Review article: Recent advances in ascites and acute kidney injury management in cirrhosis.

BACKGROUND: Better understanding of disease pathophysiology has led to advances in managing ascites and its associated complications including hepatorenal syndrome-acute kidney Injury (HRS-AKI), especially medicinal and interventional advances. AIM: To review the latest changes in the management of ascites and HRS-AKI. METHODS: A literature search was conducted in Pubmed, using the keywords cirrhosis, ascites, renal dysfunction, acute kidney injury, hepatorenal syndrome, beta-blockers, albumin, TIPS and vasoconstrictors, including only publications in English. RESULTS: The medicinal advances include earlier treatment of clinically significant portal hypertension to delay the onset of ascites and the use of human albumin solution to attenuate systemic inflammation thus improving the haemodynamic changes associated with cirrhosis. Furthermore, new classes of drugs such as sodium glucose co-transporter 2 are being investigated for use in patients with cirrhosis and ascites. For HRS-AKI management, newer pharmacological agents such as vasopressin partial agonists and relaxin are being studied. Interventional advances include the refinement of TIPS technique and patient selection to improve outcomes in patients with refractory ascites. The development of the alfa pump system and the study of outcomes associated with the use of long-term palliative abdominal drain will also serve to improve the quality of life in patients with refractory ascites. CONCLUSIONS: New treatment strategies emerged from better understanding of the pathophysiology of ascites and HRS-AKI have shown improved prognosis in these patients. The future will see many of these approaches confirmed in large multi-centre clinical trials with the aim to benefit the patients with ascites and HRS-AKI.

Towards a new definition of decompensated cirrhosis.

There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.

A guide to diagnosing and managing ascites in cirrhosis.

Combined serum and ascites fluid measurements point to the cause of ascites. For patients with modest edema, a reduced weight-loss target with diuresis may be acceptable.

Poor Outcomes of Cirrhosis due to Nonalcoholic Steatohepatitis Compared With Hepatitis B After Decompensation With Ascites.

INTRODUCTION: Decompensation with ascites portends a poor prognosis in cirrhosis. The aim of this study was to compare the outcomes of patients with nonalcoholic steatohepatitis (NASH) with hepatitis B virus (HBV) cirrhosis after decompensation with ascites. METHODS: We conducted a retrospective study to evaluate the outcomes of patients with NASH and HBV cirrhosis who were admitted to hospital for first-onset ascites from January 1, 2004, to June 30, 2015. They were followed up until death, liver transplantation, or loss to follow up. RESULTS: Patients with NASH had lower median (interquartile range) Model for End-Stage Liver Disease score (11 [9-14] vs 14 [11-17], P < 0.001). Over 60 months, patients with NASH cirrhosis had higher cumulative incidence of dilutional hyponatremia (P < 0.001) and refractory ascites (P = 0.028). They also had higher cumulative incidence of cirrhosis-related deaths and liver transplantation compared with HBV cirrhosis (65.7%; [95% confidence interval (CI) 53.6-75.4] vs 42.5% [95% CI 32.4-55.2], P = 0.008). Multivariable competing risk analysis showed that NASH (subdistribution hazard ratio [sHR] 1.88 [95% CI 1.14-3.11], P = 0.014), non-Chinese ethnicity (sHR 1.63 [95% CI 1.06-2.50], P = 0.027), history of hepatocellular carcinoma (sHR 1.76 [95% CI 1.05-2.95], P = 0.033), estimated glomerular filtration rate <60 mL/min/1.73 m2 (sHR 1.70 [95% CI 1.09-2.65], P = 0.020), and Model for End-Stage Liver Disease score ≥15 (sHR 3.26 [95% CI 2.11-5.05], P < 0.001) were independent predictors of poor transplant-free survival. DISCUSSION: Patients with decompensated cirrhosis due to NASH had much poorer prognosis compared with HBV with more complications and greater healthcare resource utilization. Greater awareness is necessary for early diagnosis of NASH before decompensation.

Dysregulated expression of mRNA and SNP in pulmonary artery remodeling in ascites syndrome in broilers.

Broiler ascites syndrome (AS), also called pulmonary artery hypertension, is a metabolic disorder that has been observed worldwide in fast-growing broilers. Pulmonary arterial remodeling is a key step in the development of AS. The precise relationship between mRNA and SNP of the pulmonary artery in regulating AS progression remains unclear. In this study, we obtained pulmonary artery tissues from broilers with AS to perform pathologic section and pathologic anatomic observation. SNP, InDel, and mRNA data analysis were carried out using GATK and ANNOVAR software to study the SNP loci of 985 previously reported genes (437 upregulated and 458 downregulated). The pathology results showed that there was a lot of yellow fluid in the abdominal cavity and pericardium, that the ascites cardiac index and hematocrit changed significantly, and that the pulmonary artery had remodeled and become thicker in the disease group. Myocardial sections showed vacuolar degeneration of myocytes and rupture of muscle fibers. In addition, ALDH7A1, IRG1, GGT5, IGSF1, DHX58, USP36, TREML2, SPAG1, CD34, and PLEKHA7 were found to be closely associated with the pathogenesis of pulmonary artery remodeling in AS progression. Taken together, our present study further illuminates the molecular mechanism of pulmonary artery remodeling underlying AS progression.

Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p (P < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders (P = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites (P = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ = -0.46, P = 0.007; and ρ = -0.41, P = 0.01, respectively) and with diminished systolic contractility (ρ = -0.55, P = 0.02; and ρ = -0.55, P = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs.

Management of Refractory Ascites Due to Portal Hypertension: Current Status.

Refractory ascites is a costly and debilitating condition that occurs most frequently in the setting of substantial cirrhotic portal hypertension, where it portends a poor prognosis. Many treatment options are available, among them medical management, serial large volume paracenteses, transjugular intrahepatic portosystemic shunts, and implanted drainage devices. Although the availability of multiple therapies ensures that most patients will achieve satisfactory results, it can be challenging for the provider to select the appropriate treatment for each specific patient. This article reviews the available therapeutic options for refractory ascites and incorporates available data and clinical experience to suggest a linear stepwise management approach to enhance patient outcomes.

Low Predictability of Readmissions and Death Using Machine Learning in Cirrhosis.

INTRODUCTION: Readmission and death in cirrhosis are common, expensive, and difficult to predict. Our aim was to evaluate the abilities of multiple artificial intelligence (AI) techniques to predict clinical outcomes based on variables collected at admission, during hospitalization, and at discharge. METHODS: We used the multicenter North American Consortium for the Study of End-Stage Liver Disease (NACSELD) cohort of cirrhotic inpatients who are followed up through 90-days postdischarge for readmission and death. We used statistical methods to select variables that are significant for readmission and death and trained 3 AI models, including logistic regression (LR), kernel support vector machine (SVM), and random forest classifiers (RFC), to predict readmission and death. We used the area under the receiver operating characteristic curve (AUC) from 10-fold crossvalidation for evaluation to compare sexes. Data were compared with model for end-stage liver disease (MELD) at discharge. RESULTS: We included 2,170 patients (57 ± 11 years, MELD 18 ± 7, 61% men, 79% White, and 8% Hispanic). The 30-day and 90-day readmission rates were 28% and 47%, respectively, and 13% died at 90 days. Prediction for 30-day readmission resulted in 0.60 AUC for all patients with RFC, 0.57 AUC with LR for women-only subpopulation, and 0.61 AUC with LR for men-only subpopulation. For 90-day readmission, the highest AUC was achieved with kernel SVM and RFC (AUC = 0.62). We observed higher predictive value when training models with only women (AUC = 0.68 LR) vs men (AUC = 0.62 kernel SVM). Prediction for death resulted in 0.67 AUC for all patients, 0.72 for women-only subpopulation, and 0.69 for men-only subpopulation, all with LR. MELD-Na model AUC was similar to those from the AI models. DISCUSSION: Despite using multiple AI techniques, it is difficult to predict 30- and 90-day readmissions and death in cirrhosis. AI model accuracies were equivalent to models generated using only MELD-Na scores. Additional biomarkers are needed to improve our predictive capability (See also the visual abstract at http://links.lww.com/AJG/B710).

Hyponatremia in Cirrhosis: An Update.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes.

BACKGROUND: Novel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC. METHODS: Using the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry. RESULTS: We demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid. CONCLUSIONS: Ascites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.

Role of Terlipressin in Cirrhotic Patients with Ascites and without Hepatorenal Syndrome: A Systematic Review of Current Evidence.

Ascites, a common complication in cirrhosis, is prone to the development of acute kidney injury or hepatorenal syndrome and can be complicated by circulatory dysfunction after paracentesis. Terlipressin has not been considered as the mainstay treatment option for ascites in cirrhosis yet. The present work aimed to systematically review the current evidence regarding the use of terlipressin in cirrhosis with ascites and without hepatorenal syndrome. PubMed, EMBASE, and Cochrane Library databases were searched for relevant studies. Twelve studies were eligible. In 3 studies (1 randomized controlled trial and 2 single-arm studies without controls) involving 32 patients who received terlipressin for nonrefractory ascites, terlipressin improved hemodynamics by decreasing the heart rate and cardiac output and increasing the mean arterial pressure and systemic vascular resistance. In 5 studies (1 randomized controlled trial, 2 single-arm studies without controls, and 2 comparative studies with controls) involving 67 patients who received terlipressin for refractory ascites, terlipressin improved renal function by increasing the glomerular filtration rate, renal blood flow, urinary sodium, and urine output and decreasing serum creatinine. In 4 studies (4 randomized controlled trials) involving 71 patients who received terlipressin for preventing from paracentesis-induced circulatory dysfunction, terlipressin prevented from paracentesis-induced circulatory dysfunction by increasing the mean arterial pressure and systemic vascular resistance and decreasing plasma renin. Terlipressin may improve hemodynamics, severity of ascites, and renal function and prevent from paracentesis-induced circulatory dysfunction in cirrhosis with ascites and without hepatorenal syndrome. However, no study has evaluated the effect of terlipressin for prevention of acute kidney injury.

Body Mass Index as a Prognostic Factor in Liver Transplantation.

OBJECTIVE: Obesity is one of the main growing epidemics of the last century and is responsible for many deaths worldwide. The aim of this study is to analyze the impact of the body mass index (BMI) of the recipient on survival and morbidity after liver transplantation (LT). MATERIAL AND METHODS: We conducted a retrospective cohort study of all transplanted recipients in a third-level hospital between 2006 and 2018. The following donor variables were analyzed: age, sex, weight, BMI, cause of death. Additionally, the following recipient variables were analyzed: age, sex, weight, height, BMI, procedure indication. Finally, outcome variables were analyzed: postoperative complications, early mortality, graft loss, and overall survival. This study strictly complies with the Helsinki Congress and the Istanbul Declaration regarding donor source. RESULTS: We analyzed 825 of 837 LTs from January 2006 to December 2018. These were grouped by BMI categories: 271 (29%) normal, 322 (34.3%) overweight, and 228 (24.3%) obesity. The overall survival at 5 years was 83% in the normal group, 76% in the overweight group, and 71% in the obesity group. These differences were statistically significant (P = .027). The early mortality rate was 4.42% in the normal weight group, 6.5% in the overweight group, and 5.26% in the obesity group. No differences were found between groups in terms of postoperative complications: hemorrhagic, vascular, biliary, respiratory, hemodynamic, digestive, renal, neurologic, rebel ascites, and infections. No differences were found regarding the need for re-operation. CONCLUSIONS: In this study, overall survival in LT decreases as the BMI of recipient increases; but overweight and obesity do not constitute a risk factor for early morbidity and mortality in LT.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.

BACKGROUND & AIMS: The safety of non-selective ß-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. ß-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, ß-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

RESPIRATORY AND SYMPTOMATIC IMPACT OF ASCITES RELIEF BY PARACENTESIS IN PATIENTS WITH HEPATIC CIRRHOSIS.

BACKGROUND: Liver cirrhosis is a highly prevalent disease that, at an advanced stage, usually causes ascites and associated respiratory changes. However, there are few studies evaluating and quantifying the impact of ascites and its relief through paracentesis on lung function and symptoms such as fatigue and dyspnea in cirrhotic patients. OBJECTIVE: To assess and quantify the impact of acute reduction of ascitic volume on respiratory parameters, fatigue and dyspnea symptoms in patients with hepatic cirrhosis, as well as to investigate possible correlations between these parameters. METHODS: Thirty patients with hepatic cirrhosis and ascites who underwent the following pre and post paracentesis evaluations: vital signs, respiratory pattern, thoracoabdominal mobility (cirtometry), pulmonary function (ventilometry), degree of dyspnea (numerical scale) and fatigue level (visual analog scale). RESULTS: There was a higher prevalence of patients classified as CHILD B and the mean MELD score was 14.73±5.75. The comparison of pre and post paracentesis parameters evidenced after paracentesis: increase of predominantly abdominal breathing pattern, improvement of ventilatory variables, increase of the differences obtained in axillary and abdominal cirtometry, reduction of dyspnea and fatigue level, blood pressure reduction and increased peripheral oxygen saturation. Positive correlations found: xiphoid with axillary cirtometry, degree of dyspnea with fatigue level, tidal volume with minute volume, Child "C" with higher MELD score, volume drained in paracentesis with higher MELD score and with Child "C". We also observed a negative correlation between tidal volume and respiratory rate. CONCLUSION: Since ascites drainage in patients with liver cirrhosis improves pulmonary volumes and thoracic expansion as well as reduces symptoms such as fatigue and dyspnea, we can conclude that ascites have a negative respiratory and symptomatological impact in these patients.

Characterization of ascites-derived aldehyde dehydrogenase-positive ovarian cancer stem cells isolated from Leghorn chickens.

Leghorn chickens are used as a preclinical model of ovarian cancer as they develop epithelial ovarian adenocarcinoma spontaneously at a very high frequency. Ovarian cancer is the most lethal disease among all gynecological malignancies in women. A small proportion of ovarian cancer stem cells are responsible for drug resistance and relapse of ovarian cancer. The objectives of this study are to isolate ovarian cancer stem cells from ascites of Leghorn chickens that spontaneously developed ovarian cancer and to determine their invasiveness, spheroid formation in three-dimensional culture devoid of extracellular matrix over several months. Ovarian cancer cells obtained from ascites were subjected to ALDEFLOUR assay that measures aldehyde dehydrogenase (ALDH) activity to separate ALDH1+ and ALDH1- cells by fluorescence-activated cell sorting. The cells were cultured using serum-free media for up to 6 mo in ultra-low attachment plates. Invasiveness of ALDH1+ and ALDH1- cells was determined by Matrigel invasion assay. Cellular uptake of acetylated low-density lipoprotein was evaluated. A small proportion (<4.75%) of ovarian cancer cells isolated from ascites were found to be ALDH1+ cells. ALDH1+ cells formed a greater number of spheroids and were also highly invasive in extracellular matrix compared to ALDH1- cells. Several spheroids developed 0.1- to 1-mm-long capillary-like tubules connecting other spheroids, thus forming a complex network that underwent remodeling over several months. Cells in the spheroids incorporated acetylated low-density lipoprotein suggestive of scavenger receptor activity. In summary, ALDH1+ ovarian cancer stem cells isolated from ascites of chickens appear to be invasive and form spheroids with complex networks of tubules reminiscent of vascular mimicry. Understanding the structure and function of spheroids and tubular network would provide valuable insight into the biology of ovarian cancer and improve poultry health.

Adaptation of the hepatic transudation barrier to sinusoidal hypertension.

The role of the hepatic transudation barrier in determining ascites volume and protein content in chronic liver disease is poorly understood. Therefore, the purpose of the present study was to characterize how chronic sinusoidal hypertension impacts hepatic transudation barrier properties and the transudation rate. The suprahepatic inferior vena cava was surgically constricted, and animals were exposed to either short-term (SVH; 2-3 wk) or long-term venous hypertension (LVH; 5-6 wk). Compared with SVH, LVH resulted in lower peritoneal fluid pressure, ascites volume, and ascites protein concentration. The transudation barrier protein reflection coefficient was significantly higher, and the transudation barrier hydraulic conductivity, transudation rate, and transudate-to-lymph protein concentration ratio were significantly lower in LVH animals compared with SVH animals. The sensitivity of transudation rates to acute changes in interstitial fluid pressures was also significantly lower in LVH animals compared with SVH animals. In contrast, there was no detectable difference in hepatic lymph flow rate or sensitivity of lymph flow to acute changes in interstitial fluid pressures between SVH and LVH animals. Taken together, these data suggest that decreased hepatic transudation barrier permeability to fluid and protein and increased reflection coefficient led to a decrease in the hepatic contribution to ascites volume. The present work, to the best of our knowledge, is the first to quantify an anti-ascites adaptation of the hepatic transudation barrier in response to chronic hepatic sinusoidal hypertension.

Impacto respiratório e sintomatológico do alívio da ascite através da paracentese em pacientes com cirrose hepática / Respiratory and symptomatic impact of ascites relief by paracentesis in patients with hepatic cirrhosis

ABSTRACT BACKGROUND: Liver cirrhosis is a highly prevalent disease that, at an advanced stage, usually causes ascites and associated respiratory changes. However, there are few studies evaluating and quantifying the impact of ascites and its relief through paracentesis on lung function and symptoms such as fatigue and dyspnea in cirrhotic patients. OBJECTIVE: To assess and quantify the impact of acute reduction of ascitic volume on respiratory parameters, fatigue and dyspnea symptoms in patients with hepatic cirrhosis, as well as to investigate possible correlations between these parameters. METHODS: Thirty patients with hepatic cirrhosis and ascites who underwent the following pre and post paracentesis evaluations: vital signs, respiratory pattern, thoracoabdominal mobility (cirtometry), pulmonary function (ventilometry), degree of dyspnea (numerical scale) and fatigue level (visual analog scale). RESULTS: There was a higher prevalence of patients classified as CHILD B and the mean MELD score was 14.73±5.75. The comparison of pre and post paracentesis parameters evidenced after paracentesis: increase of predominantly abdominal breathing pattern, improvement of ventilatory variables, increase of the differences obtained in axillary and abdominal cirtometry, reduction of dyspnea and fatigue level, blood pressure reduction and increased peripheral oxygen saturation. Positive correlations found: xiphoid with axillary cirtometry, degree of dyspnea with fatigue level, tidal volume with minute volume, Child "C" with higher MELD score, volume drained in paracentesis with higher MELD score and with Child "C". We also observed a negative correlation between tidal volume and respiratory rate. CONCLUSION: Since ascites drainage in patients with liver cirrhosis improves pulmonary volumes and thoracic expansion as well as reduces symptoms such as fatigue and dyspnea, we can conclude that ascites have a negative respiratory and symptomatological impact in these patients.

RESUMO CONTEXTO: A cirrose hepática é uma doença altamente prevalente que, em estágio avançado, geralmente causa ascite e alterações respiratórias associadas. No entanto, existem poucos estudos avaliando e quantificando o impacto da ascite e do seu alívio através da paracentese na função pulmonar e em sintomas como fadiga e dispneia em pacientes cirróticos. OBJETIVO: Avaliar e quantificar o impacto da redução aguda do volume ascítico nos parâmetros respiratórios, sintomas de fadiga e dispneia em pacientes com cirrose hepática, bem como investigar possíveis correlações entre esses parâmetros. MÉTODOS: Trinta pacientes com cirrose hepática e ascite foram submetidos às seguintes avaliações pré e pós-paracentese: sinais vitais, padrão respiratório, mobilidade toracoabdominal (cirtometria), função pulmonar (ventilometria), grau de dispneia (escala numérica) e nível de fadiga (escala visual analógica). RESULTADOS: Houve maior prevalência de pacientes classificados como CHILD B e o escore MELD médio foi de 14,73±5,75. A comparação dos parâmetros pré e pós paracentese evidenciou após a paracentese: aumento do padrão respiratório predominantemente abdominal, melhora das variáveis ventilatórias, aumento das diferenças obtidas na cirtometria axilar e abdominal, redução do nível de dispneia e fadiga, redução da pressão arterial e aumento da saturação periférica de oxigênio. Correlações positivas encontradas: cirtometria xifoide com axilar, grau de dispneia com nível de fadiga, volume corrente com volume minuto, CHILD "C" com maior escore MELD, volume drenado na paracentese com maior escore MELD e com CHILD "C". Também observamos uma correlação negativa entre volume corrente e a frequência respiratória. CONCLUSÃO: Uma vez que a drenagem da ascite em pacientes com cirrose hepática melhora os volumes pulmonares e a expansão torácica, além de reduzir sintomas como fadiga e dispneia, podemos concluir que a ascite tem um impacto respiratório e sintomatológico negativo nesses pacientes.

Furosemide Dose Changes Associated with Furosemide/Tolvaptan Combination Therapy in Patients with Cirrhosis.

BACKGROUND: Few data have demonstrated that the combination therapy comprising a natriuretic drug and an aquaretic drug has improved renal function compared with the conventional diuretic therapy of only a natriuretic drug in patients with cirrhosis. OBJECTIVE: This study aimed to assess the influence to the renal function by furosemide dose reductions after administration of tolvaptan in cirrhotic ascites patients. METHODS: A 2-center, open-label, randomized study with a 24-week treatment period was conducted in Japan. Patients who met the study's criteria were randomized to a conventional therapy group or a combination therapy group in a 1:1 ratio. The combination therapy group received tolvaptan and reduced furosemide doses compared with those received before the study enrollment. The conventional therapy group continued with the original dosage regimens. We assessed the change in estimated glomerular filtration rate (eGFR) from baseline through the duration of the study in the 2 groups. RESULTS: Twenty-nine patients were randomized to receive either the combination therapy group (n = 14) or the conventional therapy group (n= 15). The change in the furosemide dose from baseline was -35.2 ± 10.1 mg in the combination therapy group. After 24 weeks of treatment, significantly greater improvement in eGFR was observed in the combination therapy group (2.4 ± 0.4 mL/min 1.73 m2) compared with those in the conventional therapy group (-5.1 ± 1.2 mL/min 1.73 m2; p = 0.013). CONCLUSION: A combination therapy of tolvaptan and furosemide enabled furosemide dose reductions. Systematic reductions of the furosemide doses can lead to the improvement of renal function.