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.

Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases

“…These differentially expressed miRNAs include miR-638, miR-663, miR198, miR-155, and miR-146a (91,141). Similarly, acute allograft rejection, a frequent complication of renal transplantation, is associated with alterations in miRNA expression (4,84,95,143,160). Global miRNA profiling of human hypertensive nephrosclerosis biopsies also revealed a number of differentially expressed miRNAs, including miR-200a, miR-200b, miR-141, miR-429, and miR-192 (150).…”

“…Although, extensive human studies are still required, initial steps have been taken to demonstrate the potential utility of miRNAs, especially in the urine, for assessing AKI. Multiple studies (90,96,104,113,124,155,159,160) in humans and animal models have identified specific miRNAs as potential diagnostic markers for the early detection of AKI. Such approaches would be of tremendous clinical value to prevent progression from AKI to renal failure.…”

Absence of miR-182 Augments Cardiac Allograft Survival

“…Analysis of human renal allograft biopsies demonstrated that increased expression of miR-182 is associated with both antibody-mediated rejection and acute kidney injury 14,29 . Our studies, and others, have demonstrated FOXO1 as a target of miR-182 and indeed FOXO1 was significantly increased in miR-182 −/− recipients of cardiac allografts treated with CTLA4-Ig supporting a role for FOXO1 in graft survival 8,13,30 .…”

MicroRNAs in AKI and Kidney Transplantation

“…MicroRNAs are involved in the regulation of angiogenesis and apoptosis through TGF-b, endothelin, vascular endothelial growth factor, and PDGF signaling (19). Upregulation of miR-182-5p, miR-21-3p, and miR-146a have been reported (20,21). The overexpression of miR-146a probably represents a compensatory mechanism because in vitro experiments identified the role of miR-146a as a negative regulator of inflammation in tubular cells by downregulation of the NFkB/C-X-C motive chemokine ligand 8 pathway (21).…”