Gwenaelle Roussey-Kesler

Analysis of the peripheral T‐cell repertoire in kidney transplant patients

The long‐term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T‐cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T‐cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8+/CD4+ T‐cell ratio. T‐cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug‐free operationally tolerant recipients and patients with the “suspicious” form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow‐up of patients after kidney transplantation.

Mortality in pediatric renal transplantation: a study of the French pediatric kidney database.

Abstract:  Objective and Methods:  To assess patient survival in pediatric renal transplantation, we retrospectively reviewed 573 transplants in 553 patients, registered from 1995 to 2005.

Critical serum creatinine values in very preterm newborns.

Background Renal failure in neonates is associated with an increased risk of mortality and morbidity. But critical values are not known. Objective To define critical values for serum creatinine levels by gestational age in preterm infants, as a predictive factor for mortality and morbidity. Study Design This was a retrospective study of all preterm infants born before 33 weeks of gestational age, hospitalized in Nantes University Hospital NICU between 2003 and 2009, with serum creatinine levels measured between postnatal days 3 to 30. Children were retrospectively randomized into either training or validation set. Critical creatinine values were defined within the training set as the 90th percentile values of highest serum creatinine (HSCr) in infants with optimal neurodevelopmental at two years of age. The relationship between these critical creatinine values and neonatal mortality, and non-optimal neural development at two years, was then assessed in the validation set. Results and Conclusion The analysis involved a total of 1,461 infants (gestational ages of 24-27 weeks (n=322), 28-29 weeks (n=336), and 30-32 weeks (803)), and 14,721 creatinine assessments. The critical values determined in the training set (n=485) were 1.6, 1.1 and 1.0 mg/dL for each gestational age group, respectively. In the validation set (n=976), a serum creatinine level above the critical value was significantly associated with neonatal mortality (Odds ratio: 8.55 (95% confidence interval: 4.23-17.28); p<0.01) after adjusting for known renal failure risk factors, and with non-optimal neurodevelopmental outcome at two years (odds ratio: 2.06 (95% confidence interval: 1.26-3.36); p=0.004) before adjustment. Creatinine values greater than 1.6, 1.1 and 1.0 mg/dL respectively at 24-27, 28-29, 30-32 weeks of gestation were associated with mortality before and after adjustment for risk factors, and with non-optimal neurodevelopmental outcome, before adjustment.

Age dependent risk of graft failure in young kidney transplant recipients.

Background The risk of graft failure in young kidney transplant recipients has been found to increase during adolescence and early adulthood. However, this question has not been addressed outside the United States so far. Our objective was to investigate whether the hazard of graft failure also increases during this age period in France irrespective of age at transplantation. Methods Data of all first kidney transplantation performed before 30 years of age between 1993 and 2012 were extracted from the French kidney transplant database. The hazard of graft failure was estimated at each current age using a 2-stage modelling approach that accounted for both age at transplantation and time since transplantation. Hazard ratios comparing the risk of graft failure during adolescence or early adulthood to other periods were estimated from time-dependent Cox models. Results A total of 5983 renal transplant recipients were included. The risk of graft failure was found to increase around the age of 13 years until the age of 21 years, and decrease thereafter. Results from the Cox model indicated that the hazard of graft failure during the age period 13 to 23 years was almost twice as high as than during the age period 0 to 12 years, and 25% higher than after 23 years. Conclusions Among first kidney transplant recipients younger than 30 years in France, those currently in adolescence or early adulthood have the highest risk of graft failure.

Early protocol biopsies in pediatric renal transplantation: Interest for the adaptation of immunosuppression

GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid‐sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty‐eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long‐term follow‐up.

Insuffisance rénale chronique de l’enfant

Chronic kidney insufficiency (CKI) in children: Failure to thrive, feeding disorders and/or excessive thirst must evoke CKI in children. More than 50% of renal diseases in children with CKI are congenital or inherited. Major issues are growth, nutrition and renal osteodystrophy. Psychological and social management are crucial aspects of the therapeutic project. Peritoneal dialysis is the renal replacement therapy of choice, especially in children under 2 years, with an important risk of peritonitis. Kidney transplant, which can be performed in children more than 10 kg, is the best treatment of end-stage renal failure in children. Pediatric transplant specificities are increased risks of thrombosis, post-transplant lymphoproliferative disorders in EBV-negative recipients, and poor compliance to medication during adolescence.

Consideration of the switch from twice‐daily to once‐daily tacrolimus in pediatric kidney transplant in daily clinical practice: Pharmacokinetic parameters, patient satisfaction and medical practices

To the editor, Major advances in pediatric kidney transplantation have been made in the last few years, in the fields of surgical techniques, immunosuppressive (IS) therapy, prevention and treatment of infectious, and neoplastic complications. Currently, one of the preventable causes of late acute rejection and graft loss is patient non-adherence to IS medication (1). The risk of graft failure is increased seven times in non-adherent subjects (2). Non-compliance is estimated at 30% in pediatric renal transplant recipients (RTR) and up to 70% in adolescents (3, 4). Conversion to oncedaily dose maintenance immunosuppression should improve adherence and thereby may result in better long-term renal allograft survival (5, 6). Tacrolimus (Tac) is one of the commonly used IS drugs in pediatric kidney transplantation. A prolonged-released formulation of Tac is now available to allow once-daily dosing (Tac-OD) and may improve adherence. Preliminary studies have shown an equivalence in pharmacokinetic parameters for twice-daily tacrolimus (Tac-TD) and Tac-OD in both adult and pediatric kidney and liver transplantations (7–9). Accordingly, a 1:1 mg conversion from Tac-TD to Tac-OD formulation has been recommended by the European Medicine Agency and the Canadian Society of Transplantation (10, 11). Nevertheless, pharmacokinetic results from recent clinical studies differ from the initial observations (12–15). We thought it might be interesting to disclose about our study concerning the switch to Tac-OD. The aims of this study were (i) to compare the Tac dosing before the switch, at the switch (M0), and six months later (M6), (ii) to assess patient adherence and satisfaction, (iii) to evaluate medical practices concerning the conversion from Tac-TD to Tac-OD in several French pediatric transplantation centers. Retrospectively, we included patients who were transplanted between 1992 and 2012, aged under 18 at transplantation, followed in the University Hospital of Lyon, Nantes, Robert Debr e, Toulouse and Tours, and in whom Tac-OD was introduced in relay from Tac-TD or Ciclosporin. Combined liver–kidney transplantation and patients who received straightaway Tac-OD post-transplantation were excluded. The values at M0 and M6 were compared with a Wilcoxon paired test. Data were expressed as medians and interquartile range (IQR). Two different questionnaires of about 10 simple questions were composed, one for the patients and the other for the pediatric nephrologists. Thirty-seven patients were included, with a median age of 14.7 yr old at the switch. The conversion from Tac-TD to Tac-OD was proposed to improve patient adherence in 51% of the cases and to decrease gastro-intestinal complications in 20%. The median time between transplantation and the introduction of Tac-OD was 45 months (1–232 months). Patients were converted to Tac-OD on a median ratio of 1:1 mg for their total daily dose (1:0.75 mg to 1:1.5 mg). Six months after conversion, a significant increase in Tac-OD dosing of +10% (IQR = 25%, [ 25 to +100%], p = 0.0119) was necessary to obtain appropriate residual blood concentrations (C0) (Fig. 1). Fifty-five percent of patients required an increase in Tac-OD dosing, 31% no change, and 14% a decrease. Eight graft rejections occurred after the switch (median delay of four months, from one to 20 months

P376 - Devenir rénal des valves de l’urètre postérieur avec oligoamnios tardif

Objectif L’oligoamnios (OA) est un facteur predictif negatif a long terme des valves de l’uretre posterieur (VUP). Cependant le pronostic renal de l’OA tardif, apparu apres 32 semaines d’amenorrhees (SA), n’est actuellement pas bien connu. Sujets et Methodes Trente-sept cas de VUP de diagnostic prenatal ont ete pris en charge dans notre centre entre 1994 et 2008. Vingt-et-un avaient une quantite de liquide amniotique normal et 7 un OA tardif (1 grossesse interrompue) avec un âge median au diagnostic de 35,7 SA. Nous avons compare le devenir renal a long terme de ces 2 groupes. Une insuffisance renale chronique (IRC) etait definie par une creatininemie a +2DS de la normale pour l’âge. Le suivi median etait de 5,25 ans. Resultats Une IRC etait presente chez 5 des 6 cas avec OA tardif, dont 3 au stade terminal (2 transplantations renales, 1 deces), et chez 1 des 21 cas avec un liquide amniotique normal (1 transplantation renale) (p Conclusion L’OA tardif dans les VUP de diagnostic prenatal est un facteur pronostic renal negatif avec une IRC apparaissant des la premiere annee dans notre etude. Ce facteur predictif pourrait etre utile a l’information des parents lors de la consultation prenatale.