Review article: pathogenesis and pathophysiology of hepatorenal syndrome is there scope for prevention?

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1 Aliment Pharmacol Ther 2004; 20 (Suppl. 3): Review article: pathogenesis and pathophysiology of hepatorenal syndrome is there scope for prevention? S. MØLLER & J. H. HENRIKSEN Department of Clinical Physiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark SUMMARY The hepatorenal syndrome (HRS) is a functional impairment of the kidneys in chronic liver disease caused by a circulatory failure. The prognosis is poor, particularly with type 1 HRS, but also type 2, and only liver transplantation is of lasting benefit. However, recent research into the pathophysiology of ascites and HRS has stimulated new enthusiasm in their prevention and treatment. Patients with HRS have hyperdynamic circulatory dysfunction with reduced arterial blood pressure and reduced central blood volume, owing to preferential splanchnic arterial vasodilatation. Activation of potent vasoconstricting systems, including the sympathetic nervous and renin-angiotensin-aldosterone systems, counteracts the arterial vasodilatation and leads to a pronounced renal vasoconstriction with renal hypoperfusion, a reduced glomerular filtration rate, and intense sodium-water retention. Thus prevention of HRS should seek to improve liver function, limit arterial hypotension and central hypovolaemia, and reduce renal vasoconstriction and the renal and interstitial pressures. Portal pressure can be reduced with b-adrenergic blockers and transjugular intrahepatic portosystemic shunt (TIPS). Precipitating events, like infections, bleeding, and postparacentesis circulatory syndrome, should be treated to avoid further circulatory failure. Improvement in arterial blood pressure and central hypovolaemia can be achieved with vasoconstrictors, such as terlipressin (Glypressin Ò ), and plasma expanders such as human albumin. In the future endothelins, adenosine antagonists, long-acting vasoconstrictors, and antileukotriene drugs may play a role in preventing and treating HRS. INTRODUCTION In cirrhotic patients with portal hypertension the severe complications of sodium-water retention and bleeding from oesophageal varices determine the prognosis. 1 Ascites is a very common complication and often leads to progressive renal impairment; 2 patients with refractory ascites usually develop hepatorenal syndrome (HRS). 3 Renal sodium handling is abnormal during the preascitic stage. 3 The HRS is defined as a functional renal failure without significant morphological changes in kidney histology and a largely normal tubular Correspondence to: Dr S. Møller, Department of Clinical Physiology 239, Hvidovre Hospital, DK-2650 Hvidovre, Denmark. soeren.moeller@ hh.hosp.dk function. 3 Two types of HRS have been defined: 3 type 1 HRS is an acute form with a rapid decrease in renal function in which the renal failure is an independent prognostic factor with very poor survival measured in weeks; type 2 HRS is a chronic form with more stable renal dysfunction. 3 Most of today s knowledge derives from studies of type 1 HRS. In cirrhotics, splanchnic arteriolar vasodilatation leads to underfilling of the central circulation with a compensatory activation of systemic and renal vasoconstrictor systems 4 (Figure 1). A progressive afferent arterial renal vasoconstriction causes pronounced renal hypoperfusion with a reduced glomerular filtration rate (GFR) and increased tubular sodium and water reabsorption leading to severe renal failure, 3, 4 with a prognosis between weeks and months. Liver transplan- Ó 2004 Blackwell Publishing Ltd 31

2 32 S. MØLLER & J. H. HENRIKSEN Ascites Vasoconstrictors All, Adenosin, ET-1 Vasodilator NO, PG Hepatorenal reflex? Renal hypoperfusion Cirrhosis Liver failure Portal hypertension Arterial vasodilatation Arterial hypotension Central hypovolaemia HRS Baroreceptor activation SNS RAAS Vasopressin tation is the only curative treatment for HRS. 3 This scenario has changed with the use of systemic vasoconstrictors such as terlipressin (Glypressin Ò ) and 3, 5 7 plasma expanders, but more research is needed. In this review we focus on abnormalities in systemic haemodynamics, abnormal systemic and renal neurohumoral regulation, as well as the liver dysfunction as possible targets for prevention. LIVER FUNCTION AND THE HEPATORENAL SYNDROME Cardiac dysfunction Figure 1. Pathophysiological mechanisms in the development of the HRS. Increasing hepatic dysfunction is associated with the development of renal dysfunction. 3, 8 The HRS is seen in about 4 5% of cirrhotics hospitalized with ascites. 3 In decompensated patients, about 20% will develop HRS within 1 year and 40% within 5 years. 3, 8 Haemodynamic changes are illustrated in Table 1. The normalization of renal function after liver transplantation is a strong indicator that the liver is directly involved in the renal disturbances. 3, 9 In experimental studies, increases in intrahepatic pressure resulted in increased renal sympathoadrenergic activity with decreases in the renal blood flow (RBF) and GFR and increases in tubular reabsorption of sodium and water, 10 whereas hepatic denervation delayed sodium-water retention and formation of ascites. 11 In 20 cirrhotics with transjugular intrahepatic portosystemic shunt (TIPS), shunt occlusion with a balloon resulted in a reduced RBF correlating with increased portal pressure. 12 In another 10 patients, the GFR and sodium excretion improved after TIPS insertion. 13 Acute induction of portal hypertension similarly reduced the renal plasma flow with a concordant rise in renal release of endothelin-1 (ET-1), a potent renal Table 1. Hepatic, renal, and systemic haemodynamic and functional changes of importance for the development of renal failure in cirrhosis Liver function Hepatic blood flowfl fi ( ) Hepatic venous pressure gradient Postsinusoidal resistance Metabolic liver function fl Kidney function Renal blood flowfl Glomerular filtration ratefl fi Sodium excretion fl Free water clearance fl Systemic circulatory changes Plasma volume Total blood volume Noncentral blood volume Central and arterial blood volumefl ( fi ) Cardiac output Arterial blood pressurefl ( fi ) Heart rate Systemic vascular resistancefl vasoconstrictor. 14 These studies support the existence of a hepatorenal reflex. It is activated via adenosine receptors 15 as in animals, and hepatic denervation and administration of an adenosine receptor antagonist prevented an increase in sodium and water retention following a reduction in portal venous blood flow. SYSTEMIC AND RENAL HAEMODYNAMIC CHANGES The changes leading to plasma volume expansion and increased cardiac output, together with the progressive activation of the neurohumoral system seen during formation of ascites and onset of HRS, are best explained by the Ôperipheral arterial vasodilatation hypothesisõ. 3, 4 Arterial vasodilatation and circulatory dysfunction The arterial blood pressure, systemic vascular resistance, and cardiac output are often normal in the early stages of cirrhosis. As cirrhosis progresses, the circulation becomes increasingly hyperdynamic with augmented cardiac output, stroke volume, and heart rate, and low arterial blood pressure and systemic vascular resistance 16, 17 (Table 1). The circulation is primarily hyperdynamic in the supine position. 18, 19 b-adrenergic blockers may attenuate the hyperdynamic circulatory state. 20

3 REVIEW: PREVENTION OF HEPATORENAL SYNDROME 33 Table 2. Potential vasoactive mediators implicated in the haemodynamic alterations in the HRS (alphabetical order) Vasodilator systems Adrenomedullin Atrial natriuretic peptide (ANP) Bradykinin Brain natriuretic peptide (BNP) Calcitonin gene-related peptide (CGRP) Carbon monoxide (CO) Endocannabinoids Endothelin-3 (ET-3) Endotoxin Enkephalins Glucagon Histamine Interleukins Natriuretic peptide of type C (CNP) Nitric oxide (NO) Prostacyclin (PGI 2 ) Substance P Tumour necrosis factor-a (TNF-a) Vasoactive intestinal polypeptide (VIP) Vasoconstrictor systems Angiotensin II Adrenaline (epinephrine) and noradrenaline (norepinephrine) Endothelin-1 (ET-1) Neuropeptide Y Renin-angiotensin-aldosterone system (RAAS) Sympathetic nervous system (SNS) Arginine vasopressin (AVP) There is both experimental and clinical data demonstrating arteriolar splanchnic vasodilatation but the vasodilators are as yet not identified; with overproduction of circulating vasodilators, decreased degradation of intestinal or systemic ones due to the diseased liver, and bypassing through portosystemic collaterals 21 all potentially contributing to this. Potential candidates have been identified (Table 2), with nitric oxide (NO), calcitonin gene-related peptide (CGRP), adrenomedullin, endocannabinoids 25 and plasma substance P 26 receiving recent attention. Vasodilatation, predominantly splanchnic, precedes renal sodium and water retention and plasma volume expansion, correlating with activation of counterregulatory vasoconstrictor systems. 1, 21 The arterial vasodilation leads to abnormal volume distribution, so that the ability to maintain an effective blood volume is progressively lost. 4 Reduced central and arterial blood volume leads to activation of vasoconstrictor systems and secondary sodium-water retention 4 (Figure 1). Arterial hypotension Renal perfusion depends on an adequate arterial blood pressure, which is low or low-normal in cirrhotics, worsening with increasing hepatic dysfunction, with a changing balance between vasodilating and counterregulatory vasoconstricting forces. 4, 20, 27, 28 In cirrhotic rats blockade of NO-synthase (NOS), 29 as well as the endocannabinoid CB1 receptor, increased arterial blood pressure. 25 The normal circadian variation of arterial blood pressure is maintained by an arterial negative feedback baroreceptor reflex, but in cirrhotics day time arterial pressure is substantially reduced, whereas night time values are normal. 30 Normalization of the low arterial blood pressure in decompensated cirrhosis, using noradrenaline 31 or AVP 32 infusion, and 2, 7, 28 pressor doses of angiotensin II increase renal 31, 32 perfusion and sodium excretion in some patients, and cirrhotics with compensated cirrhosis and arterial hypertension have less renal dysfunction 19 (Figure 2). Prolonged administration of ornipressin combined with albumin infusion can reverse HRS. 33, 34 Thus systemic hypotension, the abnormal circadian variation in arterial blood pressure, and activation of neurohumoral systems all contribute to the sodium and fluid retention and abnormal regulation and distribution of the circulating volume in cirrhotics. Renal dysfunction With progression of cirrhosis there is decreased RBF, decreased GFR, increased sodium reabsorption, and decreased free water excretion 2 (Table 1 and Figure 3). In the preascitic phase there are only slight increases in plasma volume, and sodium excretion is reduced after a saline load, with abnormal natriuretic responses to posture. 35 The cause of the abnormal sodium metabolism is unknown, but it is not due to decreased synthesis of natriuretic peptides. 36 With increasing formation of ascites, the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) are activated. 28 Because of the arterial vasodilation, the renal perfusion pressure is low and critically dependent on the counterregulatory systems. For these reasons, blockade of these systems by angiotensin converting enzyme (ACE)-inhibitors (captopril), angiotensin II

4 34 S. MØLLER & J. H. HENRIKSEN Figure 3. Renal blood flow in controls, in compensated and decompensated cirrhosis and in HRS. Renal blood flow was assessed by the 133 Xe wash-out method. There is a progressive fall in renal blood flow with the severity of liver disease. (Adapted from Ring-Larsen H. Scand J Clin Laboratory Invest 1977; 37: ) Figure 2. Dependency of renal blood flow on arterial blood pressure in decompensated cirrhosis and decreased renal function. The arterial blood pressure was raised by intravenous infusion of angiotensin II. (Adapted from Henriksen JH, Ring-Larsen H. Hepatology 1993; 18: ) antagonists (losartan), b-adrenergic blockers, and V1 AVP antagonists may decrease RBF further. In the normal kidney, the RBF is constituted by cortical perfusion (90%), medullary perfusion (9%), and the inner medullary area (1 2%). 37 Only the cortical perfusion undergoes autoregulation. Increasing renal perfusion pressure (arterial blood pressure minus renal venous pressure) up to about 70 mmhg, 38 leads to a linear increase in RBF, but then no further increase until about 140 mmhg. Conversely, medullary blood flow increases almost linearly. 38 This is the physiological basis to increasing blood pressure leading to increased diuresis, 38 which can increase sodium excretion. 38 The renal interstitial hydrostatic pressure is constant throughout the kidney, and the balance between the afferent and efferent arteriolar tone is the most important factor regulating GFR. The renal cortical autoregulation curve shifts to the right with a lower slope so that the pressure for starting autoregulation is higher, and the overall RBF is reduced 39 (Figure 4). The kidney in cirrhotics, particularly those with severe disease and HRS, has highly elevated sympathoadrenal activation, reduced cortical blood flow, reduced renal Figure 4. Possible elements of importance in the abnormal autoregulation in cirrhosis and hepatorenal syndrome: 1, reduced renal blood flow; 2, reduced slope; 3, right-shifted break in the autoregulation curve; 4, low renal perfusion pressure.

5 REVIEW: PREVENTION OF HEPATORENAL SYNDROME 35 perfusion pressure, and increased renal interstitial pressure, all of which reduce RBF, GFR, sodium excretion, and diuresis. Many patients have passed to the left of the autoregulatory point, and any rise in renal perfusion pressure (rise in arterial blood pressure, fall in renal venous pressure) will increase the RBF, GFR, sodium excretion, and diuresis. Therefore reducing portal venous pressure, increasing arterial blood pressure, reducing renal venous pressure, paracentesis, effective blood volume expansion, etc., can improve kidney function, and thus improve HRS, or postpone its onset. The development of HRS is characterized by low arterial blood pressure, and severe renal vasoconstriction with increased plasma levels of renin, noradrenaline (norepinephrine), and AVP. 8 GFR falls below 40 ml/min with severe sodium retention (decreased filtered sodium, increased sodium reabsorption in the proximal tubules with little sodium reaching the distal nephron). Renal hypoperfusion is primarily due to increased renal vasoconstrictor activity despite production of intrarenal vasodilators like prostacyclin and NO. However, blockade of systemic NO production improves renal perfusion and function whereas adenosine impairs it, indicating greater sensitivity to 40, 41 renal vasoconstrictors. As reduced cardiac contractility and output caused by cirrhotic cardiomyopathy 42 may also be involved, spontaneous bacterial peritonitis (SBP) and other infections aggravate renal dysfunction by further systemic vasodilatation and cardiac dysfunction. 43 The reduced free water clearance leads to dilutional hyponatraemia treatable with a V2 AVP receptor antagonist, 44 or kappa-opioid antagonist in the pituitary glands. 3 NEUROHUMORAL REGULATION OF RENAL FUNCTION Activation of the RAAS contributes to reduced renal perfusion, but it may have more complex intrarenal regulatory effects. 45 AVP does not change the renal perfusion substantially 46 but noradrenaline (norepinephrine), adrenaline (epinephrine), and ET-1 are powerful renal vasoconstrictors contributing to renal hypoperfusion and sodium-water retention 3 (Table 2). Local vasodilators, like the prostaglandins, compensate, at least in part, for the progressive renal vasoconstriction, 47 as may do the natriuretic peptides (raised in HRS), as blockade in animal models reduces RBF and GFR. Low-dose theophylline increases renal venous blood flow by more than 50%, suggesting that adenosine plays a role in the renal vasoconstriction in cirrhosis. 41 Renal vasodilators Administration of COX-inhibitors to ascitic patients often leads to renal failure, which usually reverses following discontinuation. 3 Reduced production of prostaglandin E 2 and prostacyclin probably occur as there are decreased urinary concentrations compared with ascitic patients with preserved renal perfusion. 48 NO synthesized by NOS and the renal vascular endothelium is a potent vasodilator, diminishing the effect of endogenous vasocontrictors on RBF and GFR. 49 However there is a diminished release from sinusoidal 3, 50 endothelial cells in the cirrhotic liver, but in the systemic circulation there is increased enos up-regulation (related to shear stress) so that NO is involved in the peripheral vasodilation in cirrhosis. 51 Thus blockade of NO formation significantly raises arterial blood pressure and decreases plasma volume and sodium retention. RENAL VASOCONSTRICTOR SYSTEMS Sympathetic nervous system The SNS is highly activated in cirrhosis with increased circulating levels of catecholamines: plasma noradrenaline (norepinephrine) level is directly related to sympathetic nervous burst frequency. 52 In the kidney, sympathetic nerve fibres supply afferent and efferent renal vessels and mesangial, juxtaglomerular, and tubular cells; renal nervous stimulation decreases RBF and GFR. In cirrhotics, stimulation of tubular cell a- adrenergic receptors increases sodium reabsorption, whereas renin release from the juxtaglomerular apparatus is mediated by activation of b-adrenoceptors. In renal vessels a 1 -adrenergic receptors are abundant and RBF is reduced in HRS mainly due to constriction of the efferent arteriole, which is preferentially constricted. Thus the GFR may be normal or even increased in early decompensated cirrhosis, but as the liver disease progresses, there is a concomitant decrease in renal perfusion and filtration. If the efferent arteriole is constricted, GFR is less affected than RBF, owing to high filtration pressure, as found in ascitic patients. 53

6 36 S. MØLLER & J. H. HENRIKSEN Patients with HRS have high sympathetic nervous activity and RBF is low, and the GFR is substantially decreased with pronounced sodium and water retention. 21 There is a highly significant inverse correlation between noradrenaline (norepinephrine) overflow and renal vein noradrenaline (norepinephrine) concentrations and RBF, 53 and an inverse correlation between the decreased central blood volume and the renal venous noradrenaline 20, 53 (Figure 5). Attempts to reverse the renal sympathetic nervous activity by a-adrenergic blockers, such as phentolamine and phenoxybenzamine, have been disappointing. 13 The renin-angiotensin-aldosterone system The elevated plasma renin activity correlates inversely with the RBF and GFR. 45 Infusion of angiotensin II which acts mainly on efferent arterioles further reduces the RBF in some cirrhotics but may also improve it (Figure 2). Low doses of captopril induce a further reduction in GFR, filtration fraction, and in sodium excretion. 54 Infusion of losartan decreased portal pressure but had no significant effects on the renal function. 54 However a review 54 has shown that ACE-inhibitors and angiotensin II receptor antagonists are potentially dangerous in cirrhotics, as the RAAS is essential in counteracting arterial hypotension so that they may cause severe hypotension and further deterioration in renal and circulatory function. ml/g/min Renal blood flow Renal venous plasma NA r = 0.69 P < ng/ml Figure 5. Relation between renal blood flow and renal venous plasma noradrenaline (norepinephrine) indicating the dependency of renal blood flow on sympathetic nervous activity. s indicates controls, d indicates compensated cirrhosis, and n indicates decompensated cirrhosis (adapted from Henriksen JH, Christensen NJ, Ring-Larsen H. Circulating noradrenaline (norepinephrine) and central haemodynamics in patients with cirrhosis. Scand J Gastroenterol 1985; 20: ). Arginine vasopressin The potent vasoconstrictor AVP is increased in cirrhosis owing to nonosmotic pituitary release. In the distal nephron, AVP acting on the V2 receptor promotes insertion of the water channel, aquaporin-ii, contributing to the pronounced water reabsorption in advanced HRS, with increased aldosterone release. 55 AVP causes vasoconstriction through V1 receptors on splanchnic and peripheral arteries, causing hypotension. 56 In cirrhotics the AVP V2 receptor antagonist (VPA-985) improved serum sodium without causing further deterioration in the renal function or the arterial blood pressure. 44 Endothelin Endothelins are potent vasoconstrictors and increased circulating concentrations and hepatic release are found in cirrhotics; the highest levels in those with severe dysfunction and HRS. 57 Whether this system is counterregulatory for the systemic vasodilatation is not yet proven, but increased renal formation of endothelin in HRS indicates involvement in the marked renal vasoconstriction. 57, 58, 59 Human studies of endothelin antagonists and renal perfusion are awaited. 60 Autonomic and cardiac dysfunction Autonomic dysfunction in cirrhosis is correlated with liver and renal function and survival. 61 There are SNS defects, but also vagal impairment affecting sodium and fluid retention. 62 Blood pressure responses to orthostasis are impaired, due to a blunted baroreflex function 63, 64 and the cardiovascular responses to angiotensin II, noradrenaline (norepinephrine), and 65, 66 vasopressin are abnormal. Canrenone, an aldosterone antagonist, normalized cardiac responses to postural changes in compensated cirrhotic patients, i.e. there is some neuromodulation by the RAAS. 64 Thus, increased activity of the RAAS in HRS may affect the impaired cardiovascular regulation, the vascular hyporeactivity, and the autonomic dysfunction, in turn affecting renal haemodynamics and function. Cirrhotic cardiomyopathy may also affect renal function. 67 Normalization of the low systemic vascular resistance with vasoconstrictors results in a rise in the left atrial and left ventricular filling pressures. 67

7 REVIEW: PREVENTION OF HEPATORENAL SYNDROME 37 Normalizing the low cardiac afterload may unmask a latent ventricular failure, which appears to be resistant to inotropic drugs. 42 The expanded blood volume in advanced cirrhosis may increase cardiac preload and contribute to cardiac overload. 18, 68 Increased stiffness of the myocardial wall may result in impaired left ventricular filling and a diastolic dysfunction. 69 Studies of ventricular diastolic filling in cirrhosis support the presence of a sub-clinical myocardial disease with diastolic dysfunction which, in ascitic patients, improves after paracentesis and worsens after TIPS. 68, 70 An inverse correlation between diastolic dysfunction and plasma aldosterone has been shown. In addition, cardiac natriuretic peptides that reflect atrial and ventricular dysfunction, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and probnp are increased in many cirrhotics. 36 Decompensated patients with SBP and renal failure had a lower cardiac output than those without renal failure and the cardiac output further decreased despite antibiotic treatment. 43 Thus renal failure may be due to a mixed cirrhotic and septic cardiomyopathy. HRS develops as a combination of arterial vasodilatation, central hypovolaemia, cardiac dysfunction, and renal vasoconstriction and hypoperfusion. SCOPE FOR PREVENTION Prevention and early treatment of HRS should avoid or minimize further deterioration in liver and circulatory functions and renal hypoperfusion (Table 3). Furthermore, precipitating factors should be eliminated, such as administration of potentially nephrotoxic drugs, unrestricted use of diuretics, infections, and portal hypertensive bleeding. Liver dysfunction and portal hypertension Portal pressure can be reduced by drugs, e.g. b-blockers, or portal decompression, e.g. TIPS. However, administration of b-adrenergic blockers increases circulating noradrenaline (norepinephrine), enhancing a-adrenergic tone despite an almost unaltered arterial blood pressure, and inhibits the RAAS, reducing renin, angiotensin II, and aldosterone levels. 45 This results in increased water retention (enhanced a-adrenergic tone), reduced sodium retention (fall in aldosterone and angiotensin II levels), and unchanged or increased sodium and water retention (fall in cardiac output). Table 3. Potential targets for prevention of the HRS in cirrhosis Decreased liver function Portal hypertension b-receptor blockade Nitrates TIPS Decreased kidney function Renal vasoconstriction ET-antagonists Adenosine antagonists Anti-leukotriene drugs Low glomerular filtration rate Terlipressin and volume expansion Low sodium excretion Increase in arterial blood pressure Amelioration of central hypovolaemia (albumin) Diuretics thoroughly administered Dilutional hyponatraemia Vasopressin V2 antagonists Increased renal venous pressure Paracentesis Systemic circulatory dysfunction Low central and arterial blood volume Vasoconstrictors, plasma expanders High cardiac output b-receptor blockade Vasoconstrictors Low arterial blood pressure and systemic vascular resistance Vasoconstrictors Plasma expanders High heart rate b-receptor blockade Vasoconstrictors However, in combination these effects do not lead to kidney dysfunction. Conversely, nitrates may cause significant reductions in systemic vascular resistance and arterial blood pressure and a further decrease in RBF and GFR, free-water clearance, and sodium excretion with significant activation of the SNS and RAAS. Thus portal pressure reduction with sole use of nitrates is not recommended. TIPS is used to prevent variceal bleeding, refractory ascites, and as a bridge to liver transplantation in HRS. 71 In uncontrolled studies TIPS improved renal function in some patients with refractory ascites but without HRS, but had no benefit in others. 71, 72 The improvement is associated with an increase in cardiac output and a simultaneous suppression of the RAAS and SNS activities, and release of AVP. 73 Although TIPS may help in refractory ascites, it is not known whether HRS can be prevented or delayed.

8 38 S. MØLLER & J. H. HENRIKSEN Circulatory dysfunction Arterial blood pressure must be increased to improve RBF, GFR, and natriuresis (Figures 2 and 4). Vasoconstrictors alone or in combination with plasma expanders have improved arterial vasodilatation, hypotension, and 74, 75 renal function. Terlipressin, a long-acting AVP analogue acting on splanchnic V 1a -AVP receptors, increases arterial blood pressure, GFR, and urinary volume in HRS. Reversal of HRS has been observed in several studies. 5, 6, 34, 76, 77 In 99 cirrhotics with HRS, terlipressin and plasma expanders significantly improved renal function and survival. 78 In another study, terlipressin and 20% human albumin reduced serum creatinine, increased arterial blood pressure, suppressed vasoconstrictor systems, and improved survival. 34 Treatment of HRS with AVP analogues before transplantation improves the post-transplantation outcome. 79 Interestingly although terlipressin improves arterial blood pressure, systemic vascular resistance, heart rate, and central circulation time, the central and arterial blood volume only increase slightly. 76 Whether administration of vasoconstrictors in combination with human albumin in decompensated cirrhotics without HRS would improve renal function and prevent development of HRS requires study. 74, 75, 80 Circulatory dysfunction with central hypovolaemia can be seen spontaneously in 10 20% of cirrhotics and occurs after SBP and other infections, and can be prevented by volume expansion with human albumin. 81 Human albumin is preferred to other plasma expanders to avoid postparacentesis circulatory dysfunction, 82 which otherwise occurs in more than 50%. Immediately after paracentesis, the circulatory function improves with rises in cardiac output and stroke volume, and falls in right atrial pressure, and reduced activity in RAAS and SNS; 83 about 12 h later there can be a decreased cardiac output, reduced renal function and increased RAAS and SNS activity. 83 Type 1 HRS develops most frequently after SBP (30% of patients), and most used to die. 84 In cirrhotics with bleeding varices, infections occur in 50%. Prophylactic antibiotics reduce mortality by 10%. 8 Prophylactic broad-spectrum antibiotics and human albumin prevent renal impairment in patients with SBP, 8, 85 reducing the incidence of HRS from 30% to 10%. 81 In alcoholic hepatitis the TNF-a inhibitor oxpentifylline (pentoxifylline) in a single study reduced the incidence of HRS from 35% to 8%. 86 Intensive diuretic therapy adversely affects circulatory function as when diuresis exceeds the rate of ascites reabsorption this leads to intravascular volume depletion. Thus 20% of ascitic patients develop renal impairment with diuretics. 3 Careful administration of diuretics is essential to avoid hypovolaemia. Renal vasoconstriction Local renal vasodilatation with local infusion of misoprostol (synthetic prostaglandin E 1 analogue) and infusion of prostaglandin E 2 did not significantly change the GFR or sodium excretion in HRS. 47, 87 Preventive antileukotriene therapy has been suggested, but clinical trials are needed. The ET A -antagonist BQ-123 improves renal perfusion transiently. 60 A controlled trial is needed to establish both the pathogenetic and therapeutic role of the endothelin system in HRS. Dipyridamole increases adenosine concentrations and impairs renal perfusion in patients with cirrhosis and ascites; 40 conversely theophylline, an adenosine antagonist, increases renal perfusion and theoretically could ameliorate renal vasoconstriction in HRS. 41 Aquaretic drugs may have a role in preventing HRS by improving dilutional hyponatraemia. The V2 receptor antagonist VPA-985 has been shown to normalize serum sodium in 50% of treated patients, 44 so that it could be beneficial in improving free water clearance in HRS. PERSPECTIVES AND CONCLUSIONS HRS is still a major clinical challenge, as for years prognosis has remained poor. To date only liver transplantation has significantly changed the clinical course. For these reasons, attempts to prevent HRS are essential. Combining vasoconstrictors, e.g. terlipressin, and volume expanders such as albumin, is now current practice. Preventing HRS in the future will involve modifying different pathophysiological components. A multitargeted strategy should counteract the arterial vasodilatation, central hypovolaemia, and arterial hypotension through administration of potent vasoconstrictors combined with albumin, which may delay and reverse the development of HRS. Long-acting systemic vasoconstrictors would be preferable. Renal vasoconstriction could be counteracted by theophylline or other adenosine antagonists, TNF-a inhibitors, antileukotriene drugs, or endothelin antagonists. However, the

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