Impact of acute kidney injury on the risk of mortality in patients with cirrhosis: a systematic review and meta-analysis

To compare the risk of mortality in patients with cirrhosis with and without the associated acute kidney injury (AKI). We performed a systematic search in the PubMed, Embase, and Scopus databases for observational studies that were done on patients with cirrhosis. Eligible studies reported AKI in patients with cirrhosis and compared mortality among patients with and without AKI. We used a random-effects model, using STATA version 16.0, for deriving pooled effect sizes that were reported as odds ratio (OR) with 95% confidence intervals (CIs). Thirty-two studies were included. In patients with cirrhosis, AKI was significantly associated with higher in-hospital mortality (OR 5.92), and mortality at 30 days (OR 4.78), 90 days (OR 4.34), and at 1 year follow-up (OR 4.82) compared to patients without AKI. AKI is associated with an increased risk of mortality in patients with cirrhosis. Careful monitoring to identify the development of AKI and early prompt management is necessary.</p

The Notch signaling plays a predominant role in maintaining immunomodulatory activities of hUC-MSCs.

<p>A. Western blotting shows that Bortezomib alone does not affect the IFN-γ-induced IDO1 expression, does not induce apoptosis as no PARP cleavage was induced, but elevates Mcl-1 protein level. B. Western blotting shows that siNotch1 transfection can silence approximately 50% of IDO1 protein expression, but does not induce apoptosis. C. Western blotting shows that treatment with 5 nM Bortezomib does not further enhance the effect of siNotch1 transfection on IDO1 reduction. In addition, Bortezomib and siNotch1 together do not induce apoptosis as no PARP cleavage is observed. D. The flow cytometry assay shows that siNotch1 transfection alone can significantly reduce the inhibitory effect of hUC-MSCs on Th1 lymphocyte proliferation. Bortezomib alone shows no such effect and does not enhance the effect of siNotch1 either. The * indicates statistical significance with <i>p</i><0.05.</p

Both Notch signaling and proteasome pathway contributes to the osteogenesis of hUC-MSCs.

<p>The semi-quantitative RT-PCR shows that the treatment with 2.5 μM GSI-I significantly reduces RGC32 transcription at day 1 and day 3 after osteogenic induction (A). However, whereas 5 nM Bortezomib alone reduces RGC32 transcription at day 3, not day 1, of osteogenic induction, and siNotch transfection alone slightly reduces RGC32 transcription at both day 1 and day 3, the combination of both siNotch1 transfection and Bortezomib treatment significantly reduces the transcription at both day 1 and day 3 after osteogenic induction (B).</p

The GSI-I treatment reduces expression of positive MSC surface markers.

<p>Representative histogram from a flow cytometry assay shows that, while over 95% untreated hUC-MSCs are positive for CD73, CD90 and CD105 (A), the treatment significantly reduces the positivity for each surface marker with the most significance seen for CD105 reduction. The * indicates the statistical significance with <i>p</i><0.05 (B).</p

The GSI-I treatment reduces osteogenesis of hUC-MSCs.

<p>A. The treatment inhibits intracellular calcium deposition as detected by Alizarin Red staining at 14 d after osteogenic induction. B. The semi-quantitative RT-PCR shows that the osteogenic induction induces RGC32 gene expression starting at 12 h and reaching to a plateau at day 3 (B-1, B-2). However, the GSI-I treatment with greater than 2.5 μM GSI-I significantly reduces RGC32 transcription at 24 h after treatment (B-3). The cells without osteogenic induction serve as negative control.</p

The Notch1 signaling is involved in immunomodulation of hUC-MSCs through promoting IDO1 transcription.

<p>A. Luciferase assay shows that, after transfection with pIDO1-Luc, the IDO1 promoter can be significantly activated in hUC-MSCs by 2 ng/mL IFN-γ. However, such activity can be significantly inhibited by GSI-I in a dose-dependent manner. B. Luciferase assay shows that siNotch1 transfection reduces over 50% of the IDO1 promoter activity. The * indicates statistical significance with <i>p</i><0.05. C. Flow cytometry assay shows that treatment with 0.1 mM 1-L-MT during co-culturing of hUC-MSC and PBMCs can significantly reduce the effect of hUC-MSCs on inhibition of Th1 lymphocyte proliferation. The * indicates statistical significance with <i>p</i><<i>0.05</i>D. D. The flow cytometry blot data are corresponding to the results of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118168#pone.0118168.g009" target="_blank">Fig. 9C</a>. The Th1 lymphocytes circled in the plot are the CD8^-/IFN-γ⁺ lymphocytes.</p

Both Notch signaling and proteasome pathway are involved in regulating CD105 expression in hUC-MSCs.

<p>Flow cytometry assay shows that 0.25–1 μM GSI-I do not induce changes in expression of CD73, CD90 and CD105 (A), but 5–10nM Bortezomib significantly inhibits the expression of CD105, but not CD73 and CD90 (B); Moreover, while the siNotch1 transfection alone has no effect on expression of surface markers, it further increases the inhibitory effect of 10 nM Bortezomib on CD105, slightly on CD90, but not on CD73 (C). The * indicates the statistical significance with <i>p</i><0.05.</p

The GSI-I treatment inhibits hUC-MSC activities in suppressing Th1 lymphocyte proliferation and IDO1 expression.

<p>A. Flow cytometry assay shows that co-culturing of hUC-MSC with PBMC in 1:5 ratio significantly inhibits Th1 lymphocyte proliferation. However, the treatment with 2.5 μM GSI-I significantly inhibits the effect of hUC-MSCs on Th1 proliferation. A-1: bar figure; A-2: original spectrogram of a representative Th1 lymphocyte analysis. Th1 lymphocytes are CD8-/IFN-g+ cells as circled in the spectrogram. B. The GSI-I treatment reduces the IFN-γ-induced IDO1 expression. Both semi-quantitative RT-PCR (B-1) and Western blotting (B-2) show that, while 2ng/mL IFN- γ induces IDO1 expression in hUC-MSCs, greater than 2.5 M GSI-I dramatically reduces the IDO1 expression.</p

The GSI-I treatment inhibits both Notch and ubiquitin-proteasome signaling in hUC-MSCs.

<p>A. Both GSI-I and Bortezomib inhibit ubiquitin-proteasome signaling. The Western blotting following immunoprecipitation shows that the treatment with 1.0–10.0 μM GSI-I or 5–10 nM Bortezomib significantly elevates the level of ubiquitin-conjugated Mcl-1 protein. A-1 is from the data using 2.5 μM-10.0 μM of GSI-I and 2.5–5 nM Bortezomib and A-2 is from the data using 0–2.5 μM of GSI-I and 10 nM of Bortezomib. B. GSI-I, but not Bortezomib, inhibits the Notch signaling. The Western blotting shows that, whereas 0.25–1 μM GSI-I reduce levels of the cleaved form of Notch1 and Hes1 proteins (B-1), 2.5–10 nM Bortezomib however significantly increase Hes1 protein level (B-2).</p

Additional file 1: of Integrated analysis of miRNA, gene, and pathway regulatory networks in hepatic cancer stem cells

Table S1. Consistently differentially expressed miRNAs