The goal of this clinical trial is to learn if calcineurin-inhibitor therapy (a drug commonly used to prevent rejection) can be safely stopped in kidney transplant recipients with a relatively low risk of rejection (being recipients of a first transplant, without any signs of pre-existing immunity against the graft, and having a good HLA match with the donor (no mismatch in HLA-DQ)). Before stopping the calcineurin-inhibitors, the remaining therapy with mycophenolate mofetil and corticosteroids will be optimized.The main questions it aims to answer are:

Is this approach safe, in terms of preventing rejection? Is this approach well tolerated? Will this approach lead to better kidney function and/or other beneficial effects?

In summary, this pilot, prospective, single-arm open interventional study the investigators will include immune-quiescent zero-DQ mismatched kidney transplant recipients between 3-12 months post-transplant who are on a CNI-based regimen with corticosteroids and MMF. After optimization of MMF dose, targeted at an MPA AUC12 of 60 (±15) mg.h/L, CNIs will be tapered and stopped over a 4 week peri-od. Prednisolon dose will be temporarily increased to 10 mg/day at the day of CNI withdrawal for 14 days, and continued at 5 mg/d thereafter. The primary outcome is biopsy-proven rejection at 6 months after CNI withdrawal. Secondary outcomes will look at other markers of alloreactivity (dnD-SA without clinical or histological signs of rejection), tolerability of MMF in the defined range, infec-tious complications, and possible favorable effects of CNI withdrawal (on GFR, tubular function, blood pressure, lipid profile and diabetes).

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Adults ≥ 18 years old who received a first, zero-HLA-DQ mismatched kidney transplant between 3 and 12 months before screening. ((mis)matching based on the broad Eurotransplant Match determinant for DQA1 and on the split Eurotransplant Match determinant for DQB1
• Maintenance immunosuppressive therapy should consist of a calcineurin-inhibitor (tacrolimus or cyclosporine), MMF and corticosteroids
• subjects capable of giving informed consent
• eGFR ≥ 20 ml/min/1.73m² based on CKD-EPI Creatinine-Cystatin Equation at screening
• Recent HLA antibody testing (<6 weeks before screening)
• Absence of DSA (MFI > 500) at screening and in all historical samples
• Absence of subclinical rejection on a protocol kidney transplant biopsy according to latest Banff criteria (excl. borderline lesions)
• Recent assessment of CNI and MPA AUC (performed at least 8 weeks after transplantation, but <12 weeks before screening, )
• Recent OGTT in patients not on antidiabetic therapy (<3 months ago)

Exclusion Criteria:

• Receipt of a non-renal transplant
• HLA identical sibling donor transplant
• ABO incompatible kidney transplantation
• cdc-PRA at transplantation > 50%
• Ongoing treatment with immunosuppressive drugs other than CNI, MMF/MPA and cortico-steroids
• Prophylactic therapy with valganciclovir
• History of biopsy-proven acute rejection
• Unexplained rise in creatininemia >20% over the last 6 weeks
• Albuminuria > 1g/day ( based on latest 24h urine collection max 6 weeks ago)
• Chronic diarrhea or gastrointestinal disorders that interfere with the absorption or oral medi-cation
• Active peptic ulcer disease
• Active hepatitis B, hepatitis C or human immunodeficiency virus infection at the day of trans-plantation
• New diagnosis of malignancy since transplantation, except successfully treated nonmetastatic basal or squamous cell carcinoma of the skin
• Pregnancy or lactation
• Patients unwilling to use reliable anticonception during the study (Male patients or their untreated female partner must use reliable contraception during my-cophenolate treatment and for at least 90 days after stopping MMF treatment. Female patients who can get pregnant must use at least one reliable form of contraception before, during and for 6 weeks after stopping MMF treatment)