Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Combination of generalist predators, Nesidiocoris tenuis and Macrolophus pygmaeus, with a companion plant, Sesamum indicum: What benefit for biological control of Tuta absoluta?

Tuta absoluta is one of the most damaging pests of tomato crops worldwide. Damage due to larvae may cause up to 100% loss of tomato production. Use of natural enemies to control the pest, notably predatory mirids such as Nesidiocoris tenuis and Macrolophus pygmaeus, is increasingly being promoted. However, considering the potential damage caused to tomatoes by these omnivorous predators in the absence of T. absoluta, an alternative solution could be required to reduce tomato damage and improve the predators' performance. The use of companion plants can be an innovative solution to cope with these issues. The present study aimed to determine the influence of companion plants and alternative preys on the predators' performance in controlling T. absoluta and protecting tomato plants. We evaluated the effect of predators (alone or combined) and a companion plant (sesame (Sesamum indicum)) on T. absoluta egg predation and crop damage caused by N. tenuis. The influence of an alternative prey (Ephestia kuehniella eggs) on the spatial distribution of predators was also evaluated by caging them in the prey presence or absence, either on tomato or sesame plants or on both. We found that the presence of sesame did not reduce the efficacy of N. tenuis or M. pygmaeus in consuming T. absoluta eggs; hatched egg proportion decreased when N. tenuis, M. pygmaeus, or both predators were present. More specifically, this proportion was more strongly reduced when both predators were combined. Sesame presence also reduced necrotic rings caused by N. tenuis on tomato plants. Nesidiocoris tenuis preferred sesame over tomato plants (except when food was provided only on the tomato plant) and the upper part of the plants, whereas M. pygmaeus preferred tomato to sesame plants (except when food was provided only on the sesame plant) and had no preference for a plant part. Combination of predators N. tenuis and M. pygmaeus allows for better coverage of cultivated plants in terms of occupation of different plant parts and better regulation of T. absoluta populations. Sesamum indicum is a potential companion plant that can be used to significantly reduce N. tenuis damage to tomatoes.

Process of Attack on Cashew Tree Branches by Diastocera trifasciata (Coleoptera: Cerambycidae) and the Relationship between These Attacks and the Phenological Stages in the Gbêkê Region (Central Côte d'Ivoire).

Cerambycidae Diastocera trifasciata attacks were studied from October 2015 to September 2017 in three cashew tree orchards in the locality of Brobo in central Côte d'Ivoire. One hundred fifty-three (153) cashew trees, arranged on a diagonal from each orchard, were selected for sampling. The attacked plants and the branches cut per tree were counted every 15 days. Biotic parameters, namely phenological stages of trees, and abiotic factors, which are rainfall, relative humidity and average temperature, were recorded throughout the study. Attacks were observed from mid-September to January from the pre-flowering vegetative stage to the flowering stage. Attack period duration was therefore four and a half months per year. The peak of attacks was recorded in November with an attack rate of 88.02% in 2015 and 75.49% in 2016. No attack was recorded from February to mid-September, corresponding to the flowering, fruiting and post-harvest vegetative growth stages. This description of the attack process and the determination of D. trifasciata attack periods provides essential data for the implementation of an effective and sustainable control method of this species.

PRODIG (Prevention of new onset diabetes after transplantation by a short term treatment of Vildagliptin in the early renal post-transplant period) study: study protocol for a randomized controlled study.

BACKGROUND: Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make it possible to target a population at risk of developing de novo diabetes. We hypothesized that a short-term treatment with vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. METHODS/DESIGN: This is a multicenter, double-blind, placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included from ten French transplant centers. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating theatres) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, and/or with an abnormal oral glucose tolerance test. Secondary outcomes include glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months, and 12 months after transplantation. Outcomes will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, health-related quality of life, and the cost-effectiveness of prevention of diabetes with vildagliptin. DISCUSSION: We have scarce data on the pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02849899 . Registered on 8 February 2016.

Urinary mRNA for the Diagnosis of Renal Allograft Rejection: The Issue of Normalization.

Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.

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.

Ofloxacin: new applications for the prevention of urinary tract infections in renal graft recipients.

BACKGROUND: Urinary tract infections (UTIs), the most common form of bacterial infection in kidney transplant recipients, recently have been demonstrated to be detrimental for long-term graft outcome. Therefore, reinforcing antibiotic prophylaxis might be vital, in addition to basic hygiene recommendations, surgical care, and prophylaxis by trimethoprim-sulfamethoxazole. METHODS: In 2006, a Legionella pneumophila contamination of our department's water pipes meant that all the patients undergoing renal transplantation underwent a 1-month regimen of ofloxacin (OFLO) (200 mg every other day). We took this opportunity to measure the incidence of UTI, including acute pyelonephritis (APN), in 100 consecutive patients transplanted before (n = 50) and after (n = 50) this treatment decision was reached. We also studied the antimicrobial resistance profiles in our department and in the rest of the hospital. RESULTS: No patient developed Legionnaire's disease. A dramatic decrease in the incidence of UTI (-63%) was also seen in patients undergoing OFLO treatment. Logistic regression analysis demonstrated that the use of OFLO was independently associated with a reduction in UTI (odd ratio [OR] = 0.31%, 95% confidence interval [CI] 0.11-0.84, P = 0.02) and APN (OR = 0.21%, 95% CI 0.07-0.98, P = 0.045). This protection was sustained during the whole first year post transplantation. As for resistance rates, we observed a decrease in the susceptibility of Pseudomonas aeruginosa to ciprofloxacin in our nephrology department, compared with that observed in the rest of the hospital. The incidence of multi-resistant bacteria was stable. DISCUSSION: Our unintentional extension of prophylactic antibiotherapy with OFLO gave rise to a dramatic decrease in the 1-year incidence of UTI and APN in kidney recipients. Emergence of resistant strains is, however, a major concern.

Bone and joint involvement in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by deficient activity of the enzyme alpha-galactosidase A. Although the disease has progressive effects on most organ systems in the body, data is limited regarding skeletal involvement in this rare disorder. We describe four family-related patients, three men and one premenopausal female, sharing a classic phenotype of FD. Dual-energy X-ray was performed in all cases and osteoporosis or osteopenia were found in all patients and osteoporotic fractures in one. One patient also showed both neuropathic joint disease and osteonecrosis. Several mechanisms that may explain osteoporosis and osteoarthropathy in the setting of FD are emphasized.

Chronic lymphocytic leukemia: a hazardous condition before kidney transplantation.

Long-term survival of patients with chronic lymphocytic leukemia (CLL) is over 10 years, and such patients are thus potential kidney recipients in the case of superimposed end-stage renal disease. However, the renal and patient outcome in this condition is unknown. We report the charts of four patients with CLL who were engrafted in France with a deceased-donor kidney and underwent routine triple immunosuppressive therapy. The results show that these patients developed severe infectious episodes (fatal in one case) and tumoral complications including rapid progression of CLL in two cases. Moreover, the graft may be infiltrated and damaged by monoclonal B cells: one patient lost his graft 14 months after transplantation. Various therapeutic options (modifications of the immunosuppressive regimen, anti-CD20 antibodies, irradiation of the graft) showed little (if any) efficacy. Therefore, we believe that CLL is a too hazardous condition to envisage solid organ transplantation with a routine immunosuppressive regimen, and we propose a more appropriate approach.

Acute pyelonephritis represents a risk factor impairing long-term kidney graft function.

Urinary tract infections (UTIs) and acute pyelonephritis (APN) often occur after renal transplantation, but their impact on graft outcome is unclear. One hundred and seventy-seven consecutive renal transplantations were investigated to evaluate the impact of UTIs and APN on graft function. The cumulative incidence of UTIs was 75.1% and that of APN was 18.7%. UTIs occurred mainly during the first year after transplantation and Escherichia coli, Pseudomonas aeruginosa and Enteroccocus sp. were the most frequent pathogens identified. The risk of developing APN was higher in female (64%) than in male recipients, and was correlated with the frequency of recurrent UTIs (p < 0.0001) and rejection episodes (p = 0.0003). APN did not alter graft or recipient survival, however, compared to patients with uncomplicated UTIs, patients with APN exhibited both a significant increase in serum creatinine and a decrease in creatinine clearance, already detected after 1 year (aMDRD-GFR: APN: 39.5 +/- 12.5; uncomplicated UTI: 54.6 +/- 21.7 mL/min/1.73 m(2), p < 0.01) and still persistent ( approximately - 50%) 4 years after transplantation. Multivariate analysis revealed that APN represents an independent risk factor associated with the decline of renal function (p = 0.034). Therefore, APN may be associated with an enduring decrease in renal graft function.

Risk factors for early epithelial to mesenchymal transition in renal grafts.

Epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) may participate in the pathogenesis of renal fibrosis. We performed a prospective study of EMT markers in protocol biopsies obtained 3 months after engraftment from 56 patients who received deceased donor kidneys and who had stable renal function. The presence of EMT was examined, and quantified by immunohistochemical staining for vimentin and translocation of beta-catenin to the cytoplasm. EMT status was defined as the presence of EMT markers in > or = 10% of TECs. EMT features were virtually absent in implantation biopsies, whereas 41% of the grafts were EMT-positive in the absence of advanced chronic allograft nephropathy. Thirteen patients (23%) had borderline changes or acute rejection. EMT features were more frequent in these patients than in those with normal kidney grafts (vimentin expression, p = 0.003; beta-catenin translocation, p = 0.002). EMT in grafts corresponded with elevated serum creatinine of the donor before the recovery of kidney (p = 0.02) and longer cold ischemia time (p = 0.02). In contrast, the donor age had no influence on the expression of EMT markers. These results suggest that EMT is an early and frequent phenomenon in kidney transplants that could be triggered by immunological and/or ischemic tubular injury.

[Complications in kidney transplantation]. / Les complications en transplantation rénale.

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.