Investigating the Association between Steatotic Liver Disease and CKD in a Nationally Representative Sample.

BACKGROUND: Steatotic liver disease (SLD) and chronic kidney disease (CKD) are common conditions that are strongly associated. Yet, there is a paucity of data regarding the prevalence of this overlap and the factors that may drive its occurrence. METHODS: Using the National Health and Nutrition Examination survey, we examined trends among adult participants from 2005 - 2020 that defined SLD with the Fatty Liver Index. We completed correlative analyses among adult participants from 2017 - 2020 that defined SLD based on FibroScan results. We utilized multivariable survey-weighted binomial generalized linear models to determine the factors that were associated with CKD, defined as eGFR <60 or urine albumin-creatinine-ratio >30. RESULTS: Among the 76,496 participants included in the trend analyses, the estimated prevalence of CKD was 15.7% (95%CI 15.2 - 16.2%) and SLD was 42.3% (95%CI 41.4 - 43.2%). As compared to those without SLD, those with SLD had a significantly higher estimated prevalence of CKD (SLD: 15.7%, 95%CI 14.9 - 16.5% v. No SLD 11.2%, 95%CI 10.7 - 11.7%). In multivariate analyses of 3,667 participants who underwent FibroScan and had SLD by Fatty Liver Index, adjusting for control and presence of DM, HTN, and HLD, compared to those with normal liver stiffness, those with moderate scarring (F2) had similar odds of CKD (1.53, 95CI 0.91-2.56), those with severe scarring (F3) had higher odds of CKD (2.28, 95CI 1.20-4.32), and those with cirrhosis had higher odds of CKD (2.21, 95CI 1.13-4.32). CONCLUSIONS: Our findings highlight that CKD is common among patients with SLD and that higher degrees of hepatic fibrosis are associated with CKD, independent of other co-morbidities of the metabolic syndrome.

Impact of acute kidney injury response on survival and liver transplant rates in hospitalized patients with cirrhosis awaiting liver transplantation: Results from the HRS-HARMONY consortium.

Acute kidney injury (AKI) frequently complicates the course of hospitalized patients with cirrhosis and negatively affects their prognosis. How AKI response influences the timing of liver transplantation (LT) remains unclear. We sought to assess the impact of AKI response to treatment on survival and LT rates in patients with cirrhosis awaiting LT. This was a retrospective multicenter study of cirrhosis patients waitlisted for LT and hospitalized with AKI in 2019. The exposure was AKI response versus no response during hospitalization. Outcomes were 90-day overall and transplant-free survival, and rates of LT with time to transplant. We adjusted for age, sex, race, cirrhosis etiology, site, and Model for End-Stage Liver Disease-Sodium (MELD-Na) score. Among the 317 patients in this study, 170 had an AKI response (53.6%), and 147 had no response (46.4%). Compared to nonresponders, responders had better 90-day overall survival (89.4% vs. 76.2%, adjusted subhazard ratio for mortality 0.34, p =0.001), and transplant-free survival (63.5% vs. 25.2%, aHR for probability of death or transplant 0.35, p <0.001). The LT rate was lower in responders (45.9% vs. 61.2%, adjusted subhazard ratio 0.55, p =0.005); 79% of transplants in responders occurred after discharge, at a median of 103 days, while 62% of transplants in nonresponders occurred during hospitalization, with the remainder occurring postdischarge at a median of 58 days. In patients with cirrhosis waitlisted for LT who are hospitalized with AKI, AKI response to therapy is associated with improved 90-day survival, despite a reduced LT rate and longer time to LT.

Acute kidney injury in severe alcohol-associated hepatitis treated with anakinra plus zinc or prednisone.

BACKGROUND AND AIMS: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. APPROACH AND RESULTS: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005). CONCLUSIONS: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Medication burden and anticholinergic use are associated with overt HE in individuals with cirrhosis.

BACKGROUND: Polypharmacy and anticholinergic medications are associated with cognitive decline in elderly populations. Although several medications have been associated with HE, associations between medication burden, anticholinergics, and HE have not been explored. We examined medication burden and anticholinergics in patients with cirrhosis and their associations with HE-related hospitalization. METHODS: We conducted a retrospective cohort study of patients aged 18-80 with cirrhosis seen in hepatology clinics during 2019. The number of chronic medications (medication burden) and anticholinergic use were recorded. The primary outcome was HE-related hospitalization. RESULTS: A total of 1039 patients were followed for a median of 840 days. Thirty-seven percent had a history of HE, and 9.8% had an HE-related hospitalization during follow-up. The mean number of chronic medications was 6.1 ± 4.3. Increasing medication burden was associated with HE-related hospitalizations in univariable (HR: 1.09, 95% CI: 1.05-1.12) and multivariable (HR: 1.07, 95% CI: 1.03-1.11) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Twenty-one percent were taking an anticholinergic medication. Anticholinergic exposure was associated with increased HE-related hospitalizations in both univariable (HR: 1.68, 95% CI: 1.09-2.57) and multivariable (HR: 1.71, 95% CI: 1.11-2.63) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. CONCLUSIONS: Anticholinergic use and medication burden are both associated with HE-related hospitalizations, particularly in those with a history of HE. Special considerations to limit anticholinergics and minimize overall medication burden should be tested for potential benefit in this population.

Outcomes of patients with alcohol-associated hepatitis and acute kidney injury - Results from the HRS Harmony Consortium.

BACKGROUND & AIMS: The development of acute kidney injury (AKI) in the setting of alcohol-associated hepatitis (AH) portends a poor prognosis. Whether the presence of AH itself drives worse outcomes in patients with cirrhosis and AKI is unknown. METHODS: Retrospective cohort study of 11 hospital networks of consecutive adult patients admitted in 2019 with cirrhosis and AKI. AKI phenotypes, clinical course, and outcomes were compared between AH and non-AH groups. RESULTS: A total of 2062 patients were included, of which 303 (15%) had AH, as defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria. Patients with AH, compared to those without, were younger and had higher Model for End-stage Liver Disease-Sodium (MELD-Na) scores on admission. AKI phenotypes significantly differed between groups (p < 0.001) with acute tubular necrosis occurring more frequently in patients with AH. Patients with AH reached more severe peak AKI stage, required more renal replacement therapy, and had higher 90-day cumulative incidence of death (45% [95% CI: 39%-51%] vs. 38% [95% CI: 35%-40%], p = 0.026). Using no AH as reference, the unadjusted sHR for 90-day mortality was higher for AH (sHR: 1.24 [95% CI: 1.03-1.50], p = 0.024), but was not significant when adjusting for MELD-Na, age and sex. However, in patients with hepatorenal syndrome, AH was an independent predictor of 90-day mortality (sHR: 1.82 [95% CI: 1.16-2.86], p = 0.009). CONCLUSIONS: Hospitalised patients with cirrhosis and AKI presenting with AH had higher 90-day mortality than those without AH, but this may have been driven by higher MELD-Na rather than AH itself. However, in patients with hepatorenal syndrome, AH was an independent predictor of mortality.

Cystatin C and the difference between cystatin C and serum creatinine: Improved metrics to predict waitlist mortality among patients with decompensated cirrhosis.

Among patients with decompensated cirrhosis, serum creatinine (sCr) is biased by sex, frailty, and hepatic synthetic function, while Cystatin C (cysC) is not. We found that sCr would better associate with waitlist mortality and that the difference between cysC and sCr (cysCsCr diff ) would quantify this bias and be independently associated with outcomes. We measured cysC levels at ambulatory liver transplant visits among 525 consecutive patients seen at our center. We defined the cysCsCr diff as the difference between cysC minus sCr. We compared demographics and clinical characteristics in patients with low, intermediate, and high cysCsCr diff , divided by tertile. We used Cox regression to compare the association between sCr and cysC and waitlist mortality and demonstrate the independent association between cysCsCr diff and waitlist mortality. In Cox regression, cysC was significantly more associated with waitlist mortality than sCr ( p < 0.001). We found that as compared to those with a low cysCsCr diff , those with an intermediate or high cysCsCr diff were more likely to be female, have ascites, have higher frailty, and have higher MELD 3.0 scores ( p < 0.05 for all). Compared to those with a low cysCsCr diff , we found that those in the intermediate and high groups were more likely to die during follow-up (low: 6% vs. intermediate: 8% vs. high: 11%, p = 0.007). We found that after adjusting for the components of the MELD 3.0 score, each 1-point increase in the cysCsCr diff was associated with 1.72× (1.27-2.32) the hazard of waitlist mortality. Our study demonstrates that not only is cysC more associated with waitlist mortality than sCr, but that cysCsCr diff represents a novel independent metric associated with waitlist mortality.

Early Diagnostic Paracentesis Improves Outcomes of Hospitalized Patients With Cirrhosis and Ascites: A Systematic Review and Meta-Analysis.

INTRODUCTION: Diagnostic paracentesis is recommended for patients with cirrhosis admitted to the hospital, but adherence is suboptimal with unclear impact on clinical outcomes. The aim of this meta-analysis was to assess the outcomes of early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. METHODS: We searched multiple databases for studies comparing early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. The pooled odds ratio (OR) and mean difference with confidence intervals (CIs) for proportional and continuous variables were calculated using the random-effects model. Early diagnostic paracentesis was defined as receiving diagnostic paracentesis within 12-24 hours of admission. The primary outcome was in-hospital mortality. Secondary outcomes were length of hospital stay, acute kidney injury, and 30-day readmission. RESULTS: Seven studies (n = 78,744) (n = 45,533 early vs n = 33,211 delayed diagnostic paracentesis) were included. Early diagnostic paracentesis was associated with lower in-hospital mortality (OR 0.61, 95% CI 0.46-0.82, P = 0.001), length of hospital stay (mean difference -4.85 days; 95% CI -6.45 to -3.20; P < 0.001), and acute kidney injury (OR 0.62, 95% CI 0.42-0.92, P = 0.02) compared with delayed diagnostic paracentesis, with similar 30-day readmission (OR 1.11, 95% CI 0.52-2.39, P = 0.79). Subgroup analysis revealed consistent results for in-hospital mortality whether early diagnostic paracentesis performed within 12 hours (OR 0.51, 95% CI 0.32-0.79, P = 0.003, I2 = 0%) or within 24 hours of admission (OR 0.67, 95% CI 0.45-0.98, P = 0.04, I2 = 82%). Notably, the mortality OR was numerically lower when diagnostic paracentesis was performed within 12 hours, and the results were precise and homogenous ( I2 = 0%). DISCUSSION: Findings from this meta-analysis suggest that early diagnostic paracentesis is associated with better patient outcomes. Early diagnostic paracentesis within 12 hours of admission may be associated with the greatest mortality benefit. Data from large-scale randomized trials are needed to validate our findings, especially if there is a greater mortality benefit for early diagnostic paracentesis within 12 hours.

Applying Metabolomics and Aptamer-based Proteomics to Determine Pathophysiologic Differences in Decompensated Cirrhosis Patients Hospitalized with Acute Kidney Injury.

A case-control study of 97 patients hospitalized at our institution. We performed aptamer-based proteomics and metabolomics on serum biospecimens obtained within 72 hours of admission. We compared the proteome and metabolome by the AKI phenotype (i.e., HRS-AKI, ATN) and by AKI recovery (decrease in sCr within 0.3 mg/dL of baseline) using ANCOVA analyses adjusting for demographics and clinical characteristics. We completed Random Forest (RF) analyses to identify metabolites and proteins associated with AKI phenotype and recovery. Lasso regression models were developed to highlight metabolites and proteins could improve diagnostic accuracy. Results: ANCOVA analyses showed no metabolomic or proteomic differences by AKI phenotype while identifying differences by AKI recovery status. Our RF and Lasso analyses showed that metabolomics can improve the diagnostic accuracy of both AKI diagnosis and recovery, and aptamer-based proteomics can enhance the diagnostic accuracy of AKI recovery. Discussion: Our analyses provide novel insight into pathophysiologic pathways, highlighting the metabolomic and proteomic similarities between patients with cirrhosis with HRS-AKI and ATN while also identifying differences between those with and without AKI recovery.

Performance of race-neutral eGFR equations in patients with decompensated cirrhosis.

The 2021 Chronic Kidney Disease Epidemiology Collaboration equation [CKD-EPI 2021] is a race-neutral equation recently developed and rapidly implemented as a reference standard to estimate glomerular filtration rate(GFR). However, its role in cirrhosis has not been examined especially in low GFR. We analyzed the performance of CKD-EPI 2021 compared to other equations with protocol-measured GFR (mGFR) in cirrhosis. We analyzed 2090 unique adult patients with cirrhosis undergoing protocol GFR measurements using iothalamate clearance from 1985 to 2015 when listed for liver transplantation at Baylor University in Dallas and Fort Worth, Texas. Using mGFR as a reference standard, the CKD-EPI 2021 was compared to CKD-EPI 2012, Modification of Diet in Renal Disease-4, Modification of Diet in Renal Disease-6, Royal Free Hospital, and GFR Assessment in Liver disease overall and in certain subgroups (ascites, mGFR ≤ 30 mL/min/1.73 m 2 , diagnosis, Model for End-Stage Liver Disease and gender). We examined bias (difference between eGFR and mGFR), accuracy (p30: eGFR within ± 30% of mGFR) and agreement between eGFR and mGFR categories. CKD-EPI 2021 had the second lowest bias across the entire range of GFR after GFR Assessment in Liver disease (6.6 vs. 4.6 mL/min/1.73 m 2 , respectively, p < 0.001). The accuracy of CKD-EPI 2021 was similar to CKD-EPI 2012 (p30 = 67.8% vs. 67.9%, respectively) which was higher than the other equations ( p < 0.001). It had a similar performance in patients with ascites, by diagnoses, Model for End-Stage Liver Disease subgroups, by gender, and in non-Black patients. However, it had a relatively higher overestimation in mGFR ≤ 30 mL/min/1.73 m 2 than most equations (18.5 mL/min/1.73m 2 , p < 0.001). Specifically, 64% of patients with mGFR ≤ 30 mL/min/1.73m 2 were incorrectly classified as a less severe CKD stage by CKD-EPI 2021. In Blacks, CKD-EPI 2021 underestimated eGFR by 17.9 mL/min/1.73 m 2 , which was higher than the alternate equations except for Royal Free Hospital ( p < 0.001). The novel race-neutral eGFR equation, CKD-EPI 2021, improves the GFR estimation overall but may not accurately capture true kidney function in cirrhosis, specifically at low GFR. There is an urgent need for a race-neutral equation in liver disease reflecting the complexity of kidney function physiology unique to cirrhosis, given implications for organ allocation and dual organ transplant.

Controversies in terlipressin and transplantation in the United States: How do we MELD the two?

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a severe complication of cirrhosis that carries a poor prognosis. The recent Food and Drug Administration approval of terlipressin has substantial implications for managing HRS-AKI and liver allocation in the United States. Terlipressin has been available in Europe for over a decade, and several countries have adapted policy changes such as Model for End-Stage Liver Disease (MELD) score "lock" for HRS-AKI. In this article, we outline the European experience with terlipressin use and explore the question of whether terlipressin treatment for HRS-AKI should qualify for the MELD score "lock" in the United States in those who respond to therapy. Arguments for the MELD lock include protecting waitlist priority for terlipressin responders or partial responders who may miss offers due to MELD reduction in the terlipressin treatment window. Arguments against MELD lock include the fact that terlipressin may produce a durable response and improve overall survival and that equitable access to terlipressin is not guaranteed due to cost and availability. We subsequently discuss the proposed next steps for studying terlipressin implementation in the United States. A successful approach will require the involvement of all major stakeholders and the mobilization of our transplant community to spearhead research in this area.

The association between mean arterial pressure and acute kidney injury reversal among patients with decompensated cirrhosis.

BACKGROUND AND AIMS: This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology. APPROACH AND RESULTS: We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48 h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1 mm Hg, p <0.05) and a greater increase in MAP over time (0.1 mm Hg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5 mm Hg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5 mm Hg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001). DISCUSSION: Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.

From past to present to future: Terlipressin and hepatorenal syndrome-acute kidney injury.

Hepatorenal syndrome (HRS) is a rare and highly morbid form of kidney injury unique to patients with decompensated cirrhosis. HRS is a physiologic consequence of portal hypertension, leading to a functional kidney injury that can be reversed by restoring effective circulating volume and renal perfusion. While liver transplantation is the only definitive "cure" for HRS, medical management with vasoconstrictors and i.v. albumin is a cornerstone of supportive care. Terlipressin, a V1a receptor agonist that acts on the splanchnic circulation, has been used for many years outside the United States for the treatment of HRS. However, its recent Food and Drug Administration approval has generated new interest in this population, as a new base of prescribers now work to incorporate the drug into clinical practice. In this article, we review HRS pathophysiology and diagnostic criteria, the clinical use of terlipressin and alternative therapies, and identify areas of future research in the space of HRS and kidney injury in cirrhosis.

Optimization of Kidney Health in Liver Transplant Candidates: Pretransplant Considerations and Modalities.

Patients with decompensated end-stage liver disease (ESLD) are at increased risk for mortality, and only liver transplantation (LT) offers meaningful hope for survival. These patients are at risk for kidney dysfunction through the continuum of care for ESLD including LT. We discuss the role of accurate estimation and measurement of baseline glomerular filtration rate in assessment of kidney dysfunction among those with ESLD. Optimizing kidney function is a vital goal in the management of these patients before LT. In this review, we summarize salient aspects of assessing and optimizing kidney function in this patient population. Precipitating factors and different causes of acute kidney injury are discussed, including hepatorenal syndrome. We further review treatment options for acute kidney injury including volume management. The role of vasopressor therapy, renal replacement therapy, and transjugular intrahepatic portosystemic shunting are discussed.

Prognostic significance of acute kidney injury stage 1B in hospitalized patients with cirrhosis: A US nationwide study.

Understanding the prognostic significance of acute kidney injury (AKI) stage 1B [serum creatinine (sCr) ≥1.5 mg/dL] compared with stage 1A (sCr < 1.5 mg/dL) in a US population is important as it can impact initial management decisions for AKI in hospitalized cirrhosis patients. Therefore, we aimed to define outcomes associated with stage 1B in a nationwide US cohort of hospitalized cirrhosis patients with AKI. Hospitalized cirrhosis patients with AKI in the Cerner-Health-Facts database from January 2009 to September 2017 (n = 6250) were assessed for AKI stage 1 (≥1.5-2-fold increase in sCr from baseline) and were followed for 90 days for outcomes. The primary outcome was 90-day mortality; secondary outcomes were in-hospital AKI progression and AKI recovery. Competing-risk multivariable analysis was performed to determine the independent association between stage 1B, 90-day mortality (liver transplant as a competing risk), and AKI recovery (death/liver transplant as a competing risk). Multivariable logistic regression analysis was performed to determine the independent association between stage 1B and AKI progression. In all, 4654 patients with stage 1 were analyzed: 1A (44.3%) and 1B (55.7%). Stage 1B patients had a significantly higher cumulative incidence of 90-day mortality compared with stage 1A patients, 27.2% versus 19.7% ( p < 0.001). In multivariable competing-risk analysis, patients with stage 1B (vs. 1A) had a higher risk for mortality at 90 days [sHR 1.52 (95% CI 1.20-1.92), p = 0.001] and decreased probability for AKI recovery [sHR 0.76 (95% CI 0.69-0.83), p < 0.001]. Furthermore, in multivariable logistic regression analysis, AKI stage 1B (vs. 1A) was independently associated with AKI progression, OR 1.42 (95% CI 1.14-1.72) ( p < 0.001). AKI stage 1B patients have a significantly higher risk for 90-day mortality, AKI progression, and reduced probability of AKI recovery compared with AKI stage 1A patients. These results could guide initial management decisions for AKI in hospitalized patients with cirrhosis.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis.

BACKGROUND AND AIMS: Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis (mAH) as compared to severe alcohol-associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. METHODS: Patients hospitalized with alcohol-associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90-day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End-stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90-day mortality. RESULTS: 1504 AH patients were hospitalized during the study period, of whom 39% (n = 590) had mAH. Compared to sAH patients, mAH patients were older (50 vs. 48 years, p < 0.001) and less likely to have underlying cirrhosis (74% vs. 83%, p < 0.001). There were no differences between the two groups for median alcohol intake g/day (mAH 140.0 vs. sAH 112.0, p = 0.071). The cumulative proportion surviving at 90 days was 88% in mAH versus 62% in sAH (p < 0.001). On multivariable analysis, older age [HR 1.03 (95% CI 1.00-1.06), p = 0.020], corticosteroid use [HR 1.80 (95% CI 1.06-3.06), p = 0.030] and acute kidney injury (AKI) [HR 2.43 (95% CI 1.33-4.47), p = 0.004] were independently associated with 90-day mortality. CONCLUSIONS: mAH carries a 12% mortality rate at 90 days. Age, AKI and corticosteroid use were associated with an increased risk for 90-day mortality. Avoidance of corticosteroids and strategies to reduce the risk of AKI could improve outcomes in mAH patients.

Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. METHODS: We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. RESULTS: About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). CONCLUSION: Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.

Plasma exchange for acute and acute-on-chronic liver failure: A systematic review and meta-analysis.

Plasma exchange (PE) is a promising therapeutic option in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). However, the impact of PE on patient survival in these syndromes is unclear. We aimed to systematically investigate the use of PE in patients with ALF and ACLF compared with standard medical therapy (SMT). We searched PubMed/Embase/Cochrane databases to include all studies comparing PE versus SMT for patients ≥ 18 years of age with ALF and ACLF. Pooled risk ratios (RR) with corresponding 95% CIs were calculated by the Mantel-Haenszel method within a random-effect model. The primary outcome was 30-day survival for ACLF and ALF. Secondary outcomes were overall and 90-day survival for ALF and ACLF, respectively. Five studies, including 343 ALF patients (n = 174 PE vs. n = 169 SMT), and 20 studies, including 5,705 ACLF patients (n = 2,856 PE vs. n = 2,849 SMT), were analyzed. Compared with SMT, PE was significantly associated with higher 30-day (RR 1.41, 95% CI 1.06-1.87, p = 0.02) and overall (RR 1.35, 95% CI 1.12-1.63, p = 0.002) survival in ALF patients. In ACLF, PE was also significantly associated with higher 30-day (RR 1.36, 95% CI 1.22-1.52, p < 0.001) and 90-day (RR 1.21, 95% CI 1.10-1.34, p < 0.001) survival. On subgroup analysis of randomized controlled trials, results remained unchanged in ALF, but no differences in survival were found between PE and SMT in ACLF. In conclusion, PE is associated with improved survival in ALF and could improve survival in ACLF. PE may be considered in managing ALF and ACLF patients who are not liver transplant (LT) candidates or as a bridge to LT in otherwise eligible patients. Further randomized controlled trials are needed to confirm the survival benefit of PE in ACLF.

Defining an approach for therapeutic strategies in metabolic dysfunction-associated steatotic liver disease after liver transplantation.

Occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) is common following liver transplantation (LT). MASLD can be classified as a recurrent disease when it occurs in patients receiving LT for metabolic dysfunction-associated steatohepatitis (MASH) or as de novo when it occurs in patients undergoing transplantation for non-metabolic dysfunction-associated steatohepatitis etiologies of liver disease. Fibrosis progression in patients with MASLD is accelerated, with progression to cirrhosis occurring more rapidly compared with the general (ie, non-LT) population. Moreover, the metabolic burden in LT recipients with MASLD is high and synergizes with liver disease to negatively affect the clinical course. Despite the oversized clinical burden of MASLD among LT recipients, there is currently a lack of regulatory approach and pathway for therapeutics development in this patient population. The present document, thus, provides guidance for therapeutics development that incorporates nuances of transplant care in patients with post-LT MASLD to facilitate drug development.