Society: AASLD

Background: Hepatorenal syndrome (HRS) with rapidly deteriorating kidney function can be effectively reversed when treated with terlipressin, the US FDA-approved vasopressin analogue. The Phase III placebo-controlled CONFIRM study demonstrated that verified HRS reversal was achieved in significantly more patients in the terlipressin group versus placebo (29.1% vs 15.8%; P=.012). However, clinical outcomes in patients with HRS may be influenced by the presence of alcoholic hepatitis (AH), which further confounds treatment options and harbors a poor prognosis. This subgroup analysis of the CONFIRM study assessed the efficacy of terlipressin in patients with HRS and AH.

Methods: The CONFIRM study enrolled adult patients with cirrhosis, ascites, and HRS with rapidly progressing kidney failure, defined per protocol as a doubling of serum creatinine to ≥2.25 mg/dL within 14 days (d) of randomization. Patients were randomly assigned 2:1 to terlipressin (1 mg by intravenous bolus every 6 hours) or placebo; concomitant albumin was recommended (1 g/kg on Day 1 up to 100 g then 20–40 g/d as clinically indicated). Diagnosis of baseline AH was via investigator assessment. Data was retrospectively analyzed in patients with AH for verified HRS reversal (defined as the percentage of patients with 2 serum creatinine values of ≤1.5 mg/dL ≥2 hours apart, while on treatment up to 72 hours after the last dose of study drug), admission to the intensive care unit (ICU), length of ICU stay, transplant-free survival at Day 90, and incidence of renal replacement therapy (RRT) by Day 30.

Results: In CONFIRM (N=300), 41% (81/199) of patients in the terlipressin group and 39% (39/101) of patients in the placebo group had AH at baseline. In the subgroup of patients with AH (n=120), the median Maddrey discriminant function score was similar across treatment groups (terlipressin, 96.9; placebo, 97.9; P=.681). Verified HRS reversal was achieved in 30.9% (25/81) of patients in the terlipressin group versus 7.7% (3/39) in the placebo group (P=.005) (Figure 1). Median transplant-free survival was 28 d for the terlipressin group versus 15 d for placebo (P=0.207) (Figure 2). Admission to the ICU was similar for patients in the terlipressin and placebo groups (17.3% [14/81] and 17.9% [7/39]); whereas mean length of stay in the ICU was shorter for terlipressin (6.9 d) versus the placebo group (12.4 d). There was a numerical decrease in RRT by Day 30 in the terlipressin versus placebo group (21.0% [17/81] vs 25.6% [10/39]).

Conclusions: In this cohort of patients with HRS and AH from CONFIRM, significantly more patients achieved verified HRS reversal with terlipressin than placebo. Additionally, in the terlipressin group numerical improvements in clinical outcomes included shorter duration of ICU stay, longer transplant-free survival, and lower incidence of RRT compared to placebo.

Inpatients with cirrhosis are prone to multi-organ failures, including respiratory distress (RD). Albumin use in these pts is often not evidence-based & can increase fluid overload and RD. Terlipressin+albumin increased RD in the CONFIRM trial but the determinants of RD in those not exposed to terlipressin are unclear. Aim: Determine predisposing factors, including AKI & albumin use for RD in a multi-center inpatient cirrhosis cohort.
Methods: We created a consortium of 11 North American centers that enrolled up to 50 consecutive non-electively hospitalized cirrhosis pts/center, excluding prior transplant, & those unable to consent. We collected baseline & hospital course demographics, cirrhosis severity, AKI, organ failures, ICU, death, & transplant data. AKI was defined using IAC definitions & Rx (albumin, midodrine, octreotide, & noradrenaline) were collected. RD was defined as ventilation due to respiratory issues and/or Pa02/FiO2 ratio< 200/Sp02/FiO2 ratio< 214. Significant variables on univariate analysis were used to perform a multi-variable logistic regression for RD development. Albumin use details (dose, evidence-based indication vs not) and impact on RD were also evaluated.
Results: 511 patients from 12 sites (57 yrs, 58% men) with median MELD of 23 were enrolled. Prior history: 64% had prior hospitalizations, 77% had ascites, 43% had HE, 26% variceal bleed, 21% had prior LVP & 16% were listed.
Admission medications: 28% were on Beta-blockers, 37% on rifaximin, 56% on lactulose, 17% on SBP prophylaxis & 60% on PPI.
Hospital course: 46% developed AKI & 53% of those patients developed stage≥ 2, 15% developed bilirubin >12mg/dl, 11% each with high INR & grade 3-4 HE & 10% with shock. 42% of AKI pts received daily midodrine, 33% received octreotide & 6% Noradrenaline. 29% were transferred to ICU, 4% died & 9% were transplanted.
RD Development: 19% developed RD; higher percent of AKI pts developed RD. Albumin use was higher in patients with RD with a dose-response (p=0.005, OR/10 gm=1.02, 1.01-1.03,Table).
Multivariable analysis: Only AKI development (OR 2.18, 1.33-3.59, p=0.002) and IV albumin (OR 2.58, 1.43-4.66, p=0.001) were independently and significantly predictive of RD. Demographics, MELD, medications, or other factors were non-contributory.
Albumin indication: 62% received albumin; more AKI pts received albumin (82% vs 45%, p<0.0001). In those receiving albumin, 134(43%) were for evidence-based reasons. 22% given albumin for only evidence-based, 26% for other reasons & 28% for both reasons developed RD (p=0.56).
Conclusions: In a multi-center study of inpatients with cirrhosis, RD developed in almost a fifth of patients, which was independently associated with AKI & IV Albumin use even without terlipressin. Almost half of albumin use was for non-evidence-based indications and had a dose-response with respiratory distress development.

<b>Inpatients with Cirrhosis who did or did not develop Respiratory Distress </b>

Inpatients with Cirrhosis who did or did not develop Respiratory Distress

Introduction
Hepatorenal Syndrome (HRS) is a life-threatening form of renal dysfunction that results from circulatory hemodynamic dysfunction in advanced liver disease. There is an increase in recognition of HRS in cirrhotic patients, and with no approved medical therapy, there is limited success in achieving HRS reversal. Renal replacement therapy is often needed as a bridge to liver transplant. The purpose of our study was to identify preventable reasons for readmissions among HRS patients.

Methods
We used the National Readmission Database (2010-2018) and sampled every other year employing International Classification of Diseases (ICD) codes (ICD-9 and ICD-10) to include adult patients with cirrhosis. Among those, HRS patients were screened. Elective or planned readmissions were excluded. The variables adjusted for in the regression models while computing adjusted hospitalization and readmission rates were: gender, age, Charlson Comorbidity Index score, median household income for patients’ zip codes, hospital location/ bedside, hospital volume, and teaching status. We used Stata, version 14.2 to perform analyses considering 2-sided P< 0.05 as statistically significant.

Results:
A total of 2,987,156 patients were included in the analysis. 169,523 had associated HRS diagnosis. The incidence of HRS hospitalization in cirrhosis increased from 5.3% in 2010 to 5.84% in 2018 (P<0.01) (Figure. 1). 13.27% had a coexistent diagnosis of infection during the index admission. The mean age at presentation showed an increasing trend of 58.09 in 2010 to 59.69 years in 2018 (trend P<0.01), while the proportion of females with HRS diagnosis increased from 36.92% in 2010 to 38.15% in 2018 (trend P<0.01). The proportion of HRS patients presenting to teaching hospitals was 53.11% in 2010 and 77.90% in 2018 (trend P<0.01). Over the same duration, the all-cause readmission at 30 days showed an overall increasing trend from 19.81% to 19.99% (trend P<0.01). The HRS-specific readmission at 30 days following an index hospitalization ranged from 13.60-15.98, with an overall increasing trend in the study period (2010-2018). Cirrhosis, hepatic failure, and infection were uniformly the three most common causes of readmission throughout the study period (Figure. 2). The infection-specific readmission increased from 6.25% in 2010 to 12.12% in 2018 (trend P<0.01).

Discussion
A rising trend in preventable readmissions in HRS patients, especially with infection, is a cause for concern. Therefore, a high index of suspicion must be maintained, and national strategies must be developed to recognize infection as a precipitant factor leading to readmission to reduce HRS's economic burden on the healthcare system.

Figure. 1: Longitudinal readmission trends in Hepatorenal Syndrome

Figure. 1: Longitudinal readmission trends in Hepatorenal Syndrome

Figure. 2: Causes of 30-day readmission in Hepatorenal Syndrome

Figure. 2: Causes of 30-day readmission in Hepatorenal Syndrome

Zahid Ijaz Tarar

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