Date: Sunday, June 2, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Calcineurin inhibitors (CNI) remain the most effective and widely used immunosuppressive agents in kidney transplantation. Nephrotoxicity is a major secondary effect, and renal biopsy remains the best method for identify this toxicity. Hemodynamic changes are usually the cause of structural damage, usually caused by alterations in the flow of the afferent arteriole. Histological changes, although not specific, such as nodular / circumferential hyalinosis, striped fibrosis, isometric vacuolization of the tubular epithelium, or thrombotic microangiopathy are findings suggestive of CNI-induced nephrotoxicity, (CNIT) which require the physician’s rational decision to adjust the prescription of the drug. The histological findings require renal biopsy, an invasive procedure, in addition to evaluation by an expert pathologist, so non-invasive methods would be attractive to improve diagnostic performance. Exploratory and descriptive study of the gene expression behavior of representative extrinsic and intrinsic apoptotic pathways in renal biopsies of 10 patients with CNIT where compare with 10 biopsies without toxicity data.
*Methods: An Observational, descriptive cross sectional study was conducted. A convenience size of 20 renal biopsies samples were included . 10 correspond to transplanted patients with clinical, biochemical or histopathological data of calcineurin-inhibitors toxicity. The mRNA expression of renal tissue biopsies was analyzed using the RT2Profiler PCR Array platform considering genes involved processes associated with renal damage, the results where compared with no CNIT biopsies
*Results: Two of 10 patients had acute allograft dysfunction with CNIT values before the biopsy of 16ng/ml and 21 ng/ml respectively. In the rest of the cases the toxicity was an incidental finding in theannual protocol biopsy. The expression analyses of the genes associated directly with the inflammatory process (interleukins 2, 4, 6, 8, 10, TNF alpha, and TNF beta) showed in all the cases and also in the controls the absence of any detectable transcript in all the cytokines studied. In order to verify these data, we re- analyzed the expression profile for the Interleukin 10, as internal control with used GPDH. Interesting was that in all the samples an undetectable value was obtained, not even basal expression compared with the constitutive gene. The QPCR arrays showed that Bcl-2-associated X protein (BAX), Nucleolar Protein 3 (NOL3) and X-Linked Inhibitor of Apoptosis (XIAP) were consistent overexpressed only in the CNIT patients. The Mann-Whitney U test was consistent for the three evaluated genes revealed in the control group an average rank of 1.5, while the patients have three more times with respect the control. This result suggests that in the group of patients with CNIT BAX is activated, this gene is a key player in the intrinsic apoptosis pathway, suggesting that apoptosis via mitochondria is turn on probably due to the arteriolar vasoconstriction and the hypoxic state.
*Conclusions: We proposed that intrinsic apoptotic pathway plays a relevant role in the physiopathology of the CNIT.
To cite this abstract in AMA style:Queipo G, Fonsecha-Sanchez M, Sanchez J, Garcia L, Carmona M, Villanueva E, Melendez G, Morales-Buenrostro L, Alamilla M. Nephrotoxicity Caused by Calcineurin Inhibitors is Meditated by BAX, NOL3 and XIAP Apoptotic Genes Dysregulation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/nephrotoxicity-caused-by-calcineurin-inhibitors-is-meditated-by-bax-nol3-and-xiap-apoptotic-genes-dysregulation/. Accessed May 5, 2021.
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