Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Incidental Finding of a Duodenal-Type Follicular Lymphoma in Metabolic Dysfunction-Associated Steatohepatitis Cirrhosis: A Rare Malignancy With Favorable Outcomes.

Duodenal-type follicular lymphoma (DFL) are uncommon, presenting in both symptomatic and asymptomatic patients, and are generally associated with a benign clinical course. Treatment options include surgery, radiation, and chemotherapy. However, many patients can be managed conservatively with little to no treatment, as 5-year progression-free survival is greater than 70%, and 5-year overall survival ranges from 80% to 94%. Here, we present a case of incidental DFL in a patient with metabolic dysfunction-associated steatohepatitis and cirrhosis. A review of the endoscopic and histologic characteristics, as well as epidemiology, risk factors, and long-term outcomes, may guide management strategies when DFL is encountered.

INFUSE: Rationale and design of a multi-center, open label, collaborative study to treat HRS-AKI with continuous terlipressin infusion.

Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI. Methods: Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort. Conclusion: The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.

Essentials of Liver Transplantation in the Setting of Acute Kidney Injury and Chronic Kidney Disease.

Kidney dysfunction is common among liver transplant candidates with decompensated cirrhosis and has a major impact on pre- and post-liver transplant survival. Updated definitions of acute kidney injury and criteria for the diagnosis of hepatorenal syndrome allow for early recognition and intervention, including early initiation of vasoconstrictor therapy for hepatorenal syndrome. The rise of the metabolic syndrome and nonalcoholic fatty liver disease as a cause of cirrhosis has coincided with an increase in intrinsic chronic kidney disease recognized in transplant candidates and recipients. Ultimately, the ability to accurately assess kidney function and associated risk is essential to decision-making in the context of transplantation, including selection of candidates for simultaneous liver and kidney transplantation.

Terlipressin vs Midodrine Plus Octreotide for Hepatorenal Syndrome-Acute Kidney Injury: A Propensity Score-Matched Comparison.

INTRODUCTION: Evidence on the comparison of treatments for hepatorenal syndrome-acute kidney injury (HRS-AKI) in a US population is limited. An indirect comparison of terlipressin plus albumin vs midodrine and octreotide plus albumin (MO) may provide further insight into treatment efficacy. METHODS: Cohorts of patients treated for HRS-AKI characterized by inclusion of patients with serum creatinine (SCr) <5 mg/dL and baseline acute-on-chronic liver failure grades 0-2 and exclusion of patients listed for transplant if model for end-stage liver disease scores ≥35 were pooled from (i) the CONFIRM and REVERSE randomized controlled trials (N = 159 meeting eligibility criteria from N = 216 overall, treated with terlipressin) and (ii) a retrospective review of medical records from 10 US tertiary hospitals (2016-2019; N = 55 treated with MO meeting eligibility criteria from N = 200 overall). The primary end point comparing the 2 cohorts was HRS reversal defined as achieving SCr ≤1.5 mg/dL at least once during the treatment. Covariate balancing propensity scoring was used to adjust for differences in baseline characteristics. RESULTS: HRS-AKI reversal was achieved in 52.35% of terlipressin-treated patients compared with 20% of MO-treated patients (adjusted mean difference 32.35%, 95% confidence interval [CI] 17.40-47.30, P < 0.0001). Terlipressin-treated patients had increased overall survival (adjusted hazard ratio 0.57, 95% CI 0.35-0.93, P = 0.02) but similar transplant-free survival (adjusted hazard ratio 0.79, 95% CI 0.53-1.17, P = 0.24). Achievement of HRS-AKI reversal was associated with increased OS and TFS regardless of treatment ( P < 0.001). DISCUSSION: Consistent with prior reports, terlipressin plus albumin is more effective in improving kidney function and achieving HRS-AKI reversal than MO plus albumin based on indirect comparison in a US population.

Après Moi, Le Deluge: The identification and management of flood syndrome in the emergency department.

Umbilical hernias develop in approximately 20% of patients with liver cirrhosis and ascites. Flood Syndrome is an eponym describing the spontaneous rupture of these umbilical hernias due to the elevated intrabdominal pressure associated with large-volume ascites. Though rare, Flood Syndrome is associated with several life-threatening sequela including infection, organ failure, and hypovolemic shock, leading to mortality or transplant in over 30% of patients. The following case is a single patient encounter describing an 80-year-old female with long-standing ascites who presented to the Emergency Department shortly after experiencing a spontaneous extravasation of fluid from her umbilical hernia.

Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19.

Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis.

Utilizing Social Media to Identify Potential Living Donors: Learning from US Living Donor Programs.

Purpose of Review: Living donor transplantation provides the best possible recipient outcomes in solid organ transplantation. Yet, identifying potential living donors can be a laborious and resource intensive task that heavily relies on the recipient's means and social network. Social media has evolved to become a key tool in helping to bring recipients and potential living donors together given its ease of utilization, widespread access, and improved recipient's comfort with public solicitation. However, in the USA, formal guidelines to direct the use of social media in this context are lacking. Recent Findings: To better inform the landscape and opportunities utilizing social media in living donation, the OPTN Living Donor Committee surveyed US transplant programs to explore programs' experiences and challenges when helping patients use social media to identify potential living donors (September 2019). A large majority of survey participants (N = 125/174, 72%) indicated that their program provided education to use social media to identify potential living donors and most programs tracking referral source confirmed an increase utilization over time. The use of social media was compounded with program and recipient's challenges including concerns about privacy, inadequate technology access, and knowledge gaps. In this review, we discuss the results of this national survey and recent literature, and provide suggestions to inform program practices and guidance provided to patients wishing to use social media to identify potential living donors. Summary: Transplant programs should become competent in the use of social media for potential living donor identification to empower patients interested in using this tool. Social media education should be provided to all patients regardless of voiced interest and, when appropriate, revisited at multiple time points. Programs should consider developing a "team of experts" that can provide focused education and support to patients embarking in social media living donor campaigns. Care should be taken to avoid exacerbating disparities in access to living donor transplantation. Effective and timely guidance to patients in the use of social media could enhance the identification of potential living donors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40472-022-00382-1.

Ectopic Vaginal Varices With Hemorrhage After Hysterectomy.

Vaginal and uterine varices are well documented in pregnancy, although development of vaginal varices in patients with portal hypertension occurs in an exceptionally rare subset. Only 12 cases are reported in the literature; all but 3 of these cases involved patients with a history of hysterectomy, with 1 of the remaining 2 exhibiting partial obliteration of the uterine plexus due to radiation therapy for cervical cancer. We present a case of recurrent vaginal variceal bleeding in a patient with a history of hysterectomy, initially managed with vaginal tamponade and ultimately requiring definitive treatment with transjugular intrahepatic portosystemic shunt insertion.

Association of the COVID-19 pandemic with increased adherence among prevalent hemodialysis patients.

BACKGROUND: During the COVID-19 pandemic, there has been a reduction in emergency department visits and hospital admissions. We hypothesized that hemodialysis patients were decreasing their hospital visits and increasing their dialysis adherence during the COVID-19 pandemic. MATERIAL AND METHODS: This is a retrospective analysis of hemodialysis patients treated in the seven American Renal Associates (ARA) dialysis centers in the Dallas-Fort Worth metropolitan area. We conducted a "before-and-after" study using existing clinical data to examine patient adherence with hemodialysis between January 1 and March 14, 2020 (pre-COVID) and March 15 to May 18, 2020 (COVID) time periods. Data points included missed treatments, shortened treatments, post-dialysis weight, and hospital visits. Finally, we conducted an anonymous survey in which patients reported their hemodialysis adherence. RESULTS: Data analysis was performed on 556 patients. Significantly fewer patients missed a single treatment in the COVID vs. pre-COVID time periods (44.1 vs. 58.6%; p < 0.001). Significantly fewer patients finished their treatment with a post-dialysis weight more than 1 kg above their estimated dry weight in the COVID vs. pre-COVID time periods (31.7 vs. 38.9%, p = 0.01). Finally, there was a reduction in total hospital visits during the COVID vs. pre-COVID periods (12.6 vs. 19.4%; p = 0.002). The anonymous survey showed patients reporting increased adherence with hemodialysis and restriction of salt and water intake. CONCLUSION: The COVID time period was associated with increased adherence with hemodialysis and decreased hospital visits, and patients were conscious of these changes.

The mechanistic basis linking cytokine storm to thrombosis in COVID-19.

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

Estimating Glomerular Filtration Rate in Cirrhosis Using Creatinine-Based and Cystatin C-Based Equations: Systematic Review and Meta-Analysis.

Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual-organ transplantation. We performed a systematic review/meta-analysis to assess the performance of creatinine-based and cystatin C (CysC)-based eGFR equations compared with measured GFR (mGFR) in patients with cirrhosis. A total of 25 studies (n = 4565, 52.0 years, 37.0% women) comprising 18 equations met the inclusion criteria. In all GFR equations, the creatinine-based equations overestimated GFR (standardized mean difference, SMD, 0.51; 95% confidence interval [CI], 0.31-0.71) and CysC-based equations underestimated GFR (SMD, -0.3; 95% CI, -0.60 to -0.02). Equations based on both creatinine and CysC were the least biased (SMD, -0.14; 95% CI, -0.46 to 0.18). Chronic kidney disease-Epi-serum creatinine-CysC (CESC) was the least biased but had low precision and underestimated GFR by -3.6 mL/minute/1.73 m2 (95% CI, -17.4 to 10.3). All equations significantly overestimated GFR (+21.7 mL/minute/1.73 m2 ; 95% CI, 17.7-25.7) at GFR <60 mL/minute/1.73 m2 ; of these, chronic kidney disease-Epi-CysC (10.3 mL/minute/1.73 m2 ; 95% CI, 2.1-18.4) and GFR Assessment in Liver Disease (12.6 mL/minute/1.73 m2 ; 95% CI, 7.2-18.0) were the least biased followed by Royal Free Hospital (15 mL/minute/1.73 m2 ; 95% CI, 5.5-24.6) and Modification of Diet in Renal Disease 6 (15.7 mL/minute/1.73 m2 ; 95% CI, 10.6-20.8); however, there was an overlap in the precision of estimates, and the studies were limited. In ascites, overestimation of GFR was common (+8.3 mL/minute/1.73 m2 ; 95% CI, -3.1 to 19.7). However, overestimation of GFR by 10 to 20 mL/minute/1.73m2 is common in patients with cirrhosis with most equations in ascites and/or kidney dysfunction. A tailored approach is required especially for decisions regarding dual-organ transplantation.

Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome.

BACKGROUND: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).

Antibiotic Prophylaxis for Spontaneous Bacterial Peritonitis: Benefit or Risk?

Spontaneous bacterial peritonitis (SBP) is associated with risk of acute on chronic liver failure (ACLF). Current guidelines recommend primary and secondary antibiotic prophylaxis for patients with cirrhosis and ascites who are at risk of a first episode and to prevent recurrence, respectively. Factors associated with prophylaxis failure leading to SBP, ACLF, and increased mortality are not well established. Gram-positive and multidrug-resistant organisms have become more frequently associated with SBP, particularly in the setting of ACLF. Efforts to understand how long-term antibiotic therapy may affect individual risk of SBP in this population will be critical to developing optimal preventive strategies.

Race/ethnicity-based temporal changes in prevalence of NAFLD-related advanced fibrosis in the United States, 2005-2016.

BACKGROUND AND AIM: Advanced fibrosis associated with nonalcoholic fatty liver disease (NAFLD) has been reported to have a higher risk of hepatic and non-hepatic mortality. We aim to study the recent trends in the prevalence of NAFLD-related advanced fibrosis in a large population sample. METHODS: Cross-sectional data from 28,739 participants in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2016 were utilized. NAFLD was defined using the hepatic steatosis index (HSI) and the US fatty liver index (USFLI) in the absence of other causes of chronic liver disease. The presence and absence of advanced fibrosis in NAFLD was determined by the NAFLD fibrosis score, FIB-4 score, and aspartate aminotransferase-to-platelet ratio index. RESULTS: The prevalence of NAFLD-related advanced fibrosis increased from 2.6% [95% confidence interval (CI) 2.1-3.1] in 2005-2008 and 4.4% (95% CI 3.7-5.1) in 2009-2012, to 5.0% (95% CI 4.2-5.9) in 2013-2016 using HSI as the NAFLD prediction model; and from 3.3% (95% CI 2.5-4.5) in 2005-2008 and 6.4% (95% CI 3.7-5.1) in 2009-2012, to 6.8% (95% 5.3-8.7) in 2013-2016 using USFLI (p < 0.01). A similar trend was observed in entire NHANES cohort regardless of NAFLD status. While the prevalence of advanced fibrosis increased steadily in non-Hispanic whites through the duration of the study, it leveled off during 2013-2016 in non-Hispanic blacks. CONCLUSIONS: Prevalence of advanced fibrosis associated with NAFLD increased steadily from 2005 to 2016. More importantly, race/ethnicity-based temporal differences were noted in the prevalence of NAFLD-related advanced fibrosis during the study.

A Model for Glomerular Filtration Rate Assessment in Liver Disease (GRAIL) in the Presence of Renal Dysfunction.

Estimation of glomerular filtration rate (eGFR) in patients with liver disease is suboptimal in the presence of renal dysfunction. We developed a model for GFR assessment in liver disease (GRAIL) before and after liver transplantation (LT). GRAIL was derived using objective variables (creatinine, blood urea nitrogen, age, gender, race, and albumin) to estimate GFR based on timing of measurement relative to LT and degree of renal dysfunction (www.bswh.md/grail). The measured GFR (mGFR) by iothalamate clearance (n = 12,122, 1985-2015) at protocol time points before/after LT was used as reference. GRAIL was compared with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD-4, MDRD-6) equations for mGFR < 30 mL/min/1.73 m2 . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m2 , initiation of chronic dialysis) and listing or receipt of kidney transplantation within 5 years was examined in internal cohort (n = 785) and external validation (n = 68,217, 2001-2015). GRAIL had less bias and was more accurate and precise as compared with CKD-EPI, MDRD-4, and MDRD-6 at time points before/after LT for low GFR. For mGFR < 30 mL/min/1.73 m2 , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m2 as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m2 , MDRD-4: 8.82 (17.38) mL/min/1.73 m2 , and MDRD-6: 6.53 (14.42) mL/min/1.73 m2 . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m2 versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m2 by GRAIL predicted development of CKD (26.9% versus 4.6% CKD-EPI, 5.9% MDRD-4, and 10.5% MDRD-6) in center data and needing kidney after LT (48.3% versus 22.0% CKD-EPI versus 23.1% MDRD-4 versus 48.3% MDRD-6, P < 0.01) in national data within 5 years after LT. Conclusion: GRAIL may serve as an alternative model to estimate GFR among patients with liver disease before and after LT at low GFR.