1 Acute Kidney Injury in Cirrhosis Guadalupe Garcia-Tsao, 1 Chirag R. Parikh, 2 and Antonella Viola 1,3 Acute renal failure (ARF), recently renamed acute kidney injury (AKI), is a relatively frequent problem, occurring in approximately 20% of hospitalized patients with cirrhosis. Although serum creatinine may underestimate the degree of renal dysfunction in cirrhosis, measures to diagnose and treat AKI should be made in patients in whom serum creatinine rises abruptly by 0.3 mg/dl or more (>26.4 mol/l) or increases by 150% or more (1.5- fold) from baseline. The most common causes of ARF (the term is used interchangeably with AKI) in cirrhosis are prerenal azotemia (volume-responsive prerenal AKI), acute tubular necrosis, and hepatorenal syndrome (HRS), a functional type of prerenal AKI exclusive of cirrhosis that does not respond to volume repletion. Because of the progressive vasodilatory state of cirrhosis that leads to relative hypovolemia and decreased renal blood flow, patients with decompensated cirrhosis are very susceptible to developing AKI with events associated with a decrease in effective arterial blood volume. HRS can occur spontaneously but is more frequently precipitated by events that worsen vasodilatation, such as spontaneous bacterial peritonitis. Conclusion: Specific therapies of AKI depend on the most likely cause and mechanism. Vasoconstrictors are useful bridging therapies in HRS. Ultimately, liver transplantation is indicated in otherwise reasonable candidates in whom AKI does not resolve with specific therapy. (HEPATOLOGY 2008;48: ) The development of acute kidney injury (AKI) in patients with cirrhosis is an ominous event. In a systematic review of 118 studies evaluating predictors of survival in cirrhosis, parameters of liver dysfunction (Child-Pugh score and its components) and parameters of renal dysfunction (creatinine and blood urea nitrogen/azotemia) were both powerful predictors of death in decompensated cirrhosis. 1 Higher serum creatinine (SCr) consistently portends worse survival. In fact, SCr is one of three variables that form part of the model of Abbreviations: AKI, acute kidney injury; ARF, acute renal failure; ATN, acute tubular necrosis; FENa, fractional excretion of sodium; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, model of end-stage liver disease; OLT, orthotopic liver transplantation; RCT, randomized controlled trials; SBP, spontaneous bacterial peritonitis; SCr, serum creatinine; SLKT, simultaneous liver and kidney transplant; TIPS, transjugular intrahepatic portosystemic shunt; UNa, urinary sodium. From the 1 Section of Digestives Diseases, Yale University School of Medicine, New Haven, CT, and VA-Connecticut Healthcare System, West Haven, CT; the 2 Section of Nephrology, Yale University School of Medicine, New Haven, CT and VA-Connecticut Healthcare System, West Haven, CT; and the 3 Department of Clinical Medicine, University of Bologna, Italy. Received July 3, 2008; accepted August 25, Address reprint requests to: Guadalupe Garcia-Tsao, Yale University School of Medicine, Section of Digestive Diseases, One Gilbert Street, TAC, room # S241B, New Haven, CT fax: Copyright 2008 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI /hep Potential conflict of interest: Nothing to report. end-stage liver disease (MELD) score that is a good predictor of 3-month mortality and is currently used in determining priority for orthotopic liver transplantation (OLT). 2 Pretransplantation creatinine was recently found to be the most powerful predictor of survival post-olt. 3 Therefore, identifying and treating the cause of renal dysfunction in cirrhosis is essential. This review of AKI in cirrhosis expands several recent reviews on hepatorenal syndrome (HRS) 4-6 by covering causes of acute renal failure (ARF) other than HRS and expands recent reviews of ARF in cirrhosis. 7,8 Definition In response to the need for a common definition and classification of ARF, the Acute Kidney Injury Network recently developed and published a consensus definition of acute kidney injury (AKI), a new term for ARF. 9 AKI is defined as an abrupt (arbitrarily set at 48 hours) reduction in kidney function manifested by an absolute increase in SCr of 0.3 mg/dl or more ( 26.4 mol/l), equivalent to a percentage increase in SCr 50% or more (1.5-fold from baseline) or a urine output of less than 0.5 ml/kg per hour for more than 6 hours. The AKI definition has three stages that indicate the severity of renal dysfunction and are based on SCr or urine output (Table 1). The urine output criterion was included based on the predictive importance of this measure but with the awareness that urine output may not be measured routinely and 2064
2 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2065 Table 1. Classification/Staging System for Acute Kidney Injury (AKI) 9 Stage Serum Creatinine Criteria Urine Output Criteria 1 Increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4 mol/l) or increase to more than or equal to 150% to 200% (1.5-fold to 2-fold) from baseline Less than 0.5 ml/kg per hour for more than 6 hours 2 Increase in serum creatinine to more than 200% to 300% ( 2-fold to 3-fold) from baseline Less than 0.5 ml/kg per hour for more than 12 hours 3* Increase in serum creatinine to more than 300% ( 3-fold) from baseline (or serum creatinine of more than or equal to 4.0 mg/dl [ 354 mol/l] with an acute increase of at least 0.5 mg/dl [44 mol/l]) Less than 0.3 ml/kg per hour for 24 hours or anuria for 12 hours *Any patient requiring renal replacement therapy is, by definition, at a stage 3. accurately in non intensive care unit settings. These criteria include both an absolute and a percentage change in creatinine to accommodate variations related to age, sex, and body mass index and to reduce the need for a baseline creatinine but do require at least two creatinine values within 48 hours. Types of Acute Kidney Injury Traditionally, three types of ARF/AKI are identified: (1) prerenal azotemia, which results from renal hypoperfusion without a glomerular or tubular lesion; (2) intrinsic renal failure, which results from tubular cell necrosis (ischemic or toxic), glomerulonephritis, or interstitial nephritis; and (3) post-renal failure, which results from urinary tract obstruction causing hydronephrosis. Patients with cirrhosis can develop all types of AKI, 8 but they can additionally develop HRS, a type of prerenal AKI that is not responsive to volume expansion and is seen exclusively in patients with severe liver dysfunction HRS is a unique potentially reversible form of ARF secondary to renal vasoconstriction 10 that results from extreme vasodilatation. 11,12 It is therefore a functional disorder, not associated with structural kidney damage. The 1-year and 5-year probabilities of developing HRS in patients with ascites are approximately 20% and 40%, respectively 13 and are highest in patients with more marked sodium and water retention and marked activation of vasoconstrictive systems. 13,14 HRS is divided into two types (1 and 2) based on prognosis and clinical characteristics. Survival of patients with HRS-1 is shorter than that of patients with HRS-2 (median survival 1.0 versus 6.7 months). 15 HRS-1 is characterized by an abrupt deterioration in renal function that occurs mostly in an inpatient setting and often develops after a precipitating event, particularly spontaneous bacterial peritonitis (SBP). 4,16 HRS-2 is characterized by a steady or slowly progressive course that occurs mostly in an outpatient setting in patients with refractory ascites. 17 Because this more chronic form of HRS does not meet criteria for AKI, it is not considered in this review. The term HRS will refer to HRS-1, unless otherwise specified. Prevalence AKI occurs in approximately 19% of hospitalized patients with cirrhosis, and the most common cause is prerenal AKI, accounting for approximately 68% of the cases 19,23,24 (Fig. 1). AKI is mostly secondary to infection, 19,24 hypovolemia (gastrointestinal hemorrhage, aggressive diuresis, or diarrhea), use of vasodilators, and other factors that cause renal vasoconstriction such as nonsteroidal anti-inflammatory drugs or intravenous contrast agents. HRS, which is not volume-responsive, constitutes approximately 25% of the cases of prerenal ARF; that is, it accounts for only approximately 17% of cases of ARF in hospitalized patients with cirrhosis 19,23,24 (Fig. 1). Acute tubular necrosis (ATN) is more common than HRS as a cause of AKI, accounting for about a third of the cases (Fig. 1). It is mainly caused by an ischemic insult to the renal tubules as a result of a hypotensive event after bleeding or severe sepsis. However, the use of aminoglycosides, which are directly toxic to renal tubules, was found to be the most important predictor of ARF in cirrhosis in a study performed in U.S. veterans. 18 Postrenal causes of AKI in cirrhosis are rare and represent less than 1% of the cases. 23 Similarly, chronic kidney injury also appears to be a rare diagnosis in hospitalized patients, 19 although a small study has recently shown that immune-complex glomerulonephritis is quite common in patients with end-stage hepatitis C induced cirrhosis. 25 A recent review has suggested that an additional subtype of HRS should include patients with chronic kidney injury who develop superimposed AKI. 6 Mechanisms. ARF/AKI is common in cirrhosis for several reasons. Patients with cirrhosis are prone to intravascular volume depletion secondary to gastrointestinal bleeding, diuretic use, and lactulose-induced diarrhea. Moreover, these patients are often exposed to nephrotoxic agents such as nonsteroidal anti-inflammatory drugs,
3 2066 GARCIA-TSAO, PARIKH AND VIOLA HEPATOLOGY, December 2008 Fig. 1. Prevalence and types of acute renal failure (ARF)/acute kidney injury (AKI) in hospitalized patients with cirrhosis. Percentages and numbers were obtained by adding up patients in the references cited. ATN, acute tubular necrosis; GMN, glomerulonephritis; HRS, hepatorenal syndrome. *Infections precipitated this type of AKI in 51% of the cases. 19,24 contrast agents, and aminoglycosides, to which they are particularly susceptible. 18,26 Perhaps most importantly, because of the hyperdynamic circulatory state of cirrhosis, renal blood flow in patients with cirrhosis (particularly in those with more severe liver disease) is very susceptible to events associated with a further decrease in effective arterial blood volume. As recently reviewed, 12 the hyperdynamic circulation in cirrhosis is a progressive vasodilatory syndrome that was first recognized clinically in patients with cirrhosis by observing that they frequently had warm extremities, cutaneous vascular spiders, wide pulse pressure, and capillary pulsations in the nail beds. 27 Progressive vasodilatation (both splanchnic and systemic) is a key factor in the pathogenesis of many of the complications of cirrhosis, prominently in the kidney. 12 Splanchnic and systemic vasodilatation in cirrhosis is a consequence of portal hypertension and is attributable mostly to nitric oxide overproduction, although other molecules also participate in this complex process. 12 As shown in Fig. 2, vasodilatation leads to a decreased effective arterial blood volume (relative hypovolemia) and activation of neurohumoral sys- CIRRHOSIS Fig. 2. Hyperdynamic circulation in the pathophysiology of hepatorenal syndrome (HRS). Ascites, hyponatremia, and HRS in cirrhosis have a common pathophysiology. The main abnormality is splanchnic and systemic vasodilatation that leads to a decreased effective arterial blood volume (relative hypovolemia) and activation of neurohumoral systems (RAAS, renin-angiotensinaldosterone system; SNS, sympathetic nervous system; ADH, nonosmotic release of antidiuretic hormone). Relative hypovolemia initially leads to sodium and water retention (with ascites formation), increase in intravascular volume, and increased cardiac output. With progression of cirrhosis, vasodilatation worsens and activated vasoconstrictive systems lead to renal vasoconstriction. Additionally, the increased cardiac output is now insufficient to maintain perfusion pressure (high-output heart failure) and further contributes to a decrease in renal blood flow and renal failure. Decreased effective arterial blood volume Sodium and water retention Ascites and hyponatremia Portal (sinusoidal) hypertension SPLANCHNIC / SYSTEMIC VASODILATATION Activation of neurohumoral systems (RAAS, SNS, ADH) Renal vasoconstriction Decreased renal blood flow HRS Increased cardiac output High-output heart failure
4 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2067 Rapid fluid loss (GI bleed, diarrhea) Bacterial infection (SIRS/Sepsis) Hypovolemia Decreased effective arterial blood volume Further vasodilatation* Activation of VCS Renal vasoconstriction Fig. 3. Mechanisms for the development of acute renal failure (ARF)/acute kidney injury (AKI) in cirrhosis. GI, gastrointestinal; SIRS,systemic inflammatory response syndrome; VCS, vasoconstrictive systems (include renin-angiotensinaldosterone and sympathetic nervous system). *Worsening of the vasodilatation already present in the patient with cirrhosis Hypovolemic shock ARF/AKI Renal tubular injury Septic shock tems such as the renin-angiotensin-aldosterone system; sympathetic nervous system; and non-osmotic release of antidiuretic hormone). Relative hypovolemia initially leads to sodium and water retention (with ascites formation), increased intravascular volume, and increased cardiac output. With progression of cirrhosis, vasodilatation worsens and activated vasoconstrictive systems lead to renal vasoconstriction and decreased renal blood flow 11,28 (Fig. 2). Additionally, as in other forms of high cardiac output syndrome, the heart response becomes insufficient to maintain perfusion pressure (high-output heart failure) and further contributes to a decrease in renal blood flow and renal failure 12,29 (Fig. 2). It has been proposed that the sympathetic nervous system causes a rightward shift in the renal autoregulatory curve that makes renal blood flow critically dependent on renal perfusion pressure and that this further contributes to the development of renal failure. 30 Although the spontaneous development of renal failure in a patient with cirrhosis and hyperdynamic circulation indicates the presence of HRS, this syndrome often presents after a precipitating event. 4 In the setting of hyperdynamic circulation, rapid fluid loss (from gastrointestinal bleeding or diarrhea) or sepsis/systemic inflammatory response syndrome-related vasodilation leads to a further decrease in effective arterial blood volume, renal vasoconstriction, and prerenal AKI (Fig. 3). This is further complicated by the fact that these same events, through the development of circulatory shock, can lead to intrinsic renal failure from renal tubular necrosis. Intense renal vasoconstriction, as seen in HRS, can in turn lead to tubular ischemia and necrosis as demonstrated by electron microscopy 31 or by urine markers of acute tubular necrosis 32,33 (Fig. 3). Diagnosis SCr is the most established, simple, and inexpensive parameter of glomerular filtration rate (GFR) and is the primary method of detection of all forms of renal failure. However, it has several limitations. First, SCr is not helpful in distinguishing among various causes of renal injury. Second, SCr lags behind renal injury and is therefore a delayed marker of decreased renal function. 34 Third, significant renal disease can exist with minimal or no changes in SCr because of renal reserve, enhanced tubular creatinine secretion, or other factors. 35,36 Lastly, SCr is greatly influenced by numerous nonrenal factors such as body weight, race, age, sex, total body volume, drugs, muscle metabolism, and protein intake. 35 Although the simplified modification of diet in renal disease formula provides a robust estimate of GFR relative to SCr corrected by age, race, and sex in chronic kidney disease when SCr is at a steady state, it is not useful in AKI when SCr is not in equilibrium. In cirrhosis, SCr may be an even poorer reflection of kidney function because of a reduced muscle mass, particularly in patients with severe liver disease. In this setting, the release of creatinine is considerably reduced, and therefore, patients may have a normal SCr in the setting of a very low GFR. Additionally, severe hyperbilirubinema gives a falsely low value of SCr if the chemical rather than enzymatic method is used for measurement. 37
5 2068 GARCIA-TSAO, PARIKH AND VIOLA HEPATOLOGY, December 2008 Table 2. HRS New Diagnostic Criteria 17 Cirrhosis with ascites Serum creatinine 1.5 mg/dl (133 mol/l) HRS-1 doubling of the initial serum creatinine concentrations to a level greater than 2.5 mg/dl ( 226 mol/l) in less than 2 weeks No improvement in serum creatinine (decrease to 1.5 mg/dl or less) after at least 2 days of diuretic withdrawal and expansion of plasma volume with albumin (1 g/kg body weight/day up to a maximum of 100 g/day) Absence of shock No current or recent treatment with nephrotoxic drugs or vasodilators Absence of parenchymal kidney disease as indicated by proteinuria 500 mg/day, microhematuria ( 50 red blood cells per highpower field), or abnormal renal ultrasonography As recently reviewed, 38 other methods of renal function assessment also have limitations and do not correlate well with GFR. Newer serum markers such as cystatin C are promising; however, they require further validation using gold standard measures of GFR such as iodothalamate or inulin clearance. Therefore, and despite its limitations; SCr remains the key biomarker in the diagnosis of ARF in cirrhosis. Diagnosis of HRS HRS type 1 has been defined by consensus as a doubling of SCr to a level greater than 2.5 mg/dl ( 226 mol/l) in less than 2 weeks. 16,17 Per the AKI consensus criteria, this level of renal failure would correspond to a stage 2 (that is, a greater than twofold to threefold increase in SCr from baseline) 9 (Table 1). The diagnosis of HRS has been defined in two International Ascites Club consensus conferences in and in 2005 (Table 2). 17 The new definition of HRS: (1) excludes creatinine clearance because it is more complicated to perform and does not increase the accuracy of renal function estimation; (2) includes renal failure in the setting of ongoing bacterial infection (but in the absence of septic shock), indicating that the diagnosis can be established before completing antibiotic therapy; (3) determines that plasma volume expansion should be performed with intravenous albumin rather than saline solution; and (4) excludes minor diagnostic criteria (urinary indices) because these criteria have poor sensitivity and specificity. Although HRS is a diagnosis of exclusion, certain patient characteristics are more or less typical of HRS. The presence of ascites is a prerequisite for the diagnosis of HRS because the same mechanisms that lead to ascites formation lead to HRS 11 (Fig. 2). Other features that are characteristic of patients with HRS can be gathered from Table 3, which summarizes baseline characteristics of 509 patients with HRS that met International Ascites Club criteria for HRS (only 5% of whom had HRS-2) and that specified, at a minimum, age, Child-Pugh class or score, and mean arterial pressure (MAP). 14,15,23,33,39-48 Patients with HRS have advanced liver disease, as evidenced by the median Child-Pugh score in these patients being 11.2, and their low MAP (median, 74 mmhg), and low serum sodium (median, 127 meq/l), findings that are consistent with the presence of vasodilatation (low MAP), sodium retention (ascites), water retention (dilutional hyponatremia), and renal vasoconstriction (HRS) (Fig. 2). If these findings are absent, the diagnosis of HRS is unlikely. Of note, SCr levels in HRS are approximately 3.6 mg/dl and rarely exceed 6 mg/dl, and urine output is usually approximately 600 ml/day (Table 3). Differential Diagnosis Differentiation among the three main causes of AKI may be difficult in patients with cirrhosis because the clinical presentations do not match classical paradigms and, as mentioned previously, factors that lead to prerenal azotemia can precipitate HRS and can also precipitate ATN (Fig. 3). Tubular ability to reabsorb sodium and to concentrate urine is preserved in prerenal azotemia and HRS but is impaired in ATN. Prerenal azotemia and HRS are therefore classically described as sodium avid states with low ( 20 meq/l) urinary sodium (UNa), low ( 1%) fractional excretion of sodium (FENa), and elevated ( 500 mosm/kg) urine osmolality. Conversely, patients with ATN have high UNa ( 40 meq/l), high FENa (2%), and urine osmolality under 350 mosm/kg. However, in patients with HRS, particularly in those on a high dose of diuretics, UNa is consistently greater than 10 meq/l. 49 Conversely, ATN that occurs in patients with sodium avid states, such as cirrhosis, has been described as having a FENa 1%. 7,50 UNa and FENa are thus less useful in patients with cirrhosis and have been eliminated as diagnostic criteria in HRS. 17 Classic descriptions of prerenal azotemia and HRS describe a bland urine sediment, and bile-stained granular and epithelial casts are described in ATN. However, these casts may be seen as nonspecific findings in patients with advanced liver disease and jaundice. 51,52 Conversely, ATN has been described morphologically 31 and by urine biomarkers such as -2 microglobulin 32 in HRS. 33 Thus, urine sediment may not be helpful either in the differential of ARF in cirrhosis. Differentiation between prerenal azotemia and HRS also may be difficult. By definition, prerenal azotemia improves with volume expansion. However, assessment of exact intravascular volume deficit in a patient who is already total body sodium overloaded is difficult; the rate
6 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2069 Table 3. First Author Year Baseline Characteristics of 509 Patients with HRS in Different Series in the Literature that Specified, at a Minimum, Age, Child-Pugh Score/Class, and MAP N (n HRS-2) Age (years) Sex (% Male) % Alcoholic Cirrhosis (%alc hep) Child-Pugh Score MAP (mmhg) Serum Creatinine mg/dl ( mol/l) Serum Sodium (meq/l) Urine Output (ml/day) Urinary Sodium (meq/day) Angeli 99 (33) 5 (0) /4 (B/C) 76 5 (442) study group Angeli 99 (33) 8 (0) /7 (B/C) (319) controls Gulberg 99 7 (0) /7 (B/C) 74 2( 177) (39) Mulkay (0) (42) 2/10 (B/C) (301) (40) Moreau (0) (26) Most C (257) (23) Colle 02 (41) 18 (0) (39) (283) Halimi 02 (42) 18 (2) (22) (283) Duvoux (0) (345) (43) Solanki 12 (0) (257) (44) Study group Solanki (0) (195) (44) Control group Kiser 05 (45) 19 (1) (398) Group 1 Kiser 05 (45) 16 (8) (319) Group 2 Kiser 05 (45) 8 (2) (265) Group 3 Alessandria (0) (345) (15) Ruiz del Arbol 12 (0) (381) (14) Neri 08 (46) 26 (0) (248) Study group Neri 08 (46) 26 (0) (257) Control group Sanyal 08 (47) 56 (0) (36) (354) Study group Sanyal 08 (47) 56 (0) (36) (345) Control group Martin-Llahi (6) (319) (48) Study group Martin-Llahi (5) (363) (48) Control group Median (IQ Total N 54 (51 59) 68 (57 72) 57 (40 78) 11.2 (11 12) 74 (68 76) 3.6 ( ) 127 ( ) 596 ( ) 7 (6 12) range)* 509 (24) 319 ( ) All values are expressed as mean values except for Mulkay (median values). * Median (IQ range) of studies; MAP, mean arterial pressure; alc hep, alcoholic hepatitis; IQ, interquartile. of fluid administration is unspecified, and thus the rate of response in SCr is highly variable and often incomplete. The difficulty in establishing an early diagnosis of HRS leads to a significant delay in the initiation of specific therapy and is one of the barriers in the development of new agents. In noncirrhotic patients, urinary biomarkers such as interleukin-18 have an accuracy of 95% in differentiating ATN from other causes of renal dysfunction such as prerenal azotemia, urinary tract infection, and chronic kidney disease 53 and are being investigated in patients with cirrhosis.
7 2070 GARCIA-TSAO, PARIKH AND VIOLA HEPATOLOGY, December 2008 Treatment Treatment of AKI in cirrhosis depends on its cause. Prerenal azotemia should be managed by treating/discontinuing the precipitant and through volume repletion. ATN should be treated using renal replacement therapy, particularly in the presence of volume overload, hyperkalemia, or metabolic acidosis not responding to medical therapy. Because of a lack of clinical studies, there are no special recommendations for dose, intensity, and duration of dialysis in patients with cirrhosis who develop ATN. Interestingly, a recent study has demonstrated benefit of terlipressin in a consecutive series of patients with cirrhosis with ATN. 54 It is likely that mesenteric/systemic vasoconstriction induced by terlipressin will lead to renal vasodilatation with improvement of renal blood flow to the damaged renal tubules. Therapy of the complications of AKI and dialysis therapy are beyond the scope of this review. The remainder of this section deals with treatment of HRS. Liver Transplantation (OLT) OLT is the only definitive therapy for HRS, because it is the only therapy associated with improvement in survival. However, it is important to reverse HRS because improving renal function pretransplantation is associated with improved posttransplantation outcomes It has been shown that renal insufficiency, including HRS, has a negative impact on OLT outcomes, with a higher mortality and higher posttransplantation end-stage renal disease. 3,55-58 Patients who are transplanted with HRS have more complications and a higher in-hospital mortality rate than those undergoing transplantation without HRS. 56 Conversely, the outcome of OLT in patients with HRS treated with vasopressin analogs before transplantation is similar to that of patients undergoing transplantation without HRS. 60 With the implementation of the MELD score in the allocation of organs in the United States, the presence of HRS increases the possibility of obtaining an organ for transplantation. However, although survival in HRS-2 (the more benign, chronic type of HRS) correlates with the MELD score, all patients with HRS-1 have a very poor outcome, 15 suggesting that the development of HRS-1 per se should indicate a high priority for transplantation, independent of MELD. Simultaneous liver and kidney transplant (SLKT) is increasingly considered in patients with renal dysfunction undergoing OLT. 59 There is specific concern that some patients who undergo SLKT may have reversible renal failure. There is also concern that liver grafts are placed prematurely in those with end-stage renal disease. Thus, to assure allocation of transplants only to those truly in need, the transplant community met in March 2006 to review post-meld data on the impact of renal function on liver waitlist and transplant outcomes and the results of SLKT. 61 This consensus conference resulted in an evaluation algorithm that has the goal of confirming the presence of kidney disease with structural damage (preferably on biopsy) that would merit an SLKT. In the setting of chronic kidney disease, a measured creatinine clearance (or preferentially an iothalamate clearance) of 30 cc/ minute or less was considered the appropriate threshold for SLKT. 62 HRS alone should not be a reason for SLKT; however, this is now being considered in patients with HRS who become dialysis dependent and in whom there is no recovery after 6 to 8 weeks of dialysis (the usual recovery time for ATN). 61 The need for dialysis should theoretically be prevented by early treatment of HRS with the bridging therapies outlined below, particularly the use of vasoconstrictive therapy. Vasoconstrictors Plus Albumin Because the main pathogenic mechanism in HRS is splanchnic and systemic vasodilatation (Fig. 2), vasoconstrictors should ameliorate vasodilatation and improve effective arterial blood volume, renal vasoconstriction, and renal flow. Vasoconstrictors have been used in conjunction with intravenous albumin with the intention of increasing effective blood volume. Because albumin dialysis is associated with an increase in MAP attributable to the ability of albumin to bind vasodilators, it is conceivable that an improvement of renal function in patients with HRS treated with vasoconstrictors and albumin is attributable to the additive effects of both compounds in producing vasoconstriction. The need for albumin has only been examined in a nonrandomized small study that showed that treatment with terlipressin and albumin was associated with a significant decrease in SCr and an increase in MAP, changes that were not observed in a nonconcurrent group of patients treated with terlipressin alone. 63 Vasoconstrictors used in the treatment of HRS in small numbers of patients for periods greater than 3 days are associated with increases in MAP, GFR, and serum sodium and decreases in SCr and plasma renin activity (Table 4). Terlipressin is the preferred vasopressin analog because of a lower incidence of side effects and because its administration does not require continuous intravenous infusion. 23,40-42,44,46-48,63,64 Noradrenaline, in continuous infusion, has also been shown to ameliorate the hemodynamic/renal abnormalities in HRS, 43 as has the combination of midodrine plus octreotide, which has the advantage of oral/subcutaneous administration. 33,65,66 However, octreotide alone is no more effective than placebo 67 and did not improve SCr. 45 It is therefore uncertain whether the effectiveness of the
8 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2071 Table 4. Changes in Mean Arterial Pressure, Parameters of Renal Function and Plasma Renin Activity in Prospective Proofof-Concept Studies of Vasoconstrictors Albumin Administered for More Than 3 Days Author (Year) Vaso-constrictor n MAP (mmhg) Serum Creatinine (mg/dl) Serum Sodium (meq/l) Glomerular Filtration Rate (cc/min) Urine Output (cc/day) Urine Sodium (meq/l) Plasma Renin Activity (ng/ml/h) Guevara 98 (69) Or % Gulberg 99 (39) Or % Angeli 99 (33) O M % Uriz 01 (64) T % Mulkay 01 (40) T % Ortega 02 (63) T % Duvoux 02 (43) N % % % % 2 3? * 124 3?* % % 17% 1343% % 17% 1200% % 16% 1200% % 16.5% 1200% % 15% 1187% % % % % % % % % % % % % % % % % % % % All values are expressed as mean values except for Mulkay (median values). Changes in bold lettering were statistically significant. Or, ornipressin,; O M, octreotide plus midodrine; T, terlipressin; N, noradrenaline. *In responders, serum creatinine (2 72%) and serum sodium (18%). Calculated by MDRD. ng/l. combination octreotide/midodrine is attributable to midodrine alone or to the combination. Experimental studies showing that octreotide potentiates the effect of vasoconstrictors 68 would suggest the latter. Clinical outcomes of 12 uncontrolled studies including 258 patients with HRS are summarized in Table 5. 23,33,39-43,45,63-65,69 Complete response (mostly defined as a decrease in SCr to 1.5 mg/dl) was observed in 60% (156/258) overall, and in 65% (110/169) of patients who received terlipressin. 23,40-42,63,64 Interestingly, HRS recurred in only a minority of responders (22% or 16/72) once therapy was discontinued. Median survival is approximately 41 days (compared with 14 days in a group of untreated patients. 13 ). Five randomized controlled trials (RCTs) of terlipressin in HRS compared with albumin alone 46,48 or with a placebo 44,47,70 have been published. The study by Hadengue et al 70 was a proof-of-concept crossover study that showed that terlipressin (but not placebo) was associated with an increase in GFR. All other studies investigated clinical outcomes (Table 6) and, except for the study by Sanyal et al., 47 they were all open-label studies. In all of them, HRS reversal was higher in the terlipressin group (54/117 or 46%) compared with the control group (13/ 117 or 11%). In the only placebo-controlled, doubleblind multicenter trial that included the largest number of patients, 47 HRS reversal occurred in 34% of the patients, a rate significantly greater than that of placebo-treated patients (13%) but lower than that reported in uncontrolled studies. The low rate of recurrence of HRS in treated patients is confirmed in these studies (2/29 or 7%). Both controlled and uncontrolled studies agree that survival is significantly better in terlipressin responders. 23,45,47,48 Additional information from recent RCTs 46 confirms that terlipressin plus albumin has a beneficial effect in the treatment of HRS. Because survival was not improved in the two largest RCTs, 47,48 liver transplantation is still the therapy of choice for HRS, but terlipressin appears to be the bridging therapy of choice. Specifics such as the optimal time for initiation of vasoconstrictive therapy, dose and duration, failure criteria, and the influence and dose of albumin remain to be determined. Vasoconstrictor therapy has been used at different doses and with different side effects (Table 7); patients that receive higher doses appear to have a higher rate of adverse events. 71 Terlipressin needs to be compared with other vasoconstrictors (Table 7). Two recent small, open-label RCTs comparing noradrenaline with terlipressin showed that neither HRS reversal nor the rate of side effects was different between groups. 72,73 This is interesting from a pathophysiological perspective because noradrenaline does not induce splanchnic vasoconstriction, suggesting that the main effect is peripheral vasoconstriction. Transjugular Intrahepatic Portosystemic Shunt Three small prospective but uncontrolled studies have assessed the role of transjugular intrahepatic portosys-
9 2072 GARCIA-TSAO, PARIKH AND VIOLA HEPATOLOGY, December 2008 Table 5. Clinical Outcomes of Therapy with Vasoconstrictors (Plus IV Albumin) in Uncontrolled Studies Author and Year N (n HRS-2) Definition of Complete Response (CR) Vasoconstrictor Complete Response n (%) Days to CR (median value and range) HRS Recurrence: n/responders (%) Median Survival (days) Guevara 98 8 (?) 2sCr 1.5 mg/dl Or 6 (75) 7 (4 15) 2/6 (33) 60 (69) Gulberg 99 (39) 7 (0) 2-fold 1CrCl to a Or 4 (57) 14 (8 27) 2/4 (50) 90 value 40 ml/min Angeli 99 (33) 5 (0) 2sCr 2 mg/dl M O 5 (100) 20 (5 20) 0/5 (0) NA Uriz 01 (64) 9 (3) 2sCr 1.5 mg/dl T 7 (78) 6 (6 15) 0/7 (0) 39 Mulkay 01 (40) 12 (0) 2sCr 2 mg/dl T 11 (92) (2 12) 4/9 (44) 42 Ortega 02 (63) 13 (4) 2sCr 1.5 mg/dl T 10 (77) 7 (4 14) 1/10 (10) 40* Moreau 02 (23) 99 (0) 2sCr 1.5 mg/dl or T 58 (58) NA NA 21 of at least 20% from BL Colle 02 (41) 18 (0) 2sCr 1.5 mg/dl or T 11 (61) NA 7/11 (64) 24 of at least 20% from BL Halimi 02 (42) 18 (0) 2sCr at least of 30% T 13 (72) NA NA NA from BL Duvoux 02 (43) 12 (0) 2sCr 1.5 mg/dl or N 10 (83) 7 (5 10) 0/10 (0) 60 1CrCl to 40 ml/ min Wong 04 (65) 14 (0) 2sCr 1.5 mg/dl for M O 10 (71) 16 0/10 (0) NA 3 consecutive days Kiser 05 (45) 19 (1) 2sCr 1.5 mg/dl V O 8 (42) 7 NA NA without dialysis Kiser 05(45) 16 (8) O 0 (0) 7.5 NA NA Kiser 05 (45) 8 (2) V 3 (38) 6 NA NA All prospective except for Moreau, Colle, Halimi, and Kiser (retrospective). Or, ornipressin; M O, midodrine plus octreotide; T, terlipressin; N, noradrenaline; V, vasopressin; V O, vasopressin plus octreotide; scr, serum creatinine; CrCl, creatinine clearance; NA, not available; BL, baseline; CR, complete response. *Median survival for whole series (N 21; 13 with albumin, 8 without albumin). No mention of albumin administration. Mean. temic shunt (TIPS) in HRS, 65,74,75 including one performed in five patients whose renal function had improved on octreotide/midodrine. 65 These studies show a decrease in SCr in most patients, even in a few with organic renal failure, 76 but slower than that obtained using terlipressin plus albumin. Recurrence of HRS is rare as long as the shunt remains patent, but hepatic encephalopathy is a frequent complication. Post-TIPS resolution of HRS appears to improve survival. Long-term success was demonstrated in the study that explored sequential treatment with vasoconstrictors and albumin followed by TIPS. 65 Notably, a great majority of patients included in Table 6. Clinical Outcomes of Therapy with Terlipressin (Plus Albumin) in Randomized Controlled Trials Author Year Definition of Complete Response (CR) Group n Complete Response n (%) Days to Achieve CR (median and range) HRS Recurrence (%) Median Survival (days) Solanki 03 (44) Improvement in Terlipressin 12 5 (42) 15? Some 8.5 renal function Control 12 0 (0) Neri 08 (46) 2sCr 1.5 mg/dl Terlipressin (81) NA NA 90* Control 26 5 (19) NA NA 15 Sanyal 08 (47) 2sCr 1.5 mg/dl Terlipressin (34) 6 (2 14) 1/19 (5) 24 without dialysis Placebo 56 7 (13) 3 (2 7) 1/7 (14) 31 Martin-Llahi 2sCr 1.5 mg/dl Terlipressin 23 9 (39) 11 (6 16) 1/10 (10) 27% 08 (48) Control 23 1 (4) NA NA 19% scr, serum creatinine; NA, not available. *Terlipressin-responders only. Three-month survival. 30% of patients had type 2 HRS.
10 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2073 Table 7. Vasoconstrictors in HRS: Doses Used and Adverse Events Drug Dose Range Observed Adverse Events Terlipressin (23;40 42;44;46 48;63;64;70) mg intravenously every 4 6 hours GI: abdominal cramps associated with increased bowel movements, diarrhea, nausea, vomiting, intestinal ischemia Cardiac: arrhythmia (tachycardia, bradycardia, extrasystolia, AF), chest pain, MI Peripheral: livedo reticularis, finger ischemia, cutaneous necrosis at the infusion site, scrotal necrosis, skin lymphangitis Others: arterial hypertension, dyspnea, bronchospasm, respiratory acidosis Ornipressin (39;69) 2 6 U/h (continuous intravenous infusion) Abdominal cramps, intestinal ischemia with or without bleeding, tongue ischemia, cardiac arrhythmia Vasopressin (45) U/min (continuous intravenous None reported infusion) Noradrenaline (43;73) mg/h (continuous intravenous Chest pain with or without ventricular hypokinesia infusion) Octreotide Midodrine (33;65) g subcutaneously three times a day mg orally three times a day Diarrhea, tingling, goosebumps 25 g 3 25 g/h (continuous intravenous infusion) 2.5 mg/day orally GI, gastrointestinal; AF, atrial fibrillation; MI, myocardial infarction; AE, adverse events. these three studies had alcoholic cirrhosis, many with active alcoholism, and therefore the improvement observed could have resulted from improvement in an acute-onchronic process. Also, all three studies excluded patients with a Child-Pugh score equal to or greater than 12. Given the paucity of data, the efficacy of TIPS should be further explored in RCTs. Extracorporeal Albumin Dialysis In a small RCT, the molecular adsorbent recirculating system, a modified dialysis method using an extracorporeal albumin-containing dialysate, was shown to improve 30-day survival in eight patients with HRS compared with five patients treated with intermittent venovenous hemofiltration alone. 77 Because extracorporeal albumin-containing dialysate incorporates a standard dialysis machine or a continuous venovenous hemofiltration monitor and GFR was not measured, the decrease in SCr observed in most patients could be related to the dialysis process. However, clear beneficial effects on MAP and on hepatic encephalopathy were observed. Extracorporeal albumin-containing dialysate is still considered an experimental therapy, and its use in patients with type 1 HRS cannot be recommended outside of prospective studies. Approach to the Patient with Cirrhosis and ARF We propose that, as per the recent AKI consensus (Table 1), a diagnosis of HRS (type 1) be considered whenever there is an increase in SCr of 0.3 mg/dl or more ( 26.4 mol/l) or an increase of 150% or more (1.5- fold) from baseline. Delaying therapy until higher SCr levels are reached would not seem warranted because baseline SCr is a predictor of HRS reversal, 47,48,65 and the probability of HRS reversal decreases by 39% for each 1-mg/dL increase in baseline creatinine. 78 Treatment for HRS should therefore be initiated earlier, with only 1.5- fold increases in creatinine (Fig. 4). The setting in which AKI occurs is essential. In patients in whom there is a clear history of septic or hypovolemic shock, or in whom there is a recent history of nephrotoxin administration, the most likely cause is ATN. In all other patients, the first step is to discontinue diuretics, lactulose (because it is a frequent cause of diarrhea), vasodilators, and any potential nephrotoxins. Secondly, intravascular volume should be expanded with intravenous albumin at a dose of 1 g/kg body weight up to a maximum of 100 g. 17 This dose can be repeated in 12 hours if the SCr has not normalized. A reduction in SCr indicates that AKI is attributable to prerenal azotemia. Intravenous albumin is preferred over saline solution as a volume expander because sodium load is significantly lower with albumin, and it will not worsen fluid retention, and because it will not be associated with a dilutional decrease in SCr. Third, and concurrently, investigations to rule out precipitants of AKI should be undertaken, specifically diagnostic paracentesis (to rule out SBP), blood and urine bacteriological cultures, and chest x-ray (to rule out bacterial infections other than SBP) and patients treated accordingly.
11 2074 GARCIA-TSAO, PARIKH AND VIOLA HEPATOLOGY, December 2008 Patient with cirrhosis and acute renal failure (abrupt increase in creatinine by >1.5 fold from baseline) Discontinue: diuretics, lactulose, vasodilators, potential nephrotoxins Investigate and initiate treatment (if present) for infection, blood or fluid losses Albumin IV (1 g/kg of body weight QD or BID) History of shock (septic or hypovolemic), nephrotoxins, contrast Treat as ATN Improvement in creatinine Continue therapy No improvement in creatinine No granular or epithelial casts in urine? Central venous pressure >10 cmh 2 O Treat as HRS* Granular or epithelial casts in urine? Urine biomarkers of ATN? Fig. 4. Approach to the patient with cirrhosis and acute renal failure. IV, intravenously; QD, every day; BID, twice per day; ATN, acute tubular necrosis; HRS, hepatorenal syndrome. *If compatible clinical characteristics, in other words, ascites, low MAP, and hyponatremia (see text for approach to patient with suspected HRS). If SCr does not improve or continues to worsen despite these measures, the differential diagnosis is between intrinsic renal failure (ATN), HRS, and postrenal failure. Treatment of HRS can be initiated before completion of antibiotic therapy in patients with bacterial infection whose SCr does not improve despite a clear amelioration in the signs of infection. Because assessment of volume status may be uncertain, and to ensure that volume has been adequately expanded, intravascular volume should be assessed by measuring central venous pressure. A normal or increased central venous pressure indicates that the cause of renal failure is not volume-related. To rule out postrenal failure, a renal ultrasound should be obtained, although this is a rare cause of AKI in cirrhosis (Fig. 1). To rule out intrinsic renal failure, urinary sediment should be analyzed. Finding granular or epithelial casts suggests ATN but is not definitive. The differentiation between ATN and HRS is the most difficult, and studies using urine biomarkers of ATN are awaited. It has been suggested that the response to vasoconstrictors plus albumin may be used to establish this differential. 7 Approach to the Patient with HRS Once the diagnosis of HRS is suspected, specific treatment with vasoconstrictors plus albumin should be initiated. Best evidence supports the use of terlipressin, which should be started at a dose of 0.5 mg intravenously every 6 hours. If there is no early response ( 25% decrease in creatinine levels) after 2 days of therapy, the dose can be doubled every 2 days up to a maximum of 12 mg/day (in other words, 2 mg intravenously every 4 hours). Starting at lower doses will minimize potential severe adverse events from this therapy. 71 A more rational method to adjust the dose of vasoconstrictors is by monitoring MAP (an indirect indicator of vasodilatation), a method that has been used for adjusting the dose of midodrine plus octreotide, 33 an alternative to terlipressin in sites such as the United States, where terlipressin is not available. In this study, the doses of octreotide and midodrine were titrated to obtain an increase in MAP of at least 15 mmhg; midodrine was administered orally at an initial dose of 7.5 mg three times daily and, if necessary, increased to 12.5 mg three times daily; octreotide was administered subcutaneously at an initial dose of 100 g three times daily and, if necessary, increased to 200 g three times daily. 33 Other alternatives to terlipressin are vasopressin or noradrenaline. Noradrenaline is used as a continuous intravenous infusion at an initial dose of 0.5 mg/hour, adjusted to achieve an increase in MAP of at least 10 mm Hg or an increase in 4-hour urine output to more than 200 ml. If these goals are not reached, the dose is increased every 4 hours in steps of 0.5 mg/hour, up to the maximum dose of 3 mg/ hour. 43,73 Vasopressin is also used as a continuous intravenous infusion, starting at a very low dose of 0.01 U/min and titrating up to a dose of 0.5 U/min, depending on changes in MAP and urine output as well as the presence of ischemic side effects. In the study that assessed vasopressin for HRS, the mean vasopressin dose in the group of responders was U/min. 45 Albumin is administered together with the vasoconstrictor. The maintenance dose, once the diagnosis of
12 HEPATOLOGY, Vol. 48, No. 6, 2008 GARCIA-TSAO, PARIKH AND VIOLA 2075 HRS is established and vasoconstrictors are initiated, is of 25 to 50 g/day. Albumin may be discontinued if serum albumin concentration is greater than 45 g/l and should be withdrawn in case of pulmonary edema. Because this complication is uncommon, catheterization to monitor central venous pressure is not mandatory, but careful monitoring of the cardiopulmonary function is recommended. 17 Treatment can be stopped if SCr does not decrease by at least 50% after 7 days at the highest dose, or if there is no reduction in creatinine after the first 3 days. In patients with early response, treatment should be extended until reversal of HRS (decrease in creatinine below 1.5 mg/dl) or for a maximum of 14 days. 17 Vasoconstrictor therapy should be restarted if HRS recurs after discontinuation of therapy. Once creatinine normalizes, TIPS should be considered, particularly if transplantation is not foreseeable in the near future and the patient has refractory ascites. 65 Prevention Prophylaxis of AKI in cirrhosis consists of measures that will prevent/treat volume depletion or vasodilatation. Measures that prevent volume depletion include careful use of diuretics with close weight and laboratory followup, preventing weight loss of more than 1 kg/day as well as avoidance of diarrhea with the use of lactulose by adjusting its dose to obtain two to three semiformed bowel movements/day. The use of albumin after large-volume paracentesis (LVP) is a measure that can theoretically prevent the development of renal dysfunction by preventing the development of postparacentesis circulatory dysfunction, 79 an entity that has been shown to be secondary to vasodilatation 80 and is associated with development of renal dysfunction and a higher mortality. 81 Measures to prevent ATN include avoiding the use of aminoglycosides and nonsteroidal anti-inflammatory drugs, particularly in patients with ascites, and aggressively treating hypovolemia/hypotension when it occurs. It is uncertain whether HRS can really be prevented. It has been suggested that in the setting of SBP, the administration of albumin prevents HRS. This is based on a non placebo-controlled study in patients with SBP, in which the intravenous administration of albumin decreased the risk of HRS by 66% compared with antibiotic treatment alone. 82 However, the benefit of albumin is observed mainly in patients with SCr greater than 1.0, urea greater than 30 mg/dl, or a serum bilirubin greater than 4 mg/dl, that is, patients who already have some degree of renal dysfunction at the time of the diagnosis of SBP. On the other hand, a recent placebo-controlled RCT that included hospitalized patients with low ( 1.5 g/l) ascites protein who also had advanced liver failure or renal dysfunction (defined as SCr 1.2 mg/dl or blood urea nitrogen 25 mg/dl, or serum sodium level 130 meq/l) demonstrated that oral norfloxacin was associated with a reduction in the 1-year probability of HRS (28% versus 41%) and an improvement in survival at 3 but not 12 months. 85 Norfloxacin may act by ameliorating or preventing vasodilatation by preventing bacterial translocation and overt infection. 86 Notably, 79% of the patients met renal dysfunction criteria at baseline, suggesting that patients with a more altered hemodynamic status were those more likely to benefit from antibiotics and would probably benefit from vasoconstrictors. 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