Efficiency of Everolimus for the Treatment of Kidney Transplanted Patients Presenting a Missing Self-induced NK-mediated Rejection

Study Overview
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Brief Summary
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Background: Long-term success of organ transplantation is limited by the inexorable loss of graft function due to rejection. Prevalent dogma defends that allograft rejection is exclusively mediated by the adaptive immune system: T cells are responsible for cellular rejections and B cells producing Donor Specific Antibodies (DSA) are responsible for humoral rejection. Recently, we demonstrated that innate NK cells could be implicated in the generation of chronic vascular rejections lesions by sensing the absence of expression of self Major Histocompatibility Complex (MHC) class I molecules (missing self) on graft endothelial cells with their Killer cell immunoglobulin-like (KIR) receptors. Using human in vitro and murine in vivo models, we also showed that Mammalian Target Of Rapamycin (mTOR) inhibitors could efficiently prevent this new kind of rejection. Objective: The aim of our project is therefore to test in a cohort of kidney transplanted patients the efficiency of mTOR inhibitors to treat this new kind of rejection Methods: A cohort of 20 kidney transplant patients with a missing self on their graft responsible for a NK-mediated rejection will be established prospectively. An mTOR inhibitor will be introduced in these patients for 6 months in association with a calcineurin inhibitor and corticosteroids. Graft function, histological lesions and NK activability will be monitored following this modification of treatment.

Official Title
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Efficiency of Everolimus for the Treatment of Kidney Transplanted Patients Presenting a Missing Self-induced Natural Killer Cells Mediated (NK-mediated) Rejection

Conditions
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Kidney Transplant Failure and Rejection

Intervention / Treatment
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* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged > 18 years Kidney transplanted patient Having microvascular inflammation lesion on his graft biopsy associated to mild chronic lesions In absence of donor specific antibodies In presence of a missing self Exclusion Criteria: Proteinuria/urinary creatinin > 100 mg/mmol Antecedent of poor tolerance or hypersensibility to everolimus or sirolimus Severe chronic lesions Presence of donor specific antibodies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br> | Drug: Everolimus<br>* Patients will received everolimus (CERTICAN), oral form, at the necessary dose to obtain trough levels between 6 and 8 ng/ml, during 6 months. Everolimus will replace the anti-proliferative drug they have before (azathioprine or mycophenolic acid). Everolimus will be associated with corticosteroids (prednisolone) and a calcineurin inhibitor (tacrolimus or cyclosporin).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Estimated glomerular filtration rate | Glomerular filtration rate will be estimated by Chronic Kidney Disease - Epidemiology CollaborationI (CKD-EP) equation. Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0). | 6 months after start of Everolimus treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the severity of rejection lesions on allograft biopsy | Evolution of microvascular inflammation and chronic glomerular and vascular lesions graded according to Banff 2013 classification. Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0). | 6 months after start of Everolimus treatment | 
| Change in NK cell activability | Nk cell activability will be measured by looking at the expression of activation markers (CD107a and MIP1B) on circulating NK cells by flow cytometry. Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0). | 6 months after start of Everolimus treatment | 
| Change in proteinuria | Calculation of proteinuria/urinary creatinin index. Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0). | 6 months after start of Everolimus treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Missing self, NK cells, Rejection, mTOR inhibitors, Kidney transplanted patients