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Selected Publication:

Ulbing, M.
MiRNAs as new putative Biomarkers for Monitoring of Mineral Bone Disorder and Vascular Calcification in Chronic Kidney Disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. [OPEN ACCESS]
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Authors Med Uni Graz:
Advisor:
Eller Kathrin
Obermayer-Pietsch Barbara
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Abstract:
Chronic kidney disease (CKD) is a widely spread disease, which is characterized by progressive deterioration of the functionality of the kidney. CKD is not only limited to negative effects on the kidney but is associated with a multifactorial dysregulation of bone metabolism and vascular calcification and is closely linked to increased cardiovascular disease (CVD) and concomitant bone disease, generally known as CKD-MBD (mineral bone disorder). These comorbidities are responsible for an increased mortality in CKD patients. Therefore, an early detection of bone related and cardiovascular problems in this patient group would help to improve the therapeutic approach. In this study we aimed to investigate specific microRNA (miRNA) signatures in CKD patients as new biomarkers differentially regulated during the disease development, which would serve as indicators for vascular calcification and/or bone mineralization changes during CKD. An impact of kidney transplantation (KT) on these miRNA signatures was also monitored. We evaluated a cohort comprising of 73 patients in CKD stages 3 to 5, 67 CKD patients after KT, and 36 healthy controls. Preliminary, a miRNA array investigating changes of miRNA expression in CKD patients was used to select 4 miRNAs which were quantified in the entire cohort. To characterize the different groups, a spectrum of biochemical parameters including markers for kidney function, inflammation, glucose, and mineral metabolism were measured and associated to the analyzed miRNAs using a univariate approach. Additionally a prospective study was started which includes CKD stage 5 patients listed for KT, with serum samples being collected on different time points, before, during and after the KT. Expression of miRNAs is compared between the time points. The primary array results and bioinformatic evaluation lead to the selection of miR-223-3p, miR-93-5p, miR-142-3p and miR-146a-5p for further experiments. The relative expression of miR-223-3p and miR-93-5p from CKD patients in stage 4 and 5 was down-regulated compared to healthy controls, whereas miR-142-3p and miR-146a-5p did only show non-significant changes. After KT no down-regulation could be detected anymore for any of the 4 miRNAs, even when lower glomerular filtration rates (GFR) persisted. The levels were comparable to those in healthy controls. Associations for miR-223-3p and miR-93-5p were found for interleukin-6 (IL-6), eGFR levels, and by trend with interleukin-8 (IL-8), C-peptide, hematocrit, and parathyroid hormone (PTH). The analysis of follow-up patients from the prospective study also indicated lower expression levels for miR-223-3p and miR-93-5p before KT. Serum miRNA expression is altered in CKD patients. The miRNAs targeted, miR-223-3p and miR-93-5p, are putatively reflecting pathophysiological changes during CKD which are associated with inflammation, vascular calcification and changes in mineral and glucose metabolism. Identification of targets predicted for miR-223-3p and miR-93-5p strengthen these associations and indicate their possible effects during CKD-MBD. Further description and evaluation of the miRNAs and detection of additional miRNA signatures could contribute to future risk markers or future therapeutic targets in bone-, cardiovascular- and kidney-disease.

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