Nouveaux outils de pharmacodynamie des immunosuppresseurs chez des receveurs pédiatriques de greffe d’organe

L’immunosuppression optimale après greffe d’organe solide est une balance délicate et propre à chaque individu entre le risque de rejet et les risques liés à une surexposition au traitement immunosuppresseur. L’évaluation de la fonction résiduelle des lymphocytes T après stimulation par un mitogène (pharmacodynamie effective) devrait permettre de mesurer l’effet direct des médicaments immunosuppresseurs sur leur cible. Nous avons étudié différents paramètres de pharmacodynamie effective chez 34 receveurs pédiatriques de greffe d’organes solides traités par tacrolimus et mycophénolate. Les tests proposés dans ce travail sont adaptés au milieu pédiatrique et à une réalisation en temps réel. La quantification du CD25 parmi les CD4 activés par l’OKT3 permet de distinguer deux groupes de patients selon leur degré d’immunosuppression. L’âge médian est plus bas et la concentration plasmatique médiane en MPA plus élevée dans le groupe de patients plus fortement immunosupprimés. L’étude des paramètres immunologiques pouvant influencer la réponse (sécrétion des interleukines, proportion des sous-populations lymphocytaires CD4, CD8, T naïfs et Trég) ainsi que l’étude du pouvoir de restauration de la fonction lymphocytaire par l’Il-2, la guanosine ou la xanthosine, ne permettent pas de mieux comprendre les variabilités interindividuelles observées. Ces résultats devront être confirmés sur une cohorte plus grande de patients afin de juger de leur intérêt en pratique clinique.Optimal immunosuppression following solid organ transplantation is unique to each individual and requires a balance between risks of rejection and overexposure to immunosuppressive therapy. The evaluation of residual function of T lymphocytes after mitogen stimulation (effective pharmacodynamic monitoring) should allow measurement of the direct effect of immunosuppressive drugs on their target. We studied various parameters of effective pharmacodynamic monitoring in 34 paediatric patients receiving solid organ transplants and treated with tacrolimus and mycophenolate (MPA). The tests proposed in this work are adapted to the paediatric setting in real time. Quantification of CD25 among CD4 cells activated by OKT3 can differentiate two groups of patients according to their degree of immunosuppression. Median values for age and MPA plasma concentration are lower and higher, respectively, in the patient group most heavily immunosuppressed. Neither study of the parameters that may influence the response (secretion of interleukins, proportion of lymphocyte subpopulations CD4, CD8, naive and regulatory T cells) nor study of the restoration of basal cell function brought about by Il2, guanosine or xanthosine, helped to explain the observed inter-individual variability. These results should be confirmed in a larger cohort of patients in order to test their relevance in clinical practice

Hallucinations secondaires au voriconazole chez un adolescent : pertinence du suivi pharmacocinétique

Résumé Objectif : Décrire le cas d’un adolescent qui a développé une toxicité au voriconazole intraveineux alors qu’il présentait de nombreux facteurs pouvant en influencer la pharmacocinétique. Résumé du cas : Il s’agit d’un patient de 17 ans suivi après une greffe de moelle osseuse, hémodialysé trois fois par semaine, traité au voriconazole intraveineux pour une infection fongique pulmonaire qui a développé des troubles visuels et des hallucinations. Les concentrations plasmatiques de voriconazole chez ce patient étaient alors anormalement élevées. Aucune interaction médicamenteuse ne pouvait expliquer des valeurs aussi élevées. Un génotypage du CYP2C19 a révélé que le patient possédait le CYP2C19 (681G >A) responsable d’un phénotype de métaboliseur lent hétérozygote. Discussion : L’association entre les effets indésirables subis par le patient et le voriconazole est probable. Les données probantes sur ce sujet, le lien temporel et l’exclusion des autres causes possibles parlent en faveur de cette association. Conclusion : Ce cas démontre la nécessité de faire le suivi des dosages de voriconazole et l’importance de la pharmacologie dans les soins directs dispensés aux patients. Abstract Objective: To describe the case of an adolescent that developed toxicity to the use of intravenous voriconazole. Case summary: A 17-year old patient with post stem cell transplant, on hemodialysis three times a week, was treated with intravenous voriconazole for a fungal infection in the lungs. He developed visual disturbances and hallucinations. Plasma drug levels of voriconazole were reported to be high. No drug interaction could explain these elevated values. Genotyping of CYP2C19 revealed that the patient was a heterozygous slow metabolizer, as a result of having CYP2C19 (681G>A). Discussion: There is an association between the adverse effects experienced by the patient and the administration of voriconazole. The temporal link and the exclusion of other likely causes favour this association. Conclusion: This case demonstrates the necessity of monitoring voriconazole levels and the importance of collaboration with clinical pharmacologists. Key words: Adverse effects, cytochrome, drug levels, hallucinations, hemodialysis, pharmacokinetics, polymorphism, slow metabolizer, toxicity, visual disturbances, voriconazole

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy

International audienceBackground: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab.Study design: Case series of C3 glomerulopathy.Setting & participants: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada.Outcomes: Global or partial clinical renal response.Measurements: Evolution of serum creatinine and proteinuria values.Results: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders.Limitations: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases.Conclusions: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited

Eculizumab Use for Kidney Transplantation in Patients With a Diagnosis of Atypical Hemolytic Uremic Syndrome

Introduction: Recurrence of atypical hemolytic uremic syndrome (aHUS) in renal allografts is common, leading to dialysis and graft failure. Pretransplant versus posttransplant initiation of eculizumab treatment in patients with aHUS has not been rigorously investigated. We hypothesized eculizumab pretransplant would reduce dialysis incidence posttransplant.Methods: Of patients enrolled in the Global aHUS Registry (n = 1549), 344 had >= 1 kidney transplant. Of these, 188 had received eculizumab. Eighty-eight patients (47%) were diagnosed with aHUS and received eculizumab before, and during, their most recent transplant (group 1). A total of 100 patients (53%; group 2) initiated eculizumab posttransplantation. This second group was subdivided into those diagnosed with aHUS before (n = 52; group 2a) or after (n = 48; group 2b) their most recent transplant.Results: Within 5 years of transplantation, 47 patients required dialysis; the risk of dialysis after transplantation was significantly increased in group 2b (hazard ratio [HR] 4.6; confidence interval [CI] 1.7-12.4) but not 2a (HR 2.3; CI 0.9-6.2). Graft function within 6 months of transplantation was significantly better in group 1 (median estimated glomerular filtration rate of 60.6 ml/min per 1.73 m(2)) compared with 31.5 and 9.6 ml/min per 1.73 m(2) in groups 2a (P = 0.004) and 2b (P = 0.0001), respectively. One meningococcal infection (resolved with treatment) and 3 deaths (deemed unrelated to eculizumab) were reported.Conclusions: Outcomes for transplant patients with aHUS treated with eculizumab were improved compared with previous reports of patients with aHUS not treated with eculizumab. Our findings suggest delayed aHUS diagnosis and therefore treatment is associated with an increased risk of dialysis posttransplantation and reduced allograft function