Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia

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Chapter

21

Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia Arun J. Sanyal and Thomas D. Boyer

ABBREVIATIONS AKI  acute kidney injury Akt  serine/threonine protein kinase Ang  angiotensin ATP  adenosine triphosphate cAMP  cyclic adenosine monophosphate CB  cannabinoid cGMP  cyclic guanosine monophosphate CNTs  concentrative nucleoside transporters

CO  carbon monoxide eNOS  endothelial nitric oxide synthetase GFR  glomerular filtration rate

HRS  hepatorenal syndrome H2S  hydrogen sulfide HVPG  hepatic venous pressure gradient iNOS  inducible nitric oxide synthetase MDRD  Modification of Diet in Renal

PGI2  prostacyclin (prostaglandin I2) PTH  parathyroid hormone SBP  spontaneous bacterial peritonitis SLK  simultaneous liver/kidney

Disease MELD  Model for End-Stage Liver Disease NHE  Na+/H+ exchanger nNOS  neuronal nitric oxide synthetase NO  nitric oxide NSAIDs  nonsteroidal antiinflammatory drugs

TGF  tubuloglomerular feedback

Introduction Hepatorenal syndrome (HRS) is a clinical condition characterized by the development of renal dysfunction in the absence of histologically obvious renal disease in patients with advanced liver disease (Table 21-1). The hallmarks of HRS include severe renal vasoconstriction, which decreases renal perfusion and the glomerular filtration rate (GFR) and thus causes renal dysfunction.1 HRS develops in about 50% of subjects with cirrhosis and ascites and is often the harbinger of death.2 Clinically, two forms of HRS with varying rates of progression of renal dysfunction are seen. Type 1 HRS progresses relatively rapidly and is usually associated with death without specific intervention, whereas type 2 HRS follows a more subacute to chronic course. HRS typically occurs in subjects with cirrhosis and ascites. The progression from cirrhosis with ascites to refractory ascites and HRS represents a pathophysiologic continuum that is driven by the presence of sinusoidal portal hypertension and severe systemic arterial vasodilation. Given the clinical significance of HRS, a clear understanding of its pathogenesis, clinical and diagnostic features, and treatment is a cornerstone of the management of cirrhosis. 352

(transplantation) (tubuloglomerular reflex)

TIPS  transjugular intrahepatic portosystemic shunt

TNF  tumor necrosis factor VEGF  vascular endothelial growth factor

Pathophysiology of Hepatorenal Syndrome The pathophysiology of HRS is closely linked to the hemodynamic consequences of cirrhosis with sinusoidal portal hypertension and the ability of the heart and kidneys to compensate for these changes (Fig. 21-1). It is therefore germane to review these changes and their impact on renal function.

Sinusoidal Portal Hypertension and Its Role in Development of Hepatorenal Syndrome It has been appreciated for many years that HRS typically develops in patients with cirrhosis and ascites. Ascites caused by peritoneal infections and tumors is not associated with HRS. In addition, HRS is rarely if ever seen in subjects with cirrhosis who do not have ascites. The development of ascites in patients with cirrhosis requires the presence of clinically significant portal hypertension.1 Normal portal venous pressure, as measured by the hepatic venous pressure gradient



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PORTAL HYPERTENSION 1

Nitric oxide

• Endothelial stretching • Shear stress • VEGF

eNOS activity

Splanchnic vasodilation Peripheral vasodilation (Activation of the neurohormonal compensatory responses)

Central blood volume (Activation of baro and volume receptors)

Na+ and water retention

(Plasma volume, porto-systemic shunting, venous return to the heart)

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Nitric oxide

Bacterial translocation: Endotoxins, TNF-α anandamide, etc.

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2

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Fig. 21-1  Overview of the pathophysiology of portal hypertension and hepatorenal syndrome. Sinusoidal portal hypertension leads to shear stress and endothelial activation in the splanchnic vascular bed, thereby resulting in splanchnic arteriolar dilation. Simultaneously, increased gut permeability because of congestion of the intestines from increased portal venous backpressure causes increased bacterial translocation, which results in a systemic inflammatory state and further worsening of arteriolar dilation. These actions decrease the effective circulating volume and result in the activation of renal Na and water-retentive mechanisms. When renal autoregulation fails to maintain the glomerular filtration rate, renal function declines. eNOS, endothelial nitric oxide synthase; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor. (With permission from Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43(2 Suppl 1):S121–S131.)

Table 21-1  Definition of Hepatorenal Syndrome Cirrhosis with ascites Serum creatinine >1.5 mg/dl (133 µmol/L) No improvement in serum creatinine (<1.5 mg/dl) after at least 2 days of diuretic withdrawal and volume expansion with albumin (1 g/kg) Absence of shock No current or recent treatment with nephrotoxic drugs No proteinuria (<500 mg/day), microhematuria (>50 red blood cells per high-power field), and normal renal ultrasound findings From Salerno F, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318.

(HVPG), is 5 mm Hg or less. Ascites and varices do not develop until the HVPG rises to levels greater than 10 to 12 mm Hg.3 The development of sinusoidal portal hypertension in those with cirrhosis is a function of architectural disruption of the normal hepatic microvasculature and functional changes in sinusoidal blood flow on one hand and increased inflow into the portal vein because of dilation of arterioles in the splanchnic vascular bed on the other.4 Structural disruption of the hepatic microvasculature begins with the development of advanced fibrosis (bridging fibrosis) in subjects with chronic liver disease and is part and parcel of the vascular remodeling that occurs concomitantly with the progression to cirrhosis.

For the past decade it has been well recognized that the hepatic microcirculation is not simply a passive conduit for blood flow but is actively regulated locally. Regulation of the hepatic microcirculation has been reviewed in depth elsewhere5,6 and is beyond the scope of this chapter. Briefly, about 30% of the vascular resistance to flow through the liver is determined by a balance between vasoconstrictive and vasodilatory factors that regulate sinusoidal blood flow. Hepatic stellate cells, which wrap themselves around the hepatic sinusoids, play a key role in this process via their contractile properties, which allow them to constrict or dilate the sinusoids.7 Normally, nitric oxide (NO), a potent vasodilatory molecule, is a key regulator of sinusoidal vascular resistance (Table 21-2).7 Release of NO into the sinusoidal vasculature has recently been shown to be linked to the enterohepatic circulation of bile acids, which activate NO synthesis by endothelial nitric oxide synthetase (eNOS) via specific G protein–coupled (TGR5) receptors.8 eNOS activity is also affected by circulating high-density lipoproteins.9,10 In subjects with cirrhosis, several mechanisms leading to impaired eNOS activation have been identified, including impairment of serine/threonine protein kinase (Akt)-dependent phosphorylation of eNOS, which is partially reversible by statins; increased caveolin expression, particularly in cholestatic states; and deficiency of tetrahydrobiopterin.7,11,12 The availability of NO may be further impaired by its utilization for nitrosylation reactions driven by oxidative stress and increased phosphodiesterase activity. Other factors that have been implicated in intrahepatic vasoconstriction include increased endothelin activity,

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Table 21-2  Mechanisms of Sinusoidal Portal Hypertension Increased Intrahepatic Resistance Fixed architectural disruption Dynamic modulation of intrahepatic resistance to flow Decreased NO production by sinusoidal endothelial cells Increased thromboxanes Increased Splanchnic Arteriolar Vasodilation Increased NO Increased CO Increased prostacyclins Increased endogenous cannabinoids Cytokines that promote vasodilation, such as tumor necrosis factor-α VEGF Adrenomedullin CO, carbon monoxide; NO, nitric oxide; VEGF, vascular endothelial growth factor

enhanced angiotensinogen activation or sensitivity, and increased thromboxane A2 and leukotriene production.13 These factors may be counteracted by increased vasodilatory NO and carbon monoxide (CO) production.14 The role of adrenergic tone, endotoxemia, and inflammatory cytokines is currently under investigation. It is hoped that improved understanding of the dynamic regulation of sinusoidal blood flow in patients with cirrhosis will provide novel “druggable” targets for the correction of sinusoidal portal hypertension and prevention, as well as treatment of its consequences, including HRS. Sinusoidal portal hypertension contributes to the pathophysiologic cascade that leads to the development of ascites and eventually HRS in several ways. It is linked to the systemic arterial vasodilatory state, which in turn has several downstream effects that contribute to Na and water retention initially and renal dysfunction in later stages. Sinusoidal hypertension also directly leads to increased renal sympathetic nervous system activity, which causes renal vasoconstriction and thus diminishes renal perfusion.15 Furthermore, portal vein distention as a result of sinusoidal portal hypertension also contributes to increased renal sympathetic nerve activation.16 It has been shown that thoracic duct constriction, which increases sinusoidal pressure, increases renal efferent sympathetic nerve activity.17,18 These effects are mediated by hepatic baroreceptors, which increase hepatic afferent nerve activity, rather than by volume receptors.18,19 The renal hemodynamic effects are further affected by the specific nerve bundles activated.20 There are also osmoreceptors and volume receptors within the liver that can modulate renal hemodynamics via hepatic humoral responses.21 Section of the hepatic afferents to the vagus nerve does not affect these responses.

The Systemic Hemodynamic Response to Sinusoidal Portal Hypertension The hallmark of the cirrhotic state is systemic arterial vasodilation. It has long been recognized that subjects with cirrhosis and advanced liver failure have a hyperdynamic circulation

characterized by a marked decrease in systemic vascular resistance and an increase in cardiac output.13,22,23 It is further recognized that the observed decrease in systemic vascular resistance is not due to an equal decrease in the resistance of all of the vascular beds and that there are differential changes in different vascular beds. For example, femoral and brachial artery flow is not significantly altered in subjects with cirrhosis, whereas there is profound dilation in the splanchnic arterial circulation. This has been verified experimentally by both direct measurements and measurement of the resistive index of the superior mesenteric artery via sonographic methods.24 Thus splanchnic arterial dilation with relative sequestration of the circulating blood volume within the splanchnic bed is a major hemodynamic consequence of cirrhosis.

Drivers of Systemic Arterial Vasodilation Several neurohumoral mechanisms have been found to be activated in subjects with cirrhosis and contribute to the state of systemic arterial vasodilation. The humoral mechanisms act via systemic, paracrine, and autocrine pathways (Fig. 21-2). The key mechanisms involved are discussed in the following sections (see Table 21-2).

The Nitric Oxide Pathway Nitric oxide is an endothelium-derived factor with potent vasodilatory properties. It activates soluble guanylate cyclase, thereby increasing cyclic guanosine monophosphate (cGMP), which causes smooth muscle relaxation.25 Three isoforms of nitric oxide synthetase (NOS) are involved in the production of NO. Endothelial NOS (eNOS) is constitutively expressed and is the principal source of excess NO in the splanchnic vascular bed.26 Inducible NOS (iNOS) is expressed in a variety of cell types, including macrophages and vascular smooth muscle cells. It can be induced by a number of cytokines, such as tumor necrosis factor-α (TNF-α) or bacterial lipopolysaccharide (endotoxin).5,13 Surprisingly, despite increased endotoxemia, iNOS activity is not increased in the splanchnic arteries of cirrhotic animals.27 Increased iNOS expression has, however, been reported in the aortic rings in animal models of cirrhosis.28 The third form of NOS is neuronal NOS (nNOS). It has also been shown to be up-regulated in neurons and vascular smooth muscle in the superior mesenteric artery in models of cirrhosis.29 Of these isoforms, increased eNOS activity is considered to be the dominant form that contributes to the splanchnic arterial vasodilation and hyperdynamic circulation seen in cirrhotics. There are several mechanisms by which eNOS activity is increased in patients with cirrhosis. Expression of eNOS itself is regulated by several posttranslational modifications, including phosphorylation and S-nitrosylation.30,31 eNOS synthesis is Ca2+/calmodulin dependent and requires tetrahydrobiopterin as a co-factor. The increased endotoxemia in cirrhotics generates tetrahydrobiopterin, which is associated with enhanced eNOS activity.32 Moreover, increased portal pressure causes shear stress, which induces Akt/protein kinase B and thus activates eNOS.33 This may be particularly important in the early stages of arterial vasodilation in the splanchnic circulation. Vascular endothelial growth factor (VEGF) is yet another cytokine that activates Akt and thus eNOS.34 VEGF signaling is currently under evaluation as a potential therapeutic target in



Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia Agonists Adrenomedullin VEGF TNF-α

Agonists

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Hb

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Vasodilation

Fig. 21-2  Factors modulating endothelial dysfunction and arteriolar dilation in subjects with cirrhosis. A variety of metabolites and cytokines act in an endocrine, paracrine, and autocrine manner to promote arteriolar dilation in the splanchnic and other systemic arterial beds. In the arterial splanchnic circulation (right panel), agonists such as adrenomedullin, vascular endothelial growth factor (VEGF), and tumor necrosis factor-α (TNF-α) or physical stimuli such as shear stress stimulate Akt, which directly phosphorylates and activates endothelial nitric oxide (NO) synthase (eNOS). eNOS is calcium (Ca2+)/calmodulin (CaM) dependent and requires co-factors such as tetrahydrobiopterin (BH4) for its activity. Heat shock protein 90 (Hsp90) is one of the positive regulators of eNOS. In the intrahepatic circulation (central panel), decreased NO and increased thromboxane A2 (TXA2) production in sinusoidal endothelial cells causes vasoconstriction by removing the normal vasodilatory effects of NO. This is compounded by the direct constrictive effects of endothelin-1 (ET-1) in cirrhosis. AA, anachidonic acid; AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CO, carbon monoxide; COX, cyclooxygenase; CSE, cystathionine-y-lyase; EDHF, endothelium-derived hyperpolarizing factor; EET, epoxyeicosatrienoic acid; GTP, guanosine triphosphate; HO-1, heme oxygenase-1; IP3, inositol triphosphate; PGI2, prostaglandin I2 (prostacyclin); sGC, soluble guanylate cyclase; SOD, superoxide dismutase. (With permission from Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:927–934.)

patients with cirrhosis and portal hypertension. Activation of Akt can also result from the actions of adrenomedullin, levels of which are increased in patients with cirrhosis.13 Finally, it has recently been shown that the subcellular localization of eNOS profoundly affects its function. It is normally located mainly in the perinuclear region and within the Golgi apparatus35; activation of eNOS is associated with transport of it to a more cytoplasmic location in proximity to the plasma membrane.36 Palmitoylation of eNOS is important for this process and underscores the impact of the metabolic changes in cirrhosis as a determinant of the hemodynamic responses to this condition.37

Carbon Monoxide Carbon monoxide is the end product of the heme oxygenase pathway and also causes vasodilation. Heme oxygenase catalyzes the conversion of heme to biliverdin and releases CO in the process.13 It exists in a constitutive and inducible form. Inducible heme oxygenase-1, also known as heat shock protein-32, is up-regulated in the systemic and splanchnic

circulation in subjects with cirrhosis.38 CO also increases cGMP and synergizes with NO to produce splanchnic arterial vasodilation.

Endocannabinoids Endocannabinoids are endogenous ligands for the cannabinoid (CB) receptors. CB1 receptors have been identified in the splanchnic circulation and in the liver vasculature.39 Binding of appropriate ligands to these receptors produces severe vascular smooth muscle relaxation and vasodilation.40 The endogenous ligands for these receptors are derived from membrane phospholipids, and anandamide is considered to be the prototypic ligand for CB1 receptors, where it functions as an inverse agonist. Anandamide production is enhanced in circulating macrophages and platelets in subjects with cirrhosis.41 Infusion of met-anandamide, a long-acting analogue of anandamide, produces marked splanchnic arterial vasodilation and induces a hyperdynamic circulation characterized by decreased systemic vascular resistance and increased cardiac output.40 In animal models of cirrhosis, infusion of a CB1

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receptor antagonist increases systemic vascular resistance and arterial blood pressure and corrects several features of the hyperdynamic circulation that is present.41

Hydrogen Sulfide Hydrogen sulfide (H2S) is one of the newest gaseous molecules with potent signaling properties to be identified. It is synthesized from l-cysteine via the action of cystathionine-β-lyase and cystathionine-β-synthase.42 H2S can be generated endogenously and is also produced by the intestinal microbiota. It opens adenosine triphosphate (ATP)-gated potassium (KATP) channels and induces vascular smooth muscle relaxation in a non–cGMP-dependent manner.43 It has been shown to have potent vasodilatory activity in the splanchnic and hepatic circulation. However, its role in mediating the circulatory disturbances in cirrhosis has not been fully elucidated.

Prostacyclins These cyclooxygenase-derived lipids are produced by the metabolism of polyunsaturated fatty acids. Prostacyclin (prostaglandin I2 [PGI2]) increases cyclic adenosine monophosphate (cAMP) and is a potent vasodilator.44 Circulating levels of PGI2 are increased in subjects with cirrhosis.

Endothelium-Derived Hyperpolarizing Factor There are other endothelium-derived factors that also cause hyperpolarization of vascular smooth muscle cell membranes and prevent contraction that have yet to be characterized. Current candidates for this factor include other arachidonic acid–derived factors, potassium itself, gap junction–associated proteins, and hydrogen peroxide.13

Tumor Necrosis Factor-α This key cytokine is produced by cells of the innate immune system, especially macrophages, in response to a variety of activators such as endotoxin and free fatty acids. It activates iNOS, and by increasing the synthesis of tetrahydrobiopterin, it increases the synthesis of eNOS. TNF-α promotes vasodilation, and inhibition of TNF-α blunts the hyperdynamic circulation in models of cirrhosis.45,46

Endothelial Dysfunction and Systemic Arterial Vasodilation in Cirrhosis It is now recognized that the vascular endothelium and its derived factors play a key role in the regulation of vascular tone in various circulatory beds. There is substantial evidence that endothelial dysfunction plays an important role in genesis of the systemic vasodilated state in patients with cirrhosis.5 This is reflected by increased levels of circulating asymmetric dimethyl arginine.

The Cardiovascular Response to Systemic Arterial Vasodilation Altered Arterial Compliance and Afterload The arterial vasodilation in subjects with cirrhosis produces immediate functional changes in the vasculature and in the

long term induces vascular remodeling that also alters arterial compliance and the functional characteristics of the systemic arterial vasculature. In animal models of cirrhosis, it was observed that the conductive vessels undergo an intense process of vascular remodeling consisting of a decrease in the thickness and the total area of the vascular wall and a reduction in the vessels’ ability to contract.47 Two potential explanations have been put forth to explain these findings: (1) a decrease in the amount of vascular smooth muscle cells because of the inhibitory effect of NO on vascular smooth muscle cell proliferation and increased apoptosis of these cells and (2) increased expression of large-conductance calciumactivated potassium channels, which leads to prolonged hyperpolarization of vascular smooth muscle.48 These changes are partially reversible and closely associated with the arterial vasodilation that is present. Arterial compliance is an important determinant of afterload because the heart autoregulates cardiac performance in response to venous return. Because cirrhotics have marked vasodilation and fluid overload but are functionally hypovolemic (reduced preload), this condition may be an important determinant of a blunted cardiac response to severe and long-standing vasodilation, which may trigger HRS.

Volume Expansion An important consequence of arterial vasodilation is an increase in total blood volume. Blood volume tends to increase as early as in pre-ascitic cirrhosis.49,50 It is related to renal Na and water retention. This excess blood volume is not distributed uniformly throughout the body and is largely accounted for by the increased vascular space in the splanchnic circulatory bed as a result of splanchnic arterial vasodilation.51,52 In fact, the distribution of blood volume is decreased in the heart, lung, and central arterial tree, whereas it is increased in the abdomen, liver, and spleen. This leads to a state of effective hypovolemia, and despite the hypervolemia, there is activation of central volume receptors and baroreceptors that trigger Na-retentive pathways in subjects with progressive cirrhosis and ascites.

The Cardiac Response and the Role of Cirrhotic Cardiomyopathy In the early phases of cirrhosis, the decrease in systemic vascular resistance is compensated by the increase in heart rate and cardiac output (hyperdynamic circulation).53,54 Such compensation allows maintenance of renal perfusion and the GFR. However, as the disease state progresses with increasing peripheral arterial vasodilation, the cardiac response to the vasodilation is blunted and there is a modest drop in cardiac output (Table 21-3). This hyporesponsiveness of the myocardium is also referred to as cirrhotic cardiomyopathy and is discussed in depth elsewhere.54 Cirrhotic cardiomyopathy is characterized by “chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiologic abnormalities, in the absence of known cardiac disease.”54 Initially, a hyperdynamic circulation may appear or is enhanced in the supine position because of translocation of volume to the central circulation and concomitant arterial



Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia Blood pressure

Table 21-3  Key Features of Cardiac Dysfunction in Patients with Cirrhosis Physiologic Blunted cardiac response to stress Diastolic dysfunction Systolic dysfunction

+ ↑ BP → ↓ Na reabsorption “Pressure natriuresis”

Echocardiographic E/A ≤1 Prolonged deceleration time (>200 ms) Prolonged isovolumetric relaxation (>80 ms) Decrease in resting ejection fraction with severity Prolongation of the ratio of preejection to left ventricular ejection time (>0.44 s, rate corrected) E/A, early-to-late diastolic filling ratio

hyporesponsiveness to physiologic vasoconstrictors.55 Subsequently, autonomic dysfunction contributes to the myocardial hyporeactivity to precipitants of the hyperdynamic circulatory state.56,57 These impair normal baroreceptor reflexes in response to arterial vasodilation and thus lead to blunting of the cardiac response. The autonomic dysfunction along with the altered cytokine milieu and abnormal electrolytes contributes to electrophysiologic abnormalities, electrical-mechanical dyssynchrony, and inotropic and chronotropic incompetence, all of which contribute to the blunted cardiac response to vasodilation in patients with advanced cirrhosis, liver failure, and ascites. A key consequence of this worsening of the effective hypovolemia is intense activation of renal Na- and waterretentive pathways, such as renal sympathetic nerve activity, plasma renin, angiotensin, aldosterone, and antidiuretic hormone.

The Renal Response to the Hemodynamic Changes in Advanced Cirrhosis The key consequence of the systemic hemodynamic changes for the kidney is an alteration in renal perfusion and the GFR. This is accompanied by an inability to excrete Na and water.2 These changes represent one extreme of a pathophysiologic cascade of events that start as early as the pre-ascitic stage of cirrhosis and progress through the clinical stages of ascites, refractory ascites, type 2 HRS, and finally type 1 HRS.

Changes in Renal Perfusion The kidney is composed of the cortical region, which is enriched with glomeruli and renal tubules, and the medulla, which is enriched with loops of Henle and collecting ducts. Blood flow in the kidneys is closely regulated by intrarenal mechanisms to maintain effective renal perfusion (mean arterial pressure [MAP] − inferior vena cava pressure). Thus, over a substantial range of renal perfusion pressure, renal blood

+ ↑ Ang II, SNS → Vasoconstriction

↑ Cardiac output Vasoconstriction

Electrophysiologic Prolonged QT interval Impaired excitation-contraction coupling

357

↑ BP → ↓ renin, ↓ SNS

–

– ECFV +

↑ Ang II, SNS → ↑ Na reabsorption

Ang II, SNS –

↑ ECFV → ↓ Renin, ↓ SNS Fig. 21-3  Feedback relationship between blood pressure (BP), angiotensin II (Ang II), the sympathetic nervous system (SNS), and extracellular fluid volume (ECFV). (With permission from McDonough et  al. Am J Physiol Renal Physiol 2007;292:F1105-F1123.)

flow remains relatively unchanged. This autoregulation is maintained by a number of intrarenal pathways, of which prostaglandins play an important role. In addition to overall renal perfusion, a balance between cortical and medullary flow is also maintained to protect renal function. The GFR is a function of glomerular perfusion pressure, the glomerular surface available for filtration, and the permeability characteristics of the glomerulus. Glomerular perfusion pressure is determined by the balance in arterial tone of the afferent arteriole, which brings blood into the glomerulus, and the efferent arteriole, which drains the glomeruli. These arterioles act as a buffer between systemic renal perfusion pressure (i.e., MAP) and actual glomerular perfusion. This buffer allows renal filtration of plasma to proceed relatively unimpeded despite fluctuations in systemic blood pressure. This is critically important for both Na homeostasis and survival. Because changes in GFR are a major abnormality that drives the development of HRS, it is germane to review some key aspects of its regulation.

Mechanisms of Autoregulation of Renal Blood Flow and Hepatorenal Syndrome Renal blood flow is regulated at two levels: (1) systemic factors, which include MAP, sympathetic nervous system output to the kidneys, and humoral factors such as renin-angiotensin and catecholamines, and (2) intrarenal factors, which can be further broadly categorized as myogenic responses and tubuloglomerular feedback (TGF) (Fig. 21-3 and Table 21-4).58 In subjects with cirrhosis and profound systemic arterial vasodilation, MAP is reduced and there is activation of renal sympathetic nerve outflow and circulating renin-angiotensin and catecholamines. The renal sympathetic nerves and circulating angiotensin tend to induce renal arteriolar constriction at the efferent arteriolar level and thus preserve glomerular filtration. However, when HRS sets in, afferent arteriolar constriction occurs and the GFR drops.59,60 The afferent arterioles are

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Table 21-4  Factors Involved in Autoregulation of the Glomerular Filtration Rate Myogenic Tone Basal tone Response to stretch (myogenic reactivity) Postconstrictive dilation Tubuloglomerular Feedback Macula densa: Adenosine Adenosine triphosphate Nitric oxide (NO) of neuronal NO synthetase origin Factors affecting tubuloglomerular feedback: Angiotensin Interleukin-6 Prostaglandins Na intake Na+ and Cl− content of tubular fluid

particularly sensitive to the intrarenal pathways, which are considered in the following sections. MYOGENIC MECHANISMS It is known that small arteries, specifically those with a relaxed internal diameter smaller than 300 µm, respond to changes in perfusion pressure independent of neurohumoral influences.61 This is called the myogenic reflex and is mediated by mechanoreceptors that sense stretch and changes in blood vessel wall tension.62 These receptors are analogous to those found elsewhere in the body, including the gastrointestinal tract and the acid-sensitive anion channels. In the kidney, the myogenic reflex has been shown to provide a fast autoregulatory response to rapid changes in perfusion pressure and is not dependent on tubular function. Mechanotransduction of changes in wall tension leads to depolarization of the cell membrane of vascular smooth muscle cells and activation of L-type calcium channels.63 The cellular events that regulate smooth muscle arterial tone and contractility are well known and beyond the scope of this chapter, and the reader is referred to several excellent reviews of the subject.64,65 Briefly, calcium influx as a result of the opening of L-type calcium channels on the plasma membrane causes Ca2+/calmodulin–mediated phosphorylation of myosin light chain kinase, thus increasing actin-myosin crosslinkage and contraction. These contractile responses are countered by independently regulated relaxant pathways, including the constitutively activated myosin light chain phosphatase, which is regulated by phosphorylation by rho kinase.58,66,67 The key point is that renal arteriolar contraction and relaxation are both active processes and are independently regulated. Unfortunately, despite the highly characterized information on the cellular mechanisms regulating renal arteriolar tone and contractility, there is a paucity of knowledge regarding changes in these pathways in patients with cirrhosis and HRS. In persons with a consistent and long-term change in renal perfusion, additional myogenic adaptive mechanisms come into play.58 In the first phase, myogenic tone is reset. This is associated with changes in membrane potential and

intracellular calcium fluxes via L-type voltage-gated calcium channels. In the second phase, sensitization of the intracellular pathways to a given calcium level occurs and results in enhanced constriction when perfusion pressure is consistently increased. It is unclear whether a consistent decrease in MAP, as seen in cirrhosis, would result in desensitization to intra­ cellular calcium. Finally, remodeling of blood vessels takes place. In the hypertensive state, which has been studied extensively, two forms of remodeling are seen: an increase in wall thickness with either a reduction in the lumen (eutrophic remodeling) or preservation of the lumen (hypertrophic remodeling).58,61,68,69 Once again, virtually nothing is known about the cellular changes in the renal afferent and efferent arterioles in subjects with cirrhosis, and this remains an area begging to be studied. TUBULOGLOMERULAR REFLEX Tubuloglomerular reflex provides another mechanism for the kidney to adapt to more long-term changes in renal perfusion pressure. The anatomic basis for this mechanism involves the thick ascending limb of the loop of Henle and the distal tubule, which loop back and make contact with the upstream glomerulus, specifically the afferent arteriole (Fig. 21-4). This juxtaglomerular apparatus is composed of the macula densa, which mediates cross-talk between the luminal contents in the distal tubule and the afferent arteriole. Increased Na content in the distal tubule enhances afferent arteriolar constriction and reduces the GFR, whereas decreased Na content relaxes the afferent arteriole and enhances the GFR.70 It has also been suggested that the macula densa senses the osmolality of the distal tubule luminal contents. Purinergic Regulation of Tubuloglomerular Feedback Reflex The macula densa mediates afferent arteriolar constriction by the release of adenosine, which acts via adenosine-1 receptors.71 Adenosine-1 receptors mediate vasoconstriction by G protein–coupled receptors. There is synergy between the vasoconstrictive effects of adenosine and angiotensin II (Ang II),72 which is likely to be related to activation of phospholipase C and mobilization of intracellular calcium.72 Recently, ATP was also shown to be an important mediator of the vasoconstrictive effects of the macula densa. ATP receptors (P2 purinergic receptors) of both the P2X and P2Y class have been found in renal afferent arterioles.73 Adenosine and ATP have been shown to be present in the interstitial fluid of the kidney. There is, however, some controversy as to whether the adenosine is produced intracellularly and then transported by concentrative nucleoside transporters (CNTs) or whether it is produced by cleavage of phosphates from ATP in the interstitium by ecto-ATPases. It is highly likely that dysregulated TGF plays a role in the profound renal vasoconstriction and decreased GFR in patients with HRS. Once again, there is unfortunately a marked paucity of direct experimental evidence of this. Nitric Oxide and Regulation of Tubuloglomerular Feedback There are high levels of nNOS in the macula densa.74,75 NO mediates vasorelaxation in response to decreased tubular Na content. Subjects given NOS inhibitors as well as nNOS knockout mice are unable to mount this response. It is not



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80

CNT NaCI concentration (mM) Fig. 21-4  Cross-talk between tubule and arteriole. A, Schematic representation of the relationship of the nephron to the vasculature. B, Microperfusion of a microdissected rabbit afferent arteriole (Af-Art) and macula densa (MD) shown on the left and the effects of varying tubular concentrations of Na on Af-Art or the efferent arteriole (Ef-Art). C, Microperfusion of microdissected rabbit Af-Art with attached connecting duct (CNT), as shown on the left, reveals the effects of connecting duct Na concentration on Af-Art. CTGF, connecting tubule glomerular feedback; DCT, distal convoluted tubule; NE, norepinepherine; TAL, thick ascending limb; TGF, tubuloglomerular feedback. (With permission from Ren Y, Garvin JL, Liu R, Carretero OA. Cross-talk between arterioles and tubules in the kidney. Pediatr Nephrol 2009;24:31–35.)

known whether there is a paucity of macula densa NOS activity in patients with cirrhosis and whether this plays a role in the genesis of afferent arteriolar vasoconstriction in those with HRS. Other Mediators of Tubuloglomerular Feedback The angiotensin system is a key mediator of TGF and modulates the sensitivity of TGF to various stimuli. It also modulates the myogenic response to changes in perfusion pressure. Renal production of various prostaglandin derivatives, especially 20-hydroxyeicosatetraenoic acid, also plays an important role in the regulation of renal blood flow.76,77 Recently, it has been shown that there is cross-talk between the intestine and the kidney, where osmolality and the nutritional and Na content of the intestinal lumen affect changes in renal blood flow.78 This has been particularly characterized with respect to calcium and phosphate content and with changes in parathyroid hormone (PTH) levels, which also alter renal blood flow.79 This may be relevant in patients with HRS once renal insufficiency develops.

The Connecting Tubule and the Tubuloglomerular Reflex The portion of the nephron that connects the distal tubule to the collecting duct is often referred to as the connecting tubule.80 This segment is also in apposition to the afferent arteriole and affects afferent arteriolar tone. Interestingly, in contrast to classic TGF, increased Na content in this segment results in arteriolar dilation and increased GFR.81,82 The role of this phenomenon and pathway remains completely unexplored in HRS.

Renal Tubular Dysfunction and Hepatorenal Syndrome A key pathophysiologic hallmark of HRS is renal Na reabsorption. There is avid Na reabsorption in the proximal tubules, which results in the delivery of a low volume of isotonic filtrate into the loop of Henle.83 The bulk of the Na reabsorption, as in the normal state, occurs in the proximal tubule. Three sets of transporters play an important role in this process. The first is the Na+/H+ exchanger (NHE); of the various isoforms,

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Section III—Clinical Consequence of Liver Disease

NHE3 is expressed in the greatest abundance in the proximal tubule and is an important mediator of Na and bicarbonate reabsorption. The Na+-phosphate cotransporter-2 helps reabsorb Na, phosphate, glucose, and amino acids. Aquaporin receptors are involved in the water transport that accompanies Na and solute transport.84 Several isoforms have been described, and renal aquaporin 2 (AQP2) is decreased in patients with cirrhosis. AQP1 levels in urine are decreased in those with type 1 HRS.84 These transporters are regulated by both circulating cytokines and hormones, as well as by paracrine factors.85 Conditions associated with decreased Na reabsorption involve retrieval of these transporters from the cell surface into the cytoplasm, which is regulated by several transport proteins and cellular trafficking pathways. These pathways are also sensitive to intracellular calcium, and PTH is an important regulator of this process. The renin-angiotensin system is the most important intrarenal mechanism for the regulation of proximal tubular function.

The Intrarenal Renin-Angiotensin System The role of the renin-angiotensin system in Na and volume homeostasis has been recognized for many decades. Ang II is the most studied and one of the most biologically active angiotensins. Ang II directly causes smooth muscle contraction, enhances myocardial contractility, stimulates release of catecholamines from the adrenal medulla, and stimulates thirst. The systemic increase in levels of Ang II thus has several effects that have a direct impact on the pathophysiology of HRS. The kidney has specific mechanisms for the intrarenal production of Ang II, where it acts in a paracrine manner and modulates renal function (Table 21-5).86 All of the components of the renin-angiotensin system are present in the kidney. Intrarenal concentrations of Ang II are often higher than those in circulation and are regulated independently from systemic Ang II. Historically, the site of action of Ang II has been considered to be the efferent arteriole. However, it is now known to constrict both afferent and efferent arterioles.87 Ang II is also a modulator of the sensitivity of the response arm of TGF and the myogenic responses to changes in renal perfusion. In addition, Ang II is a powerful stimulator of renal Na reabsorption. This is mediated by aldosterone production, which enhances distal tubular Na+/H+ exchange. In fact, the major effect of Ang II on Na homeostasis is due to increased tubular reabsorption rather than a change in GFR. Ang II also

Table 21-5  Sites of Action of Angiotensin II within the Kidney Causing Effects on the Glomerular Filtration Rate Direct vasoconstrictor of afferent and efferent arterioles Reabsorption of Na from the proximal tubule, which affects the Na content in the lumen of the tubule Modulation of the magnitude of response by the macula densa—especially affects the afferent arteriole At low perfusion pressure, angiotensin II maintains the glomerular filtration rate by efferent arteriolar constriction (direct effect) and afferent arteriolar dilation via tubuloglomerular feedback

directly enhances proximal tubular Na reabsorption. Although the role of circulating Ang II in the pathogenesis of HRS has been recognized for many decades,50,88 the role of the intrarenal renin-angiotensin system remains relatively unexplored. Recently, it has been proposed that the I/I allele of Ang II rather than the I/D or D/D alleles increases susceptibility to HRS.89

Failure to Regulate the Glomerular Filtration Rate and the Development of Hepatorenal Syndrome The pathophysiologic hallmark of HRS is a decrease in GFR with consequent enhancement of Na and water reabsorption. The drop in GFR is clearly associated with altered renal autoregulation of blood flow, with the flow-to-MAP relationship being shifted to the right.90 Thus, with smaller changes in MAP, there are changes in renal perfusion and GFR. Moreover, the drop in MAP further contributes to the drop in GFR. Unfortunately, even though much is now known about the mechanisms of renal blood flow autoregulation, the specific changes in these pathways in cirrhotics and how they contribute to the observed decrease in GFR remain to be defined.

Hepatorenal Syndrome and the Systemic Inflammatory State It is recognized that HRS is associated with high mortality. This mortality, however, is not a simple function of azotemia because dialysis does not consistently prolong life in such cases. On the other hand, HRS is often associated with development of multiorgan failure as a preterminal event. At this stage, sepsis is also frequently present. These observations have led to emergence of the concept that HRS may represent one aspect of a systemic disturbance that leads to HRS as its renal manifestation and multiorgan failure in its full-blown form.91,92 Recently, it has been shown that a systemic inflammatory response state is often present in subjects with HRS.92 The systemic inflammatory state affects organ function by altering the microcirculation and is associated with widespread endothelial dysfunction. These effects worsen the hemodynamics that drives HRS. In addition, the proinflammatory cytokine milieu associated with the systemic inflammatory response affects renal endothelial, vascular, mesangial, and tubular function, thus further contributing another layer of complexity to the pathophysiology of HRS.93,94 The inflammatory state resolves after liver transplantation.95

The Intestinal Microbiome and Gut-Derived Infections and Hepatorenal Syndrome Spontaneous bacterial peritonitis (SBP) is a well-known precipitant of HRS. SBP is usually caused by gut-derived bacteria. The human intestine contains more than 100 trillion microorganisms representing thousands of species.96 It is now known that more than 70% of the species in the intestine cannot be cultured by traditional methods.97 There is also both an axial and radial gradient in terms of the quality and quantity of microbes in the intestine; whereas the upper part of the small intestine is relatively sparsely populated by bacteria, the colon contains 1013 to 1014 microorganisms.96 Cumulatively, the number of genes within the microbial pool exceeds



Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia

those of the human genome by 100-fold.96 Although four phyla (Firmicutes, Bacteriodetes, Actinobacteria, and Proteobacteria) represent the great majority of the intestinal microbiome, the microbial makeup of a given individual is relatively unique at a species and strain level.98 Numerous studies have confirmed the presence of small intestinal bacterial overgrowth in subjects with cirrhosis.99-106 These studies have used both quantitative bacterial culture techniques and breath hydrogen content. The latter technique is, however, mired with many limitations and does not represent an optimal way to evaluate alterations in the intestinal microbiome in the current era.107 The presence of small intestinal bacterial overgrowth is associated with changes in intestinal motility and gut permeability.108-111 It is hypothesized that increased ingress of intestinal bacteria or bacteria-derived products elicits a systemic inflammatory reaction that may be important for development of the systemic inflammatory response state observed in patients with SBP and HRS.

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Table 21-6  Causes of Acute Kidney Injury in Patients with Cirrhosis CAUSE

FREQUENCY

Prerenal

68% (of total population with AKI) 66% (of those who are prerenal)

  Volume responsive    Infection    Hypovolemia    Vasodilators    Other   Not volume responsive    HRS type1    HRS type 2

34% 25% 9%

Intrarenal (ATN, GMN)

32%

Obstructive

<1%

Nephrotoxic drugs NSAIDs, aminoglycosides, contrast agents

Summary of the Pathogenesis of Hepatorenal Syndrome Hepatorenal syndrome is a key complication of cirrhosis and results from progressive vasodilation and cirrhotic cardiomyopathy, which produce a critical degree of effective hypovolemia, altered cytokine milieu, and activation of the renal sympathetic nervous system, as well as key Na homeostatic systems that result in profound renal afferent arteriolar vasoconstriction. This diminishes the GFR and contributes to marked Na reabsorption by the kidneys, thereby resulting in impaired overall clearance of toxins by the kidney and the development of renal failure. HRS is often precipitated by infections, especially SBP, and the role of the intestinal microbiome and development of the systemic inflammatory response state following SBP in the genesis of HRS is an important area of current investigation. Relatively little is known of the molecular mechanisms of intrarenal failure to autoregulate renal blood flow and preserve the GFR in patients with HRS.

Clinical Features of Hepatorenal Syndrome

Data from Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:2064–2077. ATN, acute tubular necrosis; GMN, glomerulonephritis; HRS, hepatorenal syndrome; NSAIDs, nonsteroidal antiinflammatory drugs

(within 48 hours) increase in serum creatine of at least 0.3 mg/ dl or a 1.5-fold increase from baseline associated with oliguria. The severity of the increase is used to separate patients into three stages.112 The frequency of the different causes of AKI in patients hospitalized with cirrhosis is shown in Table 21-6. The most common cause of AKI is prerenal, and it is usually volume responsive. Only about a third of patients will have HRS. Other causes of AKI in this patient population are the use of nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) or aminoglycoside antibiotics and contrast agents for computed tomography. Shown in Table 21-7 are the urinary findings for the most common causes of AKI in hospitalized patients with cirrhosis. The two most common causes of AKI in these patients are acute tubular necrosis and HRS. Examination of the urinary sediment is the quickest way to distinguish these two causes of AKI and to institute appropriate therapy.

Acute Kidney Injury in Liver Disease

Serum Creatinine as a Measure of Renal Function in Cirrhosis

Before discussion of HRS it is important to review all of the causes of acute kidney injury (AKI) in patients with liver disease (Table 21-6). AKI is now the preferred term for acute renal failure. There are also causes of renal failure in patients with cirrhosis that will not be discussed, including membranoproliferative glomerulonephritis in patients with hepatitis B and C, diabetic nephropathy in patients with metabolic syndrome, and fatty liver and IgA nephropathy in alcoholics. These chronic forms of kidney disease can be associated with acute rises in serum creatinine. It can be difficult to determine in a patient with cirrhosis and chronic renal disease whether it is the underlying liver disease or HRS that has led to a sudden rise in serum creatinine. In general, we assume that it is the underlying renal disease. AKI is defined as an abrupt

The diagnosis of AKI is based on a rise in the serum creatinine level and the development of oliguria. There is reason to be concerned about the accuracy of serum creatinine in measuring the GFR. Patients with cirrhosis have been shown to have normal serum creatinine levels and low GFRs.113 Given the marked muscle wasting seen in cirrhotics, it is not surprising that serum creatinine is an inaccurate measure of GFR. More recently, the GFR has been estimated by using a formula called the Modification of Diet in Renal Disease (MDRD), in which age, sex, race, blood urea nitrogen, and albumin, in addition to serum creatinine, are used to estimate the GFR. Recently, the GFR was measured and that result compared with the value estimated by using a modified GFR formula that included age, race, and sex in 660 patients listed for liver

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Section III—Clinical Consequence of Liver Disease

Table 21-7  Urinary Findings in Patients with Renal Dysfunction and Cirrhosis CAUSE

OSMOLALITY (mOsm/kg)

URINE NA (mmol/L)

SEDIMENT

PROTEIN (mg/dl)

Hypovolemia

>500

<20

Normal

<500

HRS

>500

<20*

Nil†

<500

ATN

<350

>40

Granular

500-1500

AIN

<350

>40

Casts

500-1500

AG

Variable

Variable

WBCs

Prerenal

Intrinsic

>2000

RBC and casts

*May be higher if the patient received diuretics. † May have a few hyaline casts. AG, acute glomerulonephritis; AIN, acute interstitial nephritis; ATN, acute tubular necrosis; HRS, hepatorenal syndrome; RBC, red blood cell; WBCs, white blood cells

transplantation.114 There was a significant but relatively poor relationship (R2 = 0.63) between measured and estimated GFR. At GFRs higher than 50 ml/min/1.73 m2, estimated GFR values were scattered equally above and below the measured value. When the measured GFR was lower than 50 ml/ min/1.73 m2, the estimated GFR was almost always higher than the measured value. Thus, in patients with more advanced liver disease, serum creatinine or the MDRD is most likely to underestimate the severity of the renal insufficiency. In addition, small rises in serum creatinine may reflect more severe reductions in GFR than are estimated based on serum creatinine alone.

Acute renal failure (SCr >1.5)

No ascites

Not HRS

Evidence of organic renal failure

Approach to Cirrhosis with Acute Kidney Injury Shown in Figure 21-5 is an algorithm for the approach to patients with cirrhosis and AKI. If the patient has no ascites, the cause of the renal failure is not HRS but one of the other causes shown in Table 21-6. If the patient has ascites, HRS is possible and urinalysis with a careful examination of the urine sediment should be performed. In addition, the use of diuretics is stopped and the patient queried about exposure to nephrotoxic drugs, especially NSAIDs.115 If the urine sediment is clear, a fluid challenge of saline plus albumin (1 g/kg) is given. If there is a decrease in serum creatine of greater that 10% and an improvement in urine output, HRS is excluded.116 If there is no response, the patient is thought to have HRS.

Definition, Prognosis, and Prevention of Hepatorenal Syndrome Criteria for the diagnosis of HRS are shown in Table 21-1. These criteria were agreed to by a group of experts and are widely used both in clinical practice and for the design of studies.1,117 The diagnosis rests on the level of serum creatinine and response to a volume challenge. It is critical in this group of patients that infection be excluded because patients with

With ascites

Get urinalysis, urine electrolytes, renal ultrasound Rule out sepsis/SBP

Stop diuretics/nephrotoxic drugs Volume expansion

Decrease in SCr

No response

Not HRS

HRS

Fig. 21-5  Approach to a patient with cirrhosis and acute kidney injury. HRS, hepatorenal syndrome; SBT, spontaneous bacterial peritonitis; SCr, serum creatinine.

cirrhosis are commonly infected and yet lack many of the signs and symptoms of bacteremia. For example, in a recent series of 104 cirrhotic patients with ascites, 44.6% were infected. Pneumonia and urinary tract infections were most common, followed by SBP. Spontaneous bacteremia was observed in 6% of the patients.118 The presence of an infection more than doubled the risk for the development of renal failure. Finally, if the renal failure did not improve with treatment, a diagnosis of HRS was made, and this was associated with progressive renal failure and a high likelihood of death.118 HRS is separated into two groups, types 1 and 2. Type 1 is defined as a doubling in serum creatinine to greater than 2.5 mg/dl in less than 2 weeks, and in type 2 this rise occurs over a period of more than 2 weeks and usually peaks between



Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia 1.0

Probability of survival

0.8

0.6

0.4 Refractory ascites Type 2 hepatorenal syndrome

0.2 Type 1 hepatorenal syndrome 0.0 0

6

12

18

24

36

48

Months Fig. 21-6  Survival of patients with refractory ascites and types 1 and 2 hepatorenal syndrome. (Adapted from Gines P, et  al. Management of cirrhosis and ascites. N Engl J Med 2004;350:1646–1654, with permission.)

1.5 and 3.0 mg/dl.119 In addition, in those with type 2 HRS the rise frequently plateaus, whereas in those with type 1 the rise continues and progressive renal failure develops. Given the lack of accuracy of serum creatinine in reflecting GFR in patients with cirrhosis and ascites (see earlier), those with HRS clearly have advanced renal failure when the diagnosis is made. Patients in whom HRS type 1 develops generally have a precipitating cause such as SBP or have a form of acute on chronic liver disease, such as alcoholic hepatitis. The prognosis for those with type 1 HRS is poor, with a median survival of less than a month, and almost all patients are dead within 6 months of diagnosis (Fig. 21-6).120 In contrast, survival of patients with type 2 is better, with a median survival of longer than 6 months. However, their survival is still significantly worse than that in patients with refractory ascites but a normal serum creatinine level (see Fig. 21-6). The prognostic significance of serum creatinine in predicting survival in cirrhotics is demonstrated by its inclusion as one of the three independent variables in the Model for End-Stage Liver Disease (MELD) scoring system.121 The risk for HRS is dependent on the presence of ascites (essentially zero in its absence), on the severity of the liver disease, and finally, on complications of cirrhosis that increase risk for the development of HRS. In one report, 263 patients with cirrhosis and ascites were observed for a mean of 41 months. Renal failure developed in 49%. Most of the renal failure was due to volume depletion or associated with infection but was reversible. HRS developed in 7.6% of the patients. The 1-year probability of survival was 91% in those in whom renal failure did not develop but fell to 46.9% in those in whom it did.2 The most common complication of cirrhosis associated with the development of HRS is SBP. In one series, HRS developed in 33% of patients with SBP who were treated appropriately with antibiotics. This risk could be reduced to 10% if the patients received intravenous albumin in addition to

363

antibiotics. The patients who benefited most from the use of albumin were cirrhotics with the most advanced liver disease or those who had evidence of renal dysfunction at baseline. Intravenous albumin administration lowered plasma renin activity, thus suggesting that its benefit was on the abnormal hemodynamics seen in patients with cirrhosis and HRS.122 In support of this belief that infection increases the risk for development of HRS by making the hyperdynamic circulation worse is a study in which patients with low-protein ascites and advanced liver disease were given a placebo or norfloxacin. The risk for development of HRS was significantly reduced in those who received norfloxacin versus placebo.120,123 The other clinical situation in which the prophylactic use of antibiotics reduces the risk for SBP and perhaps HRS is acute variceal bleeding. Renal failure occurs in 11% of patients admitted to the hospital with variceal bleeding. The severity of the bleeding and liver disease was predictive of the development of renal failure.124 Many of the patients were also infected, and this may have contributed to the risk for development of renal failure. Use of prophylactic antibiotics in this patient population reduces the risk for all types of bacterial infection, including SBP, and improves their prognosis.125,126 Because infections, especially SBP, are known to increase the risk for development of HRS, the use of prophylactic antibiotics in cirrhotics with gastrointestinal bleeding should reduce the risk for HRS. The last risk factor for the development of HRS is the development of acute on chronic liver disease, specifically alcoholic hepatitis. In one series, HRS (mostly HRS type 1) developed in 24 of 52 patients with severe alcoholic hepatitis. Ninety-two percent of those in whom HRS developed died. When an effective therapy for alcoholic hepatitis was given to the patients, in this case pentoxifylline, the risk for development of HRS was reduced and outcome improved.127 Prevention of the development of HRS is likely to improve outcomes. The use of albumin in association with antibiotics in patients with SBP appears to be warranted based on current data, but only in patients who are jaundiced or have renal insufficiency. The prophylactic use of antibiotics in cirrhotics with gastrointestinal bleeding also appears to be warranted because the use of antibiotics is associated with a reduced incidence of infections, improved survival, and less rebleeding. Risk for HRS is also likely to be reduced. Prophylactic use of antibiotics in patients with low-protein ascites and advanced liver disease is not warranted because the use of antibiotics in this patient population increases the risk for Clostridium difficile infection and bacterial resistance. New therapies to treat diseases such as alcoholic hepatitis are needed because improvements in liver function are likely to be associated with improvements in renal function. Finally, new treatments to slow progression of the hyperdynamic circulation are needed because the hyperdynamic circulation is the driving force behind the development of refractory cirrhotic ascites and HRS.119

Management of Patients with Hepatorenal Syndrome General management of patients with AKI is no different from that in any other patient with advanced liver disease. First and foremost, the presence of a bacterial infection must be sought

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Section III—Clinical Consequence of Liver Disease

by cultures of blood, urine, and ascitic fluid. If infection is considered likely, antibiotics should be started pending the results of culture. Gram-negative enteric organisms are most common, and appropriate antibiotics should be selected. A history of the use of nephrotoxins such as NSAIDs should be sought. Diuretics should be withdrawn and the patient should undergo volume expansion with albumin, 1 g/kg intravenously. Urinalysis should be performed and the urine sediment examined by a nephrologist to exclude other causes of AKI. Once all of these measures have been completed and there is no improvement in renal function, the patient is considered to have HRS (see Table 21-1).

Renal Replacement Therapy and Liver Transplantation Acute progressive renal failure leading to symptoms of uremia is seen most commonly with HRS type 1. In patients with HRS type 2, serum creatinine infrequently exceeds 3 mg/dl, but when it does, the increase is usually due to overdiuresis of a patient with refractory cirrhotic ascites. Therefore an acute rise in serum creatinine in a patient with HRS type 2 will usually respond to volume replacement therapy. In contrast, in patients with HRS type 1 and especially in those with alcoholic hepatitis, the rise in serum creatinine is rapid and progressive and leads to the question of hemodialysis. The general consensus is that dialysis in these patients does not improve their survival and should not be performed unless they are candidates for a liver transplant.120 Patients with HRS who undergo liver transplantation clearly benefit from the liver transplant and have improved survival relative to those who do not undergo liver transplantation.128-130 In one series of patients treated with terlipressin in whom HRS was reversed before transplantation, the frequency of renal insufficiency was similar at 6 months in those who did and did not have HRS before transplantation.128 In a second series of 32 patients with HRS type 1 who underwent liver transplantation, 30 recovered renal function over a median time of 24 days (range, 1 to 234 days). The two other patients died of renal insufficiency. Dialysis was required after transplantation in eight patients.129 In a third series, renal function improved in patients with HRS (type not specified) who underwent liver transplantation. Renal function 1 year following transplantation was similar in those who did and did not have HRS before transplantation.131 With the advent of MELD for allocating organs for liver transplantation, the number of patients undergoing simultaneous liver/kidney (SLK) transplantation has increased 300%. At issue are which patients should receive an SLK transplant and which should receive a liver-only transplant despite the presence of renal dysfunction. It is clear that there is no uniformity of opinion on this issue inasmuch as rates of SLK transplantation vary widely.132 In one series, 22 patients with HRS who were maintained on dialysis for more than 30 days and who underwent SLK transplantation were compared with 148 HRS patients, 80 of whom were maintained on dialysis for less than 30 days and received a liver-only transplant. Renal function recovered in essentially all of those who received a liver-only transplant. Outcomes were similar in the two groups regarding survival and recovery of renal function.133 Hence, it would appear that most patients with HRS will recover their renal function following a liver-only

transplant. SLK transplantation for patients with AKI should be reserved for those who have been undergoing renal replacement therapy for a minimum of a month and probably 2 months preceding liver transplantation. In addition, those who have intrinsic renal disease, such as seen with diabetes, and have significant renal insufficiency are best served by SLK transplantation.132

Transjugular Intrahepatic Portosystemic Shunt Creation of a transjugular intrahepatic portosystemic shunt (TIPS) leads to improvements in GFR and decreases in plasma renin activity and aldosterone levels.134 A small number of patients with type 1 and 2 HRS have received a TIPS, and renal function improved. However, the prognosis remains poor, especially in those with HRS type 1.135,136 Recently, a small number of patients with HRS type 1 received midodrine, octreotide, and albumin, and if they responded to vasoconstrictor therapy, they received a TIPS. Five patients who responded to vasoconstrictor therapy demonstrated further improvement in renal function following the creation of a TIPS.137 Given the small number of patients studied and the lack of a control group, it is difficult to conclude that patients who respond to vasoconstrictor therapy should proceed to TIPS creation in the hope of preserving their renal function. Patients who respond to vasoconstrictor therapy in general have a sustained improvement in renal function, and the added benefit of a TIPS is unclear (see later). In addition, in patients with HRS type 1, the risk associated with creation of a TIPS is significant because they frequently have advanced liver disease and after the TIPS procedure are at risk for multiorgan failure. Urgent liver transplantation in a suitable candidate is more likely to be of benefit in this patient population than is creation of a TIPS.

Vasoconstrictor Therapy It was recognized many years ago that the so-called effective plasma volume was reduced in patients with HRS, and this led to attempts to expand the patient’s plasma volume in the hope of improving renal function. In addition, active renal vasoconstriction was recognized as being present in these patients, and vasodilators were infused. Both approaches lead to improvement in renal function; however, the improvement was not maintained when the therapy was discontinued. More recently, clarification of the role of hyperdynamic circulation and vasodilation in the splanchnic bed in the pathogenesis of HRS has led to the use of vasoconstrictors in the treatment of HRS (see earlier). Small case series have been followed by randomized controlled trials, and it is clear that vasoconstrictor therapy improves renal function in these patients and that the improvement in many is long lasting. The drug used most widely is terlipressin, and the efficacy of this agent in the reversal of HRS type 1 has been subjected to controlled trials as shown in Table 21-8.138-141 The largest study was a randomized, double-blind, placebo-controlled trial that was performed largely in the United States. One hundred twelve patients with HRS type 1 were randomized to terlipressin, 1 mg every 6 hours, plus albumin versus placebo plus albumin. The patient characteristics in the two arms were similar. Thirty-four percent of the terlipressin-treated



Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia

365

Table 21-8  Controlled Trials of Terlipressin plus Albumin in the Treatment of Hepatorenal Syndrome AUTHOR

TREATMENT GROUP

N

Terlipressin Control

12 12

42 0

100

Neri et al.139

Terlipressin Control

26 26

81 19

100

Sanyal et al.140

Terlipressin Control

56 56

34 13

100

Martin-Llahi et al.141

Terlipressin Control

23 23

39 4

56

Solanki et al.

138

patients and 13% of controls (P = .008) achieved reversal of HRS, defined as a serum creatinine level of 1.5 mg/dl or less. Mean serum creatinine levels rose in the placebo-treated patients and fell in those who received terlipressin. Overall survival was the same in both groups, but survival was significantly better in those who achieved HRS reversal than in those who did not. Although serious adverse events were similar in the treated and control groups, ischemic events were seen only in those receiving terlipressin.140 All of the trials showed a beneficial effect of terlipressin on renal function in comparison with controls (see Table 21-8). Most remarkable was the fact that about 90% of patients maintained HRS reversal for several weeks after discontinuation of treatment. Although none of the controlled trials demonstrated a survival advantage for terlipressin, a meta-analysis suggested that treatment with terlipressin plus albumin versus albumin alone reduces mortality (relative risk, 0.81; 95% confidence interval, 0.68 to 0.97).142 Factors predictive of a response to terlipressin included baseline serum bilirubin, increase in MAP following terlipressin administration, and baseline serum creatinine.143,144 Baseline serum creatinine, the presence of alcoholic hepatitis, and Child-Pugh score were predictive of survival.144 Other drugs used to treat HRS include midodrine, octreotide, and noradrenaline. Terlipressin was compared with noradrenaline in a small open-label controlled trial, and the outcomes were similar.145 Midodrine plus octreotide appeared to improve renal function in some patients with HRS but has not been subjected to controlled trials.146,147 All of these trials suggest that vasoconstrictive drugs improve renal function by causing splanchnic vasoconstriction, which increases effective arterial blood volume and hence improves renal blood flow and kidney function. In Europe, terlipressin plus albumin is used most commonly, whereas in the United States, where terlipressin is not approved, octreotide and midodrine in addition to albumin is most used for the treatment of HRS. All of these studies provide some guidance on how to use vasoconstrictors in patients with HRS. First, the diagnosis of HRS must be based on the criteria shown in Table 21-1. There are multiple causes of AKI in this patient population, and use of vasoconstrictors in those with low plasma volume or intrinsic renal disease is likely to lead to a deterioration in renal function. In patients with HRS, the more severe the renal failure, the less likely they are to respond to vasoconstrictors.

COMPLETE RESPONSE (%)

HRS TYPE 1 (%)

For example, in one report the likelihood of responding to terlipressin was 50% in those with a creatinine level lower than 3.0 mg/dl, 33% in those with a creatinine level of 3 to 5 mg/ dl, and 9% in those with a creatinine level higher than 5 mg/ dl.144 There are no data supporting the use of vasoconstrictors in patients undergoing renal replacement therapy. Although it is unclear whether one can predict a response to terlipressin based on a rise in blood pressure following the infusion, it is clear that if the patients are to respond to terlipressin, a rise in MAP is required.143,144 Finally, the response to vasoconstrictor therapy appears to be rapid, with a fall in serum creatinine seen within 48 to 72 hours of initiation of therapy. If serum creatinine does not begin to fall after 3 days, either the dose of the vasoconstrictor should be increased or the treatment is ineffective. Finally, the role of vasoconstrictors in the treatment of HRS type 2 is unclear because there are too few studies from which to draw any firm conclusions. Because patients with HRS type 2 are clinically stable and the use of vasoconstrictors is associated with side effects, their use in this group of patients should probably be limited to controlled trials.

Hyponatremia Disorders of water metabolism are common in patients with cirrhosis, especially in those with HRS. The development of hyponatremia reflects the inability of the kidney to excrete free water. The primary reason for this inability to excrete solute-free water in cirrhotics is an increase in levels of arginine vasopressin (AVP). The nonosmotic secretion of AVP in these patients is due to the same mechanism that leads to renal failure: arterial splanchnic vasodilation and arterial underfilling leading to activation of baroreceptors that regulate the release of AVP.148,149 Hyponatremia is common in cirrhotics, and the severity of hyponatremia is a marker of more advan­ced disease. The prevalence of hyponatremia (serum Na+ <135 mmol/L) was high in inpatients (57%) and outpatients (40%). Twenty-one percent of cirrhotics had a serum sodium level of 130 mmol/L or lower. The presence of hyponatremia was associated with refractory ascites, hepatic encephalopathy, and HRS. The use of diuretics was frequently stopped in those with more severe hyponatremia, thus adding to the difficulty of controlling their ascites.150 Once hyponatremia develops, a patient’s risk for dying increases, and this is independent of the MELD

Section III—Clinical Consequence of Liver Disease

score.151,152 Finally, hyponatremic patients undergoing liver transplantation appear to be at increased risk for neurologic injuries, renal failure, and infections in the immediate posttransplant period.153 The most common approach to the treatment of hyponatremia is fluid restriction. Both patients and physicians find this form of treatment difficult because it is hard for patients to do, the rate of rise in serum sodium is slow, and hospitalization is prolonged. In addition, if diuretics are continued, the serum sodium level may fail to increase.154 Infusion of hypertonic saline will correct the hyponatremia more quickly but will put the patient at risk for the development of hypernatremia and osmotic demyelination. A number of other agents, including demeclocycline, urea, and κ-opioids, have been used in the past, but complications and ineffectiveness have led to their abandonment.155 The development of a new class of drugs that block the effects of AVP on the renal tubule has led to hope that a new and effective therapy is now available for cirrhotics with hyponatremia. The effect of AVP on water homeostasis is mediated via its effect on water transport by principal cells in the collecting duct. AVP binds to the V2 receptor on the basolateral membrane of principal cells and leads to activation of the Gscoupled adenylyl cyclase system and an increase in levels of cAMP. Stimulation of protein kinase A by cAMP leads to phosphorylation of preformed AQP2, which is then translocated to the apical membrane and makes the cells more water permeable.156 An increase in AVP, as is seen in cirrhosis, causes more AQP2 to move to the apical membrane and makes the cells more permeable to water, thus decreasing solute-free water clearance and leading to the development of hyponatremia. Drugs such as tolvaptan and satavaptan bind to the V2 receptor and block the effect of AVP, which results in an increase in solute-free water clearance and correction of the hyponatremia. In addition, this group of drugs also induces a mild natriuresis, increases urine output, and causes more rapid weight loss than in patients not receiving the drug.157,158 The Food and Drug Administration (FDA) has approved tolvaptan for use in the treatment of hyponatremia in cirrhotics based on two randomized controlled trials comparing placebo with tolvaptan in patients with hyponatremia (Fig. 21-7).158 The majority of the patients in the study suffered from congestive heart failure, and only 63 cirrhotic patients received tolvaptan. Patients with a Child-Pugh score higher than 10 or sodium level lower than 120 mmol/L were excluded. Patients were treated for up to 30 days, and during the first 4 days the dose of tolvaptan could be increased, depending on the response to treatment. Serum sodium rose quickly in those receiving tolvaptan and was 135 mmol/L or higher by day 20. Discontinuation of treatment was associated with a fall in serum sodium. No mention is made of the use of diuretics in this group of patients. No difference in survival was seen with tolvaptan versus placebo, but the patients were treated for a maximum of 30 days.158 The other oral V2 receptor antagonist that has been investigated more extensively in patients with cirrhosis is satavaptan.157 In a recent report, 151 cirrhotic patients with recurrent ascites, with or without hyponatremia, were randomized to receive different doses of satavaptan or placebo. The use of satavaptan was associated with a decrease in the need for paracentesis. In addition, urine volume increased with

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Day Fig. 21-7  Response to tolvaptan versus placebo in patients with severe hyponatremia. Patients received tolvaptan (blue circles) or placebo (yellow squares) for 30 days. Asterisk, significant difference between tolvaptan-treated patients and controls. (From Schrier RW, et  al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099–2112, with permission.)

satavaptan. Somewhat surprising was observation that serum sodium remained the same in all of the groups, including placebo. Survival and side effects were similar in the two groups.159 Another study of satavaptan given in combination with diuretics to patients with cirrhosis found an increase in mortality in those receiving satavaptan.160 The reason for the increase in mortality is unclear, but the company making satavaptan (Sanofi-Aventis) has withdrawn the drug. The adverse event most feared with the use of these drugs is too rapid a rise in serum sodium (>12 mmol/L/24 hr) leading to hypernatremia, osmotic demyelination, and central nervous system injury. The FDA has included a black box warning that therapy with tolvaptan should be instituted in an inpatient setting with close monitoring of serum sodium. Patients with cirrhosis tolerate hyponatremia with minimal neurologic sequelae, and therefore the use of tolvaptan should be limited to those with a serum Na+ concentration of less than 120 mmol/L. How to use tolvaptan and other V2 receptor antagonists in combination with diuretics is unclear. Based on the experience with satavaptan it appears that better control of the patient’s ascites may be possible, but until the increase in mortality seen with satavaptan is explained, use of this class of drugs in combination with diuretics in an outpatient setting should be limited to controlled trials.161

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Chapter 21—Renal Failure in Cirrhosis, Hepatorenal Syndrome, and Hyponatremia

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