Characteristics of acute kidney injury and its impact on outcome in patients with acute-on-chronic liver failure.

OBJECTIVE: Acute kidney injury (AKI) is a common and life-threatening complication of liver failure. The purpose of this study is to construct a nomogram and online calculator to predict the development of hospital-acquired acute kidney injury (HA-AKI) in patients with acute-on-chronic liver failure (ACLF), which may contribute to the prognosis of ACLF. METHODS: 574 ACLF patients were evaluated retrospectively. AKI was defined by criteria proposed by International Club of Ascites (ICA) and divided into community-acquired and hospital-acquired AKI (CA-AKI and HA-AKI). The difference between CA-AKI and HA-AKI, factors associated with development into and recovered from AKI periods. The risk factors were identified and nomograms were developed to predict the morbidity of HA-AKI in patients with ACLF. RESULTS: Among 574 patients, 217(37.8%) patients had AKI, CA-AKI and HA-AKI were 56 (25.8%) and 161 (74.2%) respectively. The multivariate logistic regression model (KP-AKI) for predicting the occurrence of HA-AKI were age, gastrointestinal bleeding, bacterial infections, albumin, total bilirubin, blood urea nitrogen and prothrombin time. The AUROC of the KP-AKI in internal and external validations were 0.747 and 0.759, respectively. Among 217 AKI patients, 81(37.3%), 96(44.2%) and 40(18.4%) patients were with ICA-AKI stage progression, regression and fluctuated in-situ, respectively. The 90-day mortality of patients with AKI was 55.3% higher than non-AKI patients 21.6%. The 90-day mortality of patients with progression of AKI was 88.9%, followed by patients with fluctuated in-situ 40% and regression of AKI 33.3%. CONCLUSIONS: The nomogram constructed by KP-AKI can be conveniently and accurately in predicting the development of HA-AKI, and AKI can increase the 90-day mortality significantly in ACLF patients. Trial registration Chinese clinical trials registry: ChiCTR1900021539.

Comparing efficacy of drug-coated balloon-only approach and stent approach in treating de novo coronary artery lesions: A meta-analysis of randomized controlled trials. A protocol for systematic review and meta-analysis.

BACKGROUND: Drug-coated balloons (DCB) have been a novel alternative therapeutic strategy in de novo coronary artery diseases. However, the clinical feasibility of the DCB-only approach in treating small vessel disease remains controversial, while study aimed to assess the efficacy and safety of the DCB-only approach versus stent approaches in treating large vessel disease is limited. METHODS: From February 2020 to May 2020, we will search Cochrane Library, PubMed, EMBASE, ScienceDirect, Scopus, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, and Chongqing VIP Database for eligible trials comparing DCB with drug-eluting stents for treatment of de novo lesions in both small vessel disease and large vessel disease. The primary endpoint is major adverse cardiac events (MACE); the secondary endpoints include in-lesion late lumen loss, binary restenosis, myocardial infarction, target lesion revascularization (TLR), mortality and target vessel thrombosis. Meta-analysis will be conducted using Review Manager software (V.5.3). RESULTS: The results will be presented as risk ratios for dichotomous data, and weighted mean differences for continuous data. CONCLUSION: We will assess outcomes of the DCB-only approach in the treatment of de novo lesions compared with the stent approach. PROSPERO REGISTRATION NUMBER: CRD42020164484.

Prospective randomized controlled trial study of Luofengning granule in the treatment of unstable angina.

INTRODUCTION: Although the current western treatment plans for unstable angina (UA) has been optimized in past decades, UA still is a common phenotype of acute coronary syndrome and significantly influence the quality of life and endanger lives. In China, the clinical application of Chinese herb medicine is considered as an effective approach to treating UA and widely recognized by patients. In clinical practices, we found Luofengning granule (LFN-G) could improve clinical manifestations of patients with UA, but there is lack of rigorous proof of evidence-based medicine. This trial aims to further evaluate the efficacy of LFN-G in the treatment of UA. METHODS: A prospective, open-label, randomized, placebo-controlled clinical will be performed. A total of 60 patients diagnosed with UA will be randomly allocated to either the treatment group or the control group with a 1:1 ratio. The participants in the treatment group will receive LFN-G treatment and the participants in the control group will receive placebo. Meanwhile, both groups continue to undergo standard western medicine treatments. The duration of interventions is 4 weeks. The primary endpoint is the incidence of major cardiac adverse events, defined as a composite of recurrent angina, acute myocardial infarction (AMI), severe arrhythmia, heart failure, and cardiac death. Secondary outcomes include Seattle angina scale score, Chinese medicine syndromes and electrocardiograph (at weeks 0, 1, 2, 4), myocardial nuclides perfusion, measurement of wall motion score index and left ventricular ejection fraction, serum inflammation factors such as C-reactive protein, high sensitive-C-reactive protein, interleukin-6, matrix metalloproteinase-9, and so on (at weeks 0, 4). In addition, some biochemical indexes of blood and hematological indexes will be used to assess the safety of treatments. Any adverse effects of the treatment will be recorded. DISCUSSION: The results of this trial will provide compelling evidence of the efficacy and safety of LFN-G for treatment of UA and preliminarily reveal the potential mechanism of how LFN-G acts. Finally, it will widen treatment options for patients with UA.

Characteristics, Risk Factors, and Adverse Outcomes of Hyperkalemia in Acute-on-Chronic Liver Failure Patients.

BACKGROUND: Hyperkalemia is a serious complication in cirrhotic patients. However, the clinical characteristics, risk factors, and its impact on the outcomes in acute-on-chronic liver failure (ACLF) patients remain unclear. METHODS: We retrospectively recruited 650 ACLF patients in this study. The risk factors associated with hyperkalemia and its relationship with 90-day mortality were analyzed using multivariable regression models. RESULTS: Among 650 patients with ACLF, 12.2% (79/650) had hyperkalemia during hospitalization. Higher admission serum potassium levels and the presence of acute kidney injury (AKI) were independent risk factors for hyperkalemia. The prevalence rates of hyperkalemia in patients with and without AKI were 23.6% and 4.6%, respectively (P<0.001). Hyperkalemia was a predictor of mortality in AKI and non-AKI patients. The 90-day mortality rates in non-AKI patients with and without hyperkalemia were 44.4% and 24.7%, respectively (P<0.001), and in AKI patients with and without hyperkalemia were 80.3% and 56.6%, respectively (P<0.001). Hepatic encephalopathy (HE), gastrointestinal bleeding, AKI, hyperkalemia, elevated total bilirubin (TBIL) and international normalized ratio (INR) values, and higher Model for End-Stage Liver Disease (MELD) and chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores were independent risk factors for predicting the 90-day mortality in ACLF patients. CONCLUSIONS: Hyperkalemia increases the 90-day mortality in ACLF patients; hyperkalemia is associated with AKI. Patients with both AKI and hyperkalemia had the worst outcome.

Evaluation of prognostic values of inflammation-based makers in patients with HBV-related acute-on-chronic liver failure.

Systemic inflammatory responses are associated with the development and progression of liver failure. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), red cell distribution width (RDW), RDW-to platelet ratio (RPR), mean platelet volume (MPV), and MPV-to platelet ratio (MPR) are markers of systemic inflammation. This study aimed to evaluate the prognostic values of these inflammatory markers in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).203 HBV-ACLF patients, 79 cirrhosis patients (LC), 63 chronic hepatitis B (CHB), and 81 healthy subjects (HS) participated in this cohort study. Complete blood counts and biochemical examinations were obtained after overnight fasting. Multivariate analyses of 90-day outcome predictors were analyzed by Cox regression models. Survival probability curves were calculated by the Kaplan-Meier method.The levels of NLR, MLR, RDW, MPV, RPR, and MPR were significantly higher and PNI was lower in patients with liver failure at presentation compared to those in LC, CHB, and HS (P <.001). In acute-on-chronic liver failure (ACLF) patients, NLR and MLR were higher in nonsurvivors than in survivors (P <.001), while other inflammatory markers showed no difference. ROC curve analyses showed that NLR combined with MLR had the highest AUC for identified poor outcome, followed by NLR, chronic liver failure-sequential organ failure assessment (CLIF-SOFA), MLR, model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP) and TBIL. Multivariate analyses showed that TBIL, NLR, CTP, MELD, and CLIF-SOFA were independent predictors for 90-day mortality.Combination of NLR and MLR are more accurate prognostic markers for predicting poor outcome than either marker alone in ACLF patients. And this combination is superior to the CLIF-SOFA, MELD, CTP score, and TBIL in terms of prognostic ability.

Characteristics of infection and its impact on short-term outcome in patients with acute-on-chronic liver failure.

Bacterial infections are an important cause of mortality in liver failure. However, the type of infection, predictors of infection, and their impact on outcomes in patients with acute-on-chronic liver failure (ACLF) are limited.A total of 389 patients with ACLF were admitted in this retrospective, corhort study. Once admitted, clinical data including first infection site, type (community-acquired, healthcare-associated, or nosocomial), and second infection occurrence during hospitalization were collected. The outcome was mortality within 90 days. Multivariable logistic regression models were preformed to predict second infection development and 90-day mortality. Survival probability curves were calculated by the Kaplan-Meier method.Among 389 patients, 316 (81.2%) patients had infection. The 90-day mortality of patients with and without infection was 52.2% and 16.4%, respectively (P <.001). The most common first infection was healthcare associated (51.3%), followed by nosocomial (30.1%) and community-acquired infections (18.7%). Respiratory tract infection, spontaneous bacterial peritonitis, and urinary tract infection were most prevalent. Gram-positive organism was more frequently seen than gram-negative organisms. Of note, fungi accounted for 15.9% of the total infection cases. During hospitalization, 26.6% patients developed second infections. The 90-day mortality of patients developed or did not develop a second infection were 67.9% and 46.6%, respectively (P <.001). Independent predictors of 90-day mortality in infected patients with ACLF were age, white blood cell (WBC) count, model for end-stage liver disease (MELD) score, hepatic encephalopathy (HE), and second infection.Infections (regardless of first or second infection) can increase the 90-day mortality significantly in patients with ACLF. And age, WBC count, MELD score, HE, and the presence of second infection are independent risk factors affecting 90-day mortality in patients with ACLF showing infection.

Transcriptional Regulation and Transport of Terpenoid Indole Alkaloid in Catharanthus roseus: Exploration of New Research Directions.

As one of the model medicinal plants for exploration of biochemical pathways and molecular biological questions on complex metabolic pathways, Catharanthus roseus synthesizes more than 100 terpenoid indole alkaloids (TIAs) used for clinical treatment of various diseases and for new drug discovery. Given that extensive studies have revealed the major metabolic pathways and the spatial-temporal biosynthesis of TIA in C. roseus plant, little is known about subcellular and inter-cellular trafficking or long-distance transport of TIA end products or intermediates, as well as their regulation. While these transport processes are indispensable for multi-organelle, -tissue and -cell biosynthesis, storage and their functions, great efforts have been made to explore these dynamic cellular processes. Progress has been made in past decades on transcriptional regulation of TIA biosynthesis by transcription factors as either activators or repressors; recent studies also revealed several transporters involved in subcellular and inter-cellular TIA trafficking. However, many details and the regulatory network for controlling the tissue-or cell-specific biosynthesis, transport and storage of serpentine and ajmalicine in root, catharanthine in leaf and root, vindoline specifically in leaf and vinblastine and vincristine only in green leaf and their biosynthetic intermediates remain to be determined. This review is to summarize the progress made in biosynthesis, transcriptional regulation and transport of TIAs. Based on analysis of organelle, tissue and cell-type specific biosynthesis and progresses in transport and trafficking of similar natural products, the transporters that might be involved in transport of TIAs and their synthetic intermediates are discussed; according to transcriptome analysis and bioinformatic approaches, the transcription factors that might be involved in TIA biosynthesis are analyzed. Further discussion is made on a broad context of transcriptional and transport regulation in order to guide our future research.

Biomarkers of oxidation stress, inflammation, necrosis and apoptosis are associated with hepatitis B-related acute-on-chronic liver failure.

BACKGROUND AND OBJECTIVE: Hepatitis B virus related acute-on-chronic liver failure is a serious condition with a high mortality. Oxidative stress, inflammation, necrosis and apoptosis may play an important role in it. This study is to investigate whether serum AOPP, S100A12, HMGB1 and sRAGE can provide diagnostic or prognostic information in HBV-related ACLF. METHODS: We measured serum S100A12, HMGB1 and sRAGE levels in 50 patients with HBV-related ACLF, 35 patients with liver cirrhosis (LC), 35 patients with chronic hepatitis B (CHB) and 35 healthy controls by enzyme-linked immunosorbent assay. AOPP measured by spectrophotometry. RESULTS: Significantly higher AOPP, S100A12, HMGB1 and sRAGE levels on admission were found in patients with ACLF compared with LC, CHB and healthy controls (P<0.001). In ACLF patients, they were higher in nonsurvivors than survivors (P<0.001). They had a positive relationship with total bilirubin and MELD scores. AOPP, S100A12 and HMGB1 concentrations continually declined in survivors while increased in nonsurvivors, sRAGE concentrations did not change in survivors, but gradually increased in nonsurvivors during hospitalization. ROC curve analysis showed that the four biomarkers had a higher AUC than TBIL. Multivariate Cox regression analysis demonstrated that S100A12, AOPP and sRAGE were independent risk factors for poor prognosis. CONCLUSION: Serum AOPP, S100A12 and sRAGE maybe reflect the oxidation stress, inflammation levels in HBV-related acute-on-chronic liver failure. Increased AOPP, S100A12 and sRAGE may serve as important biological markers of worse outcome.

Assessment of the Clinical Utility of Glypican 3 as a Serum Marker for the Diagnosis of Hepatocellular Carcinoma.

Glypican-3 has been reported to be one of the most promising serum markers for hepatocellular carcinoma. This study aimed to assess the clinical utility of serum glypican 3 for the diagnosis of hepatocellular carcinoma. We recruited consecutive patients on a large scale, 283 with hepatocellular carcinoma, 445 with chronic hepatic diseases, and 162 normal controls, to assess the diagnostic accuracy of serum glypican 3 for hepatocellular carcinoma by enzyme-linked immunosorbent assay. In addition, we further analyzed the relationship between the serum levels of α-fetoprotein and glypican-3 in patients with hepatocellular carcinoma. The results indicated that serum glypican 3 was elevated in patients with hepatocellular carcinoma (0 ng/mL, range = 0-14.0 ng/mL, P = .033) and liver cirrhosis (0 ng/mL, range = 0-12.5 ng/mL, P = .001) compared to the levels in normal control (0 ng/mL, range = 0-4.3 ng/mL), but there was no difference between hepatocellular carcinoma and liver cirrhosis (P = .097). The area under the curve of the receiver-operating characteristics curve for hepatocellular carcinoma versus all controls was 0.519, with a sensitivity of 39.9%, a specificity of 60.6%, and an optimal cutoff value of 0.002 ng/mL. The positive and negative predictive values were 32.0% and 68.3%, respectively. No significant correlation in serum levels was observed between glypican 3 and α-fetoprotein (P > .05). The diagnostic sensitivity for hepatocellular carcinoma increased to 72.8% (206 of the 283) when glypican 3 was combined with α-fetoprotein. Glypican 3 was not a promising serum maker for the diagnosis of hepatocellular carcinoma alone, but it could be complementary to α-fetoprotein and elevate the sensitivity of hepatocellular carcinoma diagnosis.

[Comparison of different criteria to evaluate acute kidney injury and determine short-term prognosis of patients with acute-on-chronic liver failure].

OBJECTIVE: To compare the acute kidney injury classification systems of RIFLE,AKIN,KDIGO and conventional criteria for determining prognosis of acute-on-chronic liver failure (ACLF) patients. METHODS: Patients with ACLF admitted to our hospital between July 2008 and March 2014 were enrolled in the study. The incidence, stages, and outcomes of acute kidney injury were determined according to the RIFLE, AKIN,KDIGO and conventional criteria.ROC curves were generated to compare the predictive ability for 30-day mortality of the four systems.Chi-square test and Fisher's exact test were used for statistical analyses, as well. RESULTS: All four classification systems detected acute kidney injury among the patients in the study population (n =358), but the detection rates were not consistent (expressed as % of total): KDIGO criteria: 45.0%, AKIN: 38.8%, rIFLE: 35.5%, conventional criterion: 20.4%. The KDIGO and AKIN criteria showed higher sensitivity (72%), especially to early kidney injury, but the conventional criterion showed higher specificity (92%). The AUC for 30-day mortality was highest for the conventional criteria (0.75), followed by AKIN (0.72), rIFLE (0.70) and KDIGO (0.69) (all, P less than 0.05). In-hospital mortality increased with severity of AKI in a stepwise manner. CONCLUSION: Among the four common evaluation systems for acute kidney injury, the conventional criteria has the highest specificity for predicting short-term prognosis of patients with ACLF, while the AKIN and KDIGO criteria have the highest sensitivity for the presence of acute kidney injury, especially at the early stage.

Correction: Comparison of Current Diagnostic Criteria for Acute-On-Chronic Liver Failure.

[This corrects the article DOI: 10.1371/journal.pone.0122158.].

Comparison of current diagnostic criteria for acute-on-chronic liver failure.

BACKGROUND AND AIMS: Currently, acute-on-chronic liver failure (ACLF) has been defined differently by Asia-Pacific Association for the Study of the Liver (APASL) and Chinese Medical Association (CMA) in the East, as well as EASL-Chronic Liver Failure (EASL-CLIF) Consortium in the West. This study aimed to compare current different diagnostic criteria for ACLF and to determine predictors of the progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. METHODS: We retrospectively analyzed clinical data from 394 eligible cirrhotic patients fulfilling at least APASL criteria for ACLF at enrollment. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. Independent predictors of disease progression were determined using univariate analysis and multivariate Cox regression analysis. RESULTS: The 90-day mortality rate was 13.1% in patients with ACLF at enrollment defined by APASL alone, 25.3% in patients with ACLF at enrollment defined by both APASL and CMA but not EASL-CLIF Consortium, and 59.3% in patients with ACLF at enrollment defined by EASL-CLIF Consortium in addition to APASL. Baseline Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) score, and the maximum rising rates of CLIF-SOFA score, Model for End-Stage Liver Disease-Sodium (MELD-Na) score and total bilirubin were independent predictors of progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. CONCLUSION: Different diagnostic criteria for ACLF caused different patient prognosis. So, it is imperative to formulate a unifying diagnostic criteria for ACLF worldwide, thus attaining early identification and treatment, and eventual improvement in survival of ACLF patients. Baseline CLIF-SOFA score, and the maximum rising rates of CLIF-SOFA score, MELD-Na score and total bilirubin may early predict post-enrollment development of EASL-CLIF ACLF.

Elevated mean platelet volume is associated with poor short-term outcomes in hepatitis B virus-related acute-on-chronic liver failure patients.

BACKGROUND AND AIM: It has been shown that mean platelet volume (MPV) can be used as a prognostic biomarker in some chronic diseases. The aim of the present study is to investigate the possible association between MPV and clinical outcome and prognosis in patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) within 4 weeks. METHODS: This study included 64 patients with HBV-ACLF, 19 chronic hepatitis B (CHB) patients, 27 patients with hepatitis B-related cirrhosis (CR, Child-Pugh A/B), 51 healthy subjects (healthy controls [HC]). The complete blood counts and biochemical examination of blood were obtained after 12h of fasting. In the ACLF group, the relationships between the prognosis and the MPV were analyzed. RESULTS: At baseline, a statistically significant increase in MPV was shown in patients with ACLF (median 9.5, range 7.1-14.1) compared with HC (8.0, 7.2-11.9, P<0.001), CR (8.4, 5.9-11.1, P<0.001) and CHB (8.3, 7.3-12.0, P<0.001). The MPV value was positively correlated with model of end-stage liver disease (MELD) score and international normalized ratio (INR). The MPV level was significantly increased in nonsurvivors than survivors. High MPV level showed a significantly lower survival rate (P=0.001). Multivariate logistic regression analysis showed that only MPV level was independent factor predicting poor short-term outcomes. CONCLUSION: MPV values at presentation were higher among nonsurvivors than survivors, and this parameter was well correlated with liver function parameters and may be used as a predictor for 4-week mortality rate in patients with HBV-ACLF.