Terlipressin and the Treatment of Hepatorenal Syndrome: How the CONFIRM Trial Moves the Story Forward.

Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances that result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. There are no approved treatments for HRS in the United States, but multiple countries, including much of Europe, use terlipressin, a synthetic vasopressin analogue, as a first-line therapy. CONFIRM (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1), the third randomized trial based in North America evaluating terlipressin, met its primary end point of showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about the apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). We explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised, and consider the future role of terlipressin in this critical clinical area of continued unmet need.

Clinical Application of Kidney Biomarkers in Cirrhosis.

Acute kidney injury (AKI) is one of the most common and morbid complications of decompensated cirrhosis. Management of AKI is dictated by cause: prerenal AKI is treated with volume resuscitation; hepatorenal syndrome (HRS), with intravenous albumin and vasoconstrictors; and acute tubular necrosis, with supportive care. However, differentiating between causes is difficult using creatinine-based definitions of AKI alone. The use of novel kidney biomarkers in AKI and cirrhosis provides an opportunity to improve both the diagnosis and prognosis of this vulnerable population. This review examines the challenges of AKI in cirrhosis and the research experience around novel kidney biomarkers in cirrhosis. Specific focus is paid to the tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL), which has been the most studied in liver disease and has demonstrated the strongest performance in differentiating the cause of AKI (acute tubular necrosis vs functional injury such as prerenal AKI or HRS), as well as improving the prognostic performance of mortality prediction models such as the model for end stage liver disease (MELD) score. We advocate for the discussion of incorporating markers such as NGAL in the next iteration of HRS guidelines and identify areas for future research in this clinical condition.

Association of arginine vasopressin receptor 1a gene polymorphisms with hepatorenal syndrome.

OBJECTIVE: To assess the association of arginine vasopressin receptor 1a gene single nucleotide polymorphisms with type I hepatorenal syndrome. METHODS: The case-control study was conducted at the Hangzhou City Xixi Hospital, Hangzhou, China, from January 2012 to June 2014, and comprised patients with type I hepatorenal syndrome and individuals with cirrhosis who acted as the control group. Arginine vasopressin receptor 1a gene rs113481894 locus single nucleotide polymorphisms were analysed by high-resolution melting methods. Statistical analysis was performed using SPSS 17. RESULTS: Of the 60 participants, 28(46.7%) were in the hepatorenal syndrome group and 32(53.3%) were controls. The mean age was 42.21±11.30years in the hepatorenal syndrome group and 43.69±12.60in the control group (p=0.64). Mean total bilirubin, albumin and prothrombin activity levels were 154.76±51.58, 49.30±24.67 and 33.42±3.69 in the hepatorenal syndrome group compared to 181.26±64.46, 41.78±17.52 and32.98±4.81among controls (p=0.09, p=0.18 and p=0.70). Statistically significant differences were found in the distributions of arginine vasopressin receptor 1a gene rs113481894 locus T allele between type I hepatorenal syndrome patients and the control group (odds ratio= 2.230; p= 0.040). CONCLUSIONS: T allele located at arginine vasopressin receptor 1a receptor promoter rs113481894 locus may be associated with the pathogenesis of type I hepatorenal syndrome.

Pathogenesis of Hepatorenal Syndrome: Implications for Therapy.

Patients with cirrhosis are prone to develop acute kidney injury (AKI) due to a number of causes, including bacterial infections with or without septic shock, hypovolemia, administration of nephrotoxic drugs, and intrinsic kidney diseases, among others. Most importantly, patients with advanced cirrhosis develop a distinctive cause of AKI, characterized by rapidly progressive glomerular filtration rate loss associated with marked disturbances in circulatory function in the absence of obvious pathologic abnormalities in the kidneys, known as hepatorenal syndrome (HRS). Decreased kidney function results from intense renal vasoconstriction secondary to the complex circulatory changes of cirrhosis with splanchnic vasodilatation and effective hypovolemia. Beyond activation of vasoactive systems, factors including impaired renal blood flow autoregulation and systemic inflammation may play a role in the development of HRS. Most patients improve with albumin and vasopressors; however, the prognosis of HRS remains very poor. Novel biomarkers may be helpful in distinguishing HRS from other causes of AKI in patients with cirrhosis.

Hepatorenal syndrome:Response to terlipressin and albumin and its determinants.

OBJECTIVE: To determine the efficacy of terlipressin and albumin in improving renal functions in patient with hepatorenal syndrome (HRS) and to identify factors determinant of better response. METHODS: In this quasi experimental interventional study patients of liver cirrhosis and ascites with HRS type I were treated with intravenous albumin and incremental dosage of terlipressin based on response with maximum dose of 12mg/day. Decline of creatinine below 1.5mg/dl was defined as complete response. Factors predictive of response to therapy were determined via linear regression analysis. RESULTS: Twenty four patients were included with male to female ratio 3.8/1(19/5) and mean age 53.3 (±10.06). Complete response to terlipressin/albumin was seen in 14 (58.3%)patients, seven (29.2%) achieved partial response with > 25% creatinine decline while three (12.5%) had no response. Lower serum creatinine at diagnosis (P value 0.003), absence of hyperkalemia (p value 0.005) and absence of portal vein thrombosis (p value 0.05) are associated with response to treatment in HRS. Baseline serum creatinine (p value 0.003) was independent predictor of response to therapy in multivariate analysis. CONCLUSION: Terlipressin and albumin is an effective treatment for HRS type I. Patients with lower baseline serum creatinine are more likely to respond to this therapy.

Long-term renal outcomes comparison between patients with chronic kidney disease and hepatorenal syndrome after living donor liver transplantation.

Background and aims: Hepatorenal syndrome (HRS) is a disastrous renal complication of advanced liver disease with a poor prognosis. Restoring normal liver function through liver transplantation (LT) is a standardized treatment with favorable short-term survival. However, the long-term renal outcomes in patients with HRS receiving living donor LT (LDLT) are controversial. This study aimed to investigate the prognostic impact of LDLT in patients with HRS. Methods: We reviewed adult patients who underwent LDLT between July 2008 and September 2017. Recipients were classified into 1) HRS type 1 (HRS1, N = 11), 2) HRS type 2 (HRS2, N = 19), 3) non-HRS recipients with pre-existing chronic kidney disease (CKD, N = 43), and 4) matched normal renal function (N = 67). Results: Postoperative complications and 30-day surgical mortality were comparable among the HRS1, HRS2, CKD, and normal renal function groups. The 5-year survival rate was >90% and estimated glomerular filtration rate (eGFR) transiently improved and peaked at 4 weeks post-transplantation in patients with HRS. However, renal function deteriorated and resulted in CKD stage ≥ III in 72.7% of HRS1 and 78.9% of HRS2 patients (eGFR <60 ml/min/1.73 m2). The incidence of developing CKD and end-stage renal disease (ESRD) was similar between the HRS1, HRS2, and CKD groups, but significantly higher than that in the normal renal function group (both P < 0.001). In multivariate logistic regression, pre-LDLT eGFR <46.4 ml/min/1.73 m2 predicted the development of post-LDLT CKD stage ≥ III in patients with HRS (AUC = 0.807, 95% CI = 0.617-0.997, P = 0.011). Conclusions: LDLT provides a significant survival benefit for patients with HRS. However, the risk of CKD stage ≥ III and ESRD among patients with HRS was similar to that in pre-transplant CKD recipients. An early preventative renal-sparing strategy in patients with HRS is recommended.

Bacteremia (Sepsis), Hepatorenal Syndrome, and Serum Creatinine Levels Rather than Types or Microbial Patterns Predicted the Short-Term Survival of Cirrhotic Patients Complicated with Spontaneous Bacterial Peritonitis.

(1) Background: Spontaneous bacterial peritonitis (SBP) is a major and severe complication in cirrhosis patients with ascites. Over the years, advance in antibiotic treatment has led to changes in microbial patterns in some regions, including the emergence of extended-spectrum beta-lactamases resistant (ESBL)-producing bacteria and an increase in Gram-positive bacteria (GPC). In addition, three SBP types (classic SBP, culture-negative neutrophilic ascites (CNNA), and monomicrobial non-neutrocytic bacterascites (MNB)), may also have different prognoses. Therefore, the study aimed to investigate the microbial pattern and the predictors of short-term outcomes in patients with SBP. (2) Methods: Patients discharged with a diagnosis of the first episode of SBP between January 2006 and July 2017 were enrolled. Patients' clinical, demographic, hematological, and biochemical data were obtained at diagnosis, and the model for end-stage liver disease (MELD)-based scores were calculated accordingly. Patients were followed up until February 2018 or until death. (3) Results: A total of 327 patients were analyzed. The prevalence of classic SBP was nearly equivalent to CNNA. As for the microbial pattern, Gram-negative bacillus (GNB) remained more prevalent than GPC (75 vs. 25%), with E. coli being the most common bacterial species, followed by K. Pneumoniae and then Staphylococcus. The percentage of ESBL strain in culture-positive patients was 10.9%. By univariable and multivariable logistic regression survival analysis, there was no significant difference in predicting short-term mortality among the three SBP types, neither between GNB vs. GPC nor between ESBL- and non-ESBL-producing bacteria. Only bacteremia (sepsis), hepatorenal syndrome (HRS), and serum creatinine (Cr) were independent predictors of in-hospital and 3-month mortality, whereas HRS and Cr were independent predictors of 6-month mortality. (4) Conclusions: SBP types, Gram stain result, and ESBL strain did not affect survival. Only bacteremia (sepsis), HRS, and serum Cr independently predicted the short-term mortality in patients with SBP.

A systematic review and meta-analysis of treatment for hepatorenal syndrome with traditional Chinese medicine.

BACKGROUND: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver diseases. It has been reported that traditional Chinese medicine (TCM) may improve liver function, delay disease progression, alleviate symptoms, and improve quality of life in HRS patients. The study aims to systematically review the efficacy of TCM for the treatment of HRS. METHODS: Publications were searched electronically from China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, and EMBASE databases. Odds ratio (OR) and standardized mean difference (SMD) with 95% confidence interval (CI) were calculated. Heterogeneity was assessed. The Cochrane Collaboration's tool was used to assess the risk of bias. RESULTS: Fourteen randomized controlled trials involving 788 patients with HRS were included. Random generation sequence was reported in only two studies. Blinding was not used in any study. Compared to conventional treatment without TCM, TCM led to a significant survival benefit during hospitalization (OR: 0.18; 95% CI: 0.08-0.39; P<0.0001), a significantly higher complete response (OR: 3.20; 95% CI: 2.06-4.97; P<0.00001), and a significantly lower no response (OR: 0.20; 95% CI: 0.14-0.30; P<0.00001). Partial response was not significantly different between the two groups (OR: 1.39; 95% CI: 0.90-2.15; P=0.14). Regardless of TCM, blood urea nitrogen and abdominal circumference were significantly decreased, and urine volume was significantly increased after treatment. Compared to conventional treatment without TCM, TCM led to a significantly lower serum creatinine, blood urea nitrogen, bilirubin, plasma ammonia, and abdominal circumference and significantly higher urine volume after treatment. There was significant heterogeneity. CONCLUSIONS: TCM might have a better survival and a higher complete response in patients with HRS. However, the quality of published studies was unsatisfactory.

Systemic vascular resistance and fluid status in patients with decompensated liver cirrhosis with or without functional renal failure in Egypt.

BACKGROUND: Functional renal failure and cardiovascular dysfunction are common complications of liver cirrhosis. This study aimed to evaluate cardiac performance, systemic vascular resistance (SVR) and fluid status in patients with decompensated liver cirrhosis either with or without functional renal failure. METHODS: Sixty patients diagnosed as having decompensated liver cirrhosis were divided into two groups. Group 1 included 30 patients with decompensated liver cirrhosis with ascites and with creatinine values ≤ 1.5 mg/dl. Group 2 included 30 azotemic decompensated cirrhotic patients with diagnostic criteria of hepatorenal syndrome (HRS). Also, 20 healthy subjects, of matched age and sex to the Group 1 and Group 2 patients, were included in the study as the control group. All patients and normal controls were subjected to clinical examination, laboratory evaluation, ECG, abdominal ultrasonography and echocardiographic studies. RESULTS: The echocardiographic and ECG data showed significant increase in LAD (P<0.01, P<0.01), AoD (P<0.05, P<0.01), interventricular septum thickness (IVST) (P<0.01, P<0.01), posterior wall thickness (PWT) (P<0.01, P<0.01), EDD (P<0.01, P<0.01), ESD (P<0.05, P<0.01), left ventricular (LV) mass (P<0.01, P<0.01), and Corrected QT (QTc) (P<0.01, P<0.01) interval with significant decrease in SVR (P<0.01, P<0.01). Additionally, there was significant decrease in IVC diameter in both patients groups compared to the control group (P<0.01, P<0.01). CONCLUSION: Patients with decompensated liver cirrhosis have low SVR, and Doppler echocardiography provides an easy noninvasive tool to assess this finding. Also, these patients demonstrate small inferior vena cava (IVC) diameter with normal collapsibility, which indicates low effective plasma volume. Measuring IVC diameter and collapsibility are of value in the prediction of intravascular fluid status in liver cirrhosis. This is especially true with renal dysfunction. Early addition of oral vasoconstrictors in decompensated patients may correct the SVR and circulatory dysfunction and hinder HRS occurrence.