Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant

Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant

Multi‐target anti‐EBV therapy for prevent primary infection in kidney transplant recipients from deceased donor, at risk of post transplantation lymphoproliferative disorder (EBV D+/R‐)

International audienceIf all immunocompromised patients can experience Post Transplantation Lymphoproliferative Disorder (PTLD) due to EBV reactivation, EBV-seronegative recipients in which primary infection can occur, are at higher risk of developing PTLD when transplanted with an organ from an EBV seropositive donor(1,2). In our center, among 73 EBV-seronegative adult patients transplanted between 2000 and 2016 (3% of the whole), 8 developed an early PTLD and 5 others beyond one year, all EBV-related(3). EBV is most often latent and inaccessible within B cells, but occasionally it achieves a lytic infection, susceptible to some antiviral drugs, such as (val)ganciclovir, and specific antibodies

Etude des désordres immunitaires dans le syndrome néphrotique idiopathique et sa récidive après transplantation rénale

Le syndrome néphrotique idiopathique (SNI) est une glomérulopathie qui évolue dans 5 à 10% vers une insuffisance rénale terminale, nécessitant alors une transplantation. Malheureusement, la maladie initiale récidive chez 30 à 50% des patients transplantés, suggérant l'implication d'un facteur circulant peut être produit par les lymphocytes T. Dans cette étude, nous avons cherché à mieux caractériser l'implication des lymphocytes T dans le SNI et sa récidive. Nous avons montré que l'apparition des lésions chez un modèle animal spontané de SNI, était précédée d'une infiltration rénale de macrophages et de lymphocytes Th2, suggérant un rôle de ces populations dans la maladie initiale. L'étude des lymphocytes T chez des patients récidivant leur SNI après transplantation a montré que la récidive était associée à un phénotype lymphocytaire naïf et à des anomalies de régulation. Un facteur circulant potentiel surexprimé dans le sérum de ces patients et toxique pour les podocytes in vitro a également pu être mis en évidence, ouvrant de nouvelles perspectives thérapeutiques.Idiopathic nephrotic syndrome (INS) is a glomerulopathy that leads in 5 to 10% of cases to end stage renal failure, requiring renal transplantation. Unfortunately, 30 to 50% of patients recur their initial disease after transplantation, suggesting the involvement of a circulating permeability factor probably produced by T lymphocytes. In this study, we want to better characterize the involvement of T lymphocytes in INS and its recurrence. We showed that a macrophagic and Th2 infiltrate precede the apparition of initial lesions in a spontaneous animal model of INS, suggesting a role for this population in the onset of initial disease. The study of patients with INS recurrence T lymphocytes after transplantation showed that recurrence was associated with a naive phenotype and regulation abnormalities. Moreover, a potential circulating factor over-expressed in recurrent patients serum and toxic for podocytes in vitro was identified, opening new insight in the treatment of INS recurrence.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Désordres lymphoprolifératifs post-transplantation rénale (évaluation de la fonction rénale à long terme)

L'objectif de cette étude rétrospective multicentrique était d'évaluer les modalités de modification de l'immunosuppression et l'évolution de la fonction rénale après un désordre lymphoprolifératif post-transplantation rénale (PTLD). Quatre vingt dix patients ayant présenté un PTLD en moyenne 48 mois après la transplantation ont été inclus. L'âge au diagnostic était de 51+-13 ans. Les modifications du traitement immunosuppresseur étaient hétérogènes, avec principalement un arrêt des inhibiteurs de la calcineurine (n=67, 74%), puis une réduction des posologies (n=15, 17%) et plus récemment un relais en faveur d une molécule de la famille des inhibiteurs des mTOR. Au terme de 34+-39 mois de suivi après le diagnostic 44% des patients gardaient un greffon fonctionnel, 21% des patients étaient décédés avec un greffon fonctionnel, et 33% des patients avaient perdu leur greffon. La survie des greffons était moins bonne lorsque les CNI étaient arrêtés plutôt que diminués. En conclusion, nous pouvons proposer un intervalle libre de 2 à 3 ans avant la réintroduction prudente d un traitement immunosuppresseur en privilégiant les molécules du groupe des inhibiteurs des mTOR afin de préserver la fonction du greffon.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Hyalinose segmentaire et focale primitive de l'adulte (étude de la récidive précoce après une première transplantation rénale)

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Association entre le taux de vitamine D et le devenir des patients transplantés rénaux

Introduction : La vitamine D intervient dans le métabolisme glucidique et la carcinogénèse cutanée. Le diabète de novo (NODAT) et les cancers cutanés épithéliaux (NMSC) constituent deux complications fréquentes après une transplantation rénale. L'objectif de l'étude est d'étudier le lien entre le taux de vitamine D au moment d'une première transplantation rénale et la survenue du NODAT et de NMSC. Patients et Méthode : 444 patients transplantés entre janvier 2000 et décembre 2011 au CHU de Nantes ont été inclus et suivis de façon prospective. Les critères d'évaluation étaient la survenue d'un NODAT traité dans la première année, la survenue de NMSC et la survie du patient et du greffon. Nous avons analysé l'influence du taux de vitamine D au moment de la transplantation sur la survenue de ces événements. Résultats : L'incidence cumulée du NODAT traité était de 13% à 1 an. En analyse multivariée, la carence en vitamine D était un facteur de risque de NODAT (HR= 2.62 [1,09-6,34] à 1 an. L'incidence cumulée des NMSC était de 6% à 5 ans. En analyse multivariée, les sujets carencés en vitamine D avaient tendance à développer moins de NMSC que les sujets ayant un taux normal (HR=0.41 [0.11-1.49]). Enfin, le taux de vitamine D n'était pas associé au succès de la transplantation ni à la survenue des cancers solides. Discussion et Conclusion : La mesure du taux de vitamine D au moment d'une première transplantation rénale permet à la fois de prédire le risque de NODAT dans la première année et d'alerter le clinicien sur les habitudes d'expositions solaires des sujets.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use

International audiencePURPOSE OF REVIEW: Here, we review recent advances and new insights in mechanistic target of rapamycin (mTOR) biology (signalling pathway, kidney biology and immune system), and recent clinical data on mTOR inhibitors related to solid organ transplantation.RECENT FINDINGS: The mTOR pathway is a major integrator of signals governing protein and lipid biosynthesis and growth factor-driven cell cycle progression. Recent findings have emphasized a critical role of mTOR in cellular homeostasis with a crucial role in podocyte function. Beyond CD8(+) and regulatory T-cell control, mTOR protein is involved in critical biological functions of T helper cells or dendritic cells. New specific inhibitors of mTORC1/C2 are available and shed new light on mTOR functions. Finally, clinical trials have better defined the use of mTOR inhibitors and emphasized their role in cancer prevention.SUMMARY: The mTOR pathway is considered as a key integrator of multiple inputs that drives numerous biological processes in cell biology. mTOR inhibitors are potent immunosuppressive drugs for solid organ transplantation. Newly designed specific inhibitors of mTOR complex 1 and 2 offer promising therapeutic effects and a better understanding of the pathway. Many conditions may benefit from mTOR inhibition for a short period, but tolerance of treatment in a chronic setting remains a major concern

Comparison of the risk factors effects between two populations: two alternative approaches illustrated by the analysis of first and second kidney transplant recipients.

International audienceBACKGROUND: Whereas the prognosis of second kidney transplant recipients (STR) compared to the first ones has been frequently analyzed, no study has addressed the issue of comparing the risk factor effects on graft failure between both groups. METHODS: Here, we propose two alternative strategies to study the heterogeneity of risk factors between two groups of patients: (i) a multiplicative-regression model for relative survival (MRS) and (ii) a stratified Cox model (SCM) specifying the graft rank as strata and assuming subvectors of the explicatives variables. These developments were motivated by the analysis of factors associated with time to graft failure (return-to-dialysis or patient death) in second kidney transplant recipients (STR) compared to the first ones. Estimation of the parameters was based on partial likelihood maximization. Monte-Carlo simulations associated with bootstrap re-sampling was performed to calculate the standard deviations for the MRS. RESULTS: We demonstrate, for the first time in renal transplantation, that: (i) male donor gender is a specific risk factor for STR, (ii) the adverse effect of recipient age is enhanced for STR and (iii) the graft failure risk related to donor age is attenuated for STR. CONCLUSION: While the traditional Cox model did not provide original results based on the renal transplantation literature, the proposed relative and stratified models revealed new findings that are useful for clinicians. These methodologies may be of interest in other medical fields when the principal objective is the comparison of risk factors between two populations

Sirolimus for secondary prevention of skin cancer in kidney transplant recipients: 5-year results

Purpose: Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods: Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results: Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group (P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas (P, 001), 34% versus 66% for other skin cancers (P, 001), and 20% versus 37.5% for basal cell carcinomas (P, 05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion: In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.SCOPUS: ar.jinfo:eu-repo/semantics/publishe