The Use of Rifaximin in Patients With Cirrhosis.

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.

Improvement of renal function prior to liver transplantation is not associated with better long-term renal outcome or survival.

INTRODUCTION AND OBJECTIVES: Since MELD implementation renal impairment in liver transplant (LT) recipients has become of increasing importance. This is the first study evaluating the course of renal function immediately prior to LT as predictor for long-term renal and overall outcome. PATIENTS AND METHODS: In this retrospective study, 226 adults undergoing LT at the University Medical Center Hamburg-Eppendorf (2011-2015) were included. The impact of renal function over a period of 3 months prior to LT compared to renal function at the day of LT on long-term renal outcome and survival was assessed. RESULTS: According to GFR at day of LT renal function improved (≥1 CKD stage) in 64 patients (28%), remained stable in 144 (64%) or deteriorated in 18 (8%). Improvement of renal function prior to LT did neither significantly affect 90-day (13% vs. 14%, p = 0.83), nor 5-year post-LT mortality (35% vs. 41%, p = 0.57). 50 patients (22%) with hepatorenal syndrome (HRS) received terlipressin prior to LT, but only 18 (37%) showed prolonged stabilization of renal function (improvement ≥1 CKD stage). Response to terlipressin did neither improve 90-day (p=1), 5-year mortality (p = 0.52) nor long-term renal function (p = 0.843). Nevertheless, need for dialysis pre-LT (59% vs. 34%, p = 0.005) and post-LT (62% vs. 17%, p<0.001) was associated with increased 5-year mortality. CONCLUSIONS: Improvement of renal function immediately prior to LT, either spontaneously or following terlipressin therapy, did neither ameliorate long-term renal outcome nor survival in LT recipients. Future studies need to clarify the impact of terlipressin in HRS on the transplant waiting time in LT candidates.

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.

[Paradigm shift in understanding Acute kidney injury in patients with chronic liver disease: From pathophysiology to defining disease entities]. / Paradigmenwechsel im Verständnis der akuten Nierenschädigung bei chronischer Leberinsuffizienz: Von der Pathophysiologie zur Definition von Krankheitsentitäten.

The hepatorenal syndrome (HRS) is only a part of the wide spectrum of renal injury in patients with end-stage liver cirrhosis. Besides that, the advanced liver disease itself, or its underlying causes, as well as comorbidities, like diabetes mellitus, adiposity and arterial hypertension, can directly cause parenchymal renal insults (bile acid nephropathy, ischemic tubular injury, diabetic/hypertensive nephropathy, hepatitis B- and C-associated glomerulonephritis etc.). This kind of kidney injury is collectively described as non-hepatorenal syndrome AKI (non-HRS AKI. Beyond that, accumulating evidence highlights the role of systemic inflammation as an important common factor in the pathogenesis of decompensated liver cirrhosis, acute in chronic liver failure (ACLF) and renal dysfunction.In this review, we discuss recent data about definition, classification and pathophysiology of HRS, HRS-AKI and Non-HRS-AKI and exploit in this regard the diagnostic and prognostic potential of respective newer serum and urine markers.

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.

Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice.

Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, kidney injury molecule 1 (KIM-1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human-cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSION: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000-000).

Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites.

BACKGROUND & AIMS: In patients with cirrhosis, the clinical benefit of the treatment with human albumin for ascites is debated, and no data are available regarding refractory ascites. In this study, in patients with cirrhosis and refractory ascites, we assessed the effect of long-term albumin administration on emergent hospitalization and mortality. METHODS: Seventy patients with cirrhosis and refractory ascites, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, were included into the study. Forty-five patients were non-randomly assigned to receive long-term administration of human albumin at the doses of 20 g twice per week (n = 45), in addition to standard medical of care (SOC), and compared to those followed according to SOC. Patients were followed up to the end of the study, liver transplantation or death. RESULTS: The cumulative incidence of 24-month mortality was significantly lower in patients treated with albumin than in the group of patients treated with SOC (41.6% vs 65.5%; P = 0.032). The period free of emergent hospitalization was significantly longer in patients treated with long-term administration of albumin (P = 0.008). Analysing separately the causes of inpatient admission, patients treated with albumin showed a reduction in the incidence of overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non-SBP infections. In addition, a non-significant trend towards a reduced probability of hepatorenal syndrome was observed. CONCLUSION: In patients with cirrhosis and refractory ascites, long-term treatment with albumin improves survival and reduces the probability of emergent hospitalizations.

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.

Vasoconstrictors in hepatorenal syndrome - A critical review.

Hepatorenal syndrome has the worst prognosis among causes of acute kidney injury in cirrhotic patients. Its definitive treatment is liver transplantation. Nevertheless, considering its high short-term mortality rate and the shortage of liver grafts, a pharmacological treatment is of utmost importance, serving as a bridge to liver transplant. The clinical management of hepatorenal syndrome is currently based on the use of a vasoconstrictor in association with albumin. Terlipressin, noradrenaline and the combination of midodrine and octreotide could be used to treat hepatorenal syndrome. Among these options, terlipressin seems to gather the strongest body of evidence regarding efficacy and should be considered the first line of treatment whenever available and in the absence of contraindications. Treatment with a vasoconstrictor and albumin should be promptly initiated after the diagnosis of hepatorenal syndrome in order for patients to have higher chances of recovery.

Renal Function in Cirrhosis: A Critical Review of Available Tools.

Patients with cirrhosis have a high prevalence of renal dysfunction. The susceptibility to renal dysfunction is due to both the severe splanchnic arterial vasodilation and the systemic inflammation observed in these patients. An accurate assessment of renal function is recommended in all patients with cirrhosis. Indeed, the renal function assessment guides the management of patients, helps to refine prognosis and to define transplant strategies. Despite its limitations, serum creatinine is still the most used biomarker for the estimation of glomerular filtration rate (GFR) and the assessment of acute kidney injury (AKI) in patients with cirrhosis. New biomarkers of GFR such as cystatin C may improve the assessment of GFR and the prognostic stratification in these patients. AKI is a life-threatening complication and needs a timely management. The differential diagnosis between hepatorenal syndrome (HRS) and acute tubular necrosis (ATN) is tricky in clinical practice. New biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin and interleukin-18, represent useful tools in refining the discrimination between HRS and ATN. Patients with HRS need a prompt treatment with vasoconstrictors and albumin and a rapid evaluation for liver transplant eligibility. In this article, the authors reviewed the available tools in the diagnosis and management of renal dysfunction in cirrhosis.

Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats.

Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels ( P < 0.0001) and renal arterial blood flow ( P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS ( P = 0.026). Pretreatment with endothelin receptor type A (ETA) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats ( P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ETA and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats ( P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ETA upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS. NEW & NOTEWORTHY Hepatorenal syndrome (HRS) occurred in advanced cirrhosis after large-volume paracentesis or bacterial peritonitis. We demonstrated that intraperitoneal lipopolysaccharide (LPS) enhanced renal vascular reactivity to endothelin-1 (ET-1) in cirrhotic rats, accompanied by inducible nitric oxide synthase inhibition, endothelin receptor type A (ETA) upregulation, and subsequent extracellular signal-regulated kinase activation in renal medulla. Pretreatment with ETA antagonist abrogated the LPS-enhanced renal vascular response in common bile duct ligation rats. These findings suggest that further clinical investigation of ET-1-targeted therapy may be feasible in the control of HRS.

New Developments in Hepatorenal Syndrome.

Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFR more accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance of this remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed the value of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remains the definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation.

Development of an automated phenotyping algorithm for hepatorenal syndrome.

OBJECTIVE: Hepatorenal Syndrome (HRS) is a devastating form of acute kidney injury (AKI) in advanced liver disease patients with high morbidity and mortality, but phenotyping algorithms have not yet been developed using large electronic health record (EHR) databases. We evaluated and compared multiple phenotyping methods to achieve an accurate algorithm for HRS identification. MATERIALS AND METHODS: A national retrospective cohort of patients with cirrhosis and AKI admitted to 124 Veterans Affairs hospitals was assembled from electronic health record data collected from 2005 to 2013. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Five hundred and four hospitalizations were selected for manual chart review and served as the gold standard. Electronic Health Record based predictors were identified using structured and free text clinical data, subjected through NLP from the clinical Text Analysis Knowledge Extraction System. We explored several dimension reduction techniques for the NLP data, including newer high-throughput phenotyping and word embedding methods, and ascertained their effectiveness in identifying the phenotype without structured predictor variables. With the combined structured and NLP variables, we analyzed five phenotyping algorithms: penalized logistic regression, naïve Bayes, support vector machines, random forest, and gradient boosting. Calibration and discrimination metrics were calculated using 100 bootstrap iterations. In the final model, we report odds ratios and 95% confidence intervals. RESULTS: The area under the receiver operating characteristic curve (AUC) for the different models ranged from 0.73 to 0.93; with penalized logistic regression having the best discriminatory performance. Calibration for logistic regression was modest, but gradient boosting and support vector machines were superior. NLP identified 6985 variables; a priori variable selection performed similarly to dimensionality reduction using high-throughput phenotyping and semantic similarity informed clustering (AUC of 0.81 - 0.82). CONCLUSION: This study demonstrated improved phenotyping of a challenging AKI etiology, HRS, over ICD-9 coding. We also compared performance among multiple approaches to EHR-derived phenotyping, and found similar results between methods. Lastly, we showed that automated NLP dimension reduction is viable for acute illness.

Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.

BACKGROUND & AIMS: Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. METHODS: Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. RESULTS: Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P < .001). Decreases in SCr and survival were correlated (r(2) = .882; P < .001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P < .001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. CONCLUSIONS: Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.

Renal dysfunction and cirrhosis.

PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) does not represent the predominant phenotype of acute kidney injury (AKI) in cirrhosis. Early recognition of HRS helps initiate appropriate therapy. The aims of this review are to present redefinition of AKI, to list new biomarkers, to report recent data on vasopressors in HRS and to propose criteria for simultaneous liver and kidney transplantation (SLKT). RECENT FINDINGS: Urine output, which was not part of the definition of AKI might be reconsidered as it has an independent prognostic value. Biomarkers (NGAL and IL-18) could help identify ATN. However, cut-off values have to be clarified. Vasopressors with albumin represent first option in HRS. Continuous infusion of terlipressin has a better safety profile than intravenous boluses. SLKT should be considered whenever native kidney recovery is unlikely [i.e. prolonged renal replacement therapy (RRT) and/or GFR less than 25 ml/min for 6 weeks prior to transplantation]. SUMMARY: New definitions and recent biomarkers may help differentiate HRS from ATN at an earlier stage. Urine output should be reconsidered in the definitions. Even in patients who are not candidates for transplantation, a short trial of RRT is justified whenever needed. SLKT should be considered whenever posttransplant renal recovery is unlikely.

[Research advances in pathophysiology and diagnosis and treatment of hepatorenal syndrome].

Hepatorenal syndrome (HRS) is functional renal injury in patients with liver cirrhosis or fulminant liver failure and is one of the complications of progressive liver failure which threatens patients' lives. With the progression of liver diseases, hemodynamic disturbance may eventually cause HRS. Achievements have been made in the pathophysiology, diagnostic criteria, and treatment of HRS. This article introduces the research advances in the pathophysiology, diagnosis, and treatment of HRS.

Nonselective ß blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.

BACKGROUND & AIMS: Nonselective ß blockers (NSBBs) reduce portal pressure and the risk for variceal hemorrhage in patients with cirrhosis. However, development of spontaneous bacterial peritonitis (SBP) in these patients could preclude treatment with NSBBs because of their effects on the circulatory reserve. We investigated the effects of NSBBs in patients with cirrhosis and ascites with and without SBP. METHODS: We performed a retrospective analysis of data from 607 consecutive patients with cirrhosis who had their first paracentesis at the Medical University of Vienna from 2006 through 2011. Cox models were calculated to investigate the effect of NSBBs on transplant-free survival time and adjusted for Child-Pugh stage and presence of varices. RESULTS: NSBBs increased transplant-free survival in patients without SBP (hazard ratio = 0.75; 95% confidence interval: 0.581-0.968; P = .027) and reduced days of nonelective hospitalization (19.4 days/year for patients on NSBBs vs 23.9 days/year for patients not taking NSBBs). NSBBs had only moderate effects on systemic hemodynamics at patients' first paracentesis. However, at the first diagnosis of SBP, the proportion of hemodynamically compromised patients with systolic arterial pressure <100 mm Hg was higher among those who received NSBBs (38% vs 18% of those not taking NSBBs; P = .002), as was the proportion of patients with arterial pressure <82 mm Hg (64% of those taking NSBBs vs 44% of those not taking NSBBs; P = .006). Among patients with SBP, NSBBs reduced transplant-free survival (hazard ratio = 1.58; 95% confidence interval: 1.098-2.274; P = .014) and increased days of nonelective hospitalization (29.6 days/person-year in patients on NSBBs vs 23.7 days/person-year in those not taking NSBBs). A higher proportion of patients on NSBBs had hepatorenal syndrome (24% vs 11% in those not taking NSBBs; P = .027) and grade C acute kidney injury (20% vs 8% for those not taking NSBBs; P = .021). CONCLUSIONS: Among patients with cirrhosis and SBP, NSBBs increase the proportion who are hemodynamically compromised, time of hospitalization, and risks for hepatorenal syndrome and acute kidney injury. They also reduce transplant-free survival. Patients with cirrhosis and SBP should not receive NSBBs.

Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.

Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center's transplant electronic database. Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 ± 1.2 years; mean Model for End-Stage Liver Disease score, 35 ± 1) with HRS1 (serum creatinine, 3.37 ± 0.13 mg/dL) at liver transplant were enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialysis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients (75.8%) at a mean time of 13 ± 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine levels (3.81 ± 0.34 versus 3.23 ± 0.14 mg/dL, P = 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42 days] versus 10 days (95% CI, 10-18 days), P = 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days) versus 10 days (95% CI, 6-14 days), P = 0.01], and increased posttransplant mortality (P = 0.0045) in comparison with those whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6% increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1 should receive a timely liver transplant to improve their outcome.

Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival.

UNLABELLED: Type-1 hepatorenal syndrome (HRS) is a common complication of bacterial infections in cirrhosis, but its natural history remains undefined. To assess the outcome of kidney function and survival of patients with type-1 HRS associated with infections, 70 patients diagnosed during a 6-year period were evaluated prospectively. Main outcomes were no reversibility of type-1 HRS during treatment of the infection and 3-month survival. Forty-seven (67%) of the 70 patients had no reversibility of type-1 HRS during treatment of the infection. [Correction to previous sentence added March 10, 2014, after first online publication: "Twenty-three (33%)" was changed to "Forty-seven (67%)."] The main predictive factor of no reversibility of type-1 HRS was absence of infection resolution (no reversibility: 96% versus 48% in patients without and with resolution of the infection; P < 0.001). Independent predictive factors of no reversibility of type-1 HRS were age, high baseline serum bilirubin, nosocomial infection, and reduction in serum creatinine <0.3 mg/dL at day 3 of antibiotic treatment. No reversibility was also associated with severity of circulatory dysfunction, as indicated by more marked activity of the vasoconstrictor systems. In the whole series, 3-month probability of survival was only 21%. Factors associated with poor prognosis were baseline serum bilirubin, no reversibility of type-1 HRS, lack of resolution of the infection, and development of septic shock after diagnosis of type-1 HRS. CONCLUSION: Type-1 HRS associated with infections is not reversible in two-thirds of patients with treatment of infection only. No reversibility of type-1 HRS is associated with lack of resolution of the infection, age, high bilirubin, and no early improvement of kidney function and implies a poor prognosis. These results may help advance the management of patients with type-1 HRS associated with infections.

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.