Evaluation of Molecular Profiles in Calcineurin Inhibitor Toxicity Post–Kidney Transplant: Input to Chronic Allograft Dysfunction. Issue 5 (2nd April 2014)

• Record Type: Journal Article
• Authors: Maluf, D. G.; Dumur, C. I.; Suh, J. L.; Lee, J. K.; Cathro, H. P.; King, A. L.; Gallon, L.; Brayman, K. L.; Mas, V. R.
• Is Part Of: American journal of transplantation. Volume 14:Issue 5(2014:May)
• Page Start: 1152
• Page End: 1163
• Publication Date: 2014-04-02
• Subjects: Biomarkers -- calcineurin inhibitors -- kidney transplant -- toxicity; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.12696
• Languages: English
• ISSNs: 1600-6135

Abstract

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 (n = 13) and CAD with IF/TA (n = 10) were evaluated. Normal allografts (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 ∼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 nonprogressors 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 nonprogressor patients, showing CNIT at the molecular level as a nonimmunological factor involved in the progression to CAD. Abstract : A multiple‐step approach using gene expression profiling of kidney allograft biopsies shows calcineurin inhibitor toxicity molecular signatures that associate with allograft injury (in a cross‐sectional study), and contribution of the discovered calcineurin inhibitor toxicity signature in the progression to chronic allograft dysfunction with interstitial ibrosis and tubular atrophy (in a longitudinal study).