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Cirrhotic portal hypertension is characterised by development of the decompensating events of ascites, encephalopathy, portal hypertensive bleeding and hepatorenal syndrome, which arise in a setting of cirrhosis-associated immune dysfunction (CAID) and define morbidity and prognosis. CAID describes the dichotomous observations that systemic immune cells are primed and display an inflammatory phenotype, while failing to mount robust responses to pathogen challenge. Bacterial infections including spontaneous bacterial peritonitis are common complications of advanced chronic liver disease and can precipitate variceal haemorrhage, hepatorenal syndrome and acute-on-chronic liver failure; they frequently arise from gut-derived organisms and are closely linked with dysbiosis of the commensal intestinal microbiota in advanced chronic liver disease.Here, we review the links between cirrhotic dysbiosis, intestinal barrier dysfunction and deficits of host-microbiome compartmentalisation and mucosal immune homoeostasis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies targeted at restoring intestinal eubiosis, augmenting gut barrier function and ameliorating the mucosal and systemic immune deficits that characterise and define the course of decompensated cirrhosis.

We read with great interest the updated guidelines recently published by Tripathi et al 1 on behalf of the Clinical Services and Standards Committee of the British Society of Gastroenterology on the management of variceal haemorrhage (VH) in patients with cirrhosis. One of the topics of discussion was the primary prevention of VH. To our knowledge, these are the first guidelines in the literature to recommend that the initiation of non-selective β-blockers (NSBBs) in patients with small varices should be determined only by coexisting red signs and not the severity of liver disease as recommended by the recent Baveno's VI consensus (Child–Pugh C)2 and US guidelines (Child–Pugh B/C).3 We fully agree with the authors that robust data allowing any formal recommendation in patients with cirrhosis and small varices without red signs, including those with advanced liver disease, never existed. Moreover, concerns have been raised recently that NSBBs may increase the risk for hepatorenal syndrome (HRS) and mortality in patients with end-stage liver disease due to …

The demand for OLT continues to be on the rise with patients spending a long time on the waiting list; this not only increases the risk of developing further decompensation but also mortality. The complications discussed above may not only lead to removal from the waiting list in some cases but also a poorer outcome following transplantation. Therefore the appropriate prevention, recognition and treatment of the above-mentioned complications of cirrhosis will have a positive impact on the outcome before and after liver transplantation.

Background ‘Acute-on-chronic liver failure’ (ACLF) is characterised in a more advanced stage by liver failure associated with multiple other end-organ failure. The global clinical characteristics of this entity remain, however, ill-defined. Objective To characterise and evaluate the clinicopathological features of patients with ACLF compared with patients with chronic decompensated cirrhosis (CHD) in a prospective, homogeneous cohort of patients with histologically proven alcoholic cirrhosis from 2002 to 2007. Results In total 250 patients were screened (ACLF (n=70, 28%) and CHD (n=180, 72%)). Alcoholic liver disease was observed in respectively 61/70 (87%) of patients with ACLF and 72/180 (40%) of patients with CHD. After exclusion of 31 patients, 102 patients were studied: 54 with ACLF (median age 51 years; Child–Pugh 12±2; in-hospital mortality 46% (25/54)) and 48 patients with CHD (median age 53 years; Child–Pugh 10±2; in-hospital mortality 10% (5/48)). In the patients with ACLF who survived the hospital stay, the difference in transplant-free survival compared with patients with CHD tended to attenuate with time. At admission the apparent infection of patient groups was comparable but during hospitalisation infection occurred more frequently in patients with ACLF (31/53 (58%)) than in those with CHD (12/47=26%) (p=0.007). Early signs of infection, positive systemic inflammatory response syndrome (SIRS) criteria at admission and ductular bilirubinostasis (p=0.04), were early features that predicted outcome in ACLF. Conclusion Patients with ACLF have a high short-term mortality but those who survived the acute exacerbation show a long-term outcome comparable to that of patients with CHD. Infection is the most common cause of mortality in these patients. Positive SIRS criteria and ductular bilirubinostasis are early markers of ACLF and might allow more rapid identification of high-risk patients.

Refractory ascites is a frequent complication of advanced cirrhosis and is associated with hepatorenal syndrome and hepatic hydrothorax. Large volume paracentesis and pleurodesis are regarded as first-line treatments in patients who do not respond adequately to diuretics. These treatments, however, do not prevent recurrence and carry the risk of worsening of the circulatory dysfunction leading to hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt (TIPS) has been proposed as an alternative to paracentesis. TIPS reduces the rate of ascites recurrence mainly due to the reduction in the filtration pressure. In addition, TIPS results in a positive effect on renal function, including hepatorenal syndrome, demonstrated by a rapid increase in urinary sodium excretion, urinary volume, and improvement in plasma creatinine concentration. Furthermore, plasma renin activity, aldosterone, and noradrenalin concentrations improve gradually after TIPS insertion suggesting a positive effect on systemic underfilling, the factor of hepatorenal syndrome. As demonstrated recently in two meta-analyses including five randomised studies, TIPS also improves survival when compared with paracentesis. However, the evidence is based on relatively few studies with only 305 patients included. The positive effects of the TIPS are opposed by an increased frequency and severity of episodes of hepatic encephalopathy which may be reduced by both patient selection and reduced shunt diameter. Based on the present knowledge the recommended hierarchy of treatments for refractory ascites may be reconsidered upgrading TIPS in suitable candidates.

Recent studies suggest that cardiac dysfunction precedes development of the hepatorenal syndrome. In this follow-up study, we aimed to investigate the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival.Twenty-four patients with cirrhosis and ascites were included. Cardiac function was investigated by gated myocardial perfusion imaging (MPI) for assessment of cardiac index (CI) and cardiac volumes. The renal function was assessed by determination of glomerular filtration rate (GFR) and renal blood flow (RBF) and the patients were followed up for 12 months.In patients with a CI below 1.5 l/min/m(2) on MPI, GFR was lower (39 (SD 24) vs 63 (SD 23) ml/min, p = 0.03), RBF was lower (352 (SD 232) vs 561 (SD 229) ml/min, p = 0.06), and serum creatinine was higher (130 (SD 46) vs 78 (SD 29) mumol/l, p0.01). The number of patients who developed hepatorenal syndrome type 1 within 3 months was higher in the group with low CI than in the high CI group (43% vs 5%, p = 0.04). Patients with the lowest CI (N = 8) had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (N = 16), p0.05. In contrast, the Model for End-stage Liver Disease (MELD) score failed to predict mortality in these patients.The development of renal failure and poor outcome in patients with advanced cirrhosis and ascites seem to be related to a cardiac systolic dysfunction. Other parameters may be more important than MELD score to predict prognosis.

This present review is timely with the increasing use of the molecular adsorbents recirculating system (MARS) for the management of liver failure, with over 3000 patients having been treated with this device worldwide. In the UK, MARS is being used for the treatment of individual patients both in the National Health Service and also in the private sector. In order to investigate the latest position with respect to bioartificial liver devices, a meeting was held at University College London Hospital in September 2003 and this article is based on the most up to date data presented there. Liver failure, whether of the acute variety with no pre-existing liver disease (acute liver failure (ALF)) or an acute episode of decompensation superimposed on a chronic liver disorder (acute on chronic liver failure (ACLF)), carries a high mortality. In patients with ALF, lack of detoxification, metabolic, and regulatory functions of the liver leads to life threatening complications, including kidney failure, encephalopathy, cerebral oedema, severe hypotension, and susceptibility to infections culminating in multiorgan failure.1 The only established therapy for such patients is liver transplantation (LTx) but currently one third of these patients die while waiting for a transplant and the organ shortage is increasing (fig 1).2 However, liver failure, whether of the acute or acute on chronic variety, is potentially reversible, and considerable work has been carried out over many years to develop effective liver support devices. Figure 1 Annual death rates on the waiting list for liver transplantation between 1997 and 2001 in UNOS categories 1 (acute/fulminant liver failure), 2a (decompensated chronic liver disease urgently requiring transplant), and 2b (decompensated chronic liver disease requiring transplant less urgently). (Source: OPTN/SRTR data, as of 1 August 2002.) The development of these devices has been approached in two very different ways. The biological devices, which aim …

We read with interest the revised consensus recommendations for management of acute kidney injury (AKI) ) in cirrhosis by the International Club of Ascites.1 We are concerned that plasma volume expansion only with albumin is recommended for stage 2 and 3 AKI and do not believe that this represents a balanced view of the available evidence. No one doubts that fluid resuscitation is an integral part of the management of AKI; however, studies to date have not established class 1 evidence for an advantage of the use of albumin over other colloids or crystalloids.

Cirrhosis is one of the most frequent and severe chronic diseases worldwide. In the initial stages it has few or no symptoms, but advanced stages of cirrhosis are characterised by reduced liver function, complications due to portal hypertension and neuroendocrine abnormalities with increased activity of the sympathetic nervous system (SNS) and renin-aldosterone axis. The prognosis is severe, with an increasing frequency of complications including variceal bleeding, ascites and spontaneous infections with subsequent development of hepatic encephalopathy and hepatorenal syndrome. More than one-third of patients diagnosed with cirrhosis develop oesophageal varices within 3 years after the diagnosis is made. Varices develop and later bleed when the portal pressure is increased and the hepatic vein pressure gradient (HVPG) is more than 10–12 mm Hg. Life-threatening spontaneous bacterial infections are another common complication of advanced cirrhosis. The infections are mainly triggered by gut bacterial translocation, which is the migration of microorganisms from the intestinal lumen to the mesenteric lymph nodes or other extraintestinal sites.1 Small intestinal bacterial overgrowth of Gram-negative rods, structural and functional alterations of the intestinal mucosa and deficiencies in defence mechanisms contribute to bacterial translocation.2 Increased serum levels of lipopolysaccharide binding protein and circulating bacterial DNA are markers of bacterial translocation and both predict a poor outcome in cirrhosis and ascites.3 4 Selective gut decontamination prevents spontaneous bacterial infections and improves survival in advanced cirrhosis.5 Non-selective β-blockers (BB) are the only drugs shown to improve survival in patients with cirrhosis and medium to large oesophageal varices.6 BB inhibit the binding of catecholamines (norepinephrine and epinephrine) to the β1 and β2 adrenoreceptors. β1 blockade reduces the cardiac output and β2 blockade leads to splanchnic …

Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation.PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials.PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats.This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.

The transjugular intrahepatic portosystemic stent-shunt (TIPSS) has been a clinical reality for the past 10 years. The procedure is essentially a side-to-side H graft portosystemic shunt, with the expandable metallic stent being the H graft. Over this time, TIPSS has been put through the paces of assessment of technical feasibility, pilot studies through to randomised clinical trials looking at treatment of complications of portal hypertension. Following its introduction, there was an enthusiastic welcome for this procedure which was seen as an attractive alternative to shunt surgery—it did not require general anaesthesia (most of the time) or a laparotomy, and was applicable to many patients with severe liver disease unsuitable for surgery. Treatment of variceal haemorrhage, ascites, hepatic hydrothorax, hepatorenal syndrome, and Budd-Chiari syndrome using TIPSS has been studied. The initial enthusiasm was subsequently tempered by reports from these studies of shortcomings of TIPSS, namely the inevitable development of shunt stenosis and increased incidence of hepatic encephalopathy. In the light of the available evidence, what is the place of TIPSS in current clinical practice? The first application of TIPSS was in the treatment of variceal haemorrhage, and this remains the main indication for TIPSS. The prevention of rebleeding from oesophageal varices has been the area studied most intensely. There are so far eight prospective randomised clinical trials1-8 comparing TIPSS with endoscopic treatment published as papers and three9-11 published as abstracts (table 1). A meta-analysis12 of these studies has also been published recently. The ensuing discussion will be based on the eight papers as many aspects of the discussion require information not available from the abstracts. In all but one study, bleeding rates were reduced from 35–50% to 10–25%. In the first seven studies, differences in mortality between the treatment groups were not shown. These studies were designed to …

Spontaneous bacterial peritonitis (SBP) may precipitate deterioration of circulatory function with severe hepatic insufficiency, hepatic encephalopathy, and type-1 hepatorenal syndrome (HRS) and has 30% hospital mortality despite infection resolution.1 Predictors of this acute-on-chronic liver failure include ascitic fluid concentrations of granulocytes and cytokines and renal and hepatic insufficiency at diagnosis.1–3 Endotoxemia and the inflammatory response precipitate renal failure (RF) by accentuating splanchnic vasodilatation and impairing cardiac function.3–5 Compensatory activation of the renin-angiotensin and sympathetic nervous systems further decrease renal perfusion. Volume expansion with albumin (1.5 g/kg day one, 1 g/kg day three) significantly reduces the incidence of HRS and hospital mortality.2 In the sole reported trial, only patients with serum bilirubin (bili) >68.4 μmol/l, blood urea nitrogen (BUN) >30 mg/dl or serum creatinine (Cr) >88.4 μmol/l appeared …

The endothelins are a group of three related peptides with two receptor subtypes, ET(A) and ET(B). Following the discovery of endothelin 1 as a potent vasoconstrictor, there has been intense interest in the role of endothelin on vascular function in liver disease. Speculation on the role of endothelin in the pathogenesis of acute renal failure, including hepatorenal syndrome, has also been speculated.

Background Hepatorenal syndrome in cirrhosis with ascites is a well-defined entity with significant morbidity and mortality. It is unclear whether milder degrees of acute kidney injury (AKI), defined as a serum creatinine increase of over 26.4 μmol/l (0.3 mg/dl) or by 50% from baseline, also has a negative impact on patient outcomes. Objectives To determine the prevalence of AKI in cirrhosis with ascites and the impact of AKI on patient outcomes. Design Patients with cirrhosis with ascites and baseline serum creatinine less than 110 μmol/l, and no evidence of structural renal disease, prospectively underwent 4–6-weekly blood work-up for full blood count, biochemistry and liver function. Clinical assessments occurred every 4 months for the development of AKI and other complications. Results 90 patients (mean age 55.8±0.8 years) with a mean follow-up of 14.05±1.07 months were enrolled. 82 episodes of AKI occurred in 49 patients, with the majority of episodes precipitated by a disturbance in systemic haemodynamics. The mean peak serum creatinine of the AKI episodes was within the laboratory9s normal range. 73 episodes of AKI resolved; nine did not. There was no clear clinical predictor for the development or resolution of AKI. Despite resolution of most AKI episodes, a gradual and significant increase in serum creatinine and a gradual reduction in mean arterial pressure were observed during follow-up, associated with a significant reduction in survival compared with non-AKI patients. Conclusion Minor increases in serum creatinine are clinically relevant and can adversely affect survival. Every effort should be made to avoid precipitation of AKI in cirrhosis and ascites.

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.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.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.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 (p0.05), 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.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.

Although renal dysfunction is a common complication of acute liver failure (ALF) with significant prognostic implications, the pathophysiological mechanisms remain unclear. The current hypothesis suggests that the renal dysfunction may mirror the hepatorenal syndrome of cirrhosis. However, ALF has distinct clinical characteristics and the circulatory derangement may be more comparable with sepsis.To examine the relationship between the systemic inflammatory response syndrome (SIRS) and renal dysfunction in ALF, and to identify additional risk factors for renal dysfunction.A single-centre retrospective study of 308 patients with ALF was carried out. Renal dysfunction was defined according to the RIFLE criteria for acute kidney injury.67% of patients developed renal dysfunction. On univariate analysis, renal dysfunction patients were more likely to be hypothermic (p = 0.010), had a faster heart rate (p0.001), a higher white cell count (p = 0.001) and a lower PaCO(2) (p = 0.033). 78% of renal dysfunction patients and 53% of non-renal dysfunction patients had SIRS (p0.001). On multivariate analysis, the risk factors for renal dysfunction were age (p = 0.024), fulfilled Kings College Hospital prognostic criteria (p0.001), hypotension (p0.001), paracetamol-induced ALF (p0.001), infection (p = 0.077) and SIRS (p = 0.017). SIRS remained an independent predictor of renal dysfunction in the subgroup of patients with non-paracetamol-induced ALF (n = 91, p = 0.001). In contrast, in patients with paracetamol-induced ALF (n = 217), no relationship between SIRS and renal dysfunction was demonstrated (p = 0.373).SIRS is strongly associated with the development of renal dysfunction in patients with non-paracetamol-induced ALF. It is proposed that the systemic inflammatory cascade plays a key role in its pathogenesis.

Introduction Hepatorenal syndrome (HRS) is a feared complication of cirrhosis characterised by intense renal vasoconstriction. The pathophysiology remains unclear, pharmacotherapy is limited and mortality is high. We investigated vascular responsiveness and the pathogenesis of renal vasoconstriction in models of advanced rat cirrhosis. Additionally,we determined the mechanism of action of the vasoactive peptide relaxin (RLN), previously shown to increase renal blood flow (RBF) in experimental cirrhosis (Snowdon V et al ., BSG 2013). Methods We induced cirrhosis,reduced RBF and renal dysfunction in male SD rats by carbon tetrachloride (16 wk) or bile duct ligation (4 wk). Arteries from renal (renal, segmental, interlobar) and splanchnic circulation were isolated for functional assessment using wire myography. qPCR array for vasoactive signalling genes,western blot for eNOS signalling proteins and NOS activity assay were undertaken in cirrhotic and control kidneys. Markers of oxidative stress and inflammatory cytokines were measured in serum by ELISA. We studied the effects of s.c. infusion of recombinant human RLN(seralaxin;72 h, 4 µg/h) on these parameters. Doppler USS measured changes in cardiac output (CO) and renal arterial resistive index (RRI) in response to i.v. RLN (4 µg). Kidney endothelial morphology was assessed by electron microscopy, H+E and PAS stained kidney by light microscopy. Results In renal arteries from control and cirrhotic rats endothelial vasodilatation was eNOS-dependent. In cirrhotic rats endothelium-dependent relaxation (acetylcholine; 10–9–3 × 10–5 M) was dramatically reduced (p Conclusion Renal vascular endothelial dysfunction characterises experimental cirrhosis, through a reduction in renal eNOS activity. This impairment may contribute to the renal vasoconstriction seen in cirrhosis and is a promising target for therapeutic modulation. RLN treatment restored renal endothelial vasodilatation. The potential for recombinant forms of RLN as a haemodynamic modulator in human cirrhosis and HRS merits investigation in translational studies. Disclosure of Interest None Declared.

Introduction Terlipressin is used in the management of VB and HRS. Studies have suggested decrease in Na levels on terlipressin, usually in VB. We set out to report the incidence of fall in serum Na in patients receiving terlipressin for VB or HRS. Methods Consecutive patients admitted to Gwent Liver Unit who received terlipressin were identified. Main outcome measure was fall in Na level during and up to 5 days post therapy. Results 60 patients were analysed (32 HRS, 28 VB). Median Na pre-treatment was 133 and 29/60 (48%) had existing hyponatraemia; 16 (27%) had Na Na fell in 34/60 patients (57%) and was less likely if baseline hyponatraemia existed (38% VS 74% p = 0.004). A fall of ≥5mmol/l occurred in 23%. Median time to nadir Na was 3 days and time to recovery to pre-treatment Na was 6.5 days. No complications of hyponatremia were observed. Patients with VB were more likely (vs HRS patients) to have any fall in Na or a ≥5mmol/l reduction (68% vs 47% p = 0.1 and 32% vs 16% p = 0.12 respectively) but failed to reach significance. Mortality was 22% overall and a fall in Na was actually associated with reduced mortality –9% vs 34% (p = 0.01). Conclusion Serum Na falls in >50% receiving terlipressin and a fall ≥5mmol/l noted in 23%. However, no significant complications occurred and a fall in serum Na was actually associated with improved mortality. Patients with VB treated with terlipressin trended towards a greater likelihood of Na reduction versus those with HRS. Disclosure of Interest None Declared.

Liver cirrhosis is a leading cause of mortality in Western countries and the major risk factor for the development of hepatocellular carcinoma, a difficult to treat malignancy with a poor prognosis. In recent years, the management of cirrhotic patients has considerably improved due to better ability to deal with complications such as portal hypertensive bleeding, hepatorenal syndrome and hepatocellular carcinoma. Unless the causal agent is removed, no therapies are currently available to slow down the progressive worsening of hepatic function after the development of cirrhosis, and liver transplantation remains the only approach that has an impact in the long term. Considerable advancements have also been made in the understanding of the pathophysiology of hepatic fibrosis, and the pivotal role played by hepatic inflammation has been clearly defined. Inflammation is part of the tissue ‘wound healing’ response, and leucocyte populations differentially modulate the process of fibrogenesis, that leads to the development of cirrhosis.1 Monocytes and activated macrophages contribute to the development and progression of fibrosis via expression of numerous cytokines, such as platelet-derived growth factor and transforming growth factor-β1, or generation of reactive oxygen intermediates. The role of T cells is more complex, and the available data indicate that a Th1-polarised response is associated with reduced deposition of extracellular matrix, partly mediated by secretion of interferon (IFN)-γ, whereas Th2-related cytokines such as interleukin (IL)-4 and IL-13 cause a more rapid progression of fibrosis.1 Once cirrhosis has been established, the presence of inflammation and the related hyperproduction of cytokines, including tumour necrosis factor (TNF)-α, in the splanchnic district and in the systemic circulation, is responsible for the worsening of portal hypertension and appearance of hyperdynamic circulation.2 …

BACKGROUND/AIMS—C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is considered to be involved in the regulation of vascular tone. Furthermore, the recent demonstration of CNP in human kidney and urine may indicate a role for CNP in fluid and electrolyte homeostasis. Therefore, the aim of the present study was to investigate the possible role of CNP in renal function disturbances in patients with cirrhosis of the liver. METHODS—Peripheral venous and urinary concentrations of CNP were determined in samples from 11 healthy controls, 20 cirrhotic patients with normal renal function (creatinine clearance 117 (8) ml/min), and 20 cirrhotic patients with impaired renal function (creatinine clearance 35 (4) ml/min). In a second protocol, arterial and renal venous plasma concentrations of CNP were determined in 37 patients with cirrhosis of the liver to estimate renal extraction ratios of CNP. A sensitive and specific radioimmunoassay was applied after solid phase extraction of samples. RESULTS—Plasma CNP was lower in cirrhotic patients with normal and impaired renal function than in controls (3.0 (0.4) and 2.7 (0.2) v 4.2 (0.4) pg/ml, respectively; p< 0.05; mean (SEM)). In contrast, urinary CNP was higher in patients with impaired renal function compared with those with normal renal function and healthy controls (47.2 (7.4) v 20.8 (1.9) and 17.0 (3.0) ng CNP/g creatinine, respectively; p

BACKGROUND—Recent small studies on hepatorenal syndrome (HRS) indicate some clinical benefit after transjugular intrahepatic portosystemic stent-shunt (TIPS) but sufficient long term data are lacking. AIM—We studied prospectively feasibility, safety, and long term survival after TIPS in 41 non-transplantable cirrhotics with HRS (phase II study). PATIENTS AND METHODS—HRS was diagnosed using current criteria (severe (type I) HRS, n=21; moderate (type II) HRS, n=20). Thirty one patients (14 type I, 17 type II) received TIPS (8-10 mm) while advanced liver failure excluded shunting in 10. During follow up (median 24 months) we analysed renal function and survival (Kaplan-Meier). RESULTS—TIPS markedly reduced the portal pressure gradient (21 (5) to 13 (4) mm Hg (mean (SD)); p

Recent small studies on hepatorenal syndrome (HRS) indicate some clinical benefit after transjugular intrahepatic portosystemic stent-shunt (TIPS) but sufficient long term data are lacking.We studied prospectively feasibility, safety, and long term survival after TIPS in 41 non-transplantable cirrhotics with HRS (phase II study).HRS was diagnosed using current criteria (severe (type I) HRS, n=21; moderate (type II) HRS, n=20). Thirty one patients (14 type I, 17 type II) received TIPS (8-10 mm) while advanced liver failure excluded shunting in 10. During follow up (median 24 months) we analysed renal function and survival (Kaplan-Meier).TIPS markedly reduced the portal pressure gradient (21 (5) to 13 (4) mm Hg (mean (SD)); p0.001) with one procedure related death (3.2%). Renal function deteriorated without TIPS but improved (p0.001) within two weeks after TIPS (creatinine clearance 18 (15) to 48 (42) ml/min; sodium excretion 9 (16) to 77 (78) mmol/24 hours) and stabilised thereafter. Following TIPS, three, six, 12, and 18 month survival rates were 81%, 71%, 48%, and 35%, respectively. As only 10% of non-shunted patients survived three months, total survival rates were 63%, 56%, 39%, and 29%, respectively. Multivariate Cox regression analysis revealed bilirubin (p0.001) and HRS type (p0.05) as independent survival predictors after TIPS.TIPS provides long term renal function and probably survival benefits in the majority of non-transplantable cirrhotics with HRS. These data warrant controlled trials evaluating TIPS in the management of HRS.