Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: input to chronic allograft dysfunction.
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.
University of Virginia, Department of Surgery PO Box 800679, Charlottesville, VA 22908-0679.
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DG
Maluf
University of Virginia, Department of Pathology PO Box 800904, VA 22908-0214.
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CI
Dumur
University of Virginia, Department of Surgery PO Box 800679, Charlottesville, VA 22908-0679.
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JL
Suh
University of Virginia, Division of Biostatistics PO Box 800717, VA 22298-0717.
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JK
Lee
University of Virginia, Department of Pathology PO Box 800904, VA 22908-0214.
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Cathro
Virginia Commonwealth University, Division of Nephrology PO Box 980662, VA 23298-0662.
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King
Northwestern University, Division of Nephrology, Department of Internal Medicine, Comprehensive Transplant Center Chicago, IL 60611.
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Gallon
University of Virginia, Department of Surgery PO Box 800679, Charlottesville, VA 22908-0679.
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KL
Brayman
University of Virginia, Department of Surgery PO Box 800679, Charlottesville, VA 22908-0679.
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VR
Mas
D000328:Adult; D064591:Allografts; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood*; D065095:Calcineurin Inhibitors / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000097:blood / Q000145:classification* / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000601:surgery*; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies
D015415:Biomarkers; D065095:Calcineurin Inhibitors
Biomarkers; calcineurin inhibitors; kidney transplant; toxicity