These results suggest the involvement of specific miRNAs and mRNAs in biological pathways associated with the progression of CKD.

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.

A small set of serum protein biomarkers identified using a systems biology approach, combined with clinical variables, enhances the prediction of renal function loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD.

Acute kidney injury (AKI) remains a major clinical event with high mortality rates. We previously identified renal miR-182 as the main driver of post-transplantation AKI. Therefore, we tested the causal inference of miR-182 by inhibiting its renal expression in vivo. In 45 rats AKI was induced by right nephrectomy and contralateral clamping of the renal pedicle for 40 minutes. Systemically administered antisense oligonucleotide (ASO) inhibited miR-182 in the kidneys up to 96 hours. The maximum creatinine elevation was on day 2 after injury (mg/dL; median and interquartile range): ASO 2.5mg/kg: 1.9 (1.3; 3.2), ASO 25mg/kg: 2.8 (0.7; 5.0), mismatch oligonucleotide (MM) 25mg/kg: 5.7 (5,0; 5.8), saline: 4.4 (3.5; 5.8) (P = 0.016, analysis of variance). Blinded semiquantitative histologic evaluation of renal biopsies showed better preserved morphology in both ASO groups than saline- and MM-treated kidneys (median and interquartile range of overall injury scores): ASO both concentrations 1 (1, 1), saline 3 (3, 3) and MM 3 (3, 3) (P< 0.001, analysis of variance). ASO facilitated cell proliferation, metabolism, and angiogenesis on a genome-wide level. ASO when applied in normothermic kidney machine perfusion reduced renal miR-182 expression by more than two magnitudes. In summary, we showed that in vivo inhibition of miR-182 by ASO improved kidney function and morphology after AKI. This technique may be applicable to reduce the high rate of AKI in the human renal transplantation setting.