The guanine-hypoxanthine permease GhxP of Erwinia amylovora facilitates the influx of the toxic guanine derivative 6-thioguanine.

AIM: Erwinia amylovora is the causal agent of fire blight, a devastating disease of apples and pears. This study determines whether the E. amylovora guanine-hypoxanthine transporter (EaGhxP) is required for virulence and if it can import the E. amylovora produced toxic analogue 6-thioguanine (6TG) into cells. METHODS AND RESULTS: Characterization of EaGhxP in guanine transport deficient Escherichia coli reveals that it can transport guanine, hypoxanthine and the toxic analogues 8-azaguanine (8AG) and 6TG. Similarly, EaGhxP transports 8AG and 6TG into E. amylovora cells. EaGhxP has a high affinity for 6TG with a Ki of 3·7 µmol l-1 . An E. amylovora ⊿ghxP::Camr strain shows resistance to growth on 8AG and 6TG. Although EaGhxP is expressed during active disease propagation, it is not necessary for virulence as determined on immature apple and pear assays. CONCLUSIONS: EaGhxP is not required for virulence, but it does import 6TG into E. amylovora cells. SIGNIFICANCE AND IMPACT OF THE STUDY: As part of the disease establishment process, E. amylovora synthesizes and exports a toxic guanine derivative 6TG. Our results are counter intuitive and show that EaGhxP, an influx transporter, can move 6TG into cells raising questions regarding the role of 6TG in disease establishment.

Propensity score-based comparison of the graft failure risk between kidney transplant recipients of standard and expanded criteria donor grafts: Toward increasing the pool of marginal donors.

From a prospective and multicentric French cohort, we proposed an external validation study for the expanded criteria donor (ECD), based on 4833 kidney recipients transplanted for the first time between 2000 and 2014. We estimated the subject-specific effect from a multivariable Cox model. We confirmed a 1.75-fold (95% confidence interval [CI] 1.53-2.00, P < .0001) increase in graft failure risk if a given patient received an ECD graft compared to a graft from a donor with standard criteria (standard criteria donor [SCD]). Complementarily, we estimated the population-average effect using propensity scores. We estimated a 1.34-fold (95% CI 1.09-1.64, P = .0049) increase in graft failure risk among ECD patients receiving an ECD graft compared to receiving a SCD graft. With a 10-year follow-up, it corresponded to a decrease of 8 months of the mean time to graft failure due to ECD transplantation (95% CI 2-14 months). The population-average relative risk due to ECD transplantation and the corresponding absolute effect seem finally not so high. Regarding the increase of quality of life in transplantation, our study constitutes an argument to extend the definition of marginality by considering more grafts at high risk and thereby enlarging the pool of kidney grafts.

Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials.

BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Treatment Response and Outcomes in Post-transplantation Lymphoproliferative Disease vs Lymphoma in Immunocompetent Patients.

Posttransplantation lymphoproliferative disorder (PTLD) after solid organ transplantation may carry a poorer prognosis than lymphoma in immunocompetent individuals, but comparative data are lacking. In a retrospective, single-center, case-control study, 21 cases of PTLD were identified in patients undergoing kidney transplantation since 2000, and compared to 42 nontransplanted controls cared for in the same institution and matched for age, prognostic index, and cerebral localization. Two-year and 5-year overall survival was 57% and 44%, respectively, in PTLD patients and 71% and 58% in controls (log-rank test P = .20). On multivariable analysis, overall survival was similar for PTLD and control patients (hazard ratio 1.71, 95% confidence interval 0.81 to 3.61, P = .16). Response rate to first-line chemotherapy was similar between the 2 groups. Death was due to progression of the disease in 46% vs 94% of PTLD and control patients, respectively (P < .01), or sepsis in 31% vs 0% (P = .03). Treatment-related mortality was significantly higher in PTLD (19%) than in controls (0%, P = .03). In conclusion, response to first-line chemotherapy and overall survival are similar in PTLD and control patients, whereas causes of death were significantly different. Better prevention and management of infectious complications could improve the results in PTLD patients.

[Appropriate medication prescribing in older people]. / Bon usage des médicaments chez le sujet âgé.

Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.

Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study.

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study.

One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n=99) or no CS (-CS; n=98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the -CS group (5-year follow-up, p=0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p=0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p=0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p=0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in -CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels (≤11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value<10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p<0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p=0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p<0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: the infinity study.

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.

Metabolic syndrome performs better than the individual factors in predicting renal graft outcome.

AIM: Individual components of the metabolic syndrome (MS), especially obesity and hypertension, have a deleterious effect on renal graft outcome. Whether MS is better than its individual components in predicting the decline of renal function is unknown. We studied the presence of MS and its individual components at 12 months post-transplantation according to the Adult Treatment Panel III classification and their influence on measured graft function. METHODS: A cohort of 322 patients who underwent transplantation between 1996 and 2003 and who agreed to have their glomerular filtration rate (GFR) measured by urinary clearance of technetium 99m (Tc*-DTPA) (measured GFR [mGFR]) at 3, 12, 48, 60, and 96 months after transplantation were included. The patients were followed up until patient death, graft loss, or December 2009 (mean follow-up: 3 ± 2.8 years). The linear mixed effect model for longitudinal repeated measures was applied. To compare MS versus its components we used the Akaike information Criterion (AIC) to determine the best model according to the Anderson and Burnham method. RESULTS: Univariate and multivariate analyses models using MS were more efficient than those using the individual components, which consisted of waist circumference, low high-density lipoprotein-cholesterol, hypertriglyceridemia, hyperglycemia, and systolic and diastolic blood pressure. The AIC was the lowest with MS models indicating better prediction on graft function than the individual components. CONCLUSION: MS is a better predictor of mGFR decline than its individual components. It is a valid and precious tool to assess outcomes.

Different classifications yield variance in metabolic syndrome prevalence and dynamics in renal transplant recipients.

INTRODUCTION: The metabolic syndrome (MS) is a combination of factors that are associated with increased cardiovascular diseases. High MS prevalence was reported in renal transplant recipients. However, little is known about the longitudinal prevalence and its dynamic properties in this population. We studied the longitudinal prevalence of MS at 3 and 12 months post-transplantation using 3 classifications. PATIENTS AND METHODS: We studied a cohort of 322 patients who underwent transplantation between 1996 and 2003 who had isotopic measurement of transplant glomerular filtration rate and MS assessment at 3 and 12 months after transplantation. Prevalence and change of MS status in terms of acquisition or regression were analyzed based on World Health Organization (WHO), International Diabetic Federation (IDF), and The Adult Treatment Panel-III (ATP-III) classifications. RESULTS: The prevalences at 3 and 12 months were as follows: WHO, 8.4% and 8.1%; IDF, 25.8% and 29.8%; and ATP-III, 34.3% and 36.6%, respectively. Change in MS status was noted in 9.7%, 16.4%, and 20.5% of subjects within WHO, IDF, and the ATP-III classifications, respectively. Prevalence was significantly lower with WHO than IDF and ATP-III. Prevalence was the highest with ATP-III. However, the difference with IDF was significant only at 3 months post-transplantation. Depending on the classification used, 10%-21% of subjects change MS status within the first year of transplantation. CONCLUSION: Longitudinal analysis confirms the high prevalence of MS and also highlights the dynamics of MS. We think both prevalence and dynamics should be accounted for when studying outcomes.

Continuous glucose monitoring after kidney transplantation in non-diabetic patients: early hyperglycaemia is frequent and may herald post-transplantation diabetes mellitus and graft failure.

OBJECTIVES: New onset of diabetes after transplantation (NODAT) is a known complication of renal transplantation, but early glycaemic status after transplantation has not been described prospectively. This study aimed to assess blood glucose (BG) levels immediately following kidney transplantation in non-diabetic subjects and to explore their relationship to later graft outcomes and NODAT occurrence. PATIENTS AND METHODS: Over a 9-month period, 43 consecutive non-diabetic patients who received a kidney transplant were prospectively investigated. During the first 4 days after transplantation, fasting BG was measured and the 24-h BG profile assessed by continuous glucose monitoring (CGM). Capillary BG was measured on hospital admittance and at least four times a day for CGM calibration thereafter. All adverse events were recorded, and fasting BG and HbA1c were assessed at 3, 6 and 12 months and at the last visit to our centre. RESULTS: Immediately following renal transplantation, capillary BG was 12.2 ± 3.8 mmol/L. On day 1 (D1), fasting BG was 9.9 ± 4.3 mmol/L and decreased to 6.0 ± 1.5 mmol/L on D3. The CGM-reported mean 24-h BG (mmol/L) was 10.2±2.4 on D1, 7.7 ± 1.3 on D2 and 7.5 ± 1.1 on D3. From D1 to D4, 43% of patients spent>12h/day with BG levels>7.7 mmol/L. While morbidity during the 3 months following transplantation appeared unrelated to BG, the first post-transplantation capillary BG measurement and fasting BG on D1 tended to be higher in patients who developed diabetes 3 months later. Tacrolimus treatment was associated with a higher incidence of dysglycaemia at 3 and 6 months. After a mean follow-up of 72 months, NODAT was frequently seen (18.6%), and was associated with tacrolimus medication (P<0.01) and a higher rate of renal transplantation failure (RR: 3.6, P<0.02). CONCLUSION: Hyperglycaemia appears to be a nearly constant characteristic immediately following transplantation in non-diabetic kidney recipients. Higher BG values could identify patients at risk for later post-transplant diabetes and graft failure.

Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

An epidemic of Pneumocystis jiroveci pneumonia in a renal transplantation center: role of T-cell lymphopenia.

Although only 2 cases of Pneumocystis jiroveci pneumonia were observed in our center between 2004 and 2009, we diagnosed 9 cases in 2010. Each patient had been in contact in the hospital with at least 1 other patient suffering P jiroveci pneumonia. Genotyping of P jiroveci pneumonia strains demonstrates a total homogeneity of the DNA sequences in the 7 patients already analyzed. CD4+ lymphocyte count was significantly lower at M3 in P jiroveci pneumonia patients than in controls. Our clinical and molecular data confirm that interhuman transmission of P jiroveci is possible, particularly to lymphopenic transplant recipients.

Is renal allograft dysfunction a risk factor for severe infection in kidney transplant recipients?

The ANTICIPE study is a cross-sectional, multicenter, French study. The aim of this study was to describe clinical and biological parameters observed in a cohort of 1446 stable renal transplant recipients, according to the stage of chronic kidney disease. Severe infection was defined as an infection necessitating ≥ 7 days of hospital stay. We observed a negative correlation between declining glomerular filtration rate and occurrence of severe infection (P < .0001). In multivariate analysis, severe infection was associated with age, female gender, chronic kidney disease stage (Kidney Disease Outcomes Quality Initiative classification), and number of acute rejection episodes. Our study suggested that renal allograft function is a predictor not only of cardiac death and cardiovascular complications, but also of severe infections.

Accuracy of GFR predictive equations in renal transplantation: validation of a new turbidimetric cystatin C assay on Architect c8000.

OBJECTIVES: To evaluate the Sentinel-PETIA cystatin C on Architect c8000 analyzer. DESIGN AND METHODS: We assessed analytical performances and clinical relevance by comparison with a reference isotopic method in kidney transplant recipients. RESULTS: This assay exhibited reliable precision and was close to the non standardized Siemens-PENIA method. All tested equations allowed reliable assessment of GFR. CONCLUSIONS: Cystatin C improved GFR determination at the critical level of 60 mL/min/1.73 m². New formulas might be necessary after IFCC standardization.

Monthly screening for BK viremia is an effective strategy to prevent BK virus nephropathy in renal transplant recipients.

BACKGROUND: BK polyomavirus virus (BKV) nephropathy (BKVN) is the most common viral infection that affects renal allografts. Because a specific antiviral therapy is lacking, BKVN may result in graft dysfunction and/or loss. We prospectively analyzed whether monthly nucleic acid testing (NAT) for BKV replication in blood and immediate reduction of immunosuppression (IS) could prevent BKVN. METHODS: NAT was performed at monthly intervals for 6 months and then at 12 months in 119 de novo renal transplant recipients. In viremic patients (presumptive BKVN), a graft biopsy was systematically performed and IS was immediately reduced. RESULTS: BKV viremia occurred in 13 (10.9%) patients after a median time of 90 days (23-241); 77% of patients were viremic before month 4. After reduction of IS, viral load was undetectable in 11 patients, remained low in 1, and continued to increase in 1 patient who developed definitive BKVN despite reduction of IS, and finally returned to dialysis 6 months after transplantation. CONCLUSION: BKV infection is an early complication. Monthly NAT in blood during the first 6 months and immediate reduction of IS in viremic patients almost completely prevent definitive BKVN.

[Thrombotic microangiopathy following kidney transplantation revealing factors H and I deficiencies]. / Microangiopathie thrombotique de novo post-transplantation rénale révélant un déficit en facteur H et en facteur I.

A 52-year-old man with an end stage renal failure of undetermined aetiology was hemodialysed in 2002. He received a cadaveric kidney transplantation in 2004. After an episode of diarrhea, a thrombotic microangiopathy was diagnosed in July 2009 and during this episode, a low C3 serum level was identified. Plasma exchanges were beneficial. Exploration of the low C3 serum level revealed both factor H and factor I deficiencies. We think that the renal failure of undetermined aetiology was probably an unnoticed haemolytic and uremic syndrome which recurred more than five years after transplantation.

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study.

This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.