hepatorenal syndrome: a severe, but treatable, …...in practice hepatorenal syndrome: a severe, but...

In Practice

Hepatorenal Syndrome: A Severe, but Treatable, Cause ofKidney Failure in Cirrhosis

Cláudia Fagundes, MD, and Pere Ginès, MD, PhD

Hepatorenal syndrome (HRS) is a unique type of kidney failure that occurs in advanced cirrhosis. It ischaracterized by functional impairment of the kidneys due to vasoconstriction of the renal arteries in the settingof preserved tubular function and absence of significant histologic abnormalities. Renal vasoconstriction inHRS is due to severe vasodilation of the splanchnic arteries associated with portal hypertension, leading to adecrease in effective arterial blood volume and arterial pressure. HRS commonly develops after a trigger,usually a bacterial infection, that disrupts the arterial circulation, but it also may occur spontaneously. There are2 forms of HRS: type 1 is characterized by an acute progressive decrease in kidney function and very shortsurvival without treatment, whereas type 2 features stable less severe kidney failure and longer survivalcompared with type 1. A liver transplant is the preferred treatment for HRS. Pharmacologic treatment withvasoconstrictors to reverse splanchnic vasodilation, together with albumin, is effective in 40%-50% of patientswith type 1 HRS and improves survival. The drug of choice is the vasopressin analogue terlipressin. Renalreplacement therapy should not be used as first-line therapy.Am J Kidney Dis. xx(x):xxx. © 2012 by the National Kidney Foundation, Inc.

INDEX WORDS: Cirrhosis; ascites; chronic liver diseases.

CASE PRESENTATIONA 45-year-old man with cirrhosis due to hepatitis C virus

infection was admitted to the liver unit with weakness and increas-ing jaundice of recent onset. The patient had long-standing cirrho-sis with previous episodes of ascites and hepatic encephalopathyand was listed for liver transplant 3 months before the admission.He was not receiving prophylaxis with quinolones for preventionof spontaneous bacterial peritonitis. The most recent laboratorytest results showed serum creatinine level of 1 mg/dL (88 �mol/L;corresponding to estimated glomerular filtration rate [eGFR] of 98mL/min/1.73 m2 [1.63 mL/s/1.73 m2] using MDRD [Modificationof Diet in Renal Disease] Study equation), serum bilirubin level of4.8 mg/dL (82 �mol/mL), serum albumin level of 2.8 g/dL (28g/L), and prothrombin time of 42%. There was no evidence ofexcessive urinary losses, marked loss of body weight, vomiting,diarrhea, or gastrointestinal bleeding. Daily medications includedspironolactone, 100 mg, and furosemide, 40 mg. On physicalexamination, the patient showed marked jaundice, lethargy, flap-ping tremor, large ascites without abdominal tenderness, and pedaledema. Blood pressure was 100/60 mm Hg and heart rate was 90beats/min. Laboratory data at admission showed decreased kidneyand liver function, with serum creatinine level of 3 mg/dL (265�mol/L; eGFR, 28 mL/min/1.73 m2 [0.47 mL/s/1.73 m2]), serumsodium level of 127 mEq/L (127 mmol/L), serum bilirubin level of18 mg/dL (308 mmol/L), serum albumin level of 2.7 g/dL (27 g/L),and prothrombin time of 45%. Urinalysis showed no signs ofinfection or intrinsic acute or chronic kidney diseases, with proteinexcretion of 100 mg per gram of creatinine, sodium excretion of 5mEq/L (5 mmol/L), urine osmolality of 450 mOsm/Kg, andabsence of red blood cells or casts. Blood and urine culture resultswere negative. Paracentesis was diagnostic of spontaneous bacte-rial peritonitis, with 1,500 leukocytes/�L (90% polymorphonu-clear cells) and yielded a culture positive for Escherichia coli.Diuretics were withheld and intravenous (IV) ceftriaxone (2 gfollowed by 1 g/24 h) therapy was started. Albumin was given at adose of 1.5 g/kg the first day and 1 g/kg at day 3 of treatment.Blood tests taken 48 hours after diuretics were withheld showedplasma renin activity of 11.6 ng/mL/h (reference range, 1-1.2ng/mL/h), plasma aldosterone concentration of 122 ng/dL (3.38
nmol/L; reference range, 25-40 ng/dL [0.69-1.11 nmol/L]), and
Am J Kidney Dis. 2012;xx(x):xxx

plasma norepinephrine concentration of 652 pg/mL (3.85 nmol/L;reference range, 200-214 pg/mL [1.18-1.26 nmol/L]), findingsconsistent with reduced effective arterial blood volume. Despiteimprovement of infection with antibiotics, there was a progressivedecrease in kidney function, with serum creatinine level reaching 5mg/dL (442 �mol/mL; eGFR, 15 mL/min/1.73 m2 [0.25 mL/s/1.73m2]) at the time of resolution of the infection. Arterial pressure didnot decrease throughout the infection.

A diagnosis was made of type 1 hepatorenal syndrome (HRS)triggered by spontaneous bacterial peritonitis. Treatment withterlipressin (1 mg/4 h IV) and albumin (1 g/kg the first day,followed by 40 g/d) was started. Treatment was not started earlierbecause of the lack of data for the efficacy and safety of terlipressinin patients with type 1 HRS and ongoing infections. The patientwas not treated with renal replacement therapy (RRT) becausethere was no severe volume overload, hyperkalemia, or metabolicacidosis. Administering albumin and terlipressin was associatedwith marked improvement in kidney function, with a decrease inserum creatinine level, increase in arterial pressure (Fig 1), andmarked decreases in plasma renin activity, aldosterone, and norepi-nephrine concentrations (3.8 ng/mL/h, 46 ng/dL [1.28 nmol/L],and 250 pg/mL [1.48 nmol/L], respectively, at the end of treatmentcompared with 11.6 ng/mL/h, 122 ng/dL [3.38 nmol/L], and 652pg/mL [3.85 nmol/L] at baseline), indicating a remarkable improve-ment in circulatory function. HRS did not recur after withdrawal of

From the Liver Unit, Hospital Clínic and University of Barce-lona School of Medicine, Institut d’Investigacions BiomèdiquesAugust Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas yDigestivas (CIBERHED), Insituto Reina Sofia de InvestigaciónNefrológica (IRSIN), Barcelona, Catalunya, Spain.

Received July 29, 2011. Accepted in revised form December 7,2011.

Address correspondence to Pere Ginès, MD, PhD, University ofBarcelona, Hospital Clinic, Villarroel 170, Barcelona 08036,Spain. E-mail: [email protected]

© 2012 by the National Kidney Foundation, Inc.0272-6386/$36.00
doi:10.1053/j.ajkd.2011.12.032
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Fagundes and Ginès

terlipressin therapy, and at the time of liver transplant, his serumcreatinine level was 1.2 mg/dL (107 �mol/L; eGFR, 79 mL/min/1.73 m2 [1.32 mL/s/1.73 m2]). Evolution after transplant wasunremarkable.

This case emphasizes the importance of infections, particularlyspontaneous bacterial peritonitis, as triggering factors of HRS andthe usefulness of pharmacologic therapy with terlipressin andalbumin in the management of this condition.

INTRODUCTION

Investigations performed in the late 1950s to early1970s provided conclusive evidence indicating thatHRS is a unique form of kidney failure that occurs inpatients with cirrhosis and is due to marked vasocon-striction of the renal circulation.1-3 Since then, it hasbecome evident that the kidney failure of HRS is ofcirculatory origin. An extremely dilated splanchnicarterial bed triggers a marked disturbance in thesystemic circulation, ultimately leading to kidneyfailure due to vasoconstriction of the kidney arteries.Although once considered an irreversible and untreat-able condition (except for liver transplant), studiesperformed within the past decade have shown thatHRS may be reversible with pharmacologic treat-ment. This review provides an overview of the patho-genesis, clinical findings, differential diagnosis, andmanagement of HRS, with particular emphasis onpharmacologic treatment.

DEFINITION AND INCIDENCE

The current definition of HRS proposed by theInternational Ascites Club states that “HRS is a poten-tially reversible syndrome that occurs in patients withcirrhosis, ascites and liver failure that is characterizedby impaired kidney function, marked alterations in

Figure 1. Serum creatinine concentration and mean a

cardiovascular function, and over-activity of the sym-

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pathetic nervous system and renin-angiotensin sys-tem. Severe renal vasoconstriction leads to a decreaseof GFR. HRS may appear spontaneously or can fol-low a precipitating event.” This definition was firstproposed in 1999 and subsequently modified in2007.4,5 In the former definition, the existence of anongoing bacterial infection precluded the diagnosis ofHRS, whereas in the most recent definition, HRS maybe diagnosed in the presence of an infection, except ifthere is septic shock.5

The definition of acute kidney injury (AKI) pro-posed by the Acute Kidney Injury Network (AKIN)for kidney failure developing in the general popula-tion of hospitalized patients has been suggested toalso apply to kidney failure that occurs in patientswith cirrhosis.6,7 However, this classification has notbeen validated in patients with cirrhosis. Therefore, itseems reasonable to keep the term HRS for the uniqueform of kidney failure of functional origin, withpreserved tubular function, that occurs in cirrhosisand wait until prospective studies evaluating the use-fulness of the AKI definition in cirrhosis are reported.In the future, the use of kidney biomarkers theoreti-cally may help differentiate HRS from AKI. In thisregard, 2 recent studies suggest that urine neutrophilgelatinase-associated lipocalin (NGAL) levels couldbe useful in the differential diagnosis between HRSand AKI in cirrhosis.8,9

There are very few studies of the incidence of HRS.Older studies indicated that the incidence of HRS in ageneral population of patients with cirrhosis and as-cites was high, �40% after 5 years of follow-up.10

Recent data indicate a much lower incidence of 11%at 5 years.11 However, the latter study included only

l pressure in the patient described in the case vignette.

patients experiencing an initial episode of ascites;


Hepatorenal Syndrome

these individuals have less advanced disease, whichmay be associated with a lower incidence of HRSrelative to the wider population of patients with as-cites.

PATHOPHYSIOLOGY

The characterization of HRS as being a functionaldefect has been established by the absence of signifi-cant morphologic abnormalities in the kidney histol-ogy,12 normalization of or improvement in kidneyfunction after liver transplant,13,14 and reversibility ofthe syndrome by pharmacologic treatment with vaso-constrictors and albumin.15 A substantial amount ofevidence indicates that the main cause of decreasedkidney function leading to HRS in cirrhosis is impair-ment in circulatory function.16-22 The defect in sys-temic arterial circulation involves reduced systemicvascular resistance caused by primary arterial vasodi-lation of the splanchnic circulation, which in turn iscaused by portal hypertension.4,16,17,23 The vasodila-tion of the splanchnic arterial circulation likely is aresult of greater production and activity of vasodila-tors, in particular, nitric oxide, endogenous cannabi-noids, and carbon monoxide.4,17,23-25 Experimentaland clinical studies of patients with cirrhosis suggestthat bacterial translocation from the intestinal lumento mesenteric lymph nodes may be an important factorin circulatory dysfunction in advanced cirrhosis.26,27

Bacterial translocation elicits an inflammatory re-sponse, with proinflammatory cytokines produced ingreater amounts in the splanchnic area, leading tovasodilatation of the splanchnic arterial vessels.28,29

Bacterial translocation’s key role in circulatory dys-function is substantiated by the observation that admin-istering the antibiotic norfloxacin, which selectivelydecontaminates the intestinal tract, improves circula-tory function and reduces the likelihood of the devel-opment of HRS.30-32

The pathophysiology of HRS is summarized in Fig2. In early stages of cirrhosis, when patients generallyexperience no symptoms, the increased resistance toblood flow within the liver is moderate and thereforeportal hypertension is also moderate. Mechanismsleading to portal hypertension involve a passive in-crease in intrahepatic resistance due to fibrosis, dys-function of liver endothelial cells, and increased por-tal blood flow due to vasodilation of splanchnic arteries(reviewed in33). In this context, there is a smalldecrease in systemic vascular resistance as a result ofsplanchnic arterial vasodilation. The effect of thedecrease in systemic resistance in arterial pressure isbalanced by increased cardiac output, so that arterialpressure and effective arterial blood volume are main-tained at normal levels (Fig 1).16,17 In advanced
stages of cirrhosis, the vasodilation of the splanchnic

arteries increases due to progressive bacterial translo-cation and enhanced synthesis of vasodilator factors.Neoangiogenesis in mesenteric arteries and impairedresponse to vasoconstrictors also contribute to thereduced vascular resistance in the splanchnic circula-tion.33 The progressive decrease in arterial resistancein the splanchnic circulation is associated with anunrelenting reduction in total systemic vascular resis-tance. This occurs primarily because the splanchniccirculation is a major part of the systemic arterialcirculation, yet other mechanisms, such as the releaseof vasodilator factors from the splanchnic to thesystemic circulation, also may contribute (reviewedin34). In advanced stages, systemic vascular resistanceis so greatly reduced that additional increases incardiac output cannot make up for it. As a result, thereis underfilling of the arterial circulation due to thedisparity between intravascular blood volume and thegreatly enlarged intravascular arterial circulation, acondition known as effective arterial hypovole-mia.16,17,21,35,36 Moreover, evidence indicates thatthere is a decrease in cardiac output, probably relatedto the so-called cirrhotic cardiomyopathy, that alsocontributes to arterial underfilling.18,19,37,38 Althoughrelative adrenal insufficiency has been reported incirrhosis, to date, no evidence has been presented tosuggest that it may contribute to circulatory dysfunc-tion in HRS.39 In the scenario of extreme underfillingof the arterial circulation, the body seeks to maintainarterial pressure by activating the vasoconstrictor sys-tems, including the sympathetic nervous system, renin-angiotensin system, and, in late stages, nonosmotichypersecretion of arginine vasopressin.17 Althoughthese systems assist in preserving effective arterialblood volume and arterial pressure, they stronglyinfluence kidney function, particularly retention ofsodium and solute-free water. As a consequence,ascites and edema develop, as well as hypervolemichyponatremia. If the vasoconstriction systems areactivated to a high degree, renal vasoconstrictionoccurs, which leads to greatly decreased glomerularfiltration and the development of HRS4,15-17 (Fig 2).

Vasoactive mediators, which act on intrarenal circu-lation, also may contribute to HRS. Increased synthe-sis of a number of vasoactive factors in the intrarenalcirculation, such as thromboxane A2, cysteinyl leuko-trienes, F2-isoprostanes, and endothelin 1, has beendescribed, yet their contributions to the pathogenesisof HRS are still undefined.16 It is unlikely that endo-thelin 1 has a role because treatment with the endothe-lin antagonist tezosentan does not lead to improve-ment in kidney function in patients with type 2 HRS.40

Contrary to classic belief, vascular beds other thanthose in renal circulation also are vasoconstricted in
HRS; for example, in the extremities and cerebral
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Fagundes and Ginès

circulation.41,42 In HRS, cardiopulmonary pressuresremain within normal limits and there is no evidenceof circulatory overload despite the intense sodium andfluid retention.18,20,43,44 The likely explanation forthis behavior is that the fluid retained within thekidneys exists from the intravascular compartment,particularly in the splanchnic venous circulation, thusforming ascites because of the high hydrostatic pres-sure and increased filtration coefficient in the splanch-nic capillaries.45 In addition, fluid exits from thecapillaries of the legs to form edema.

CLINICAL TYPES OF HRS

HRS may occur in 2 different clinical patterns,according to the severity and rate of progression ofkidney failure4,5,46 (Box 1). The main clinical featuresof type 1 HRS are those of acute kidney failure with arapid increase in serum creatinine level.4,5 If un-

Figure 2. Pathogenesis of circulatory abnormalities in (left) cfrom Ginès & Schrier15 with permission of the Massachusetts Me

treated, serum creatinine levels usually increase rap-

4

idly to �5 mg/dL (�440 �mol/L). In approximatelytwo-thirds of cases, there is hypervolemic hyponatre-mia on account of disruptions to solute-free waterexcretion.46 Serum potassium levels usually are aroundthe upper normal limit or slightly higher. Potassium-sparing diuretics obviously are absolutely contraindi-cated because they may induce severe hyperkalemia.

nsated cirrhosis and (right) hepatorenal syndrome. ReproducedSociety.

Box 1. Clinical Types of HRS

Type 1: Rapidly progressive decrease in kidney function,defined as a 100% increase in serum creatinine to a final value�2.5 mg/dL (�221 �mol/L) in �2 weeks. The clinical presenta-tion is usually that of acute kidney failure. Average mediansurvival is only 2 weeks if not treated.

Type 2: Stable or slowly progressive decrease in kidneyfunction that does not meet the criteria of type 1. The clinicalpicture is that of ascites refractory to diuretic therapy. Averagemedian survival is �6 months.

Abbreviation: HRS, hepatorenal syndrome.
Source: Salerno et al.5


Given that HRS constitutes functional kidney failure,the urine features are similar to those of prerenalazotemia, including low urine sodium and fractionalexcretion of sodium and high urine osmolality andurine to plasma osmolality ratio.4 Ascites and edemaare constantly present. Urine volume usually is notextremely reduced and some patients may have nor-mal urine volumes.47 A transition from HRS to acutetubular necrosis (ATN) in patients with progressivekidney failure not responding to treatment has beensuggested, but no studies have been reported to dateevaluating this possibility.

In addition to severe kidney failure, patients withtype 1 HRS have signs of severe circulatory dysfunc-tion, evidenced by arterial hypotension (mean arterialpressure usually is �70 mm Hg) and very low sys-temic vascular resistance. This arterial hypotensionoccurs despite marked activation of the vasoconstric-tor systems and severe vasoconstriction in extrarenalvascular beds.4,41,42 In some patients, the differentialdiagnosis between type 1 HRS and severe sepsis isdifficult and represents a clinical challenge. As dis-cussed later, all patients with cirrhosis presenting withacute kidney failure should be checked for signs ofinfection. Cardiac output may be low in patients withtype 1 HRS, either in absolute values or relative to thedecrease in total systemic vascular resistence.18-20,38

Despite this possible decrease in cardiac output, pa-tients with type 1 HRS do not show signs of circula-tory overload.18,44,48

Finally, in addition to kidney and circulatory fail-ure, the great majority of patients with type 1 HRShave features of advanced liver disease, with jaun-dice, coagulopathy, low albumin levels, hepatic en-cephalopathy, poor nutritional status, and large ascitesand edema. A significant proportion of patients withtype 1 HRS have acute-on-chronic liver failure.49

In sharp contrast to the progressive kidney failureof type 1 HRS, some patients have moderately severekidney failure of functional origin that remains stablefor variable periods. This condition is known as type 2HRS, and patients usually have serum creatinine lev-els of �2.0 mg/dL (�176.8 �mol/L). Patients withtype 2 HRS generally have less severe clinical con-cerns than those with type 1 HRS and their mainclinical problem is ascites, which usually is resistantto diuretic therapy because of the combined influenceof profound sodium retention, reduced GFR, andmarkedly increased levels of aldosterone and norepi-nephrine.4,5,46 During follow-up, some patients withtype 2 HRS develop type 1 HRS,50 which may arisespontaneously or as a result of some complication,usually a bacterial infection. Patients with type 2 HRShave much longer survival expectancy than their
counterparts with type 1 HRS (Fig 3).46 It currently is

unknown whether type 1 and type 2 HRS represent 2different entities or a single entity with the sameunderlying pathophysiology, but different intensity.

PRECIPITATING FACTORS

HRS develops without a discernable trigger insome patients, whereas in others, it occurs directlyafter effective arterial blood volume is decreased byanother condition.51-55 Bacterial infections and, inparticular, spontaneous bacterial peritonitis, are lead-ing triggers of HRS.4,5,51-54 Approximately one-thirdof patients with spontaneous bacterial peritonitis de-velop HRS at the time of infection or immediatelythereafter, in the absence of septic shock.5,52 Of thesepatients, about one-third experience reversal of HRSwhen the infection is resolved.55-58 However, in theremainder, the condition is not reversible and theydevelop either stable (type 2) or progressive HRS(type 1).55,56,59 Patients who develop type 1 HRS as aresult of spontaneous bacterial peritonitis have a dis-mal outcome, with almost 100% hospital mortality ifnot treated appropriately (discussed later).53-55 Infec-tions other than spontaneous bacterial peritonitis alsomay cause HRS, but its frequency and severity usu-ally is lower than that of patients with spontaneousbacterial peritonitis.56,57,60

Other conditions that may act as precipitating fac-tors of HRS are gastrointestinal bleeding and large-volume paracentesis (�5 L) in the absence of albuminadministration. Even so, the development of kidneyfailure after gastrointestinal bleeding is not very com-mon in patients who have cirrhosis (�10%) and it isalmost fully confined to patients with hypovolemicshock. In most instances, it is associated with isch-emic hepatitis, which implies that the kidney failuremost likely is related to ATN and not HRS.47,61

Large-volume paracentesis without albumin may triggerHRS in 15% or more of cases.62 This risk is one of themain rationales for administering IV albumin when

Figure 3. Survival of patients with cirrhosis according to typeof hepatorenal syndrome (HRS). Reproduced from Alessandriaet al46 with permission of John Wiley & Sons.

large-volume paracenteses are performed.63 Diuretic

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treatment also has been suggested as a potential triggerof HRS, but there are no clear supportive data for this.

Several factors have been suggested to be linked toan increased risk of HRS, including severe sodiumretention, hypervolemic hyponatremia, low mean arte-rial blood pressure (�80 mm Hg), and low cardiacoutput. Of note, there is no demonstrated correlationwith either the extent of liver failure, gauged bytypical assessments of liver function (serum bilirubin,albumin, and prothrombin time) or Child-Pugh classi-fication.10,18,19,64

DIAGNOSIS

Currently, the diagnosis of HRS rests on severalcriteria (Box 2).5 The minimum serum creatininelevel required to diagnose HRS is 1.5 mg/dL (133�mol/L), which corresponds to GFR �30 mL/min/1.73 m2.65 In patients treated with diuretics, serumcreatinine should be measured again after the diuretictherapy is withdrawn because serum creatinine levelmay decrease after stopping diuretics.

Because no specific laboratory tests exist for diag-nosing HRS and kidney failure from other causes(drug-induced nephrotoxicity, ATN, prerenal failuredue to volume depletion, and glomerulonephritis inpatients with hepatitis B or C, among others) can arisein patients with advanced cirrhosis, the key step indiagnosing HRS is to exclude the possibility of kidneyfailure secondary to these conditions.4,5,15,66 Gastroin-testinal fluid losses as a result of vomiting or diarrheaor kidney fluid losses arising from diuresis should besought in all patients with cirrhosis who present withkidney failure. If the kidney failure is secondary tovolume depletion, kidney function will improvequickly after volume repletion (ie, with IV salinesolution or albumin) and treatment of the underlyingcause. Shock, either septic or hypovolemic, is anothercondition frequently seen in patients with cirrhosis,

Box 2. Diagnostic Criteria of HRS

1. Cirrhosis with ascites2. Serum creatinine �1.5 mg/dL (�133 �mol/L)3. No improvement in serum creatinine level (decrease to �1.5

mg/dL [�133 �mol/L]) after at least 2 days with diureticwithdrawal and volume expansion with albumin. The recom-mended dose of albumin is a single infusion of 1 g/kg of bodyweight (maximum, 100 g)

4. Absence of shock5. No current or recent treatment with nephrotoxic drugs6. Absence of parenchymal kidney disease as indicated by

proteinuria �500 mg/d, microhematuria (�50 red blood cells/high-power field), and/or abnormal renal ultrasonography

Abbreviation: HRS, hepatorenal syndrome.Adapted from Salerno et al5 with permission of the BMJ

Publishing Group Ltd.

and this may cause kidney failure through ATN. In

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patients with septic shock, HRS sometimes is mistak-enly diagnosed if indicators of infection (such as cellcount in ascitic fluid) are not carefully consideredbecause the low arterial pressure of sepsis may errone-ously be attributed to arterial hypotension of HRS.Treatment with nonsteroidal anti-inflammatory drugsunfortunately is another relatively common reason foracute kidney failure in patients with cirrhosis andascites; this condition manifests in a manner clinicallyidentical to HRS.47,57,67,68 Before making a diagnosisof HRS, it is vital that clinicians always satisfy them-selves that treatment with nonsteroidal anti-inflamma-tory drugs was not a factor. Patients with cirrhosiswho have been treated with aminoglycosides also areat increased risk of developing kidney failure.67 Inaddition, patients with cirrhosis may reach kidneyfailure because of glomerulonephritis and patientswith cirrhosis arising from nonalcoholic steatohepati-tis have a high incidence of chronic kidney dis-ease.69-71 In cases of glomerulonephritis, proteinuriaand/or hematuria usually are present and help guidediagnosis, which in selected instances may be con-firmed by kidney biopsy.47,72

MANAGEMENT OF HRS

GeneralMeasures

The general management of patients with cirrhosisand HRS depends on the severity of kidney failureand associated complications. Patients with type 1HRS who are waiting for a liver transplant are man-aged appropriately in an intensive care setting. Consid-ering the high mortality rate of type 1 HRS, decisionsabout the management of patients who are not candi-dates for transplant or who have important comorbidconditions should be made on an individual basis. Acentral venous catheter is important to keep track ofcentral venous pressure in patients who will be treatedwith vasoconstrictors and albumin.73 Use of a bladdercatheter may be associated with urinary tract infectionand is not necessary except when marked oliguria ispresent. There should be vigilant monitoring of thepossibility of associated complications, in particularbacterial infections and gastrointestinal bleeding, andany that arise should be treated as quickly as possible.IV fluids should be administered carefully because ofsevere kidney failure together with sodium and solute-free water retention due to cirrhosis. Excessive admin-istration of fluids may result not only in an increase inascites and edema, but also in substantial increases incentral venous pressure and pulmonary edema.

Patients with type 2 HRS without associated com-plications are managed as outpatients. Spironolactoneand other potassium-sparing diuretics generally shouldbe avoided because of the risk of hyperkalemia,
whereas loop diuretics, such as furosemide, usually


lack efficacy.63 Thus, treatment of ascites is based onrepeated large-volume paracentesis and albumin ad-ministration (8 g/1 L of ascites removed).63,74

Management of Type1HRS

Administration of vasoconstrictor drugs currentlyis considered the best therapy for managing type 1HRS.15,63 This approach is intended to cause vasocon-striction of the greatly dilated splanchnic arterial bed,thus improving circulatory function. This in turn alle-viates arterial underfilling, lessens the activation ofthe endogenous vasoconstrictor systems, and in-creases kidney perfusion and GFR. Treatment withvasodilator drugs is ineffective. Albumin infusionalone improves cardiac function, but is not associatedwith an improvement in kidney function.73 The avail-able vasoconstrictors are vasopressin analogues, suchas terlipressin, which acts on V1 vasopressin recep-tors in vascular smooth muscle cells, and �-adrener-gic agonists, such as noradrenaline or midodrine,which act on �1-adrenergic receptors in vascularsmooth muscle cells. In most published reports, vaso-constrictors (frequently terlipressin) are given with IValbumin to further alleviate the arterial underfilling.75-82

Results from randomized controlled studies and sys-tematic reviews show that treatment with the combina-tion of terlipressin and albumin is associated withreversal of HRS in 40%-50% of patients, making thisapproach the preferred initial therapy (Box 3).63 Re-sponse to treatment with terlipressin and albumin isassociated with a progressive decrease in serum creat-inine concentration, increased urine output, and im-

Box 3. Pharmacologic Treatment of HRS

Vasoconstrictors

● Terlipressin: 1 mg/4-6 h intravenously; the dose is increasedup to a maximum of 2 mg/4-6 h after 3 days if there is noresponse to therapy, defined by a decrease in serum creati-nine �25% of pretreatment values. Response to therapy isindicated by a marked decrease in the high serum creatininelevels, at least �1.5 mg/dL (�133 �mol/L). Treatment isusually given from 5-15 days

● Midodrine: 7.5 mg orally 3�/d, increased to 12.5 mg 3�/d ifneeded

● Octreotide: 100 �g subcutaneously 3�/d, increased to 200�g 3�/d if needed

● Norepinephrine: 0.5-3 mg/h as continuous intravenous infu-sion aimed at increasing mean arterial pressure by 10 mmHg. Treatment is maintained until serum creatinine de-creases �1.5 mg/dL (�133 �mol/L)

Albumin administrationConcomitant administration of albumin together with vaso-

constrictor drugs (1 g/kg body weight at day 1 followed by20-40 g/d)

Abbreviation: HRS, hepatorenal syndrome.

provement in hyponatremia.80,81 Factors that predict a


response to treatment are an increase in arterial pres-sure during treatment and low baseline creatininelevel.83-86 �-Adrenergic agonists, such as noradrena-line or midodrine, are a reasonable alternative toterlipressin due to their low cost and broad availabil-ity; however, data for their use are limited.48,87-89 Asystematic review of randomized controlled studieshas shown that vasoconstrictor therapy of HRS im-proves survival.82 Responders to terlipressin and albu-min in terms of improvement in kidney function aftertherapy have increased survival compared with nonre-sponders. After withdrawal of therapy, HRS recurs in�15% of patients, and in these cases, a second treat-ment with terlipressin usually is effective. The inci-dence of side effects (usually ischemic) that mandatediscontinuation of treatment is �12%. Attention shouldbe paid to early detection of ischemic side effects.

RRT has been used in patients with type 1 HRS,particularly in candidates for liver transplant.90 Disap-pointingly, RRT has not been evaluated side by sidewith other forms of therapy in randomized compara-tive studies. RRT is not considered the first-line treat-ment for patients with type 1 HRS because it does notcorrect the underlying pathogenesis. Nevertheless,either continuous or intermittent RRT is an option forpatients with type 1 HRS for whom vasoconstrictorsare ineffective and who present signs of uremia,volume overload, severe metabolic acidosis, or hyper-kalemia. The best modality of RRT is still an unre-solved issue. In recent years, alternative methods toconventional RRT have been evaluated in type 1HRS. These include molecular readsorbent recirculat-ing systems (an alternative to dialysis that clearsalbumin-bound substances, including vasodilators) andfractionated plasma separation and adsorption (thePrometheus system), but more evidence is needed ifthese procedures are to be accepted as having therapeu-tic value for HRS.91-93 A recent small study evaluat-ing a molecular readsorbent recirculating system asrescue therapy in patients with type 1 HRS not re-sponding to treatment with vasoconstrictors showedno improvement in GFR and renal blood flow.94

An implantable stent inserted through a transjugu-lar approach that reduces portal pressure by establish-ing communication between the portal vein and ahepatic vein (known as TIPS [transjugular intrahe-patic portosystemic shunt]) has been proposed as analternative treatment for type 1 HRS, but informationis very limited.95,96 As a result, the current role of thisdevice in the management of this condition is un-known. A recent study including a very small numberof patients showed that vasoconstrictor therapy fol-lowed by stent placement was effective in patientswith type 1 HRS.87 This approach using a sequential
therapy merits evaluation in larger studies.
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Liver transplant is the first choice of treatment forpatients with cirrhosis and type 1 HRS. Becausekidney failure is reversible after liver transplant, pa-tients should not be treated with combined liver-kidney transplant. Combined liver-kidney transplantis appropriate only for patients who have been onRRT for more than 6-8 weeks who have a lowlikelihood of recovery of kidney function.97,98 Asubstantial problem in liver transplant for patientswith type 1 HRS is the high mortality rate forpatients on the waiting list owing to the short lifeexpectancy and long waiting times at many trans-plant centers. This may be dealt with by assigningthese patients a high priority for transplant. Thequestion arises as whether to treat patients withtype 1 HRS with vasoconstrictors before transplantwith the aim of performing transplant on patientswith normal or near-normal kidney function. Excel-lent survival has been reported with the 2 ap-proaches, “transplant-without treating HRS” or“treat HRS before transplant.”99-101 However, infor-mation is scarce and studies either did not assess compli-cations after transplant or included a small number ofpatients. Therefore, use of pharmacologic treatment oftype 1 HRS before transplant remains an open question,although transplant of patients without kidney failuretheoretically seems better than transplant of patients withacute severe kidney failure.102 A proposed algorithm ofmanagement of type 1 HRS based on the current knowl-edge is shown in Fig 4.

Management of Type2HRS

There are very few data regarding the use of vaso-constrictors in combination with albumin for patientswho have type 2 HRS. Uncontrolled trials support the

8

efficacy of vasoconstrictors in improving kidney func-tion, but recurrence after treatment withdrawal is veryfrequent (P. Ginès, unpublished observations). Morestudies are required to more fully understand the rolethat vasoconstrictors plus albumin may have in treat-ing type 2 HRS.48,81 TIPS may improve kidney func-tion and reduce the risk of progression to type 1HRS,103 but randomized studies are lacking. RRT isnot indicated in the management of patients with type2 HRS because of the lack of a severe decrease inkidney function. A proposed algorithm of manage-ment of type 2 HRS based on current knowledge isshown in Fig 5.

PREVENTION OF HRS

As discussed, the chance of HRS is considerable inpatients with cirrhosis and spontaneous bacterial peri-tonitis, and a study published in 1999 showed that IVadministration of albumin (1.5 g/kg body weight atdiagnosis and 1 g/kg 48 hours later) can greatlyreduce this risk.55 In that study, it was observed thatpatients with normal serum creatinine levels and nor-mal or slightly increased serum bilirubin levels at thetime of diagnosis of spontaneous bacterial peritonitishad very low risk of developing HRS even if albuminwas not given. This has led to the suggestion thatpatients of this type should not be given albumintreatment. Nevertheless, because this was not a pre-defined subanalysis of the study, it seems reasonableto suggest that albumin should be administered to allpatients with spontaneous bacterial peritonitis untilthis observation is confirmed in further prospectivestudies, as proposed in the guidelines of the EuropeanAssociation for the Study of the Liver (EASL).63

Long-term oral administration of norfloxacin (400

Figure 4. Proposed treatment algo-rithm for patients with type 1 hepatorenalsyndrome (HRS). Abbreviation: MELD,Model for End-Stage Liver Disease.aPotentially reversible chronic liver dis-eases (alcoholic hepatitis, acute-on-chronic liver failure, etc) with no impor-
tant associated comorbid conditions.

albu


mg/d) in patients with ascitic fluid protein �15 g/Land associated decreased liver and/or kidney function(bilirubin �3 mg/dL [�51.3 �mol/L], Child-Pughscore �10, serum sodium �130 mEq/L [�130 mmol/L], and/or serum creatinine �1.2 mg/dL [�106.1�mol/L]) reduces the risk of HRS and improvessurvival.32 These effects probably are related to pre-vention of bacterial translocation, suppression of pro-inflammatory cytokines, and improvement in circula-tory function.26,27,30,31 In patients with acute alcoholichepatitis, pentoxifylline was shown to decrease theincidence of HRS in one study104; however, theseresults were not confirmed in a study recently pub-lished in abstract form.105 Although hyponatremia inpatients with ascites is a risk factor for HRS,10 thereare no studies assessing whether vaptans, drugs thatimprove serum sodium levels by antagonizing selec-tively the V2 receptors in the kidney,106 may helpprevent HRS.

MANAGEMENT OF HRS ACCORDING TOGUIDELINES OF INTERNATIONAL SOCIETIES

The most recent guidelines, published in 2010 bythe European Association for the Study of the Liver(EASL), recommend terlipressin (1 mg/4-6 h as IVbolus) together with albumin as first-line treatment forpatients with type 1 HRS.63 The aim of treatment is todecrease serum creatinine levels to �1.5 mg/dL (�133�mol/L). Modifications of the dose are guided bychanges in serum creatinine concentration; if serumcreatinine level decreases by at least 25% after 3 daysof treatment, the dose is maintained, and if not, thedose is increased to 2 mg/4-6 h. If there is recurrenceat any time after treatment discontinuation, patientsshould be re-treated with terlipressin and albumin.Alternatives to terlipressin are noradrenaline and mido-

S

Priorrepeaand a

Repeated largeparacentesis and

Figure 5. Proposed treatment algo-rithm for patients with type 2 hepatorenalsyndrome (HRS). Abbreviations: SCr, se-rum creatinine; Tx, transplant. aOnly inpatients without adverse reactions to di-uretics and with sodium excretion underdiuretic treatment of �30 mEq/d. bEitherterliprerssin if available or norepineph-rine; therapy with a combination of midro-dine and octreotide also could be anoption.

drine plus octreotide, both in combination with albu-


min, yet information about efficacy is very limited.Patients treated with vasoconstrictors should be fol-lowed up carefully throughout treatment for earlydetection of side effects, particularly cardiovascularevents and pulmonary edema. Main contraindicationsto vasoconstrictor drugs are severe cardiovasculardiseases. The use of TIPS is not recommended andRRT should be used only in patients not responding tovasoconstrictors who fulfill criteria for kidney sup-port. As far as patients who are candidates for trans-plant is concerned, EASL guidelines recommend treat-ment of HRS with vasoconstrictors before livertransplant. Moreover, liver transplant alone is appro-priate, with combined liver-kidney transplant re-served for only patients who have been on RRT formore than 6-8 weeks. Although the guidelines statethat vasoconstrictor therapy is effective for the treat-ment of type 2 HRS, no specific recommendation ismade to treat these patients due to limited data.

The AASLD (American Association for the Studyof the Liver) guidelines published in 2009 recom-mend that patients with type 1 HRS be treated withmidodrine and octreotide together with albumin.107 Itshould be noted that terlipressin is not available in theUnited States. These guidelines also emphasize thatpatients who are candidates for liver transplant shouldbe referred immediately to transplant centers becauseof their low survival expectancy.

ACKNOWLEDGEMENTS

Support: Dr Fagundes was recipient of a grant from the InstitutoReina Sofía de Investigación Nefrológica (IRSIN). Some of thestudies reported in this review were performed with the support ofgrants from the Fondo de Investigación Sanitaria (FIS PI080126and EC/90077) and Ciber de Enfermedades Hepáticas y Digestivas(CIBEREHD). CIBEREHD is funded by the Instituto de Salud

Candidate for Tx Not candidate for Tx

SCr SCr increasing

Evaluate for liver transplant

luate kidney function

atients on transplant list;rge-volume paracentesis in; norfloxacin, 400 mg/d

Repeated large-volume paracentesis and albumin;

norfloxacin, 400 mg/d

me min

Treat with vasoconstrictorsb

Type 2 HRS

iureticsa

table

Eva

itize pted lalbum

-volu

D

Carlos III, Ministerio de Sanidad, España.

9

Fagundes and Ginès

Financial Disclosure: Dr Ginès has been an advisor for OtsukaPharmaceuticals, Orphan Therapeutics, Ikaria, and Ferring Int. DrFagundes declares that she has no relevant financial interests.

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hepatorenal syndrome: a severe, but treatable, …...in practice hepatorenal syndrome: a severe, but...

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