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Background: Low physical activity (PA) is increasingly recognized as a risk factor for children with chronic conditions. A few published studies have measured the exercise capacity of solid organ transplant patients; however, no studies have examined the PA intensity of pediatric kidney transplant patients (PTx) using accelerometry. Therefore, our objective was to complement a gold standard exercise capacity protocol with an objective measure to quantify PA intensity levels of PTx., Methods: Sixteen PTx (nine girls), 4.9 ± 2.9 years posttransplant, mean age 13.1 ± 4.0 years, participated. Mean diethylenetriamine pentaacetic acid glomerular filtration rate (DTPA GFR) = 76.7 ± 18.0 ml/min/1.73 m(2). Laboratory data included assessment of cardiopulmonary functioning [peak oxygen uptake (VO(2peak))] from cycle ergometry and body composition [dual-energy X-ray absorptiometry (DEXA)]. PA was quantified by triaxial accelerometry (3 days). Field testing (FITNESSGRAM) included progressive aerobic cardiovascular endurance run (PACER), curlups, and sit/reach tests. Sex- and age-based criterion standards were used as reference., Results: Below normative values for VO(2peak) was found in eight children (mean = 27.4 ± 3.3). Accelerometry data identified only three children who fulfilled daily recommended moderate-vigorous PA level; 58.5% of their time was spent in sedentary activity., Conclusion: Accelerometry data highlights that not only are PTx patients inactive, the activity they do perform is overall of low intensity. PTx also show compromised exercise capacity and physical fitness. Our results suggest the need to assess PA barriers among PTx. Further research is needed to determine appropriate PA recommendations for children posttransplant.

Background: The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal., Methods: Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr)., Results: Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to ΔCP/GCr. A negative association to ΔCP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set., Conclusion: The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

Purpose: Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide. Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir, in order to provide clinicians with insight into the management of actual and potential drug interactions., Summary: A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA (1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir, pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and telaprevir is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvastatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and experience is gained with these agents, clinicians will need to be careful when administering in high-risk populations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV patients taking antiretrovirals and patients taking chronic immunosuppression as these populations are at increased risk of experiencing clinically significant interactions.

Background: When xenotropic murine leukemia virus-related virus (XMRV) was first reported in association with chronic fatigue syndrome, it was suggested that it might offer a risk to blood safety. Thus, the prevalence of the virus among blood donors and, if present, its transmissibility by transfusion need to be defined., Study Design and Methods: Two populations of routine blood donor samples (1435 and 13,399) were obtained for prevalence evaluations; samples from a linked donor-recipient repository were also evaluated. Samples were tested for the presence of antibodies to XMRV-related recombinant antigens and/or for XMRV RNA, using validated, high-throughput systems., Results: The presence of antibodies to XMRV could not be confirmed among a total of 17,249 blood donors or recipients (0%; 95% confidence interval [CI], 0%-0.017%); 1763 tested samples were nonreactive for XMRV RNA (0%; 95% CI, 0%-0.17%). Evidence of infection was absent from 109 recipients and 830 evaluable blood samples tested after transfusion of a total of 3741 blood components., Conclusions: XMRV and related murine leukemia virus (MLV) markers are not present among a large population of blood donors and evidence of transfusion transmission could not be detected. Thus, these viruses do not currently pose a threat to blood recipient safety and further actions relating to XMRV and MLV are not justified., (© 2012 American Association of Blood Banks.)

Background: Age at transplant and graft failure risk are associated in young kidney transplant recipients. The risk of graft failure may also vary by current age, irrespective of age at transplant. We sought to estimate age-specific graft failure rates in young kidney transplant recipients and to estimate the relative hazards of graft failure at different ages, compared with at the age of 25 to 29 years., Methods: We evaluated 90,689 patients recorded in the United States Renal Data System database who received a first transplant when younger than 40 years (1988-2009); 18,310 were younger than 21 years at transplant. Time-dependent Cox models with time-varying covariates were used to estimate the association between age (time-dependent) and death-censored graft failure risk, adjusted for time since transplant and other potential confounders., Results: There were 31,857 graft failures over a median follow-up of 5.9 years (interquartile range, 2.5-10.5 years; maximum, 21.8 years). Crude age-specific graft failure rates were highest in 19 year olds (6.6 per 100 person-years). Compared with individuals with the same time since transplant observed at 25 to 29 years of age, death-censored graft failure rates were highest in 17 to 24 year olds (hazard ratio, 1.20; [95% confidence interval 1.13, 1.27] for 17-20 year olds and 1.20 [1.13, 1.26] for 21-24 year olds; both P<0.0001) and lowest in 5 to 12 year olds (hazard ratio, 0.60; [0.53, 0.68] for 5-9 year olds and 0.56 [0.49, 0.64] for 10-12 year olds; both P<0.0001)., Conclusion: Among first kidney transplant recipients younger than 40 years, older adolescents and young adults (17-24 years) have the highest risk of graft failure, irrespective of age at transplant.

Background: A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD., Methods: Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated., Results: Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar., Conclusions: This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality of life in lung transplant recipients (LTR)., Methods: Twelve LTR and 7 age-matched healthy subjects underwent exercise training (ET, 12-wk, 3×/wk, 40 min). Peak aerobic capacity VO2peak, endurance time (T(end)), minute ventilation (VE) quadriceps strength, percentage of type I fiber (%Ifb), fiber diameters and chronic respiratory questionnaire were assessed before and after ET. A positive response to ET was defined as an improvement in T(end) at least comparable to the mean change observed in healthy subjects., Results: Training significantly improved T(end) (+12 ± 11 min), isowatt during exercise (-5.5 ± 2.6L/min), muscle strength (+4.6 ± 2.6 kg) and dyspnea score (+0.6 ± 0.9) in LTR (p < 0.05), leading to recovery of T(end) and muscle strength up to healthy subjects' values. In responders (n = 6), VO2peak, %Ifb and fatigue score were improved after training (p < 0.05). Non-responders had lower %Ifb and greater delay between surgery and the beginning of the study than responders (56 [21-106] vs. 8 [2-59] months respectively, p = 0.03)., Conclusions: Home-based ET was effective to improve exercise tolerance, muscle strength and quality of life in LTR but more successful in patients with moderate muscle dysfunction and in the first years after transplantation. Multicenter and controlled-studies are needed to confirm the benefits and optimal modalities of home training in LTR., (Copyright © 2011. Published by Elsevier B.V.)

Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (<2.3 g/kg; P<0.0001). In this low KwRw ratio group, the graft filtration rate remained stable between 6 months and 7 years but then decreased at a mean rate of 3.17 ml/min per yr (P<0.0001). In addition, low KwRw ratios conferred greater risk for proteinuria, more antihypertensive drugs, and segmental or global glomerulosclerosis. Moreover, a KwRw ratio<2.3 g/kg associated with a 55% increased risk for transplant failure by 2 years of follow-up. In conclusion, incompatibility between graft and recipient weight is an independent predictor of long-term graft survival, suggesting that avoiding kidney and recipient weight incompatibility may improve late clinical outcome after kidney transplantation.

The need for kidney transplantation among Asian Americans is increasing owing to hypertension, diabetes mellitus, and the shortage of available organs. This need is likely to increase as the relatively young Asian population ages. However, knowledge about organ donation and transplantation in this population has been little investigated. The objectives of this study was to develop an Organ Donation and Transplantation Knowledge Survey for use in Asian Americans and to examine its psychometric properties. Internal consistency (Cronbach alpha) and factor analyses were used to determine the reliability and validity of the survey in 121 Asian American adolescents residing on the Big Island of Hawaii. Our results indicate that the survey had adequate reliability and was psychometrically valid for evaluating knowledge about organ donation and transplantation. More studies are needed to validate the usefulness and psychometric properties of the Organ Donation and Transplantation Knowledge Survey in other groups.

Background: Traditional, cohort-based survival analysis approaches may provide outdated graft and patient survival estimates in times when clinical progress is rapid. Period analysis, a survival analysis method that uses left truncation and was shown to provide more up-to-date survival estimates than traditional, cohort-based methods in other medical fields, may improve the timeliness of survival monitoring in transplantation., Methods: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we evaluated, through a series of comparisons, how well most up-to-date 5-year survival estimates potentially derivable by two commonly used cohort-based methods and the period method would have been able to predict the later observed survival of corresponding most recent transplants in the dataset between 1992 to 1994 and 2001 to 2003., Results: In the analysis of overall survival, period analysis provided a best prediction for 93 of the 100 evaluated point estimates, whereas among 350 evaluated point estimates of age-specific survival, period analysis provided a best estimate on 254 occasions (72.6%), compared with 49 (14.0%) and 82 (23.4%) occasions for the cohort-based approaches. Mean average absolute differences between period estimates and the later observed survival were meaningfully lower than those obtained by traditional methods, indicating that period estimates may provide much better survival predictions for recently transplanted grafts and patients than estimates derivable at the same time by traditional survival analysis approaches., Conclusion: The timeliness of survival monitoring can be meaningfully improved by the application of period analysis. The use of period analysis for providing more up-to-date survival estimates in transplantation may be encouraged.

A total of 78 day 10 horse embryos were transferred non-surgically to recipient mares that had ovulated 9, 7, 6, 5, 4, 3, 2 or 1 day after (negative asynchrony), on the same day (synchronous), or 2 or 4 days before (positive asynchrony) the donor (n=6 or 8 mares per group). Pregnancy rates between 100% (6/6) and 63% (5/8) were seen in recipient mares that were between +2 and -6 days asynchronous. Embryo survival to the heartbeat stage declined in recipients that were -7 days asynchronous and no embryos survived in recipients that were -9 days asynchronous. Irrespective of uterine asynchrony, cessation of embryo mobility and fixation at the base of a uterine horn occurred when the conceptus was approximately 17 days old. Conceptus growth and development was slowed when embryos were placed in negatively asynchronous uteri. At the greatest degree of negative asynchrony at which embryos survived to the heartbeat stage, i.e. -7 and -6 days, development of the embryo proper and allantois was retarded. Luteostasis was achieved in recipient mares when day 10 embryos were transferred to recipient mares at any stage of asynchrony between -9 and +2 days with respect to the donor. These results indicate that in the horse, there is a wide window for establishment of pregnancy following embryo transfer to asynchronous recipients. Although progesterone priming of the uterus to a stage equivalent to that of the transferred embryo does not appear to be a prerequisite for embryo survival, it does nonetheless influence embryonic development.

Introduction: National renal transplant registries routinely report on centre-specific patient and graft survival following renal transplantation. However, other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important indicators of quality of care., Methods: Transplant activity and incident graft survival data were obtained from NHS Blood and Trans-plant, laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients., Results: Increasing live and nonheartbeating donors were responsible for the increasing transplant activity. Graft failure occurred in 2.9% of prevalent transplant patients and death rates remained stable at 2.4/100 patient years. In transplant recipients with a specified cause of death, 21% died due to malignancy and 21% as a consequence of cardiac disease. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post-transplant recipients. Analysis of prevalent transplants by chronic kidney disease stage showed 14.7% with an eGFR <30 ml/min/1.73 m(2) and 2.1% <15 ml/min/1.73 m(2). Of those with CKD stage 5T, 40.4% had Hb concentrations <10.5 g/dl, 25.9% phosphate concentrations >or=1.8 mmol/L, 9.0% adjusted calcium concentrations >or=2.6 mmol/L and 40.8% PTH concentrations >or=32 pmol/L. With the exception of PTH, transplant recipients with CKD stage 5T were less likely to achieve the UK standards compared to prevalent dialysis patients., Conclusion: Wide variations in clinical and biochemical outcomes amongst transplant recipients continue to exist and may reflect differences in healthcare delivery across the UK., ((c) 2010 S. Karger AG, Basel.)

Prolonged exhaustive exercise has a great impact on the immune system of athletes and leads to a transient weakening of the immune system. A host of studies has documented changes of immune parameters in peripheral blood following exercise. Concerning the effect of exhaustive exercise in transplant recipients there is little knowledge at present. We analysed peripheral blood in healthy athletes and transplant recipients who participated in the "Euregio cycling tour 2009" before and immediately after they performed 81 km of cycling that included ascending more than 1800 m in altitude. A full blood count and an automated differential count as well as microarray analysis were performed before, immediately after and one day after exercise in 10 male patients carrying a kidney transplant and in 10 controls matched in age and gender. Comparing the absolute increase in neutrophils in these two groups, we detected that the relative increase in neutrophils was significantly smaller in transplant recipients compared to their corresponding controls after exhaustive exercise. While both groups were comparable in performance, microarray analysis revealed a markedly different pattern of gene expression in transplant recipients compared to their controls. From the 130 genes that were significantly upregulated in controls immediately after exercise, only 12 genes were also upregulated in transplant recipients. 64 different genes were upregulated in transplant recipients only. Our findings may be related to the immunosuppressive medication that the transplant recipients took and therefore it should also be discussed that regular exercise might reduce the need for immunosuppressive medication in transplant recipients.

In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.

This study suggests that paternal age may be inversely associated with reproductive outcome, as demonstrated by a decline in fertilization, blastocyst formation, implantation and cryopreservation rates with advancing age.

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.

The regulation of the interaction between the immune system and antigens, which may lead to the induction of immune tolerance, is critical both under physiologic conditions and in different pathological settings. In the past few years, major strides have been made in our understanding of the molecular and cellular bases of this process. Novel pathways have been identified and several novel therapeutic agents are currently under clinical investigation for those diseases in which the normal balance between activation and suppression of the immune response is altered. The tryptophan catabolic enzyme, indoleamine 2,3-dioxygenase (IDO), is one of the key players involved in the inhibition of cell proliferation, including that of activated T cells. Recent works have demonstrated a crucial role for IDO in the induction of immune tolerance during infection, pregnancy, transplantation, autoimmunity, and neoplasias, including hematologic malignancies. In this review, the role of IDO in the induction of immunologic tolerance is addressed with a specific focus on its recently discovered effect on hematologic malignancies.

The effect that gonadotrophin-releasing hormone (GnRH) antagonists exert on endometrial receptivity has not yet been elucidated. GnRH antagonists might directly affect oocytes, the embryo and/or the endometrium. The aim of this study was to investigate the direct effect of GnRH antagonists on the endometrium in oocyte donation cycles. In an oocyte donation programme, oocytes from each donor (n = 49), stimulated with gonadotrophins and a GnRH antagonist, were equally shared between two different matched recipients. Recipients were randomly allocated to either receive a GnRH antagonist concomitant to donor during their endometrial priming with oestradiol (group I, n = 49) or to solely continue with their endometrial preparation (group II, n = 49). Pregnancy rate was 55.1% in group I and 59.1% in group II. Implantation rate was 26.1% in group I and 24.4% in group II. Endometrial thickness was also similar between the two groups on the day of human chorionic gonadotrophin injection to the donor. In conclusion, GnRH antagonist administration during the proliferative phase at a dose of 0.25 mg per day does not appear to adversely affect endometrial receptivity in oocyte recipients.

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

The feasibility, value and risk of percutaneous renal biopsy (PRB) in liver transplant candidates with renal failure are unknown. PRB was performed on 44 liver transplant candidates with renal failure of undetermined etiology and glomerular filtration rate (GFR) <40 mL/min/1.73 m(2) (n = 37) or on renal replacement therapy (RRT) (n = 7). Patients with >or=30% interstitial fibrosis (IF), >or=40% global glomerulosclerosis (gGS) and/or diffuse glomerulonephritis were approved for simultaneous-liver-kidney (SLK) transplantation. Prebiopsy GFR, urinary sodium indices, dependency on RRT and kidney size were comparable between 27 liver-transplant-alone (LTA) and 17 SLK candidates and did not relate to the biopsy diagnosis. The interobserver agreement for the degree of IF or gGS was moderate-to-excellent. After a mean of 78 +/- 67 days, 16 and 8 patients received LTA and SLK transplants. All five LTA recipients on RRT recovered kidney function after transplantation and serum creatinine was comparable between LTA and SLK recipients at last follow-up. Biopsy complications developed in 13, of these, five required intervention. PRB is feasible in liver transplant candidates with renal failure and provides reproducible histological information that does not relate to the pretransplant clinical data. Randomized studies are needed to determine if PRB can direct kidney allocation in this challenging group of liver transplant candidates.

With apologies to Sherlock Holmes, "You can never foretell when any one man's kidney transplant will fail, but you can say with precision when an average number will fail. ... So says the statistician."

Data on exposure to mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), in pediatric renal transplant recipients beyond the first year posttransplant are scarce. The authors therefore analyzed the long-term pharmacokinetics of MPA in 25 pediatric patients treated with 600 mg MMF/m body surface area twice a day in conjunction with cyclosporine A and prednisone. Plasma samples for 12-hour pharmacokinetic profiles were collected on day 7, and after 3, 9, 24, and 36 months posttransplant. Both the actual and the dose-normalized MPA-area under the concentration-time curve (AUC0-12) increased approximately 2-fold between day 7 and month 9 but stabilized thereafter. Both the actual and the dose-normalized MPA-AUC0-12 at months 24 and 36 were comparable to that at month 9. Presuming a therapeutic window of 30-60 mg h/L, 15 (60%) of 25 patients at day 7 had an MPA-AUC0-12 <30 mg h/L, indicating potential underexposure, whereas the proportion of patients with an MPA-AUC0-12 <30 mg h/L between months 3 and 36 was low (5%-17%). These data suggest that the recommended MMF dose of 600 mg/m body surface area twice a day in conjunction with cyclosporine A leads to MPA underexposure early posttransplant in a significant subset of patients, indicating a need for a higher initial MMF dose. Dose-normalized MPA exposure increases in the first 9 months posttransplant, consistent with a reduced MPA metabolism and increased enterohepatic recycling of MPA.

The rate of mycophenolic acid (MPA) absorption after oral administration of mycophenolate mofetil (MMF) is delayed in patients with diabetes. Cyclosporine (CsA) decreases MPA exposure by inhibiting enterohepatic recirculation of MPA/MPA glucuronide, and tacrolimus (TRL) may alter the rate and extent of MPA absorption due to its prokinetic properties especially in patients with diabetic gastroparesis. This study evaluated the effect of changing from CsA to TRL on pharmacokinetics of MPA in stable renal transplant recipients with long-standing diabetes. Eight patients were switched from a stable dose of CsA to TRL while taking MMF 1 g twice daily. The 12-hour steady-state total plasma concentration-time profiles of MPA and MPA glucuronide were obtained after oral administration of MMF on 2 occasions: first while taking CsA and second after changing to TRL. Pharmacokinetic parameters of MPA were calculated by the noncompartmental method. Changing from CsA to TRL resulted in significantly increased MPA exposure (area under the concentration-time curve from 0 to 12 hours, AUC0-12) by 46 +/- 32% (P = 0.012) and MPA predose concentration (C0) by 121 +/- 67% (P = 0.008). The magnitude of change in MPA exposure did not correlate well with MPA-C0 or CsA trough concentration. Switching to TRL had minimal impact on peak concentration of MPA (15.0 +/- 6.9 mg/L with CsA versus 16.1 +/- 9.7 mg/L with TRL, P = 0.773) and time to reach the peak concentration (1.0 +/- 0.4 hours with CsA versus 1.2 +/- 0.8 hours with TRL, P = 0.461). Highly variable and unpredictable changes in MPA exposure among renal transplant patients with diabetes do not support a strategy of preemptively adjusting MMF dose when switching calcineurin inhibitors in this population.

Mycophenolic acid (MPA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the phenolic MPA glucuronide (MPAG). MPAG is excreted by transporters such as organic anion-transporting polypeptide (gene SLCO), multidrug resistance protein 2 (gene ABCC2), breast cancer resistance protein (BCRP, gene ABCG2) or P-glycoprotein (gene ABCB1). This study investigated the association of UGTs, SLCOs, ABCB1, ABCC2, and ABCG2 polymorphisms with MPAG pharmacokinetics in 80 Japanese renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (0900 and 2100). On day 28, after renal transplantation, plasma concentrations of MPA and MPAG were measured by high-performance liquid chromatography. There were no significant differences in the area under the plasma concentration-time curve (AUC) ratio of MPAG/MPA between UGT1A1, UGT1A6, UGT1A7, UGT1A8, and UGT1A9 I399C/T genotypes. On the other hand, the median dose-adjusted AUC0-12 of MPAG in SLCO1B1 1a/1a+1a/1b+1b+1b (n = 53) and 1a/*15 + 1b/*15+*15/*15 (n = 27) were 1549 and 1134 mg.h L g, respectively (P = 0.03004 in multivariate analysis). The median dose-adjusted AUC0-12 of MPAG in SLCO1B3 334T/T+T/G (699G/G+G/A, n = 46) and 334G/G (699A/A, n = 34) was 1191 and 1580 mg.h L g, respectively (P = 0.02792 in multivariate analysis). There were no significant differences in the dose-adjusted AUC0-12 of MPAG between the ABCB1 C3435T and ABCC2 C-24T genotypes. However, the dose-adjusted AUC0-12 of MPAG was significantly lower in recipients with ABCG2 421C/A+A/A (n = 44) than in those with C/C (n = 36) (P = 0.0295). In conclusion, our findings showed that MPAG pharmacokinetics were significantly influenced by SLCO1B1 and SLCO1B3 polymorphisms and not by UGT polymorphisms. BCRP rather than multidrug resistance protein 2 seems to be the transporter associated with biliary excretion of MPAG.

Transplantation of pluripotent embryonic stem cells (ESC) into immune-deficient mice results in the formation of complex teratomas consisting of derivatives from all three germ layers. The highly sophisticated tissue organization found therein resembles structures normally found in the embryo and adult. Used as a functional proof of pluripotency of ESC, teratoma characterization has been restricted to identification of derivatives from all three germ layers. This paper aims to provide a thoughtful analysis of teratoma formation from a range of stem cells on the basis of published information, in an attempt to gain insight into tissue development during embryogenesis and provide a useful model for studying human development in normal as well as abnormal situations and toxicity studies. Furthermore, it is believed that studies on teratomas might lead to novel approaches in many research areas, including oncology and bioengineering.

Although small, localized injuries can be healed through the body's normal reparative process, large traumatic injury overwhelms this system and may result in a deficit of functional recovery, despite the use of conventional reconstructive modalities. Cell-based approaches using tissue engineering and regenerative medicine techniques have offered new opportunities for treatment. Although the fundamental principles of cell-based therapies have been demonstrated clinically on multiple tissue systems, usually a donor tissue biopsy and ex vivo cell manipulation prior to implantation in vivo are necessary. The goal of the present study was to investigate whether host biologic resources and environmental conditions could be used for in situ tissue regeneration, which may eliminate the need for donor cell procurement and subsequent in vitro cell manipulation. To address this aim, we implanted a common biomaterial into mice and characterized the infiltrating cells to determine their regenerative potential. We showed that host cell infiltrates are not entirely comprised of inflammatory and fibroblast-like cells and the normal inflammatory process can be altered by incorporating anti-inflammatory agents that influence the formation of scar tissue. In addition, the infiltrating cells are capable of differentiating into multiple cell lineages, including osteogenic, myogenic, adipogenic, and endothelial lineages, if appropriate conditions are provided. These results suggest that it is possible to recruit a predominance of cells with multilineage potential into a biomaterial scaffold. Therefore, it may be possible to enrich the infiltrate with such cell types and control their fate, provided the proper substrate-mediated signaling can be imparted into the scaffold for in situ tissue regeneration.

Introduction: To date, a specific marker to evaluate and predict the clinical course or complication of the liver-transplanted patient is not available in clinical practice. Increased procalcitonin (PCT) levels have been found in infectious inflammation; poor organ perfusion and high PCT levels in the cardiac donor appeared to predict early graft failure. We evaluated PCT as a predictor of early graft dysfunction and postoperative complications., Methods: PCT serum concentrations were measured in samples collected before organ retrieval from 67 consecutive brain-dead donors and in corresponding recipients from day 0, before liver transplantation, up to day 7 after liver transplantation. The following parameters were recorded in donors: amount of vasopressive drug doses, cardiac arrest history 24 hours before retrieval, number of days in the intensive care unit, age of donor, and infection in donor, and the following parameters were recorded in recipients: cold and warm ischemia time, veno-venous bypass, transfusion amount during orthotopic liver transplantation (OLT), and occurrence of postoperative complication or hepatic dysfunction., Results: In the donor, the preoperative level of PCT was associated with cardiac arrest and high doses of catecholamines before organ retrieval. In the recipient, elevated PCT levels were observed early after OLT, with a peak at day 1 or 2 after OLT, then a decrease until day 7. A postoperative peak of PCT levels was associated neither with preoperative PCT levels in the donor or the recipients nor with hepatic post-OLT dysfunction or other postoperative complications, but with two donor parameters: infection and cardiac arrest., Conclusion: PCT level in the donor and early PCT peak in the recipient are not predictive of post-OLT hepatic dysfunction or other complications. Cardiac arrest and infection in the donor, but not PCT level in the donor, are associated with high post-OLT PCT levels in the recipient.

Selection criteria for organ transplantation have evolved over time. Age has been revisited periodically. We studied the outcome of lung transplant adjusted by age in a single center transplant population. We matched the 42 lung graft recipients older than 60 years transplanted by July 1999 to younger controls by lung disease, transplant era within 2 years, type of transplant and gender. The female to male ratios were 17/25 among the older cohort (median age 61.6 years), and 15/27 (median age 51.9 years) among the matched younger. Survival analysis demonstrated a significant difference: at 1 year, 60% versus 86%, and at 5 years, 37% versus 57%, for older and younger, respectively, p=0.005. Excess annual mortality, calculated with the declining exponential approximation to life expectancy (DEALE), showed an older/younger ratio of 1.9. Eleven deaths occurred within 6 months among the older patients, 10 due to infection. After 6 months, there were 20 more deaths, 6 due to malignancy, 5 to Bronchiolitis Obliterans Syndrome (BOS), 3 to infection and 6 to other causes. Among the younger there were 6 deaths within 6 months and 12 more thereafter; among the latter, 8 were due to BOS. Despite stringent selection, lung transplant recipients older than 60 years show increased mortality even after adjusting for their expected higher age-related mortality.

The ability to generate genetically manipulated mice has revolutionized the study of development, cell biology, immunobiology and transplantation. Conventional gene targeting approaches lead to inactivation of the target gene in all tissues. This approach often has unintended consequences, such as embryonic lethality, which preclude studying the originally intended tissue. Newer approaches allowing conditional gene expression in a tissue-specific or temporally controlled fashion have the advantage of normal development with gene deletion only in the desired tissues. While nuances to these techniques continue to be developed, the underlying concepts remain consistent. This minireview focuses on the use of conditional gene targeting in mice using the Cre-loxP system and drug inducible gene expression using the tetracycline system.

Study Objective: To study the prevalence and impact of pain on the quality of life (QOL) of lung transplant recipients., Design and Patients: Prospective, observational, cross-sectional study. Ninety-six lung transplant recipients (> 3 months after transplantation) completed questionnaires measuring the severity and impact of pain (Brief Pain Inventory), anxiety (State Trait Anxiety Inventory), QOL (Short Form-36 version 2 [SF-36v2]), and depression (Beck Depression Inventory [BDI])., Setting: University medical center lung transplant outpatient clinic., Results: The prevalence of pain in lung transplant recipients was 49%. Patients with pain were older, more likely to have undergone unilateral lung transplantation (64% vs 40%, p = 0.03), and were more likely to have lung emphysema (55% vs 38%, p = 0.004). Only a pulmonary diagnosis of lung emphysema remained an independent predictor for postoperative pain in a logistic regression model. Average (+/- SD) score of the BDI was 9.6 +/- 7.8 and 5.8 +/- 5.8 (p = 0.005) for patients with and without pain, respectively. Patients with and without pain did not significantly differ in terms of anxiety. Pain-free patients had a significantly higher physical component score than patients with pain in the SF-36v2 (mean, 48.7 +/- 8.6 vs 38.6 +/- 9.8, p < 0.0001, respectively), while the mental component scores were not statistically different between the two groups., Conclusions: Lung transplant recipients have a high prevalence of pain. Patients with lung emphysema as their preoperative diagnosis are more likely to have pain. The occurrence of pain is associated with a decreased QOL in lung transplant recipients.

Objective: The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioavailability. The objective was to investigate the association between Cyp3A4, Cyp3A5, and MDR-1 polymorphisms and tacrolimus pharmacokinetics in the early period after renal transplantation., Methods: Forty-four renal transplant recipients were genotyped for 8 Cyp3A4, 7 Cyp3A5, and 5 MDR-1 genetic variants affecting the proteins' expression and/or function. Dose-adjusted tacrolimus though levels were determined during the first week after transplantation and correlated with corresponding genotype., Results: We found no correlation between Cyp3A4 polymorphism and tacrolimus pharmacokinetics. Patients who do not carry both Cyp3A5*3 alleles achieved lower mean dose-adjusted tacrolimus blood concentrations (p<0.001) and needed a longer time to reach the target concentration (10-12 ng/ml; p<0.001) compared to Cyp3A5*3 homozygotes. Patients with less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms, associated with reduced expression of P-glycoprotein, had also lower dose-adjusted tacrolimus blood concentrations compared to patients having equal to or greater than three copies of MDR-1 genetic variants (P=0.003). There was no difference in the rate of biopsy-confirmed acute rejection among groups during the first 3 months after transplantation., Conclusion: The complete absence of Cyp3A5*3 allele and the accumulation of less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms are associated with lower tacrolimus blood levels identifying these genotypes as markers for patients requiring higher tacrolimus doses.

Cardiac transplant recipients often anticipate and suffer varying degrees of discomfort during surveillance endomyocardial biopsy (EMBx). We performed a randomized, blinded, placebo-controlled trial to determine whether topical anesthetic was associated with reduced pain and to identify factors associated with increased pain perception during EMBx. In 225 EMBxs, use of the eutectic mixture of lidocaine and prilocaine (EMLA) decreased pain score (-7.3 compared with placebo; p = 0.04); the other significant predictors of increased pain scores were time to achieve access (+2.3 per minute; p = 0.001) and female gender (+12.7 compared with males; p = 0.003). Topical anesthetic cream is associated with decreased pain during EMBx, even after adjusting for other predictors of pain, including female gender and longer time to achieve access. A better understanding of the factors affecting pain during EMBx could improve the comfort level of this procedure.

Distinguishing transplant recipients who will benefit from a reduction in, or even the withdrawal of, immunosuppression from those who require intensive, lifelong immunosuppression will be dependent on developing strategies for immune monitoring. Currently, no assays have been shown to accurately predict the development or presence of donor-specific tolerance in humans after transplantation. In this overview we describe and discuss those assays that we believe may be useful for identifying tolerant transplant recipients. Validation of "tolerance" assays will be critical for the safe development of tolerance regimens in humans.

Background: Initial interruption of immunosuppression for 72 hr was analyzed in renal transplant recipients according to Calne et al.'s "window of opportunity for immunologic engagement" (WOFIE) concept., Methods: This pilot study was designed as a randomized, open-label, prospective trial of 40 recipients (20 in the WOFIE group, 20 in the control group) of cadaveric kidney transplants who were followed up for 2 years. Immunosuppression comprised tacrolimus (trough levels 5-8 ng/mL), daclizumab (1 mg per kilogram of body weight on day 0 and after 2, 4, 6, and 8 weeks), mycophenolate mofetil (1-2 g/day), and prednisolone (maintenance dose of 10 mg/day). After induction with daclizumab, prednisolone, and mycophenolate mofetil, immunosuppression was interrupted for 72 hr in the WOFIE group. Steroid withdrawal followed in both groups within 12 to 16 weeks posttransplant., Results: Patient and graft survival did not differ significantly between the two cohorts. However, the WOFIE group experienced less acute rejection episodes and developed better graft function. Although all but one of the patients in the WOFIE group successfully discontinued steroid treatment, permanent steroid withdrawal was achieved in only 76.4% of the control group. After daclizumab discontinuation, the WOFIE group demonstrated an increase of CD4CD25 T cells in peripheral blood (P<0.05 vs. control group), which was stable over time and strongly correlated with a significantly higher expression level of Foxp3-mRNA., Conclusions: Initial interruption of immunosuppression for 72 hr correlates with the induction of regulatory immunologic mechanisms and allows early and reliable minimization of immunosuppressive treatment.

Aims: This study investigates the association between renal function and change in weight after kidney transplantation., Methods: Retrospective analyses of 165 transplant patients on maintenance steroids who were followed-up for 6.2 +/- 2.4 years., Results: 101 males and 64 females participated in the study. Results are expressed as mean +/- SD. At the first post-transplant outpatient visit (time 0), BMI was 25.3 +/- 4.8 kg/m2. It increased significantly by 7.7 +/- 10.8% and 10.9 +/- 12.6% at 1 and 5 years. 18 and 29% of patients had a BMI > 30 kg/m2 at times 0 and 5 years, respectively. Thereafter, diminishing glomerular filtration rate (GFR) was associated with the loss of the excess weight. Multivariate analysis showed that GFR, but not age, race, sex, source of graft, number of HLA mismatches or length of dialysis was significant to post-transplant weight gain. 38 patients gained weight > 1 SD above the mean of the population and were designated the high weight gain (HWG) group. 41 patients gained weight < the mean - 1 SD of the population and were designated the low weight gain (LWG) group. GFR in the high and low weight gain groups at time 0 was 71.8 +/- 20.3 ml/min/1.73 m2 and 66.4 +/- 23.1 ml/min/1.73 m2, respectively (p = NS), as compared to 77.4 +/- 23.3 ml/min/1.73 m2 and 61.5 +/- 24.5 ml/min/ 1.73 m2 at 6 months, respectively (p < 0.01) and continued to be significant thereafter (72.7 +/- 17.2 ml/min/1.73 m2 and 58.9 +/- 19.8 ml/min/1.73 m2, p < 0.05 at 6 years)., Conclusions: Patients with relatively better renal transplant function gained more weight, suggesting a pivotal role of improved appetite on weight gain post transplantation. Most of the weight gain occurred during the first year.

The field of proteomics is developing at a rapid pace in the post-genome era. Translational proteomics investigations aim to apply a combination of established methods and new technologies to learn about protein expression profiles predictive of clinical events, therapeutic response, and underlying mechanisms. However, in contrast to genetic studies and in parallel with gene expression studies, the dynamic nature of the proteome in conjunction with the challenges of accounting for post-translational modifications requires the translational proteomics investigator to understand the strengths and limitations of proteomics approaches. In this review, we provide an overview of proteomics approaches and techniques, and proteomics informatics for clinical transplantation investigators. We also review recent publications pertaining to transplantation proteomics, and discuss the implications and utility of urine proteomics for non-invasive investigation of transplant outcomes.

Mycophenolic acid (MPA), the active metabolite of the immunosuppressive agent mycophenolate mofetil (MMF), was for the first time quantified in the serum of transplant recipients using micellar electrokinetic capillary chromatography (MEKC). Sample preparation was carried out with solid phase extraction (SPE) using octadecyl-modified endcapped silica (C18 EC) as sorbent. Extremely varying recovery rates in preliminary experiments showed both the importance of pH monitoring during the single SPE steps and the necessity of an internal standard. MPA carboxy butyl ether (CBE), a specifically developed reference standard, was employed. Furthermore, optimisation of the MEKC parameters detection wavelength and injection time was of primary importance in order to enable the quantitation of therapeutic trough serum levels of MPA in the range lower than 5 microg x mL(-1). Under optimised conditions, a limit of quantitation of 1.0 microg x mL(-1) was achieved allowing the determination of MPA in the serum of patients.

Purpose: The purpose of our study was to evaluate short- and long-term results of transplants from cadaver donors who have died of poisoning by various substances., Materials and Methods: The actuarial survival rate of organs from intoxicated donors was calculated using the Kaplan-Meier method., Results: Among the 507 donors between January 1998 and December 2002, 5 (0.98%) had a cause of brain death of poisoning, namely, organo-phosphates (n = 2), methanol (n = 1), cyanide (n = 1) and acetylsalicilic acid(n = 1), from whom were procured 10 kidneys, 1 liver, 2 corneas, and 1 set of bones. The follow up for patients receiving solid organs was 15.2 months (range, 0-48 months). At 3 months, 90% of kidneys had normal function. No delayed graft function rejection episodes or major complications were reported in any recipient. None showed evidence of acute or chronic poisoning. Two died, 1 early mortality was due to anesthetic complications and the other at 17 months to an unknown cause. Actuarial kidney survival rates were 90% and 80% at 12 and 24 months, respectively. The liver recipient was well at the end of follow up., Conclusion: Using organs of poisoned donors is feasible with comparable graft survival rates to other recipient.