Evaluation of Molecular Profiles in Calcineurin Inhibitor Toxicity Post–Kidney Transplant: Input to Chronic Allograft Dysfunction

Abstract

The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: 1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study), and 2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n=14), acute rejection (AR, n=13), and CAD with IF/TA (n=10) were evaluated. Normal allografts (NA, n=18) were used as controls. To test CNIT contribution to CAD progression, an independent set of biopsies (n=122) from 61 KT patients collected at 3 and at ~12 months post-KT (range=9-18) were evaluated. Patients were classified based on 2-year post-KT graft function and histological findings as progressors (n=30) or non-progressors to CAD (n=31). Molecular signatures characterizing CNIT samples were identified. Patients classified as progressors showed an overlap of 7% and 22% with the CNIT signature at 3 and at ~12 months post-KT respectively, while the overlap was <1% and 1% in non-progressors patients, showing CNIT at the molecular level as a non-immunological factor involved in the progression to CAD.

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…The data sets comprised 1,697 biopsy samples from renal (11 data sets, 1,571 samples), cardiac (3 data sets, 94 samples), and lung transplants (1 data set, 32 samples; Table 1). Four of these data sets included only protocol biopsies (7,(17)(18)(19)(20), six included only for-cause biopsies (21)(22)(23)(24)(25)(26), and five included both protocol and for-cause biopsies (7,(27)(28)(29). We curated each data set to identify allograft biopsies from AR and stable (STA) patients.…”

Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease

“…DCXR was also found to be negatively associated with cortical interstitial fractional volume by Nair and colleagues (36). In addition, calcineurin inhibitor treatment after renal transplantation had a detrimental effect on DCXR gene expression based on a microarray study by Maluf and colleagues (37). DCXR protein concentration was also found to be upregulated around 2-fold in glomerular tissue from patients with diabetes mellitus who were being protected from development of diabetic kidney disease (38).…”

Increase of Th17 Cell Phenotype in Kidney Transplant Recipients with Chronic Allograft Dysfunction

“…The first issue of this study was how to include and classify the patient populations. For the CAD group, we selected KTRs who were at least 2 years post-KT and showed not only morphological evidence of presence of IF/TA but also functional deterioration, usually defined as estimated glomerular filtration rate (eGFR) below 40 mL/min/1.73 m 2 [ 23 , 24 ]. However, the definition of long-term stable patients is ambiguous and has not been clearly established.…”