Albumin in Advanced Liver Diseases: The Good and Bad of a Drug!

Human serum albumin is the most abundant plasma protein, and it regulates diverse body functions. In patients with advanced and decompensated cirrhosis, serum albumin levels are low because of a reduction in the hepatocyte mass due to disease per se and multiple therapeutic interventions. Because of their oncotic and nononcotic properties, administration of human albumin solutions (HAS) have been found to be beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis. Albumin also improves the functionality of the immune cells and mitigates the severity and risk of infections in advanced cirrhosis. Its long-term administration can modify the course of decompensated cirrhosis patients by reducing the onset of new complications, improving the quality of life, and probably providing survival benefits. There is, however, a need to rationalize the dose, duration, and frequency of albumin therapy in different liver diseases and stages of cirrhosis. In patients with acute-on-chronic liver failure, potentially toxic oxidized isoforms of albumin increase substantially, especially human nonmercaptalbumin and 2, and nitrosoalbumin. The role of administration of HAS in such patients is unclear. Determining whether removal of the pathological and dysfunctional albumin forms in these patients by "albumin dialysis" is helpful, requires additional studies. Use of albumin is not without adverse events. These mainly include allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements. Considering their cost, limited availability, need for a health care setting for their administration, and potential adverse effects, judicious use of HAS in liver diseases is advocated. There is a need for new albumin molecules and economic alternatives in hepatologic practice.

News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document.

Renal dysfunction is a common, life-threatening complication occurring in patients with liver disease. Hepatorenal syndrome (HRS) has been defined as a purely "functional" type of renal failure that often occurs in patients with cirrhosis in the setting of marked abnormalities in arterial circulation, as well as overactivity of the endogenous vasoactive systems.4,5 In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2).5 HRS-1 is characterised by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a moderate and stable or slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterised by acute renal failure while HRS-2 is mainly characterised by refractory ascites. Nevertheless, after these two entities were first described, new concepts, definitions, and diagnostic criteria have been developed by nephrologists for renal dysfunction in the general population and hospitalised patients. In particular, the definitions and characterisation of acute kidney injury (AKI), acute kidney disease and chronic kidney disease have been introduced/refined.6 Accordingly, a debate among hepatologists of the ICA led to a complete revision of the nomenclature and diagnosistic criteria for HRS-1, which was renamed HRS-AKI.7 Additionally, over recent years, greater granularity has been gained regarding the pathogenesis of HRS; it is now increasingly recognised that it is not a purely "functional" entity with haemodynamic derangements, but that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly to its development. That is, HRS has an additional structural component that would not only make traditional diagnostic criteria less reliable, but would explain the lack of response to pharmacological treatment with vasoconstrictors plus albumin that correlates with a progressive increase in inflammation. Because classification, nomenclature, diagnostic criteria and pathogenic theories have evolved over the years since the traditional classification of HRS-1 and HRS-2 was first described, it was considered that all these novel aspects be reviewed and summarised in a position paper. The aim of this position paper authored by two hepatologists (members of ICA) and two nephrologists involved in the study of renal dysfunction in cirrhosis, is to complete the re-classification of HRS initiated by the ICA in 2012 and to provide an update on the definition, classification, diagnosis, pathophysiology and treatment of HRS.

Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-ß-D-glucosaminidase.

BACKGROUND AND AIM: For appropriate management of acute kidney injury (AKI) in cirrhotic patients, accurate differentiation of the types of AKI, prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN) is very important. Urine N-acetyl-ß-D-glucosaminidase (NAG) has been proposed as a good tubular injury marker in many studies, but its efficacy in cirrhosis is unclear. This study was performed to evaluate the usefulness of urine NAG in patients with decompensated cirrhosis. METHODS: In 114 hospitalized patients with decompensated cirrhosis, we assessed serum creatinine, cystatin C, and urine NAG levels as markers for AKI differentiation and development and patient mortality. RESULTS: Thirty patients diagnosed with AKI at baseline had significantly higher serum creatinine and cystatin C levels, urine NAG levels, and Child-Pugh scores than those without AKI. Only urine NAG levels were significantly higher in patients with ATN than those with PRA or HRS (116.1 ± 46.8 U/g vs 39.4 ± 20.2 or 54.0 ± 19.2 U/g urinary creatinine, all P < 0.05). During a median follow up of 6.1 months, AKI developed in 17 of 84 patients: PRA in nine, HRS in six, and ATN in three. Higher serum cystatin C and urine NAG levels were independent predictors of AKI development in patients with decompensated cirrhosis. Survival was significantly associated with low serum cystatin C and urine NAG levels. CONCLUSION: Serum cystatin C and urine NAG levels are useful to differentiate types of AKI and are strong predictors for AKI development and mortality in patients with decompensated cirrhosis.

Free Cortisol Is a More Accurate Marker for Adrenal Function and Does Not Correlate with Renal Function in Cirrhosis.

BACKGROUND: The accuracy of diagnosis and clinical implications of the hepatoadrenal syndrome, as currently diagnosed using total cortisol, remain to be validated. AIM: The aim of this study was to assess adrenal function using free cortisol in stable cirrhosis and study the potential implications of any abnormalities for renal and/or cardiac function. METHODS: Sixty-one stable consecutively enrolled patients with cirrhosis underwent assessment of adrenal function using the low-dose short Synacthen test, renal function by 51Cr-EDTA glomerular filtration rate (GFR), and cardiac function by two-dimensional echocardiography. RESULTS: Eleven patients (18%) had total peak cortisol (PC) < 500 nmol/L, but no patient had free PC < 33 nmol/L indicating that diagnosis of AI using total cortisol is not confirmed using free cortisol. Free cortisol did not correlate with GFR or parameters of cardiac function. Patients with higher Child-Pugh class had progressively lower free cortisol. Patients with low GFR < 60 mL/min (N = 22) had more frequently grade II-III diastolic dysfunction (66.7% vs. 17.6%; p = 0.005) and had higher Child-Pugh and MELD score compared to those with normal GFR. CONCLUSIONS: Diagnosis of AI using total cortisol is not confirmed using free cortisol and is thus considered unreliable in cirrhosis. Free cortisol is not associated with renal or cardiac dysfunction. Lower free cortisol in more advanced stages of liver disease might be secondary to decreased synthesis due to lower cholesterol levels. Irrespective of free cortisol, parameters of cardiac dysfunction are associated with renal impairment supporting the cardio-renal hypothesis.

Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). CONCLUSION: Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241).

Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: a pilot study.

BACKGROUND: Acute kidney injury (AKI) in cirrhotic patients may be functional (hepatorenal syndrome [HRS]) or structural (acute tubular necrosis [ATN]). The differentiation between these two conditions remains challenging; no definite biomarker with a clear cutoff value had been declared. miRNAs seem to be attractive innovative biomarkers to identify the nature of kidney injury in cirrhotic patients. This study aimed to investigate the possibility of using miR-21, miR-210 and miR-146a as differentiating markers between HRS and ATN. METHODS: This pilot case control study included 50 patients with liver cirrhosis; 25 with HRS and another 25 with ATN beside 30 healthy controls. Real-time qPCR was used to measure the circulating miRNA tested. RESULTS: Higher levels of miR-21 were observed in both ATN and HRS vs. controls with statistically significant difference between ATN and HRS. The means were 9.466±3.21 in ATN, 2.670±1.387 in HRS and 1.090±0.586 in controls. miR-146a and miR-210 were both significantly lower in ATN and HRS compared to controls with statistically significant differences between ATN and HRS. The means of miR-210 were 1.020±0.643, 1.640±0.605 and 3.0±0.532 in ATN, HRS and controls, respectively. The means of miR-146a were 2.543±1.929, 4.98±1.353 and 6.553±0.426 in ATN, HRS and controls, respectively. ROC analyses proved that the three studied mi-RNAs can be used as differentiating biomarkers between ATN and HRS with the best performance observed with mi-21 achieving specificity and sensitivity equal 96%. CONCLUSIONS: miR-21, miR-210 and miR-146a may be candidate differentiating markers between HRS and ATN in cirrhotic patients.

Oxidative stress, NOx/l-arginine ratio and glutathione/glutathione S-transferase ratio as predictors of 'sterile inflammation' in patients with alcoholic cirrhosis and hepatorenal syndrome type II.

Continuous intake of alcohol leads to liver cirrhosis because of imbalance of oxidative stress/antioxidative defense and chronic 'sterile inflammation'. Hepatorenal syndrome (HRS) is the most severe complication of liver cirrhosis. The aim of our study was to assess: (1) the oxidative stress/antioxidative defense markers such as malondialdehyde (MDA), oxidative glutathione (GSH) and glutathione S-transferase (GST), (2) inflammation [C-reactive protein (CRP)], and (3) nitrate/nitrite levels (NOx) and its substrate L-arginine level. The study enrolled three groups: a group with cirrhosis and HRS (48 patients), a group with cirrhosis without HRS (32 patients), and a control group (40 healthy blood donors). All the patients with cirrhosis and HRS had type II HRS. MDA concentration was significantly higher in the groups with cirrhosis with and without HRS. Significant positive correlation was documented between the MDA level and de Ritis coefficient (AST/ALT), a marker of liver damage severity; between MDA and inflammation (CRP); between MDA and NOx concentration in the groups with cirrhosis with and without HRS. The correlation between MDA and creatinine level was significant in the group with HRS. The levels of GSH and GST were significantly lower in the groups with cirrhosis with and without HRS. The results of the study revealed that an increase in MDA and NOx concentration, along with decreased values of antioxidative defense and L-arginine, may indicate that liver damage can have an influence on progression to renal failure.

Renal dysfunction in cirrhosis.

PURPOSE OF REVIEW: Renal dysfunction causes significant morbidity in cirrhotic patients. Diagnosis is challenging because it is based on serum creatinine, which is used to calculate estimated glomerular filtration rate, which itself is not an ideal measure of renal function in patients with cirrhosis. Finding the exact cause of renal injury in patients with cirrhosis remains problematic due to the limitations of the current diagnostic tests. The purpose of this review is to highlight studies used to diagnose renal dysfunction in patients with renal dysfunction and review current treatments. RECENT FINDINGS: New diagnostic criteria and classification of renal dysfunction, especially for acute kidney injury (AKI), have been proposed in hopes of optimizing treatment and improving outcomes. New biomarkers that help to differentiate structural from functional AKI in cirrhotic patients have been developed, but require further investigation. Vasoconstrictors are the most commonly recommended treatment of hepatorenal syndrome (HRS). Given the high mortality in patients with type 1 HRS, all patients with HRS should be evaluated for liver transplantation. When renal dysfunction is considered irreversible, combined liver-kidney transplantation is advised. SUMMARY: Development of new biomarkers to differentiate the different types of AKI in cirrhosis holds promise. Early intervention in cirrhotic patients with renal dysfunction offers the best hope of improving outcomes.

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

BACKGROUND: Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. METHODS: Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. RESULTS: Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. CONCLUSIONS: This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of treatment for type 1 HRS and furnishes guidance for the design of future dose-ranging studies.

Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study.

BACKGROUND & AIMS: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis which is characterized by renal dysfunction and associated with poor survival. Neutrophil gelatinase-associated lipocalin (NGAL) is a troponin-like biomarker for human acute kidney injury. We aimed to investigate levels of plasma and urine NGAL in HRS and predictive ability of these markers for all-cause mortality, in HRS, stable cirrhosis and control subjects. METHODS: A total of 64 patients with cirrhosis (8 patients with type 1 HRS, 22 with type 2 HRS, and 34 without HRS) and 23 control subjects were included in the study. Blood and urine samples were measured with Human NGAL sandwich ELISA. Patients were followed up prospectively. RESULTS: Patients with type 1 and type 2 HRS had significantly higher plasma and urine NGAL levels compared with stable cirrhosis and control subjects. Cox regression analysis showed that plasma NGAL and MELD-Na scores were independent predictors of mortality. ROC-curve analysis showed that the plot of the plasma NGAL, urine NGAL, MELD-Na and Child-Turcot-Pugh score could predict all-cause mortality in cirrhotic patients' area under the curve (AUC 0.819, 0.686, 0.807 and 0.795 respectively). CONCLUSIONS: NGAL could predict mortality in patients with HRS independent of other commonly used risk factors.

Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.

Cholemic nephrosis represents a spectrum of renal injury from proximal tubulopathy to intrarenal bile cast formation found in patients with severe liver dysfunction. However, the contribution of this diagnosis has been largely forgotten in the modern literature. To more precisely define this, we conducted a clinicopathologic study of 44 subjects (41 autopsies and 3 renal biopsies) from jaundiced patients at the University of Chicago. Of these, 24 patients had bile casts with involvement of distal nephron segments in 18 mild cases and extension to proximal tubules for 6 severe cases. Eleven of 13 patients with hepatorenal syndrome and all 10 with cirrhosis (due to alcoholism) had tubular bile casts. These casts significantly correlated with higher serum total and direct bilirubin levels, and a trend toward higher serum creatinine, AST, and ALT levels. Bile casts may contribute to the kidney injury of severely jaundiced patients by direct bile and bilirubin toxicity, and tubular obstruction. Both mechanisms are analogous to the injury by myeloma or myoglobin casts. Accounting for the presence of renal bile casts provides a more complete representation of the renal injury that can occur in this unique clinical setting. Thus, bile cast nephropathy is an appropriate term for the severe form of injury observed in the spectrum of cholemic nephrosis. Additional studies are needed to establish the significance of this parameter for patient management in different clinical settings.

Serum sodium identifies patients with cirrhosis at high risk of hepatorenal syndrome.

BACKGROUND: Although the precipitating events of hepatorenal syndrome (HRS) development have been well characterized, the actual baseline risk of these events resulting in HRS is much less studied. AIM: To assess the predictive value of hyponatremia in the development of HRS. PATIENTS AND METHODS: We performed a retrospective observational cohort study including consecutive patients with decompensated liver cirrhosis and normal creatininemia admitted to tertiary center in Slovakia. Patients were censored at two months, development of renal failure, classified either as HRS or renal failure not fulfilling criteria of HRS, was the main outcome. RESULTS: Out of 202 patients 18 developed HRS and 14 renal failure not fulfilling the HRS criteria. A significant difference was found between patients with and without HRS in serum sodium (135.76 ± 5.01 vs. 130.78 ± 3.574 mmol/l; p < 0.0001), creatinine, (81 ± 20.11 vs. 98.18 ± 25.032 µmol/l; p = 0.006), bilirubin (90.4 ± 104.82 vs.175.42 ± 174.12 µmol/l; p < 0.0001), MELD (15.17 ± 5.52 vs. 21.61 ± 6.0; p < 0.0001) and MELD-Na score (19.96 ± 6.0 vs. 25.89 ± 4.96; p < 0.0001). Sodium, creatinine, bilirubin, MELD, MELD-Na score were found to be significant predictors of HRS in univariate analysis. Multivariate analysis two prediction models (Model 1: Bilirubin, creatinin, sodium and Model 2: Sodium, MELD) showed that sodium together with creatinine are the strongest HRS predictors, followed by bilirubin or MELD score. CONCLUSION: Serum levels of sodium, creatinine and parameters of liver function are important predictors of hepatorenal syndrome.

Diagnostic significance of nitrates and nitrites and L-arginine, in development of hepatorenal syndrome in patients with end stage alcoholic liver cirrhosis.

Hepatorenal syndrome (HRS) represents a complication of the end-stage liver cirrhosis. The aim of the present study was to analyze concentrations of nitrates and nitrites (NO2 + NO3) and L-arginine in patients with liver cirrhosis and HRS as a possible predictive marker for the development of HRS. The research was performed in a group of 28 patients with cirrhosis and HRS, a group of 22 patients suffering from cirrhosis without HRS and a control group comprised of 42 healthy voluntary blood donors. In patients with end-stage alcoholic liver cirrhosis, with HRS, the concentrations of NO2 + NO3 increased and correlated with the degree of cirrhosis progression, compared to patients without HRS and significantly higher compared to the control group. The level of NO2 + NO3 was in a positive correlation with the degree of liver damage de Ritis coefficient (HRS = 0.72; cirrhosis: = 0.55; control = -0.10). Significant positive correlation was found between NO2 + NO3 concentration and inflammatory marker C-reactive protein (HRSC = 0.75; cirrhosis = 0.70, control = -0.25). The correlation between NO2 + NO3 concentration and creatinine concentration in patients with HRS was significantly higher compared to patients without HRS (HRS = 0.82; cirrhosis = 0.32; control = -0.25). By using binary regression analysis, on the basis of clinical criteria of HRS diagnosis, the strongest independent positive predictor for HRS development was NO2 + NO3, associated with 45.02 times higher incidence of HRS, compared to arginine (12.7 times higher incidence), creatinine (13.1 times higher incidence), and AST/ALT ratio (10.55 higher incidence of HRS). Since the determination of NO2 + NO3 represents a reliable and easily applicable method, it may be used as an early predictive marker for HRS development.

Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.

BACKGROUND & AIMS: Various vasoconstrictors are useful in the management of hepatorenal syndrome (HRS). Terlipressin is the drug of choice; however, it is expensive. In this study, we evaluated safety and efficacy of terlipressin and noradrenaline in the treatment of HRS. METHODS: Forty-six patients with HRS type 1 were managed with terlipressin (group A, N=23) or noradrenaline (Group B, N=23) with albumin in a randomized controlled trial at a tertiary center. RESULTS: HRS reversal could be achieved in 9 (39.1%) patients in group A and 10 (43.4%) patients in group B (p=0.764). Univariate analysis showed baseline Child Turcotte Pugh score (CTP), model of end stage liver disease (MELD), urine output on day 1(D1), albumin, and mean arterial pressure (MAP) were associated with response. However, on multivariate analysis only CTP score was associated with response. Fourteen patients in group A and 12 in group B died at day 15 (p>0.05). Noradrenaline was less expensive than terlipressin (p<0.05). No major adverse effects were seen. CONCLUSIONS: The results of this randomized study suggest that noradrenaline is as safe and effective as terlipressin, but less expensive in the treatment of HRS and baseline CTP score is predictive of response.

Cystatin C is a good predictor of hepatorenal syndrome and survival in patients with cirrhosis who have normal serum creatinine levels.

BACKGROUND/AIMS: We evaluated the usefulness of cystatin C as a prognostic marker in patients with liver cirrhosis and normal serum creatinine. METHODOLOGY: We retrospectively analyzed prospectively enrolled patients with liver cirrhosis and normal serum creatinine from February 2007 to March 2008. We checked liver function and kidney variables including serum creatinine, cystatin C and glomerular filtration rate from 51Cr-EDTA on the same day for all patients. The endpoints of the study were either development of hepatorenal syndrome or mortality. RESULTS: In total, 112 patients with liver cirrhosis were enrolled in the study (87 men and 25 women, age 52 ± 12 years). Twelve (11%), 59 (53%) and 41 (36%) patients were in Child-Pugh class A, B and C, respectively. Cystatin C was better correlated with glomerular filtration rate from 51Cr-EDTA than creatinine. The 1-year cumulative incidence of hepatorenal syndrome and the 1-year survival rate of patients were 20.5% and 79.5%, respectively. Cystatin C, Model for End-Stage Liver Disease and serum sodium were the independent predictive factors for hepatorenal syndrome. Cystatin C, serum sodium and prothrombin time were the independent factors for predicting survival. CONCLUSIONS: In patients with liver cirrhosis and normal creatinine levels, cystatin C is a useful marker for predicting hepatorenal syndrome and survival.

Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.

BACKGROUND & AIMS: Administration of terlipressin plus albumin is effective in reversing type 1 HRS as compared to albumin alone. However, only about 1/3 of patients respond to treatment, therefore, predictors of response and survival would help identify the patients most likely to benefit from treatment. METHODS: We analyzed our controlled trial of terlipressin vs. placebo (Gastroenterology 2008;134:1360) to define factors predictive of a response and to correlate hemodynamic changes to changes in renal function. RESULTS: Single variant analysis showed treatment with terlipressin, MELD score, and baseline serum creatinine to be predictive of HRS reversal. Alcoholic hepatitis, baseline serum creatinine, and MELD score were predictive of survival. When treatment was not considered as a variable, only baseline serum creatinine predicted HRS reversal. Baseline serum creatinine, presence of alcoholic hepatitis, and Child-Pugh score were also predictive of survival on multivariate analysis. The rise in mean arterial pressure (MAP) following terlipressin administration was not predictive of HRS reversal. However, in those who achieved HRS reversal from terlipressin, there was a significant rise in MAP from beginning to end of treatment. CONCLUSIONS: The most consistent predictor of response to terlipressin and of survival is the baseline serum creatinine. Patients most likely to benefit from terlipressin have earlier onset renal failure (i.e. serum creatinine <5.0mg/dl). A sustained rise in MAP is required for HRS reversal. As MAP is a surrogate marker for the hyperdynamic circulation, it is only with improvement in the hyperdynamic circulation that HRS reversal is observed.

[Application of the MELD scale for the estimation of treatment efficacy in patients with hepatic cirrhosis and hepatorenal syndrome type II using extracorporeal methods of hemocorrection].

The results of treatment of 69 patients, suffering hepatic cirrhosis (HC) in decompensation stage with hepatorenal syndrome, were analyzed, in whom extracorporeal methods of hemocorrection (extracorporeal sorption with ultrafiltration of ascitic liquor and the albumin peritoneal dialysis) were applied. The patients state severity as well as the therapy efficacy were estimated in accordance with the MELD (Model of End-Stage Liver Disease) scale. High informativity of the abovementioned estimation system was established, concerning prognosis for their life duration in the patients, suffering HC.

Molecular adsorbent recirculating system is ineffective in the management of type 1 hepatorenal syndrome in patients with cirrhosis with ascites who have failed vasoconstrictor treatment.

BACKGROUND: The pathogenetic mechanism of hepatorenal syndrome (HRS) is paradoxical renal vasoconstriction consequent upon systemic and splanchnic arterial vasodilatation. Molecular adsorbent recirculating system (MARS) is a specialised form of dialysis that clears albumin-bound substances, including vasodilators, and therefore can potentially reduce systemic vasodilatation in cirrhosis. OBJECTIVE: To assess the efficacy of MARS in improving systemic and renal haemodynamics in patients with cirrhosis with refractory ascites and type 1 HRS not responding to vasoconstrictor therapy. METHODS: A pilot study was carried out in an academic teaching hospital. The study group comprised six patients with cirrhosis, refractory ascites and type 1 HRS not responding to vasoconstrictor treatment. All patients received 5 days of 6-8 h of MARS dialysis. The main outcome measures were pre-MARS and post-MARS measurements of glomerular filtration rate, renal blood flow, neurohormones, cytokines and nitric oxide (NO), as well as daily biochemistry, haematology and urinary volume. RESULTS: There were no significant changes in systemic haemodynamics and GFR following MARS treatments, despite a significant reduction in NO concentrations (111.5+/-18.8 micromol/l pre-MARS, to 65.1+/-8.2 micromol/l post-MARS, p=0.05). There was a transient reduction in serum creatinine (p<0.05), Child-Pugh and MELD (Model End-Stage Liver Disease) scores with MARS, but no significant difference was observed in neurohormone and cytokine levels. Four of six patients died following MARS treatments. CONCLUSIONS: In patients with cirrhosis, refractory ascites and type 1 HRS not responding to vasoconstrictor treatment, MARS is ineffective in improving systemic haemodynamics and renal function despite reduction in NO levels, suggesting that vasodilatation in advanced cirrhosis is not due to excess systemic vasodilators alone. Transient reduction in serum creatinine indicates direct removal by MARS, and may not represent improved renal function.

Cholemic Nephrosis: An Autopsy Study of a Forgotten Entity.

OBJECTIVE: The aim of the study is to do a clinicopathologic study of post mortem kidney biopsies with significant deposition of bilirubin pigment within tubular epithelial cells and in the lumen of distal tubules as a bile cast. MATERIAL AND METHOD: All post mortem specimens with acute tubular necrosis, with the presence of bile casts in tubules or bile pigment deposition in the tubular epithelium during the period 2015-2018 were examined for gross and histopathology along with biochemical parameters and viral markers. RESULTS: Bile casts with sloughed renal tubular epithelial cells and occasional macrophages were present in the distal convoluted tubule in 78.6% of biopsies (11/14). The plugging of distal convoluted tubule with casts was similar to that seen in myeloma and myoglobin cast nephropathies. Bilirubin pigment deposition was present in 35.7% (5/14) of cases. The frequency of bile casts in each biopsy was variable and it did not have any association with serum bilirubin levels or etiology of liver dysfunction. A striking difference from earlier studies is the high number of toxin-induced liver damage including six cases of paraquat and 2 cases of yellow phosphorus poisoning. CONCLUSION: This study proves importance of the bile cast nephropathy as a reason for kidney injury, especially with varied hepatotoxic etiologies, especially paraquat and yellow phosphorus.

Terlipressin therapy for reversal of type 1 hepatorenal syndrome: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease and carries a poor prognosis. Recent trials have indicated that terlipressin may be effective in reversing HRS. Our aim was to evaluate the efficacy of terlipressin therapy in reversing type 1 HRS defined as a serum creatinine <1.5 mg/dL during treatment. METHODS: Randomized controlled trials in which patients with type 1 HRS received at least 3 days of terlipressin therapy and albumin in the intervention arm were included after a systematic search of the published English reports. Studies with other vasoconstrictor therapies in the control group were excluded. RESULTS: A total of 223 patients with HRS type 1 in four different trials, were included in the final analysis. Alcohol-related cirrhosis was the most common underlying etiology. The risk ratio for reversal in type 1 HRS with terlipressin therapy was 3.66 (95% confidence interval 2.15-6.23). Recurrence of HRS was low (8%). Serious side-effects requiring discontinuation of therapy were seen only in 6.8% of patients on terlipressin therapy. There was a trend towards improved transplant-free survival at 90 days in the terlipressin group (relative risk 1.86 95% confidence interval 1.0-3.4, P = 0.05). CONCLUSIONS: Terlipressin is effective in reversing HRS type 1. Recurrence of HRS is rare with at least 14 days of therapy. Serious side-effects requiring discontinuation of therapy are less common. There appears to be a survival benefit in patients with HRS treated with terlipressin.