Antibody mediated rejection (ABMR) is a major cause of graft loss after kidneytransplantation (KT) and is mainly associated with preformed anti-HLA donor specificantibodies (DSAs) (phenotype 1) or de novo DSAs (dnDSAs) (phenotype 2). PreexistingDSA-associated ABMR have superior graft survival compared with dnDSA-associated ABMR,which could partly be explained by the fact that patients with de novo DSA-associatedABMR have biopsy later, when graft dysfunction and/or proteinuria are already present.ABMR is a progressive process with an early stage called subclinical ABMR (sABMR), inwhich histological lesions are present in the kidney graft without clinical graftdysfunction. These early lesions are now well recognized as risk factors for transplantglomerulopathy and poor graft survival in phenotype 1 ABMR (ref 5). The impact of sABMRassociated with dnDSA at any time post-transplant has been less studied and reported.Recently, we published a retrospective multicenter study within the Spiesser Group thatincluded 123 patients without graft dysfunction who underwent graft biopsy because of thepresence of dnDSA (One Lambda, MFI > 1000). Performing a kidney graft biopsy after dnDSAindentification without renal dysfunction leads to the diagnosis of active sABMR in 35 %of cases. Nevertheless, we did not observe any effect of standard of care treatment inactive sABMR. Very recently, an expert consensus for the recommended treatment for ABMRafter KT was published. They concluded the clear lack of evidence but a standard of carefor ABMR was nevertheless defined. Therefore, we propose to evaluate a new strategy foractive sABMR, testing a conversion from calcineurin inhibitor (CNI) to belataceptassociated with the recently recommended standard of care (SOC) compared to continuingCNI. Belatacept might help to manage nonadherence, decrease the toxicity of CNI on anendothelium already affected by microvascular inflammation, and reduce DSA titers.The monitoring of dnDSA after KT and an indication graft biopsy in case of appearance,even in the absence of graft dysfunction, is not part of a routine clinical practice inall KT centers. This strategy could be a valuable option, in order to begin treatment ofABMR before graft dysfunction occurs, and therefore to improve prognosis associated withphenotype 2 ABMR. Parajuli et al.4 suggested that early diagnosis and treatment of sABMRwith SOC, using DSA monitoring may improve outcomes after KT, but this is a retrospectiveand no-randomized study. This study will be the first prospective randomized study in thecontext of de novo DSA. We will evaluate a new combination of treatment for ABMR in thecontext of dnDSA with subclinical lesions and in the same time may help to determine thereal incidence of sABMR in KT recipients with subclinical dnDSA. The use of belatacept inthe context of sABMR to improve the non-adherence and to decrease the endothelialtoxicity had never been evaluated in a prospective way.
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Drug: Conversion to Belatacep
CNI will be tapered within 3 months: 75 % of initial dose on the first month, 50 % on the
second month, 25 % on the third month, and stopped and a conversion to Belatacept will be
performed. It will be administered (6mg/kg) every 2W for the first 2 months and then
every month until kidney graft survival.
Drug: Standard of care treatment (SOC regimen) with Tacrolimus
Tacrolimus will be continued until kidney graft survival with objective of whole blood
through levels between 6 and 8 ng/mL
Inclusion Criteria:
1. Screening inclusion criteria:
- Kidney transplant recipient
- Adult
- De novo DSA (MFI > 1000 using the Luminex single antigen beads assay or
positive with the manufacturer criteria according to the Luminex assay) absent
on the day of kidney transplantation and in the sera prior to kidney
transplantation
- No clinical graft dysfunction at time of DSA detection (< 20 % variation of
eGFR compared to last 3 months before detection and < 0,5 g/g
proteinuria/creatinuria ratio)
- Affiliation with, or beneficiary of a Social security (national health
insurance) category
- Person having read and understood the information letter and signed the consent
form
- Women of childbearing potential with effective contraception/very-effective
contraception (Cf. CTFG) (oestro-progestatives or intra-uterine device or tubal
ligation) and a negative blood pregnancy test.
- Women surgically sterile (absence of ovaries and/or uterus)
- Postmenopausal women: confirmation diagnostic (non-medically induced amenorrhea
for at least 12 months prior to the inclusion visit)
2. Randomization inclusion criteria:
- Patients with active sABMR, according Banff 2019 classification, with very
slight transplant glomerulogathy (cg = 0 or 1).
Exclusion Criteria:
1. Screening exclusion criteria:
- Minor
- Specific treatment for DSA occurrence before kidney graft biopsy: IVIG or
rituximab or plasmapheresis or immunoabsorption
- ABO incompatible kidney transplantation
- Combined transplantation
- Transplant recipients who are Epstein-Barr virus (EBV) seronegative or
serostatus unknown.
- Hypersensitivity to the active substance or to any of the excipients - Pregnant
or parturient or breastfeeding woman or absence of contraception
- Person deprived of liberty by an administrative or judiciary decision or person
placed under judicial protection, under guardianship or supervision
- Person consenting to the research participating to another trial
- Medical history or psychological or sensorial abnormality prone to inhibit the
subject to understand the conditions required for his/her participation to the
protocol or unable him/her to give an informed consent
- No signed ICF
2. Randomization exclusion criteria:
- No sABMR or chronic active sABMR (cg > 1) on initial biopsy
- History of severe opportunistic infection before randomization
- Acute or chronic infection with HBV, HCV or HIV
- EBV negative serology
- History of post-transplant lymphoproliferative disorder.
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