CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C(0)). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C(0). Whether this improvement will affect clinical outcomes requires further evaluation.
ObjectiveTo develop and validate an integrative system to predict long term kidney allograft failure.DesignInternational cohort study.SettingThree cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States.ParticipantsDerivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).Main outcome measureAllograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.ResultsAmong the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.ConclusionAn integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.Trial registrationClinicaltrials.gov NCT03474003.
Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation. In a multicenter noninferiority trial, we randomized 2037 kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m at post-transplant month 12 using a 10% noninferiority margin. In the intent-to-treat population (everolimus =1022, MPA=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events. In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.
Eculizumab (anti-C5) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome (aHUS). However, the lack of series precludes any firm conclusion about the optimal use of anti-C5 for preventing or treating aHUS posttransplant aHUS recurrence. We thoroughly studied 22 renal transplant recipients with aHUS who received offlabel therapy with anti-C5, including 12 cases, which have not been reported yet. Nine patients, all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence, received prophylactic anti-C5 therapy to prevent posttransplant recurrence. Eight of them had a successful recurrencefree posttransplant course and achieved a satisfactory graft function, while the remaining patient experienced early arterial thrombosis of the graft. Thirteen renal transplant recipients were given anti-C5 for posttransplant aHUS recurrence. A complete reversal of aHUS activity was obtained in all of them. Importantly, the delay of anti-C5 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement. Three patients in whom anti-C5 was subsequently stopped experienced a relapse. Altogether these data suggest that long-term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence. Our study also indicates that anti-C5 should be promptly started if a recurrence occurs.
Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimusmycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02-1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/lL achieved in a mean of 1.5 ± 0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.
Induction of allograft-specific tolerance and the detection of a "tolerance" state in recipients under immunosuppression with long-term stable graft function are major challenges in transplantation. Clinical "operational tolerance," defined as stable and acceptable graft function without immunosuppression for years, is a rare event. There is no report on the clinical history of such patients. In this article, we report on the medical history of 10 kidney recipients who display an immunosuppressive drug-free "operational tolerance" for 9.4 ± 5.2 years. Clinical factors that may favor such a tolerant state are underlined. Firstly, most of the patients interrupted immunosuppression over a long time period (until 4 years), which mimics the procedure of intentional immunosuppression weaning following liver transplantation. Secondly, donor age was younger (median 25 years) than the one of the general transplanted population, suggesting that graft quality is one of the conditions favoring "operational tolerance." Moreover, the "operationally tolerant" recipients may be 'low responders' to blood transfusions (PRA 6 ± 5.4%, six blood transfusions). We also show that "operational tolerance" occurs in the presence of anti-donor class II antibodies, as assessed in two patients. Finally, two patients degraded their renal function 9 to 13 years after treatment withdrawal, however only one presented histological lesions of chronic rejection.
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