Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Novel urinary protein panels for the non-invasive diagnosis of non-alcoholic fatty liver disease and fibrosis stages.

BACKGROUND & AIMS: There is an unmet clinical need for non-invasive tests to diagnose non-alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). METHODS: We collected urine samples from 100 patients with biopsy-confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy-confirmed NAFLD and 45 healthy controls, urinary enzyme-linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. RESULTS: The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of .863 (95% CI: .725-1.000) and 0.858 (95% CI: .712-1.000) in the training set; and .837 (95% CI: .711-.963) and .916 (95% CI: .825-1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded .90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded .80. CONCLUSIONS: Our newly developed models constructed from urine protein biomarkers have good accuracy for non-invasively diagnosing liver fibrosis in NAFLD.

The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Several susceptibility gene variants predisposing to nonalcoholic fatty liver disease (NAFLD) have been identified in chronic kidney disease (CKD). Evidence supports that 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) rs72613567 plays a role in NAFLD development by affecting lipid homeostasis. Since lipid droplets may accumulate in the kidneys and contribute to renal injury, we investigated the association between the HSD17B13 rs72613567 variant and markers of renal function/injury in NAFLD. METHODS AND RESULTS: We measured estimated glomerular filtration rate (eGFR), urinary/serum neutrophil gelatinase-associated lipocalin (NGAL), and urinary albumin-to-creatinine ratio (u-ACR) in individuals with biopsy-proven NAFLD. Multivariable regression analyses were undertaken to examine the associations between the HSD17B13 rs72613567 variant and markers of renal function/injury. Individuals were stratified by HSD17B13 rs72613567 genotypes into -/-, A/- and A/A groups. HSD17B13 rs72613567 genotypes were not significantly associated with eGFR and urinary/serum NGAL levels. Conversely, the prevalence of abnormal albuminuria in the A/- + A/A group was lower than in the -/- group (4.92% vs. 19.35%, p = 0.001). Additionally, the mean u-ACR levels were lower among carriers of the A/- or A/A genotypes with coexisting hypertension or diabetes, than among those with the -/- genotype. The risk of abnormal albuminuria (adjusted-odds ratio 0.16, p = 0.001) remained significantly lower in the A/- + A/A group after adjustment for established renal risk factors and histologic severity of NAFLD. CONCLUSION: HSD17B13 rs72613567: A allele is associated with a lower risk of having abnormal albuminuria, but not with lower eGFR or urinary/serum NGAL levels, in patients with biopsy-proven NAFLD.

PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.

BACKGROUND & AIMS: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. METHODS: Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. RESULTS: The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P < .001), higher albuminuria (P = .039) and greater prevalence of chronic kidney disease (CKD; P = .046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (ß-coefficient: 22.29, 95% CI: 0.99-43.60, P = .041). CONCLUSION: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI.

WISP1 silencing confers protection against epithelial-mesenchymal transition of renal tubular epithelial cells in rats via inactivation of the wnt/ß-catenin signaling pathway in uremia.

Uremia can affect hepatic metabolism of drugs by regulating the clearance of drugs, but it has not been clarified whether gene silencing could modulate the epithelial-mesenchymal transition (EMT) process in uremia. Hence, we investigated the effect of WISP1 gene silencing on the renal tubular EMT in uremia through the wnt/ß-catenin signaling pathway. Initially, microarray-based gene expression profiling of uremia was used to identify differentially expressed genes. Following the establishment of uremia rat model, serum creatinine, and urea nitrogen of rats were detected. Renal tubular epithelial cells (TECs) were transfected with shRNA-WISP1 lentivirus interference vectors and LiCI (the wnt/ß-catenin signaling pathway activator) to explore the regulatory mechanism of WISP1 in uremia in relation to the wnt/ß-catenin signaling pathway. Then, expression of WISP1, wnt2b, E-cadherin, α-SMA, c-myc, Cyclin D1, MMP-2, and MMP-9 was determined. Furthermore, TEC migration and invasion were evaluated. Results suggested that WISP1 and the wnt/ß-catenin signaling pathway were associated with uremia. Uremic rats exhibited increased serum creatinine and urea nitrogen levels, upregulated WISPl, and activated wnt/ß-catenin signaling pathway. Subsequently, WISP1 silencing decreased wnt2b, c-myc, Cyclin D1, α-SMA, MMP-2, and MMP-9 expression but increased E-cadherin expression, whereas LiCI treatment exhibited the opposite trends. In addition, WISP1 silencing suppressed TEC migration and invasion, whereas LiCI treatment promoted TEC migration and invasion. The findings indicate that WISP1 gene silencing suppresses the activation of the wnt/ß-catenin signaling pathway, thus reducing EMT of renal TECs in uremic rats.

MAFLD as part of systemic metabolic dysregulation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications.

Farnesoid X receptor activation protects against renal fibrosis via modulation of ß-catenin signaling.

OBJECTIVE: Activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice. METHODS: We investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and ß-catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and ß-catenin was further verified. RESULTS: Mice were fed by a 60% kcal fat diet for 20 weeks developed the typical traits of metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal ß-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected ß-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox-LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) ß-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) ß-catenin, nuclear translocation and ß-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with ß-catenin via the AF1 domain, and disrupt the assembly of the core ß-catenin/TCF4 complex. CONCLUSION: These experimental data suggest that FXR activation, via modulating ß-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease.

BACKGROUND: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

Association of metabolic dysfunction-associated fatty liver disease with kidney disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption and other secondary causes of hepatic steatosis. In 2020, the more inclusive term metabolic (dysfunction)-associated fatty liver disease (MAFLD) - defined by broader diagnostic criteria - was proposed to replace the term NAFLD. The new terminology and revised definition better emphasize the pathogenic role of metabolic dysfunction and uses a set of definitive, inclusive criteria for diagnosis. Diagnosis of MAFLD is based on evidence of hepatic steatosis (as assessed by liver biopsy, imaging techniques or blood biomarkers and scores) in persons who are overweight or obese and have type 2 diabetes mellitus or metabolic dysregulation, regardless of the coexistence of other liver diseases or excessive alcohol consumption. The known association between NAFLD and chronic kidney disease (CKD) and our understanding that CKD can occur as a consequence of metabolic dysfunction suggests that individuals with MAFLD - who by definition have fatty liver and metabolic comorbidities - are at increased risk of CKD. In this Perspective article, we discuss the clinical associations between MAFLD and CKD, the pathophysiological mechanisms by which MAFLD may increase the risk of CKD and the potential drug treatments that may benefit both conditions.

MAFLD and risk of CKD.

BACKGROUND/AIMS: Whereas nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and extra-hepatic diseases is not known. The aim of this cross-sectional study was to compare the prevalence of chronic kidney disease (CKD) in patients with either MAFLD or NAFLD, and then to examine the association between the presence and severity of MAFLD and CKD and abnormal albuminuria. METHODS: A total of 12,571 individuals with complete biochemical and liver ultrasonography data from the Third National Health and Nutrition Examination Survey (1988-1994) were included in the analysis. Multivariable logistic regression analyses were performed to test the independence of associations between MAFLD or MAFLD severity as the key exposures and CKD (defined as either CKD stage ≥1 or stage ≥3) or abnormal albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol) as the outcomes. RESULTS: The prevalence of MAFLD and NAFLD was 30.2% (n = 3794) and 36.2% (n = 4552), respectively. MAFLD individuals had a lower eGFR (74.96 ±â€¯18.21 vs. 76.46 ±â€¯18.24 ml/min/1.73 m2, P < 0.001) and a greater prevalence of CKD (29.60% vs. 26.56%, P < 0.05) than NAFLD individuals. Similarly, there was a higher prevalence CKD in MAFLD than in non-metabolic dysfunction-associated NAFLD (P < 0.05). Notably, after adjustment for sex, age, ethnicity, alcohol intake and diabetes, the severity of MAFLD (i.e. NAFLD fibrosis score ≥ 0.676) was associated with 1.34-fold higher risk of prevalent CKD (P < 0.05). CONCLUSIONS: MAFLD identifies patients with CKD better than NAFLD. MAFLD and MAFLD with increased liver fibrosis score are strongly and independently associated with CKD and abnormal albuminuria.

Metabolic Acidosis in Critically Ill Cirrhotic Patients with Acute Kidney Injury.

Background and Aims: The metabolic acid-base disorders have a high incidence of acute kidney injury (AKI) in critically ill cirrhotic patients (CICPs). The aims of our study were to ascertain the composition of metabolic acidosis of CICPs with AKI and explore its relationship with hospital mortality. Methods: Three-hundred and eighty consecutive CICPs with AKI were eligible for the cohort study. Demographic, clinical and laboratory parameters were recorded and arterial acid-base state was analyzed by the Stewart and Gilfix methodology. Results: Net metabolic acidosis, lactic acidosis, acidosis owing to unmeasured anions, acidemia, and dilutional acidosis were less frequent in the non-survival group compared to the survival group of CICPs. The presence of acidemia, acidosis owing to unmeasured anions, and lactic acidosis were independently associated with increased risk of intensive care unit 30-day mortality, with hazard ratios of 2.11 (95% confidence interval (CI): 1.43-3.12), 3.38 (95% CI: 2.36-4.84), and 2.16 (95% CI: 1.47-3.35), respectively. After full adjustment for confounders, the relationship between acidosis owing to unmeasured anions with hospital mortality was still significant, with hazard ratio of 2.29 (95% CI: 1.22-4.30). Furthermore, arterial lactate concentration in combination with chronic liver failure-sequential organ failure assessment and BEUMA had the strongest ability to differentiate 30-day mortality (area under the receiver operating characteristic curve: 0.79, 95% CI: 0.74-0.83). Conclusions: CICPs with AKI exhibit a complex metabolic acidosis during intensive care unit admission. Lactic acidosis and BEUMA, novel markers of acid-base disorders, show promise in predicting mortality rate of CICPs with AKI.

Serum lactate level accurately predicts mortality in critically ill patients with cirrhosis with acute kidney injury.

BACKGROUND AND AIM: Serum lactate levels are routinely measured in critically ill patients with cirrhosis, and hyperlactatemia is a common finding, but its prognostic value remains controversial. Our aim was to examine whether serum lactate level could be used as a predictor of outcome in critically ill patients with cirrhosis (CICP) with acute kidney injury (AKI). PATIENTS AND METHODS: In this study, we included 480 consecutive patients with cirrhosis admitted to ICU, complicated with AKI, and were followed up for 365 days. Patients were divided into four groups (Q1-Q4) by serum lactate quartiles: Q1≤1.8 mg/dl, Q2=1.9-2.4 mg/dl, Q3=2.5-4.0 mg/dl, and Q4≥4.1 mg/dl. The hazard ratio (HR) and 95% confidence intervals (CIs) for hospital mortality were calculated across each quartile of serum lactate, using the Q1 as reference, and four models were built to adjust for the HR of mortality. RESULTS: Compared with patients in the survival group, nonsurvivors had higher serum lactate levels. Mortality rate increased progressively as the serum lactate level increased (Q1: 56.06%, Q2: 62.16%, Q3: 72.73% and Q4: 75.86%), and this relationship remained statistically significant after rigorous control of confounding factors in Q2, Q3, and Q4 with HRs of 1.03 (95% CI: 0.73-1.46), 1.40 (95% CI: 1.01-1.95), and 1.84 (95% CI: 1.28-2.64), respectively. CONCLUSION: Our study brings a new perspective to the role of lactate monitoring in CICP with AKI. Elevated serum lactate levels are associated with a higher mortality rate in CICP with AKI. Elevated serum lactate levels should be part of rapid diagnosis and initiation of therapy to improve clinical outcome.

AKI-CLIF-SOFA: a novel prognostic score for critically ill cirrhotic patients with acute kidney injury.

Critically ill cirrhotic patients with acute kidney injury (AKI) are associated with high mortality rates. The aims of this study were to develop a specific prognostic score for critically ill cirrhotic patients with AKI, the acute kidney injury - Chronic Liver Failure - Sequential Organ Failure- Assessment score (AKI-CLIF-SOFA) score. This study focused on 527 cirrhotic patients with AKI admitted to intensive care unit and constructed a new scoring system, the AKI-CLIF-SOFA, which can be used to prognostically assess mortality in these patient population. Parameters included in this model were analysed by cox regression. The area under the receiver operating characteristic curve (auROC) of AKI-CLIF-SOFA scoring system was 0.74 in 30 days, 0.74 in 90 days, 0.72 in 270 days and 0.72 in 365 days. Additionally, this study demonstrated that the new model had more discriminatory power than chronic liver failure- sequential organ failure assessment score (CLIF-SOFA), SOFA, model for end stage liver disease (MELD), kidney disease improving global outcomes (KDIGO) and simplified acute physiology score II (SAPS II) (auROC: 0.72, 0.66, 0.64, 0.62, 0.63 and 0.65 respectively, all P < 0.05) for the prediction of the 365-days mortality. Therefore, AKI-CLIF-SOFA demonstrated a valuable discriminative ability compared with KDIGO, CLIF-SOFA, MELD, SAPS II and SOFA in critically ill cirrhotic patients with AKI.

Comparative efficacy of vasoconstrictor therapies for type 1 hepatorenal syndrome: a network meta-analysis.

INTRODUCTION: The outcome of a comparative efficacy and safety of vasoconstrictor therapies for treatment of patients with type 1 hepatorenal syndrome (HRS-1) remain inconclusive. Areas covered: We searched literature databases for randomized controlled trials (RCTs) until 31 January 2016, and included ten eligible RCTs. In conclusion, terlipressin was the most efficacious vasoconstrictor drug for HRS-1, but had a higher probability of causing AEs. Norepinephrine was an attractive alternative to terlipressin and associated with less AEs. Expert commentary: To date, most previous traditional meta-analyses included trials with a limited population and compared terlipressin alone or with albumin against no intervention or albumin. Since different HRS types have different diagnoses and show different responses to vasoconstrictors, it may be questionable to combine data from patients with type 1 and type 2 HRS, which has been reported for most previous meta-analyses. Thus, performing a high-quality network meta-analysis of the existing literature is a valuable way to interrogate published data and to draw conclusions which may inform on the best interventional strategy.

Remodeling the model for end-stage liver disease for predicting mortality risk in critically ill patients with cirrhosis and acute kidney injury.

Serum creatinine measurement demonstrates a poor specificity and sensitivity for the early diagnosis of acute kidney injury (AKI) in patients with cirrhosis. The existing model for end-stage liver disease (MELD) score reveals multiple pitfalls in critically ill patients with cirrhosis and acute kidney injury (CAKI). The aim of this study was to re-evaluate the role of creatinine values in the existing MELD score and to develop a novel score for CAKI, named the "acute kidney injury-model for end-stage liver disease score" (AKI-MELD score). We extracted 651 CAKI from the Multiparameter Intelligent Monitoring in Intensive Care database. A time-dependent Cox regression analysis was performed for developing remodeled MELD scores (Reweight-MELD score, Del-Cr-MELD score, and AKI-MELD score). The area under the receiver operating characteristic curve provided the discriminative power of scoring models related to outcome. The hazard ratio of creatinine was 1.104 (95% confidence interval [CI], 0.945-1.290; P = 0.211). Reweight-MELD score and Del-Cr-MELD score (decreasing the weight of creatinine) were superior to the original MELD score (all P < 0.001). The new AKI-MELD score consists of bilirubin, the international normalized ratio, and the ratio of creatinine in 48 hours to creatinine at admission. It had competitive discriminative ability for predicting mortality (area under the receiver operating characteristic curve, 0.720 [95% CI, 0.653-0.762] at 30 days, 0.688 [95% CI, 0.630-0.742] at 90 days, and 0.671 [95% CI, 0.612-0.725] at 1 year). Further, AKI-MELD score had significantly higher predictive ability in comparison with MELD score, MELD-Na score, and Updated MELD score (all P < 0.001). Conclusion: The predictive value of creatinine for CAKI should be re-evaluated. AKI-MELD score is a potentially reliable tool to determine the prognosis for mortality of CAKI. (Hepatology Communications 2017;1:748-756).

Serum uric acid: a new therapeutic target for nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a major, worldwide public health problem. NAFLD is recognized as a major cause of liver-related morbidity and mortality. However, physicians are currently limited by available treatment options. Recently, numerous studies have reported a correlation between serum uric acid (SUA) and NAFLD with numerous clinical and experimental studies demonstrating a significant correlation. This review will focus on the role of SUA in the development of NAFLD and its potential role as a new target for therapeutic intervention. AREAS COVERED: This review discusses SUA as a significant independent factor in the development of NAFLD. Moreover, we introduce the causal relationship between SUA, metabolic syndrome, and NAFLD. We discuss two major theories of insulin resistance and inflammasomes as potential explanations of the mechanistic link between SUA and NAFLD. In addition, we review current and emerging therapeutic medications to control appropriate SUA levels. EXPERT OPINION: There is an urgent need to develop novel, safe and effective therapies for the growing NAFLD epidemic. Reduction of SUA may be a promising potential treatment for patients with NAFLD. Clinical studies are required to determine the therapeutic effect of attenuation of hyperuricemia in humans with NAFLD.

Increased levels of low-density lipoprotein cholesterol within the normal range as a risk factor for nonalcoholic fatty liver disease.

OBJECTIVES: Dyslipidemia exists within the setting of NAFLD and the relationship of a normal level of low-density lipoprotein cholesterol (LDL-c) with NAFLD is largely unknown. This large population-based study aimed to investigate the association between LDL-c levels within the normal range and the incidence of NAFLD. METHODS: A total of 60527 subjects from 2 medical centers who had undergone liver ultrasonography were initially enrolled into this study. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver disease. Subjects were divided into 4 groups (Q1 to Q4) by normal LDL-c quartiles : Q1: ≤ 2.00, Q2: 2.10-2.35, Q3: 2.36-2.68 and Q4: 2.69-3.12 mmol/L. The odds ratios (OR), hazard ratio (HR) and 95% confidence intervals (CIs) for NAFLD were calculated across each quartile of LDL-c, using the Q1 as reference. RESULTS: The prevalence rates of NAFLD in a cross-sectional population from Q1 to Q4 were 19.34%, 25.86%, 35.65% and 42.08%, respectively. The OR for NAFLD in the cross-sectional population were 1.31 (95% CI 1.14-1.54), 1.73 (95% CI 1.46-2.04), and 1.82 (95% CI 1.49-2.23), respectively, after adjusting for known confounding variables. The HR for NAFLD in the longitudinal population were 1.23 (95% CI 1.12-1.35), 1.57 (95% CI 1.44-1.72) and 2.02 (95% CI 1.86-2.21), compared with Q1. Subjects with higher LDL-c level within the normal range had an increased cumulative incidence rate of NAFLD. CONCLUSIONS: Increased levels of LDL-c within the normal range may play a significant role in the prevalence and incidence of NAFLD, independent of other confounding factors.