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Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.

ABSTRACT: Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p?=?0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI.

SUBMITTER: Wilflingseder J

PROVIDER: S-EPMC4122455 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.

Wilflingseder Julia J Sunzenauer Judith J Toronyi Eva E Heinzel Andreas A Kainz Alexander A Mayer Bernd B Perco Paul P Telkes Gábor G Langer Robert M RM Oberbauer Rainer R

PloS one 20140805 8

Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the ...[more]

PMID: 25093671

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Project description:Background and Objectives: Kidney transplant recipients represent a unique population with metabolic abnormalities, altered nutritional and immune status, as well as an imbalanced regulation of adipocytokine metabolism. Leptin is a hormonally active protein mainly produced by fat tissue that modulates appetite, satiety, and influences growth, energy, and bone metabolism. There has been great interest in the role of this hormone in chronic kidney disease-related protein energy wasting; thus, a positive leptin correlation with body mass index and fat mass was confirmed. This study was designed to determine the association of pre and post-kidney transplant leptin concentration with nutritional status and body composition. Materials and Methods: We studied 65 kidney transplant recipients. Nutritional status was evaluated before kidney transplantation and 6 months later using three different malnutrition screening tools (Subjective Global Assessment Scale (SGA), Malnutrition Inflammation Score (MIS), and Geriatric Nutritional Risk Index (GNRI)), anthropometric measurements, and body composition (bioelectrical impedance analysis (BIA)). Demographic profile, serum leptin levels, and other biochemical nutritional markers were collected. Statistical analysis was performed with R software. Results: Median age of the studied patients was 45 years, 42% were females, and 12% had diabetes. Leptin change was associated with body weight (p < 0.001), waist circumference (p < 0.001), fat mass (p < 0.001) and body fat percentage (p < 0.001), decrease in parathyroid hormone (PTH) (p < 0.001) transferrin (p < 0.001), diabetes mellitus (p = 0.010), and residual renal function (p = 0.039), but not dependent on dialysis vintage, estimated glomerular filtration rate (eGFR), or delayed graft function at any time during the study. After adjustment for age and sex, body mass index (BMI) (p < 0.001), fat mass (p < 0.001), and body fat percentage (p < 0.001) were independent variables significantly associated with post-transplant leptin change. Lower leptin values were found both before and after kidney transplantation in the SGA B group. GNRI as a nutritional status tool was strongly positively related to changes in leptin within the 6-month follow-up period. Conclusions: Kidney transplant recipients experience change in leptin concentration mainly due to an increase in fat mass and loss of muscle mass. GNRI score as compared to SGA or MIS score identifies patients in whom leptin concentration is increasing alongside an accumulation of fat and decreasing muscle mass. Leptin concentration evaluation in combination with BIA, handgrip strength measurement, and GNRI assessment are tools of importance in defining nutrition status in the early post-kidney transplant period.

Project description:Several studies have investigated miRNA and mRNA co-expression to identify regulatory networks at the transcriptional level. A typical finding of these studies is the presence of both negative and positive miRNA-mRNA correlations. Negative correlations are consistent with the expected, faster degradation of target mRNAs, whereas positive correlations denote the existence of feed-forward regulations mediated by transcription factors. Both mechanisms have been characterized at the molecular level, although comprehensive methods to represent miRNA-mRNA correlations are lacking. At present, genome-wide studies are able to assess the expression of more than 1000 mature miRNAs and more than 35,000 well-characterized human genes. Even if studies are generally restricted to a small subset of genes differentially expressed in specific diseases or experimental conditions, the number of potential correlations remains very high, and needs robust multivariate methods to be conveniently summarized by a small set of data.Nonparametric Kendall correlations were calculated between miRNAs and mRNAs differentially expressed in livers of patients with acute liver failure (ALF) using normal livers as controls. Spurious correlations due to the histopathological composition of samples were removed by partial correlations. Correlations were then transformed into distances and processed by multidimensional scaling (MDS) to map the miRNA and mRNA relationships. These showed: (a) a prominent displacement of miRNA and mRNA clusters in ALF livers, as compared to control livers, indicative of gene expression dysregulation; (b) a clustering of mRNAs consistent with their functional annotations [CYP450, transcription factors, complement, proliferation, HLA class II, monocytes/macrophages, T cells, T-NK cells and B cells], as well as a clustering of miRNAs with the same seed sequence; and (c) a tendency of miRNAs and mRNAs to populate distinct regions of the MDS plot. MDS also allowed to visualize the network of miRNA-mRNA target pairs.Different features of miRNA and mRNA relationships can be represented as thematic maps within the framework of MDS obtained from pairwise correlations. The symmetric distribution of positive and negative correlations between miRNA and mRNA expression suggests that miRNAs are involved in a complex bidirectional molecular network, including, but not limited to, the inhibitory regulation of miRNA targets.

Dataset Information

Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.

Publications

Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.

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