The kidneys are differentially affected in patients with cirrhosis with or without liver failure. Patients with ACLF with AKI have more structural AKI, greater potential for reversibility despite higher progression as well as higher mortality compared to patients with ADC. Prevention and early detection of AKI should be considered in patients with ACLF.
BackgroundMicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls.ResultsWe found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10-6, FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster.ConclusionWe provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.ReviewersReviewed by: Prof. Gregory J Goodall and Dr. Alexander Max Burroughs
Background and Aims: The role of bile cast nephropathy (BCN) in pathogenesis of hepatorenal syndrome (HRS) in decompensated cirrhosis and acute on chronic liver failure (ACLF) is unknown. This study aimed to determine the frequency of BCN detected on postmortem renal biopsy among patients with decompensated cirrhosis and ACLF who had been admitted with acute kidney injury due to HRS (HRA-AKI) and expired during that hospitalization.Methods: One-hundred-twenty-seven postmortem renal biopsies with adequate size (>1 cm in length) were included for analysis. These were obtained from 84 patients with decompensated cirrhosis and 43 patients with ACLF.Results: BCN was detected in 57 of the total 127 (44.8%) renal biopsy specimens. Patients with BCN had significantly higher levels of serum total bilirubin, total leukocyte count and model for end-stage liver disease score, as compared to those without BCN. BCN was detected in 32/43 (74.4%) of the patients with ACLF, as compared to 25/84 (29.7%) of the patients with decompensated cirrhosis (p < 0.001). On multivariate analysis, direct bilirubin (OR (95% CI): 1.27 (1121–1.698); p < 0.001) and presence of ACLF (OR (95% CI): 2.603 (1.054–7.111); p = 0.041) were found to be significant predictors of BCN on postmortem renal biopsy.Conclusion: BCN was found in 72.1% of patients with ACLF and 27.4% patients with decompensated cirrhosis who had been hospitalized with an admitting diagnosis of HRS-AKI and who expired during that hospitalization and underwent postmortem renal biopsy. Direct serum bilirubin and presence of ACLF were found to be significant predictors of BCN on postmortem renal biopsy.
The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.
Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than −6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A – C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patients identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain.
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