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

Kidney Transplant Failure and Rejection Clinical Trial

— STARR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03955172
• Other study ID #: 69HCL17_0706
• Status: Recruiting
• Phase: N/A
• Start date: December 3, 2020
• Est. completion date: December 3, 2024

Study information

• Verified date: May 2023
• Source: Hospices Civils de Lyon
• Contact: Alice KOENIG, MD
• Phone: 472110178
• Email: alice.koenig[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 3, 2024
• Est. primary completion date: December 3, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Kidney Transplant Failure and Rejection

Intervention

Drug:
• Everolimus
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).

Locations

Country	Name	City	State
France	Service de transplantation, néphrologie et immunologie clinique, Hôpital Edouard Herriot (HCL)	Lyon

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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