectious Diseases Community of Practice and the Transplant Infectious Diseases section of The Transplantation Society (TTS) developed a guidance document for novel H1N1. In this paper, we discuss current guidance for H1N1 as it relates to solid organ transplantation. We include discussion around clinical presentation, diagnosis, therapy and prevention specifically addressing areas such as chemoprophylaxis, immunization and donor-derived infection. Although this document addresses conditions specific to novel H1N1, many principles could be applied to future pandemics. As new information emerges about novel H1N1, updates will be made to the electronic version of the document posted on the websites of the AST and TTS.

National Survey of Anemia Prevalence After Kidney Transplantation in Argentina

Anemia is prevalent in kidney transplant recipients and likely contributes to morbidity and mortality. The definition of anemia as established by the World Health Organization and subsequently adopted by the American Society of Transplantation is a hemoglobin concentration of 12 g/dL or less in women and 13 g/dL or less in men. Using this definition, the prevalence of anemia is nearly 30%. The National Survey of Post Transplant Anemia (PTA) in kidney transplant recipients in Argentina was conducted to evaluate the incidence of PTA at 1 year and its relationship to variables that influence transplantation outcome. At 1 year posttransplantation, mean (SD) hemoglobin concentration was 12.43 (1.77) g/dL (n = 379), hematocrit concentration was 38.26% (5.59%) (n = 379), serum creatinine concentration was 1.51 (0.72) mg/dL (n = 380), and creatinine clearance was 60.8 (22.47) mL/min (n = 334). The prevalence of PTA in Argentina at 1 year posttransplantation was 42.25%. At univariate analysis, female sex, immunosuppression regimen (mycophenolate mofetil plus mammalian target of rapamycin), and pediatric age group were associated with anemia. At multivariate analysis, only renal function and pediatric age group were associated with anemia. The mean hemoglobin level at year of transplant was 12.43 g/dL +/−1.77 and the prevalence of PTA in Argentina at year of transplant is 42.25%. Results of our survey show a correlation between Hb levels and graft function and pediatric recipient.

Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor

No official document has been published for primary care physicians regarding the management of liver transplant patients. With no official source of reference, primary care physicians often question their care of these patients. The following guidelines have been approved by the American Society of Transplantation and represent the position of the association. The data presented are based on formal review and analysis of published literature in the field and the clinical experience of the authors. These guidelines address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, preventive medicine, malignancies, disability and productivity in the workforce, issues specific to pregnancy and sexual function, and pediatric patient concerns. These guidelines are intended to provide a bridge between transplant centers and primary care physicians in the long-term management of the liver transplant patient.

Predicting Risk of Nonmelanoma Skin Cancer and Premalignant Skin Lesions in Renal Transplant Recipients

Nonmelanoma skin cancer (NMSC) and associated premalignant lesions represent a major complication after transplantation, particularly in areas with high ultraviolet radiation (UVR) exposure. The American Society of Transplantation has proposed annual NMSC screening for all renal transplant recipients. The aim of this study was to develop a predictive index (PI) that could be used in targeted screening. Data on patient demographics, UVR exposure, and other clinical parameters were collected on 398 adult recipients recruited from the Princess Alexandra Hospital, Brisbane. Structured interview, skin examination, biopsy of lesions, and review of medical/pathologic records were performed. Time to presentation with the first NMSC was assessed using Cox's regression models and Kaplan-Meier estimates used to assess detection of NMSC during screening. Stepwise selection identified age, outdoor UVR exposure, living in a hot climate, pretransplant NMSC, childhood sunburning, and skin type as predictors. The PI generated was used to allocate patients into three screening groups (6 months, 2 years, and 5 years). The survival curves of these groups were significantly different (P<0.0001). Jack-knife validation correctly allocated all patients into the appropriate group. We have developed a simple PI to enable development of targeted NMSC surveillance strategies.

Managing anaemia in kidney transplant patients with chronic kidney disease

The definition of anemia is established by the World Health Organization and was subsequently adopted by the American Society of Transplantation, which defines anemia as hemoglobin concentration <12 g/dl in women and <13 g/dl in men. PREVALENCE OF ANEMIA POSTTRANSPLANTATION: Varies throughout the posttransplantation period and is associated with the degree of renal graft function. The relationship between hemoglobin levels and glomerular filtration does not behave the same way as in the population with chronic kidney disease. The results of various studies show a high prevalence in the first months after transplantation (<6 months), which decreases from the first year posttransplantation and then increases related to loss of graft function. European study on the management of anemia showed a prevalence of anemia in 38.6% and only 18% of patients with severe anemia were treated with erythropoietin (EPO). There is a decrease in the synthesis of erythropoietin (EPO) or an increase in resistance to EPO. There are many factors that can cause anemia post-transplantation. Some of these factors are specific to transplanted patients whilst others are common to all patients with chronic kidney disease. Among the common factors there are: the degree of renal function and iron deficiency and among the factors of transplantation there are acute rejection, post-transplantation medications, infections and malignancies. The available data evaluating the association of anemia with morbidity and mortality of the patient and graft survival are scarce. Most studies are retrospective and analyze experiences of individual centers. They showed a higher mortality and morbidity among patients with a hemoglobin <11 g/dl. (Evidence B). TREATMENT OF POST-TRANSPLANTATION ANEMIA: Erythropoiesis-stimulating agents (ESA) and replenishment of iron deposits (Evidence A). RESPONSE TO TREATMENT: In transplant patients there may be some resistance to treatment with erythropoiesis- stimulating agents (ESA) due to the use of myelosuppressive medications, chronic inflammation and other factors. - Adverse effects of treatment with ESA: There are few controlled studies failed to show respect to the ESA that are effective and unlikely to accelerate the deterioration of renal function but may aggravate hypertension.

Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK)

A consensus conference sponsored by the American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), United Network for Organ Sharing (UNOS) and American Society of Nephrology (ASN) convened to examine simultaneous liver-kidney transplantation (SLK). Directors from the 25 largest liver transplant programs along with speakers with recognized expertise attended. The purposes of this conference were to propose indications for SLK, to establish a prospective data registry and, most importantly, to recommend standard listing criteria for these patients. Scientific registry of transplant recipients data, and single center data regarding chronic kidney disease (CKD) and acute kidney injury (AKI) in conjunction with liver failure as a basis for SLK was presented and discussed. The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: (i) End-stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient >/= 10 mm Hg (ii) Liver failure and CKD with GFR </= 30 mL/min (iii) AKI or hepatorenal syndrome with creatinine >/= 2.0 mg/dL and dialysis >/= 8 weeks (iv) Liver failure and CKD and biopsy demonstrating > 30% glomerulosclerosis or 30% fibrosis. The RRB would evaluate all other requests to determine appropriateness.

Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease

The role of T helper (Th) 1 and Th2 polarization in acute graft-vs-host-disease (GVHD) is unclear. We investigated the role of Th2 cytokine secretion by utilizing donor T cells that cannot make interleukin (IL)-4, IL-5, IL-9, and IL-13 from quadruple cytokine-deficient (Quad-KO) animals in a well-characterized BALB/c-->C57BL/6 model of allogeneic bone marrow transplantation. B6 recipients of BALB/c Quad-KO T cells demonstrated greater clinical severity, target organ damage, and mortality from GVHD than recipients of BALB/c wild-type (WT) T cells. When compared with donor T cells that are deficient in signal transducers and activators of transcription 6 signaling or the signature Th2 cytokine, IL-4, Quad-KO T cells demonstrated greater GVHD mortality. Mechanistic studies demonstrated that Quad-KO T cells demonstrated enhanced T-cell proliferation than WT T cells when stimulated with either allogeneic antigen-presenting cells or with nonspecific stimuli, such as anti-CD3 monoclonal antibody. Quad-KO T cells also secreted greater amounts of Th1 cytokines and IL-17 compared to WT T cells. Deficiency of Th2 cytokines, however, did not alter the allospecific cytotoxic responses, the numbers of immunoregulatory CD4(+)CD25(+) Foxp3(+) T cells or their suppressive functions. Our data thus unequivocally demonstrate that deficiency of the four classical Th2 cytokine enhances T-cell proliferative responses and aggravates GVHD.

Survival of Patients Identified as Candidates for Intestinal Transplantation: A 3-Year Prospective Follow-Up

The US Medicare indications for intestinal transplantation are based on failure of home parenteral nutrition. The American Society of Transplantation also includes patients at high risk of death from their primary disease or with high morbidity intestinal failure. A 3-year prospective study evaluated the appropriateness of these indications. Survival on home parenteral nutrition or after transplantation was analyzed in 153 (97 adult, 56 pediatric) candidates for transplantation and 320 (262 adult, 58 pediatric) noncandidates, enrolled through a European multicenter cross-sectional survey performed in 2004. Kaplan-Meier and chi-square test statistics were used. The 3-year survival was 94% (95% CI, 92%-97%) in noncandidates and 87% (95% CI, 81%-93%) in candidates not receiving transplants (P = .007). Survival was 80% (95% CI, 70%-89%), 93% (95% CI, 86%-100%), and 100% in parenteral nutrition failure, high-risk primary disease, and high-morbidity intestinal failure, respectively (P = .034). Fifteen candidates underwent transplantation. Six died, including all 3 of those who were in hospital, and 25% of those who were at home at time of transplantation (P = .086). Survival in the 10 patients receiving a first isolated small bowel transplant was 89% (95% CI, 70%-100%), compared with 85% (95% CI, 74%-96%) in the candidates with parenteral nutrition failure not receiving transplants because of central venous catheter complications, or 70% (95% CI, 53%-88%) in those with parenteral nutrition-related liver failure (P = .364). The results confirm home parenteral nutrition as the primary therapeutic option for intestinal failure and support the appropriateness and potential life-saving role of timely intestinal transplantation for patients with parenteral nutrition failure.

Exotic donor-transmitted infections in solid-organ transplantation: can seemingly random events inform policy?

Purpose of review There have been several recent reports of uncommon infections in solid-organ transplant recipients transmitted from donors through the transplanted allograft. The most recent and noteworthy reports will be described, with an aim towards a synthesis of their broad implications. Recent findings In 2006, two unrelated cases of Chagas' disease (due to Trypanosoma cruzi infection) transmission via cardiac transplantation occurred in one large metropolitan area. In late 2006, a commercial screening assay for T. cruzi was approved for blood donor screening in the US. Further investigation has been performed into case clusters of rabies, West Nile virus, and lymphocytic choriomeningitis virus infections transmitted via multiorgan transplantation. Attempts to expand the pool of eligible donors with successful use of organs recovered from septic donors were published. Updated recommendations for screening, monitoring and reporting of infectious complications in trials of immunosuppressive agents were published by the American Society of Transplantation. Summary Recent incidents of unusual infections transmitted via organ transplantation are not isolated occurrences. Much can be learned from the systematic analysis of these events.

The D&amp;T Report

The D&amp;T Report

Pertinent issues in pretransplant recipient workup

Renal transplantation is recognized as the treatment of choice in most patients with end-stage renal disease. The evaluation of the candidate for kidney transplantation has been the recent subject of clinical practice guidelines published by the European Renal Association- European Dialysis Transplant Association and the American Society of Transplantation. The purpose of this article is to review the current literature for urological evaluation and treatment of patients prior to renal transplantation. In India, urologists are involved in evaluating not only the genitourinary problems but also vascular access and, vascular anatomy and pathology especially related to major pelvic vessels. Hence, evaluation of the transplant recipient should include assessment of vascular access for hemodialysis, access for peritoneal dialysis, assessment of pelvic vessels to which renal allograft vessels need to be anastomosed and genitourinary system. In addition, review of the serological tests for infective viral diseases like hepatitis and human immunodeficiency viruses should always be done before starting clinical evaluation. A note of the evaluation performed by other specialists like nephrologist, cardiologist, endocrinologist, pulmonologist, anesthetist etc. should always be reviewed.

Disparities in Solid Organ Transplantation for Ethnic Minorities: Facts and Solutions

The Diversity and Minority Affairs Committee of the American Society of Transplantation (AST) convened a symposium to examine organ transplantation in underserved and minority populations. The goals of the meeting included 'benchmarking' of solid organ transplantation among minority populations, review of the epidemiology of end-organ damage, exploration of barriers to transplantation services and development of approaches to eliminate disparities. Participants noted that minority populations were more likely to be adversely affected by limited preventive medical care, lack of counseling regarding transplant options, and delays in transplant referrals for organ transplantation. These features largely reflect economic disadvantage as well as the reduced presence of minority professionals with training in transplant-related specialties. Participants in the conference noted that recent changes in organ allocation policies had improved access to minority individuals once listed for renal transplantation. Similar advances will be needed for other organs to address inequities in pretransplant care and underrepresentation of minorities among transplant professionals. The biologic basis of differences in transplant outcomes for minority recipients has not been adequately studied. Research funds must be targeted to address biologic mechanisms underlying disparate transplant outcomes including the impacts of environment, education, poverty and lifestyle choices.

A prospective study of anaemia and long-term outcomes in kidney transplant recipients

Anaemia is prevalent in kidney transplant recipients (KTR), and only few KTR with anaemia receive treatment with erythropoietin. Some have claimed that this undertreatment might contribute to suboptimal outcomes such as mortality and cardiovascular events in these patients. However, no evidence is currently available that anaemia is actually associated with such risks in KTR. We merged two cohorts of KTR to study the associations between anaemia and two outcomes: all-cause mortality and kidney allograft loss. Detailed information on the demographic and clinical characteristics of these 825 patients was available at baseline. As recommended by the American Society of Transplantation, anaemia was considered present if the haemoglobin concentration was < or =13 g/dl in men or < or =12 g/dl in women. Patients were followed using the Austrian Dialysis and Transplant Registry. After 8.2 years of follow-up, 251 patients died and 401 allografts were lost. In multivariate analyses, anaemia was not associated with all-cause mortality (HR: 1.08; 95% CI: 0.80-1.45), but it was associated with 25% greater risk of allograft loss (HR = 1.25; 95% CI: 1.02-1.59). This association was even more pronounced in death-censored analyses. Analyses using haemoglobin as a continuous variable or in categories also found no association with mortality. Anaemia may not be associated with mortality in KTR. In light of the recent findings of increased mortality in chronic kidney disease patients with higher haemoglobin treatment target, further evidence is needed to guide clinicians in the treatment of anaemia in these patients.

World Transplant Congress

The World Transplant Congress (WTC) is the first joint international transplant meeting co-organised by the Transplantation Society, the American Society of Transplantation (AST) and the American Society of Transplant Surgeons (ASTS). It was the first meeting of this calibre that was being held by three world-renowned authorities in the field of transplantation. Under the direction of the congress president, AB Cosimi, the attendance of this meeting is a ‘must’ for all working in the field of transplantation. The congress had provided an important forum for the exchange of new scientific and clinical information that is relevant to solid organ and tissue transplantation. In addition, it also created an arena for the interchange of ideas regarding the care and management of transplant recipients. There were many sessions that were engineered in order to facilitate the discussion of socioeconomic, ethical and regulatory issues related transplantation. On the whole, the meeting has set a very high standard for any future transplant congresses to match – providing the delegates with updates on transplantation with the new scientific prospectives in T cell costimulation, innate immunity (dendritic cells), anatomy of immune response and regulatory T cell biology. More importantly, it has highlighted the potentials of harnessing these new findings for future biological therapies in preventing rejection and inducing tolerance.

Esot presidential address by Prof. Jan Lerut ? 19 October 2005

Esot presidential address by Prof. Jan Lerut ? 19 October 2005

The Global Alliance for Transplantation

In 2002, The Transplantation Society proposed the creation of a Global Alliance for Transplantation, with the purpose of reducing the existing disparity regarding transplantation activities across the globe. This alliance should include major international scientific societies, international governmental organizations, and pharmaceutical companies. Consultations with each of these parties have taken place during the past 18 months and three Strategic Programs have been initiated: (1) the collection of information on transplantation; (2) the expansion of education in transplantation; and (3) the development of professional guidelines for organ donation and transplantation.

Transplantation and Islet Topics

This is the fourth in a series of articles on presentations at the American Diabetes Association Annual Meeting, Orlando, Florida, 4–8 June 2004. The American Society of Transplantation (www.a-s-t.org) held a symposium at the June ADA meeting addressing the importance of diabetes following transplantation (1). Martha Pavlakis (Boston, MA) introduced the symposium, pointing out the importance of “long-term management, now that our focus is no longer [merely] getting the patient to survive 1 year.” Among the risks of transplantation are those of the surgery itself, those of chronic immunosuppression, and now those of new-onset diabetes, which “definitely affects graft and patient survival.” Fernando G. Cosio (Rochester, MN) gave an overview of new-onset diabetes after transplantation in the U.S. Defining posttransplant diabetes mellitus (PTDM) as new onset of abnormal glucose metabolism following transplantation, he noted that it is common, that the incidence is increasing, and that the pathogenesis is complex. PTDM is associated with unexpectedly high risk of patient death, as well as with risk to the graft. One important question is whether this is “really new onset,” as the level of glucose tolerance of many patients is not carefully characterized before transplantation, and few studies assess patients for impaired glucose tolerance (IGT), or even for impaired fasting glucose (IFG). Indeed, rather crude diagnostic criteria are often used, such as the need for insulin administration, need for any glucose-lowering medicine, or assignment of billing codes for diabetes, so certainly many patients have diabetes that is not recognized. Given these reservations, the incidence of diabetes has been shown to increase with time after transplantation and appears to be higher among patients treated with tacrolimus than those treated with cyclosporine, at ∼15 vs. 10% for kidney and 18 vs. 8% for liver transplantation. Cosio reviewed his studies, with a linear increase in PTDM …

Morbid obesity is not a contraindication to kidney transplantation

Background Concern that morbidly obese (body mass index [BMI] 35) kidney transplant recipients have worse outcomes than non-morbidly obese recipients leads many transplant centers to deny them the benefit of kidney transplantation. These concerns are supported by guidelines recently published by the American Society of Transplantation. However, successfully transplanted morbidly obese persons have a survival advantage over those that remain on dialysis. It is our practice to evaluate morbidly obese transplant candidates for transplantation under the same criteria used for nonobese candidates. This report reviews our experience with morbidly obese kidney transplant recipients having a three year follow-up. Methods Outcomes for 23 morbidly obese (BMI 35, range 37 to 56) kidney transplant recipients transplanted between January 1995 and February 2000 were compared with 224 nonobese (BMI 25) kidney recipients transplanted during the same period. Results Patient and graft survivals were similar between both groups. Although 3-year graft survival for morbidly obese recipients of cadaver organs was 75% compared with 90% for the nonobese group, this finding was not statistically significant, and 3-year graft survival was 100% for morbidly obese recipients of living donor organs compared with 91% for nonobese recipients. Morbidly obese recipients had significantly longer hospital stays, higher readmission rates, and a higher wound infection rate than nonobese recipients. Conclusions We found that morbidly obese persons have 3-year graft and patient survivals similar to nonobese persons. Although they also have greater complications and greater numbers of days in the hospital, we believe these reasons are not sufficient to deny morbidly obese persons the survival and quality-of-life advantages of kidney transplantation.