Lionel Rostaing

A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors

Delayed graft function (DGF) is a common complication in kidney transplantation and is known to be correlated with short- and long-term graft outcomes. Here we explored the possibility of developing a simple tool that could predict with good confidence the occurrence of DGF and could be helpful in current clinical practice. We built a score, tentatively called DGFS, from a French multicenter and prospective cohort of 1844 adult recipients of deceased donor kidneys collected since 2007, and computerized in the Données Informatisées et VAlidées en Transplantation databank. Only five explicative variables (cold ischemia time, donor age, donor serum creatinine, recipient body mass index, and induction therapy) contributed significantly to the DGF prediction. These were associated with a good predictive capacity (area under the ROC curve at 0.73). The DGFS calculation is facilitated by an application available on smartphones, tablets, or computers at www.divat.fr/en/online-calculators/dgfs. The DGFS should allow the simple classification of patients according to their DGF risk at the time of transplantation, and thus allow tailored-specific management or therapeutic strategies.

The safety of calcineurin inhibitors for kidney-transplant patients

Introduction: Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related. Areas covered: The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers. Expert opinion: In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.

Rituximab therapy prevents focal and segmental glomerulosclerosis recurrence after a second renal transplantation.

Preventive treatment of focal and segmental glomerusclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (<3u2003months) recurrence of FSGS that was either resistant to plasmapheresis therapy in two cases or had escaped to this therapeutic management in the two others. After the second renal transplantation, all patients were free of FSGS recurrence during follow‐ups that were between 12 and 54u2003months long. These preliminary results demonstrate for the first time that Rituximab therapy may constitute an attractive prophylactic option for patients being considered for a second renal transplantation because of recurrent FSGS in their first graft.

Poor Long-Term Outcome in Second Kidney Transplantation: A Delayed Event

Background Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate. Methodology To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (Nu200a=u200a3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization. Results We showed that STR have a higher risk of graft failure than FTR (HRu200a=u200a2.18, pu200a=u200a0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HRu200a=u200a1.01, pu200a=u200a0.9675) or steroid-resistant ARE (HRu200a=u200a1.27, pu200a=u200a0.4087). Conclusions The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally.

Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T‐cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis

To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a lifethreatening syndrome characterized by severe systemic inflammation and uncontrolled activation of natural killer (NK) and cytotoxic CD8+ T-cells, which both contribute to organ damage. In patients with HLH, overproduction of Th1 [interferon gamma (IFN-γ), interleukin 2 (IL-2), IL-6, IL-12 and tumour necrosis factor alpha (TNF-α)] cytokines contrasts with low levels of Th2 cytokines (IL-4) [1]. Overproduction of IL-10 is observed during the acute phase of the disease, as expected during IFN-γ overproduction [2]. Diagnostic criteria of HLH were developed in the HLH-2004 protocol and include an increased soluble CD25 (sCD25) [3]. The association of high levels of IFN-γ and IL-10 with normal or moderately elevated levels of IL-6 differentiates HLH from infection [4]. Besides primary/familial HLH mainly observed in childhood, most secondary forms occur in the setting of infection, malignancy or rheumatologic disorders. Corticosteroids, cyclosporine, etoposide or TNF-α can reverse HLH in most patients with underlying systemic disease or cancer [5]. To date, no firm consensus treatment emerged, and the treatment of refractory HLH remains challenging. In 2013, a 59-year-old patient was referred to our intensive care unit (ICU) for acute renal and respiratory failure and features of HLH including hemophagocytosis in bone-marrow aspirate, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, anaemia and low platelet count, a slightly enlarged spleen, and a dramatic increase of sCD25. Two months before his admission, he developed autoimmune manifestations characterized by arthritis, myositis, lung interstitial disease, acral cutaneous sclerosis and dry syndrome. Immunological tests showed low complement C3, C4, CH50 components, type III cryoglobulin, polyclonal hypergammaglobulinemia, positive Coombs’ test, high levels of anti-SSA, anti-SSB, anti-PMScl, anti-double strand DNA and anti-citrullinated peptides antibodies. He had been receiving corticosteroids for 2months (0.5–1mg/kg/day) without any improvement of the autoimmunity-related organ disorders. At admission in the ICU, diagnosis of HLH was retained. Abnormal liver tests, acute renal failure requiring dialysis and a moderate encephalopathy were observed.

Mortality Prediction after the First Year of Kidney Transplantation: An Observational Study on Two European Cohorts.

After the first year post transplantation, prognostic mortality scores in kidney transplant recipients can be useful for personalizing medical management. We developed a new prognostic score based on 5 parameters and computable at 1-year post transplantation. The outcome was the time between the first anniversary of the transplantation and the patient’s death with a functioning graft. Afterwards, we appraised the prognostic capacities of this score by estimating time-dependent Receiver Operating Characteristic (ROC) curves from two prospective and multicentric European cohorts: the DIVAT (Données Informatisées et VAlidées en Transplantation) cohort composed of patients transplanted between 2000 and 2012 in 6 French centers; and the STCS (Swiss Transplant Cohort Study) cohort composed of patients transplanted between 2008 and 2012 in 6 Swiss centers. We also compared the results with those of two existing scoring systems: one from Spain (Hernandez et al.) and one from the United States (the Recipient Risk Score, RRS, Baskin-Bey et al.). From the DIVAT validation cohort and for a prognostic time at 10 years, the new prognostic score (AUC = 0.78, 95%CI = [0.69, 0.85]) seemed to present significantly higher prognostic capacities than the scoring system proposed by Hernandez et al. (p = 0.04) and tended to perform better than the initial RRS (p = 0.10). By using the Swiss cohort, the RRS and the the new prognostic score had comparable prognostic capacities at 4 years (AUC = 0.77 and 0.76 respectively, p = 0.31). In addition to the current available scores related to the risk to return in dialysis, we recommend to further study the use of the score we propose or the RRS for a more efficient personalized follow-up of kidney transplant recipients.

A prospective study in male recipients of kidney transplantation reveals divergent patterns for inhibin B and testosterone secretions

BackgroundMale patients with chronic kidney disease often exhibit the biological and clinical hallmarks of an abnormal hypothalamo–pituitary–gonadal axis. It is known that dialysis does not reverse this impaired endocrine status; however, the impact of kidney transplantation (KT) is still controversial. The aim of our study was to investigate the levels of serum gonadotropins, testosterone, and inhibin B during dialysis and after KT.MethodsA longitudinal and prospective single center study was led in an academic setting. Blood hormones levels were assayed by immunoassays in 53 men (mean age: 37xa0years) receiving dialysis (T0) and at 6xa0months post-KT (T180). These data were compared with those from 46 fertile semen donors (mean age: 37xa0years). The main outcome measure was the between-groups differences in hormones levels. A second criterion was the comparison of T0 and T180 hormones levels according to the immunosuppressive regimen.ResultsFor patients ongoing dialysis, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) mean levels were high, whereas testosterone and inhibin B mean levels remained normal. After KT, LH levels returned to normal whereas FSH was significantly increased. Testosterone levels remained normal whereas inhibin B levels significantly decreased. We found that the combination tacrolimus plus mycophenolic acid significantly decreased post-KT inhibin B levels. Moreover, we found that pre-graft inhibin-B level was independent of testosterone and could predict low post-operative inhibin B level with a sensitivity of 77% and a specificity of 92%.ConclusionsOur study suggests that endocrine secretions of Leydig and Sertoli cells are differently impacted by dialysis, KT and immunosuppressive regimen raising new issues to explore.AbstractContexteLes hommes insuffisants rénaux chroniques présentent souvent des signes cliniques et biologiques d’une atteinte de l’axe hypothalamo-hypophyso-testiculaire. Il est bien établi que la dialyse n’améliore pas ces anomalies endocriniennes mais l’impact de la transplantation rénale reste encore controversé. Le but de l’étude est d’explorer les taux circulants des gonadotrophines, de la testostérone et de l’inhibine B durant la période de dialyse et après la greffe de rein.Patients et MéthodesCette étude longitudinale et prospective est réalisée dans un centre hospitalo-universitaire. Les taux sériques des hormones sont mesurés par immunodosage chez 53 patients (âge moyen : 37 ans) durant la période de dialyse (T0) et 6 mois après la greffe rénale (T180). Ces données sont comparées à celles de 46 donneurs de sperme fertiles (âge moyen : 37 ans). Le principal critère de jugement est la différence des taux hormonaux entre les trois groupes. Le critère secondaire est la comparaison des taux pré- et post-greffe en fonction du traitement immunosuppresseur.ResultatsDurant la période de dialyse, les taux moyens de LH et de FSH sont élevés alors que ceux de testostérone et inhibine B sont normaux. Après la greffe, la LH revient à la normale alors que la FSH augmente. Les taux de testostérone restent normaux mais ceux d’inhibine B augmentent significativement. Par ailleurs, l’étude montre que la combinaison tacrolimusu2009+u2009mycophénolate diminue clairement les taux post-greffe d’inhibine B. Elle montre également que les taux pré-greffe d’inhibine B sont indépendants de ceux de la testostérone et qu’ils peuvent prédire les taux bas d’inhibine B avec une sensibilité de 77% et une spécificité de 92%.ConclusionsL’étude suggère que les sécrétions endocrines des cellules de Leydig et de Sertoli sont impactées de manière différente par la dialyse, la transplantation rénale et le traitement immunosuppresseurs ouvrant ainsi de nouvelles perspectives d’investigation.

Belatacept prophylaxis against organ rejection in adult kidney-transplant recipients.

ABSTRACT End-stage renal disease is a major health problem worldwide, with kidney transplantation being the treatment of choice. Calcineurin inhibitors are still the cornerstone of immunosuppressive therapy. However, they have well-known nephrotoxic affects and increase the risk of cardiovascular disease and cancer. In contrast, belatacept is a biological immunosuppressive agent that inhibits the T-cell co-stimulation. It is approved by the US Food and Drug Administration and the European Medicine Agency for use in adult kidney-transplant recipients to prevent acute rejection. Developmental studies show that belatacept is as efficient as calcineurin inhibitors at preventing acute rejection. In addition, kidney function is better and cardiovascular risk factors are reduced in patients given belatacept. Herein, the authors review the published evidence concerning the efficacy and safety of belatacept and discuss its potential specific indications.

Occult Hepatitis C Virus Infection: Where are We Now?

Hepatitis C virus (HCV) is the major cause of chronic liver disease worldwide. Up to 30% of infected individuals spontaneously resolve their acute infection, while others develop chronic hepatitis C and replicate the virus seemingly indefinitely, but the features of the host and virus that are responsible for this difference are not yet clear. The persistence of the virus in the liver can lead to cirrhosis and hepatocellular carcinoma. End-stage liver disease due to a chronic HCV infection is currently the number one reason for liver transplantation in many parts of the world. No prophylactic vaccine is presently available and the current antiviral therapy successfully suppresses HCV replication in fewer than 50% of patients with a chronic infection. Until recently, patients who had eliminated HCV spontaneously or after treatment were considered to be definitively cured. But reports of low HCV RNA concentrations in the plasma, peripheral blood mononuclear cells and livers of patients who had cleared HCV has led to uncertainty in both patients and physicians. This new form of HCV infection is called occult HCV infection. This chapter summarises the data presently available on occult HCV infections and discusses its significance and reality.