Transplant Clinicians Research Articles

Comment on ‘Tolerance Versus Immunosuppression: A Perspective’

Comment on ‘Tolerance Versus Immunosuppression: A Perspective’

Medication-taking among adult renal transplant recipients: barriers and strategies

Medication adherence is essential for the survival of kidney grafts, however, the complexity of the medication-taking regimen makes adherence difficult. Little is known about barriers to medication-taking and strategies to foster medication-taking. This cross-sectional study involved semi-structured interviews with 82 kidney transplant recipients approximately 2 months post-transplant on medication-related adherence, barriers to medication-taking, and strategies to foster medication-taking. Although self-reported adherence was high (88%), qualitative analysis revealed that half of the patients (49%) reported experiencing at least one barrier to medication-taking. The most common barriers were: not remembering to refill prescriptions (13%), changes to medication prescriptions or dosages (13%), being busy (10%), forgetting to bring medicines with them (10%), and being away from home (10%). The most common strategies to foster medication-taking were: maintaining a schedule of medication-taking (60%), organizing pills using pillboxes, baggies, cups (42%), bringing medicines with them (34%), organizing pills according to routine times (32%), and relying on other people to remind them (26%). Understanding the range of barriers to adherence and strategies kidney recipients devised to promote medication-taking may help transplant clinicians to better educate transplant recipients about appropriate medication-taking, mitigate the risk of medication nonadherence-related rejection, and may help inform patient-centered interventions to improve medication adherence.

Transplantation, immunosuppression and infection

Recipient infection is now the primary reason for post-transplant hospitalisation, morbidity and mortality (23% in some studies). The incidence has increased due to increased numbers of transplants, use of potent immunosuppressive drugs, and longer term survival of a greater range of transplanted patients, causing increased numbers of different types of infections that need to be monitored by the laboratory. The availability of increasingly sensitive and specific molecular tests for pathogens means the pathologist and clinician have a widening armamentarium of available assays. Some of these are well established (PCR for cytomegalovirus [CMV], bacterial 16S rDNA) where development of new algorithms, such as the use of multiplexing, and combination with culture-enhanced detection, means more sensitive detection of a broader range of pathogens. Newer assays in transplantation are being directed towards specific problems, e.g., genotyping of resistance genes in MRSA, detection of resistance genotypes in CMV. It is essential to cross-talk between transplant clinicians, the transplant community, transfusion services and laboratories to maintain optimal diagnosis and ongoing developmental programs.

A Transplant Website in Today's World

With the aid of a professional developer, the South West Transplant Centre designed and launched a website in September 2006 to provide patient friendly information in all aspects of renal transplantation and health professionals with transplant related e-book protocols alongside research materials, printable referral forms and statistical data including survival figures. The aim of this paper is to report on our experience of the first year of operating such a website. The website consists of approximately 500 pages covering subjects ranging from transplant related procedures to the transplant procedure itself. During the first year the total number of hits on SWTC website were 70,971 with April 2007 having a peak of 10,357 hits. There was sustained interest in the website throughout the year and the amount of information (kilo- bytes) downloaded was highest during the first three months. Regular visitors to the website come from several countries across the globe including the United Kingdom, New Zealand, Seychelles, Canada, France and the US. A well-designed website is a useful tool for increasing awareness of Unit activities, increasing organ donation, providing information and in some instances training people in geographically remote areas. To maintain relevance transplant websites require to be upgraded on a regular basis by transplant clinicians and relevant sections expanded to meet the needs of the public.

Utility of monitoring mycophenolic acid in solid organ transplant patients

To investigate whether monitoring concentrations of mycophenolic acid (MPA) in the serum or plasma of persons who receive a solid organ transplant will result in a lower incidence of transplant rejections and adverse events versus no monitoring of MPA. To investigate whether the incidence of rejection or adverse events differs according to MPA dose or frequency, type of MPA, the form of MPA monitored, the method of MPA monitoring, or sample characteristics. To assess whether monitoring is cost-effective versus no monitoring.The following databases were searched from their dates of inception (in brackets) until October 2007: MEDLINE (1966); BIOSIS Previews (1976); EMBASE (1980); Cochrane Database of Systematic Reviews (1995); and Cochrane Central Register of Controlled Trials (1995).Studies identified from the data sources went through two levels of screening (i.e., title and abstract, full text) and the ones that passed were abstracted. Criteria for abstraction included publication in the English language, study design (i.e., randomized controlled trial [RCT], observational study with comparison group, case series), and patient receipt of allograft solid organ transplant. Additionally, any form of MPA had to be measured at least once in the plasma or serum using any method of measurement (e.g., AUC0-12, C0). Furthermore, these measures had to be linked to a health outcome (e.g., transplant rejection). Certain biomarkers (e.g., serum creatinine, glomular filtration rate) and all adverse events were also considered health outcomes.The published evidence on MPA monitoring is inconclusive. Direct, head-to-head comparison of monitoring versus no monitoring is limited to one RCT in adult, kidney transplant patients. Inferences about monitoring can be made from some observational studies, although the evidence is equivocal for MPA dose and dose frequency, nonexistent for type of MPA, inconclusive for form of MPA monitored or method of monitoring, and nonexistent for cost-effectiveness. Some studies suggest gender and concomitant use of calcineurin inhibitors will affect pharmacokinetic parameters, but the impact of these findings has not been assessed in relation to monitoring versus no monitoring.The state of knowledge about therapeutic drug monitoring of MPA in solid organ transplants is still in its infancy. Until there is more evidence on the utility of routine MPA monitoring in solid organ transplant recipients, patients, clinicians, and other stakeholders (e.g., public and private insurers) will have to decide on a case by case basis whether the possible but uncertain benefits are worth the extra time and expense of monitoring.

Assessment and management of psychosocial challenges in pediatric liver transplantation

Assessment and management of psychosocial challenges in pediatric liver transplantation

Protective Effects of FR167653 on Chronic Allograft Nephropathy by Inhibiting p38 MAPK in Rats

Background Chronic allograft nephropathy (CAN) remains a challenge for transplant clinicians. Some novel intervention strategies may shed new light on its treatment. Methods An orthotopic kidney transplant model in Fisher-to-Lewis rats was used with administration of cyclosporine alone or in combination with FR167653 (30 mg/kg/d subcuntaneously) to recipients. We analyzed renal function and urinary protein excretion. Animals were sacrificed at 30 weeks posttransplantation for histological and immunohistochemical studies. Results Renal function among vehicle-treated rats deteriorated progressively with substantial proteinuria compared with FR167653-treated rats. FR167653 administration significantly prevented the morphlogical features of CAN and prolonged rat survivals. p38 mitogen-activated protein kinase (MAPK) expression was markedly reduced by FR167653 treatment. Meanwhile, transforming growth factor-β1 and monocyte chemotactic protein-1 expression were significantly down-regulated among FR167653-treated hosts. Conclusion p38 MAPK phosphorylation correlated with CAN progression and inhibition of p38 MAPK by FR167653 may provide a potent novel therapeutic target for its prevention.

Responding to offers of altruistic living unrelated kidney donation by group associations: an ethical analysis

Members of a religious community presented to our institution and offered to be altruistic unrelated living kidney donors en masse. This situation raised a number of ethical concerns related to the situation specifically and to altruistic unrelated living kidney donation in general. Based on our ethical analysis, we made the following conclusions. Altruism is a legitimate motive for living unrelated kidney donation, and altruistic acts can be based legitimately on religious beliefs. Retrieval of kidneys from living donors is generally safe, and altruistic donors may derive benefit from donating (eg, enhanced self-esteem) assuming they are autonomous and free of coercion. Separate teams should evaluate and care for potential donors and recipients to avoid compromising the donor screening process and to ensure potential donors satisfy medical and psychosocial criteria for donation. Indeed, transplant clinicians should not assume that potential unrelated living kidney donors are not susceptible to coercion. In fact, in our situation, coercion was our biggest concern. Appointing a donor's advocate can facilitate donor understanding of the risks, benefits, and alternatives to organ donation and can help discern coercion. Furthermore, an experienced social worker should assess all potential donors and discern if coercion is present; potential donors should be referred to a psychologist or psychiatrist as appropriate. Although concerns regarding allocation were not raised by our specific situation, ethical concerns regarding allocation of kidneys donated by altruistic unrelated kidney donors exist (eg, requesting that such donations be allocated to recipients with specific characteristics).

Further Exploration: Maturity and Adherence in Adolescent and Young Adult Heart Transplant Recipients

Pediatric transplant clinicians note high rates of nonadherence with medications, appointment keeping, and laboratory tests and high rates of engagement in high-risk behaviors among older adolescents and young adult recipients. The caregivers also report symptoms of identity confusion, social immaturity, and failure to appreciate consequences of risky behavior among recipients. To build on an earlier study that identified developmental characteristics that distinguish poor from good adherers. Qualitative methods were used to explore key themes identified in the first study with heart transplant recipients and their significant others. This research confirmed the themes of developmental maturity suggested by the first study: good adherers were able to integrate the transplant into sense of self, become independent adults, and achieve normalcy; poor adherers continued to "push away" the transplant experience and worried that they would never be normal. The good adherers, their parents, and friends had views of relationships that were congruent, acknowledging difficulties, discussing them, and moving toward mutual satisfaction. The poor adherers, their parents, and friends expressed incongruent views of the relationships, avoiding discussion of problems and idealizing relationships. Strategies for clinicians, family, and friends to increase maturity and independence among older adolescent and young adult heart transplant recipients are described.

465: Priority Concerns of Patients Receiving Autologous or Allogeneic Stem Cell Transplants at the Seattle Cancer Care Alliance

Purpose: In a focused history, transplant clinicians may not address the issues perceived to be most important to patients. Studies indicate that while oncologists are attentive to adverse symptoms, communication tends to be clinician-oriented with interruptions and closed-ended questions. The use of touchscreen computers by stem cell transplant (SCT) patients to report symptom and quality of life (QOL) measures has been investigated at the SCCA. The purpose of this analysis was to identify priority concerns reported at the time of nurse teaching (T1) and after transplant (T2), using a self-report assessment program for cancer (ESRA-C).

Costimulation blockade: towards clinical application

Organ transplantation is an increasingly successful therapy for many forms of organ failure, but its success depends upon drug therapies to prevent immunologic destruction of the transplanted organ also known as rejection. Most therapies designed to prevent rejection alter the immune system in a rather broad, antigen independent way, and thus alter protective immunity as well as immune responses directed against the transplanted organ. Over the past 3 decades, however, it has been realized that a class of surface molecules known as costimulatory receptors are required to generate a fully productive immune response, and that blockade of these receptors during allo-antigen recognition can be used to influence the immune system's future response to that particular allo-antigen. Costimulation blockade has thus been developed as a specific field of interest towards achieving improved antigen specific control over transplant rejection while minimizing broad attenuation of protective immunity seen with conventional immunosuppressives. This field has grown rapidly in the past decade and is now poised to become a valuable therapeutic option for transplant clinicians. This review will outline the basic premise of costimulation biology, review the seminal experimental basis for its use in preventing organ rejection, and discuss the relevant data derived from its initial use in clinical transplant trials. Specific attention will be focused on two major costimulatory pathways, the CD28/CD80-CD86 and the CD40-CD154 pathways, and the clinically applicable data supporting their validity as therapeutic targets. Newly discovered costimulatory pathways will also be discussed as potential therapeutic targets for future clinical drugs.

Screening for sickle trait among potential live kidney donors: policies and practices in US transplant centers

Sickle cell trait is common in the United States (US) and associated with abnormalities of renal function. Little is known, however, about the potential risk of sickle cell trait to live kidney donors. Using an original questionnaire, we assessed the policies and practices of US renal transplant centers with regard to screening for sickle trait among potential live kidney donors. Fifty-four percent (137/252) of centers responded. Eighty-three percent (113/137) of transplant centers had no policy to screen donors for sickle trait. Thirty-four percent (46/135) of centers reported actually screening donors for sickle trait in practice. Thirty-seven percent (39/105) of centers reported excluding donors with sickle trait always or most of the time. High volume centers (>100 live donor transplants/year) were more likely to screen for sickle trait (Fisher's exact, P = 0.03), but not more likely to exclude potential donors with sickle trait from donating. Most US renal transplant centers do not screen donors for sickle trait. Wide variation is evident in center practice regarding exclusion of donors on the basis of sickle trait. Research into the potential impact of sickle trait on renal function after donation is needed to guide transplant clinicians.

Risk Factors for Posttransplant Diabetes Mellitus: A Review of the Literature

The development of diabetes after solid organ transplantation is a known complication, and many published studies have examined prevalence rates and risk factors for specific categories of transplant recipients. However, fewer articles have compared rates of posttransplant diabetes and risk factors among different types of transplant recipients. This article provides an overview of the literature on this subject and compares similarities and differences related to posttransplant diabetes for different categories of organ transplant recipients. Awareness of the various risk factors for different organ transplant recipients will enhance transplant clinicians' knowledge related to this complication so that appropriate monitoring can be started.

Risk factors for posttransplant diabetes mellitus: a review of the literature

The development of diabetes after solid organ transplantation is a known complication, and many published studies have examined prevalence rates and risk factors for specific categories of transplant recipients. However, fewer articles have compared rates of posttransplant diabetes and risk factors among different types of transplant recipients. This article provides an overview of the literature on this subject and compares similarities and differences related to posttransplant diabetes for different categories of organ transplant recipients. Awareness of the various risk factors for different organ transplant recipients will enhance transplant clinicians' knowledge related to this complication so that appropriate monitoring can be started.

Protective Effects of Sirolimus by Attenuating Connective Tissue Growth Factor Expression in Human Chronic Allograft Nephropathy

Background Chronic allograft nephropathy (CAN) remains a great challenge for the transplant clinician. The introduction of sirolimus (RAPA) with cyclosporine (CsA) reduction maybe shed new light to improve graft survival. The aim of this study was to investigate the overall effects of sirolimus conversion on biopsy-proven CAN. Methods One hundred and ten renal transplant recipients with biopsy-proven CAN were randomized into two groups: 54 for CsA reduction and 56 for sirolimus conversion treatment. After 24-month follow-up, the outcome variables included graft function and survival as well as CAN Banff grading and intrarenal expression of connective tissue growth factor (CTGF) via repeated biopsy. Results Graft function and survival rate were significantly better in the RAPA group. CAN grading worsened in the CsA group, whereas they were stable in the RAPA group. There was weak expression in the RAPA group but significant, increased expression of CTGF in glomeruli and interstitial area in the CSA group ( P < .01) both by immunhistochemical staining or real-time polymerase chain reaction detection. Conclusion Sirolimus conversion provided a beneficial strategy to improve long-term graft survival in CAN. Attenuation of renal CTGF expression maybe one of its antifibrotic and antiproliferation effects.

The janus face of immunosuppression – de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.

The quality of information about kidney transplantation on the World Wide Web

Websites on the Internet are used increasingly by patients and those caring for them as a source of medical information. This study investigated the nature and quality of the kidney transplant-related information currently available on the World Wide Web (WWW). Four common search engines were used to explore the Internet using the keywords "kidney transplantation." Each website was assessed on the following categories: source, language, accessibility, presence of kitemarks, and quality/depth of information. Websites were scored independently by four transplant clinicians (two surgeons and two physicians), and a weighted Information Score (IS) was created to assess the overall clinical and educational value of the site. A total of 200 potential websites were identified of which 94 websites were suitable for scoring. The remaining 106 were repetitions or non-accessible links. The overall median weighted IS for the sites assessed was 21 (IQR 0-61). Median weighted IS of sites originating from Europe and USA were 47 (IQR = 21-61) and 45 (IQR = 15-61) respectively (p = 0.27). Websites belonging to academic institutions scored higher with a median weighted IS of 49 (IQR = 20-61) when compared with kitemarked websites (median 21, IQR = 5-45, p = 0.01). However, there was no statistically significant difference in weighted IS of kitemarked, professional (median 22, IQR = 2-53), commercial (median 20, IQR = 0-45), and individual websites (median 9, IQR 3-12). There was a good agreement between the observers who scored the websites with an intraclass correlation coefficient (ICC) of 0.79 and an associated 95% CI (0.73-0.90) for the four observers on the 94 websites. The educational material currently available on the WWW about kidney transplantation is often of poor quality and more input is required from transplant clinicians. Quality seals in the form of kitemarks may give a false sense of security. The gaps in validity and accuracy of the information available on complex topics such as kidney transplantation should be filled; otherwise poor quality information will continue to be the norm rather than the exception.

Tolerance in Heart Transplantation: The Holy Grail, or an Attainable Goal?

The father of cardiac transplantation, Norman Shumway, famously predicted that tolerance was the future of the field, and always would be. Although his prediction remains true to date, significant progress has been made toward this goal, the "Holy Grail" for transplant clinicians. Current efforts are fueled by disappointing long-term outcomes associated with chronic immunosuppression, and the promise that partial or complete tolerance will impact long-term results favorably. This article provides a clinical definition of tolerance primarily based on lessons learned from animal heart allograft models. It reviews several promising strategies for inducing tolerance and detecting its presence through the use of biomarkers in peripheral blood or the graft, and outlines a possible path toward making this vision a clinical reality.

Feasibility and Reproducibility of the NIH Consensus Criteria To Evaluate Response in Chronic Graft Versus Host Disease (cGvHD).

Background The lack of standardized response criteria is a major obstacle to the development of therapeutic agents for cGvHD. Consensus criteria for evaluating response in cGvHD have been recently published (BBMT , 2006; 12:252). We report on 3 pilot trials evaluating the feasibility and reproducibility of these proposed response criteria.Methods Oncology clinicians (n=27) with limited experience with cGvHD, participated in a 2.5 hour training session and received a syllabus and a photo atlas illustrating common manifestations of cGvHD. Feasibility and inter-rater agreement between experts in cGvHD (transplantation, dermatology, oral medicine, and rehabilitation medicine) and novice raters were evaluated using 15 pediatric and adult patients with varying manifestations of cGvHD. Data from each trial were used to strengthen the criteria and the teaching tools, and these materials were then re-tested. Intraclass correlation coefficients (ICCs) and percent agreement (#Agreements/[#Agreements + #Disagreements] × 100) were used in the analysis.ResultsResponse CriterionTrial 1 (8 novices; 4 adult patients)Trial 2 (10 novices; 6 pediatric patients)Trial 3 (9 novices; 5 adult patients)Oral(Median ICC/Range).50(−.62–.84).44(.14–.81).57(−.06–.74)Erythema(Median ICC/Range).88(.12–.93).07(−.01–.97).47(.08–.82)Movable Sclerosis(Median ICC/Range).33(−.65–.71).21(−.38–.81).60(.11–.91)Non-movable Sclerosis(Median ICC/Range).23(−.06–.62).16(−.45–.77).62(.37–.96)Ulcers(%agreement)97%95%67%Gastrointestinal(%agreement)83%–100%57%–93%68%–100%Functional Performance(% novices within 95% confidence interval of expert)2 Minute Walk:66%;Grip Strength:75%Not evaluated2 Minute Walk:60%;Grip Strength:66%Performance Status(novices within +/−20% of expert)100%80%100%The concordance between expert and novices for global ratings of cGvHD severity and disease course was also evaluated. The median time to perform and document the evaluation, which includes a Schirmer test, ranged from 32–36 minutes. In the third trial, the agreement among experts for the dimensions of oral manifestations (ICC=0.7) and skin erythema (ICC=0.54) approached satisfactory values. Overall, interobserver agreement was modest; although in the third trial the median ICCs between novices and experts for movable sclerosis, non-movable sclerosis, and oral findings began to approach the 0.7 level.Conclusions These data provided critical information to guide the successive refinement of the response criteria and training materials resulting in improved reproducibility in specific domains, such as oral and movable and non-movable sclerosis. While these data offer preliminary evidence of feasibility, it was challenging for novices to acquire in a single session the skills necessary to grade these patients reliably. Work is ongoing to refine the training materials, and future efforts will examine whether experienced transplant clinicians who receive this educational program can apply the response criteria with greater reproducibility.

Health Locus of Control After Lung Transplantation: Implications for Managing Health

Health locus of control (HLC) beliefs may influence the health behaviors that patients perform on their own behalf. Likewise, the HLC beliefs that clinicians consider desirable may influence how active they encourage patients to be in managing health. It remains unclear how involved lung recipients want to be and how involved transplant clinicians believe they should be. The aims of this study were to describe HLC beliefs and behaviors manifested by recipients and clinicians in the setting of lung transplantation. Mixed-methods were used, including quantitative techniques to measure demographics, clinical characteristics, and HLC using the Multidimensional Health Locus of Control Scale (MHLC), and qualitative techniques to explore how HLC beliefs were manifest in the clinical setting. Nearly all participants manifested behaviors consistent with high internality and externality, highlighting the importance of holding ‘dual health locus of control’ beliefs for optimal health management and lending support for recipients and clinicians to share responsibility for managing post-transplant health.