Added Value of 18 FDG Pet-scanner in Diagnosis and Management of Subclinical Rejection in Kidney Transplant Patients

Subclinical rejection (SCR) has been defined as "the documentation by light histology of unexpected evidence of acute rejection (AR) in a stable patient". The diagnosis of SCR is important given that the treatment of subclinical T-cell-mediated AR results in similar long-term graft survival to that in patients without rejection. Surveillance transplant biopsies are, by definition, required for the diagnosis of SCR. Still, only 17% of transplant centers in the United States perform surveillance biopsies in all patients, whereas 62% do not perform surveillance biopsies at all because the incidence of SCR is low3. Non-invasive biomarkers may thus be developed as "rule out" tests, with the highest negative predictive value, in order to reduce the indiscriminate use of allograft biopsies in stable kidney transplant recipients (KTR). Beside urine-derived and blood-based biomarkers of SCR, the investigators have recently reported in a monocentric prospective pilot study that 18F-Fluorodeoxyglucose Positron Emission Tomography coupled with Computed Tomography (18F-FDG PET/CT) non-invasively rules out SCR at \~3 months post kidney transplantation (KTx).

In previous 92-patient cohort published by the investigators, the ratio between the mean standardized 18F-FDG uptake values (SUVs) of the renal allograft and the psoas muscle (used as reference tissue) was significantly higher in the group with biopsy-proven SCR versus the group with strictly normal histology. The area under the ROC curve (AUC) reached 0.79, with a negative predictive value of 98% using an mSUVR threshold of 2.4.

All adult KTR who undergo surveillance transplant biopsy at \~3 months post KTx are eligible for the present study, except pregnant women and patients PCR-proven BK nephropathy. Written informed consent will be obtained. KTx will be performed in accordance with the Declaration of Istanbul. Surveillance biopsies will be locally (in each participating centers) and centrally (at ULiège CHU) assessed by pathologists blinded to the results of 18F-FDG PET/CT. Banff 2017 classification will be conventionally used. Total inflammation (ti) will take into account interstitial inflammation in both non-sclerotic and sclerotic areas. C4d staining will be performed in all cases. PET/CT will be performed with late acquisitions (\~180 minutes) after 18F-FDG intravenous injection (\~3 Mbq/kg) within a 48-hour period around the biopsy, before any modification of immunosuppressive regimens. The mean standardized uptake value (mSUV) of kidney cortex will be measured and averaged from 4 volumes of interest (VOI) distributed in the upper (n=2) and lower (n=2) poles, both locally (in each participating centers) and centrally (at ULiège CHU)10. The mSUV of kidney will be normalized to the mSUV of psoas muscle (VOI of 20 ml) or the liver (VOI of 20 ml), considered as reference tissues in order to obtain the corresponding mean SUV Ratios (mSUVR).

The patients will be afterwards in one of these three categories :

1. The renal biopsy shows signs of humoral rejection: the patient is excluded from the study and is treated "as usual" on the basis of the histological results. 2. The renal biopsy does not show signs of humoral rejection but the 18FDG PET / CT shows a high metabolic activity of the graft (\> 2.4): the patient is treated "as usual" on the basis of histological findings. 3. The renal biopsy does not show signs of humoral rejection and the 18FDG PET / CT shows a weak metabolic activity of the graft (\<2.4): the immunosuppressive treatment is gradually weaned off corticosteroids.

The goals are :

(i) to use the measurement of renal accumulation of the 18FDG marker at the level of the renal graft as a non-invasive indicator of the absence of a subclinical cellular rejection and to use the information from the renal biopsy only if the metabolic activity of the graft is increased.

(ii) to use the measurement of renal accumulation of the 18FDG marker in the renal graft as a non-invasive indicator of the absence of cell rejection and to initiate the withdrawal of corticosteroids if the metabolic activity of the graft is normal.

• Allograft rejection [Time frame: at 6 months and 1year]