The purpose of the study is to assess the efficacy of bortezomib, in association with steroids, plasma exchange, and polyclonal intravenous immunoglobulins, in the treatment of chronic antibody mediated rejection due to donor specific anti-HLA antibodies, in kidney transplant recipients

Chronic active antibody-mediated rejection (AMR) is considered as a main cause of late allograft losses in kidney transplant recipients. It is due to the occurrence of de novo donor-specific anti-HLA antibodies (DSA), i.e. antibodies synthetized by the recipient after transplantation against its transplant. There is currently to efficient treatment. The purpose of our study is to determine the efficacy of bortezomib, a proteasome inhibitor, in the treatment of chronic active antibody-mediated rejection, in association with steroids, plasma exchanges, and polyclonal intravenous immunoglobulins. Patients are recipients of a first or a second kidney transplant for more than 3 months. They display de novo DSA i.e. DSA not detected the day of transplantation and in pre-transplant sera.. They display signs of chronic active AMR on kidney biopsy i.e. a glomerulitis (g) + peritubular capillaritis (ptc) Banff score g+ptc ≥ 2, with or without severe chronic glomerulopathy (Banff score cg<3). Kidney biopsy may have been performed systematically or because of: :

1. detection of de novo DSA ,
2. and /or proteinuria (> 0.5 g/24h)
3. and /or slow graft dysfunction protocol biopsy Primary endpoint is a combined endpoint one year after inclusion, consisting of the stabilization of histological lesions on a new kidney biopsy (delta g+ptc ≤1 and delta cg < 1) and a decrease in DSA mean fluorescence intensity > 50%.

Inclusion Criteria:

• recipients of a first or a second kidney transplant for more than 3 months

• age over 18 years

• with de novo donor specific antibodies (DSA), i.e. antibodies not detected the day of transplantation and in pre-transplant sera

• with histological lesions of chronic active antibody-mediated rejection (glomerulitis + peritubular capillaritis banff score and chronic glomerulopathy (g+ptc ≥ 2) on a graft biopsy performed because of renal function deterioration, proteinuria, detection of de novo DSA, or on a systematic biopsy

• written informed consent

• Given the teratogenic risks described in the SPCs of Velcade and Cellcept:

  • Women of child bearing age must have a negative pregnancy test the day of the inclusion and should use at least one effective contraceptive method before start of medication during the treatment and during the study
  • Men old enough to procreate have to use condoms during the treatment and at least 90 days after the last intake of the treatment during the study. Moreover, given SPCs of Cellcept, it is recommended that female partners to use an effective method of contraception treatment and for 90 days after the last mycophenolate intake by the partner male

• affiliated with social security health insurance

• patients with cell rejection lesions associated with chronic humoral rejection lesions active may be included in the study. This rejection can be treated with 3 boluses of 500 mg of methyl prednisolone prior to inclusion.

Exclusion Criteria:

• patient with preformed DSA
• recipient of a 3rd or 4th kidney transplant
• recipient of a transplant combined with another not renal organ
• patient with a history of humoral acute rejection during the current transplantation
• estimated GFR below 20 ml/min/1,73m2
• severe transplant glomerulopathy (cg score = 3)
• severe peripheral neuropathy, thrombopenia < 100 000 mm3 , neutropenia < 1000 mm3 and/or an uncontrolled evolutionary infection
• chronic active hepatitis B (positive HBs antigen or HBV DNA), positive chronic hepatitis C and/or known HIV infection
• allergy to bore or bortezomib or to one of the excipient
• hepatic failure, abnormal liver tests (bilirubin >3N, transaminases >3n), infiltrative pneumopathy, pericarditis
• risk of non-adherence to treatment or protocol
• inclusion in another clinical therapeutic trial