Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: Input to chronic allograft dysfunction

D. G. Maluf, C. I. Dumur, J. L. Suh, J. K. Lee, H. P. Cathro, A. L. King, L. Gallon, K. L. Brayman, V. R. Mas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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. 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).

Original languageEnglish (US)
Pages (from-to)1152-1163
Number of pages12
JournalAmerican Journal of Transplantation
Volume14
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Biomarkers
  • calcineurin inhibitors
  • kidney transplant
  • toxicity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: Input to chronic allograft dysfunction'. Together they form a unique fingerprint.

Cite this