Living kidney donor evaluation for all candidates with normal estimated GFR for age.

Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is <90 ml/min/1.73 m2 (KDIGO guidelines) or 80 ml/min/1.73 m2 (most US centres). However, age-related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in-depth screening should be proposed to all candidates with a normal eGFR for age. We compared the evolution of eGFR after donation between three groups of predonation eGFR: normal for age (Sage ) higher than 90 or 80 ml/min/1.73 m2 (S90 and S80, respectively); across three age groups (<45, 45-55, >55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S90 than in S80 or Sage but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in-depth screening for all candidates to donation with a normal eGFR for age.

Power Output and Pacing During International Cross-Country Mountain Bike Cycling.

PURPOSE: To characterize the physiological profiles of elite cross-country mountain-bike (XCO-MTB) cyclists and to examine their pacing and power-output (PO) distribution during international races. METHODS: Over 2 competitive seasons, 8 male XCO-MTB cyclists (VO2max 79.9 [5.2] mL·min-1·kg-1, maximal aerobic power [MAP] 411 [18] W and 6.3 [0.4] W·kg-1) regularly undertook incremental tests to assess their PO and heart rate (HR) at first and second ventilatory thresholds (VT1 and VT2) and at VO2max. During the same period, their PO, HR, speed, and cadence were recorded over 13 international races (total of 30 recorded files). RESULTS: Mean PO, speed, cadence, and HR during the races were 283 (22) W (4.31 [0.32] W·kg-1, 68% [5%] MAP), 19.7 (2.1) km·h-1, 68 (8) rpm, and 172 (11) beats·min-1 (91% [2%] HRmax), respectively. The average times spent below 10% of MAP, between 10% of MAP and VT1, between VT1 and VT2, between VT2 and MAP, and above MAP were 25% (5%), 21% (4%), 13% (3%), 16% (3%), and 26% (5%), respectively. Both speed and PO decreased from the start loop to lap 1 before stabilizing until the end of the race. CONCLUSIONS: Elite off-road cyclists demonstrated typical values of world-class endurance cyclists with an excellent power-to-mass ratio. This study demonstrated that XCO-MTB races are performed at higher intensities than reported in previous research and are characterized by a fast start followed by an even pace.

Recurrence of Renal Cell Cancer After Renal Transplantation in a Multicenter French Cohort.

BACKGROUND: Renal cancer accounts for 3% of adult malignancies; renal cell carcinoma (RCC) represents 80% of all renal cancers, and is characterized by late recurrences. Recurrences after kidney transplantation are associated with a high mortality rate. We aimed to determine if recurrences are linked to tumor characteristics and to delays between diagnosis and transplantation. METHODS: We retrospectively analyzed data from French kidney-transplanted patients with medical histories of pretransplant renal cancer, focusing on the most common histological subtypes: clear cell and papillary cancers. Characteristics of the tumors, patients, and kidney transplantations were documented, and posttransplant patient survival was analyzed. RESULTS: Of 143 patients, 13 experienced cancer recurrence after kidney transplantation. The mean delay in recurrence was 3 ± 2.3 years posttransplantation, and the cumulative incidences of recurrence were 7.7% at 5 years and 14.9% at 10 years. The risk of recurrence was higher in patients with clear cell RCC (13% vs 0%, P = 0.015). There was no correlation between posttransplant recurrence and the interval before transplantation. Factors associated with a higher risk of cancer recurrence were histological clear cell RCC (P = 0.025), tumor stage pT2 (P = 0.002), and Fuhrman grade IV (P < 0.001). Recurrences were associated with a high mortality rate; 76.9% of patients with recurrences had died by the end of the follow-up period. CONCLUSIONS: Recurrences of clear cell RCC are not uncommon after kidney transplantation and are associated with very poor prognoses. These results should be considered before listing patients with a history of renal cancer for transplantation.

Progression of pulse pressure in kidney recipients durably exposed to CsA is a risk factor for epithelial phenotypic changes: an ancillary study of the CONCEPT trial.

In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year.

A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity.

Following allogenic hematopoietic stem cell transplantation (HSCT), patients with autoimmune disease or hematopoietic malignancy may develop acute or chronic graft-versus-host (GvH) disease. B lymphocytes, from the recipient as well as from the donor, have recently been implicated in the pathogenesis of such disturbances. Their deleterious effects are accounted for by other tasks B lymphocytes accomplish than the antibody production. We highlight herein some recent observations in the context of B cells in the GvH disease.

Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial.

BACKGROUND: Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant. METHODS: Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation. RESULTS: Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively). CONCLUSIONS: There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.

CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients.

OBJECTIVE: Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation. METHODS: A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12. RESULTS: Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36). CONCLUSION: We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

Patient characteristics influencing ciclosporin pharmacokinetics and accurate Bayesian estimation of ciclosporin exposure in heart, lung and kidney transplant patients.

BACKGROUND AND OBJECTIVES: Population pharmacokinetic studies of ciclosporin microemulsion are needed to identify the individual factors influencing ciclosporin pharmacokinetic variability in transplant patients and to design efficient tools for the accurate estimation of ciclosporin overall exposure (area under the plasma concentration-time curve from 0 to 12 hours [AUC12]). In the present retrospective study, a large database of heart, lung (with or without cystic fibrosis) and kidney (both adult and paediatric) transplant patients receiving ciclosporin microemulsion was analysed with the aims of (i) building a population pharmacokinetic model and finding the main covariates linked with ciclosporin microemulsion pharmacokinetic parameters; and (ii) developing a maximum a posteriori probability Bayesian estimator (MAP-BE) to estimate ciclosporin microemulsion pharmacokinetic parameters using a limited-sampling strategy. METHODS: 3,072 concentration data from 147 patients (i.e. 309 full pharmacokinetic profiles) were analysed using the nonlinear mixed-effects model program NONMEM. The influence of numerous covariates was tested, and the final model was validated by data splitting. For Bayesian estimation, the best limited-sampling strategy was determined based on the D-optimality criterion, and validation performed in an independent group of 60 patients. RESULTS: The pharmacokinetics of ciclosporin microemulsion were accurately described by a two-compartment model with Erlang distribution for the absorption process. The type of graft and post-transplantation period were identified as significant sources of variability of the absorption parameter. Both apparent volume of the central compartment after oral administration (V1/F) and apparent oral clearance (CL/F) increased with bodyweight. The best limited-sampling strategy for Bayesian estimation was 0 hour, 1 hour and 3 hour post-dose, providing accurate estimation of ciclosporin microemulsion AUC12 in all patients of the test group, with a mean bias of 2.0 +/- 10.5% (range: -19.1% to -21.4% and 95% CI -0.6, +4.7). CONCLUSION: Population pharmacokinetic analysis of ciclosporin microemulsion in allograft transplants resulted in the design of a new pharmacokinetic model for ciclosporin microemulsion, identification of significant covariates and the design of an accurate MAP-BE based on three blood concentrations and these covariates.

A reverse transcription-nested PCR assay for HHV-6 mRNA early transcript detection after transplantation.

Monitoring of human herpesvirus-6 (HHV-6) reactivation is important, especially in immunocompromised patients such as transplant recipients. Reverse transcription PCR (RT-PCR) is a useful method to distinguish between latent and active infection. Here, a RT-nested PCR coupled with a colorimetric plate hybridization assay was established to detect HHV-6 types A and B U79/80 mRNAs. After confirming the reliability of the assay on HHV-6 cultures, it was applied to the detection of HHV-6 reactivation after renal (27 patients), bone marrow (14 patients) or heart (7 patients) transplantation. A total of 206 blood samples were tested from renal (137), bone marrow (58) and heart (11) transplant recipients. U79/80 mRNAs were found in 32 samples that were considered as indicative of HHV-6 reactivation: 15, 13 and 5 from kidney, bone marrow and heart transplant recipients, respectively. Finally, U79/80 mRNA detection was correlated with clinical manifestations including leucopenia, skin rash, graft rejection or dysfunction and diarrhoea.

Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.

Successful renal retransplantation after post-transplant lymphoproliferative disease.

Post-transplant lymphoproliferative disease (PTLD) is a rare but severe complication of renal transplantation. Reduction of immunosuppression is essential for controlling PTLD but may induce graft loss. Retransplantation after PTLD is considered dangerous, because immunosuppressive treatment resumption may trigger hematological relapse. We retrospectively report six patients (five adults, one child) who underwent a second renal transplantation after successfully treated PTLD. Epstein-Barr virus (EBV) serology was positive before the first transplantation in all patients except the child. Post-transplant lymphoproliferative disease was detected 6.6 months (range 4.5-9.4) after transplantation. Lymphoproliferation was always monomorphic, B-cell, and EBV-related. Post-transplant lymphoproliferative disease was confined to the renal allograft (n = 4), multilocular (n = 1) or cerebral (n = 1). Immunosuppression tapering (6/6) and transplantectomy (5/6) led to hematological remission in all patients. Retransplantation was performed 77 months (range 50-128) after PTLD diagnosis. Immunosuppression included steroids (n = 6), ATG (n = 2), anti-CD25 (n = 2), cyclosporine (n = 4), tacrolimus (n = 2), mycophenolate mofetil (n = 4) and azathioprine (n = 1). After a median follow up of 30 months (range 24-47) patient survival was 100%, with no recurrence of PTLD. In conclusion, renal retransplantation can be considered in patients with monomorphic PTLD history, without major risk of hematological recurrence.

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients.

BACKGROUND: Therapeutic drug monitoring of mycophenolic acid (MPA) may minimise the risk of acute rejection after transplantation. Area under the curve (AUC) rather than trough concentration-based monitoring is recommended and models for AUC estimation are needed. OBJECTIVES: To develop a population pharmacokinetic model suitable for Bayesian estimation of individual AUC in stable renal transplant patients. PATIENTS AND METHODS: The population pharmacokinetics of MPA were studied using nonlinear mixed effects modelling (NONMEM) in 60 patients (index group) receiving MPA on a twice-daily basis. Ten blood samples were collected at fixed timepoints from ten patients and four blood samples were collected at sparse timepoints from 50 patients. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements and covariates. The predictive performances of the Bayesian procedure were evaluated in an independent group of patients (test group) comprising ten subjects in whom ten blood samples were collected at fixed timepoints. RESULTS: A two-compartment model with zero-order absorption best fitted the data. Covariate analysis showed that bodyweight was positively correlated with oral clearance. However, the weak magnitude of the reduction in variability (from 34.8 to 28.2%) indicates that administration on a per kilogram basis would be of limited value in decreasing interindividual variability in MPA exposure. Bayesian estimation of pharmacokinetic parameters using samples drawn at 20 minutes and 1 and 3 hours enabled estimation of individual AUC with satisfactory accuracy (bias 7.7%, range of prediction errors 0.43-15.1%) and precision (root mean squared error 12.4%) as compared with the reference value obtained using the trapezoidal method. CONCLUSION: This paper reports for the first time population pharmacokinetic data for MPA in stable renal transplant patients, and shows that Bayesian estimation can allow accurate prediction of AUC with only three samples. This method provides a tool for therapeutic drug monitoring of MPA or for concentration-effect studies. Its application to MPA monitoring in the early period post-transplantation needs to be evaluated.

Influence of host-recipient origin on clinical aspects of posttransplantation lymphoproliferative disorders in kidney transplantation.

BACKGROUND: Posttransplantation lymphoproliferative disorder (PTLD) is a well-known complication of immunosuppression associated with solid organ transplantation. The donor or host origin of PTLD may influence the outcome of the disease as it has been reported that a donor origin may be associated with a better prognosis. The aim of the study was to determine the origin (recipient or donor) of 12 PTLD occurring in kidney transplant recipients and to correlate the results with clinical findings. METHODS: Origin of PTLD was determined using HLA DRB1 molecular typing, analysis of multiple short-tandem repeat microsatellite loci, and HLA class I antigen expression by immunohistochemistry. RESULTS: Combining the three techniques, we found that eight cases originated from the recipient and four cases originated from the donor. The results of the three techniques were concordant and altogether assigned the origin of the tumors. All the donor-origin PTLD were strictly localized to the kidney graft, developed after a mean time of 5 months after transplantation, and regressed after reduction of immunosuppression. In contrast, seven of the eight recipient-origin PTLD presented as multisystemic disease, occurred a mean time of 75.7 months after the transplantation, and had a worse outcome (mortality, five deaths of eight patients, 62.5%). CONCLUSIONS: These results suggest that PTLD originating from the donor arise in the first year after transplantation into the graft, and that recipient-origin PTLD develop later as an invasive disease. Because it permits simultaneously the analysis of cell morphology and tumor origin, immunohistochemistry is a more reliable technique in the case of graft tumors associated with allograft rejection. The determination of the origin of the tumors seems to be of value in the management of PTLD to predict the outcome and to adapt therapy.