International Journal of Clinical Medicine, 2014, 5, 102-110
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International Journal of Clinical Medicine, 2014, 5, 102-110 Published Online January 2014 ( http://www.scirp.org/journal/ijcm ) http://dx.doi.org/10.4236/ijcm.2014.53018 OPEN ACCESS IJCM Hepatorenal Syndrome Tyree H. Kiser
Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, USA. Email:
ty.kiser@ucdenver.edu
Received November 13 th , 2013; revised December 10 th , 2013; accepted January 5 th , 2014
Copyright © 2014 Tyree H. Kiser. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accordance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual property Tyree H. Kiser. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.
Hepatorenal Disorder; Cirrhosis; Portal Hypertension; Transplantation; Vasopressors 1. Introduction Hepatorenal syndrome (HRS) is the most significant he- patorenal disorder affecting patients with advanced cirr- hosis. If not treated, patients with HRS Type I survive only a median of 2 weeks and 95% of patients die within the first 30 days after onset. The median survival time is 4 to 6 months in patients with Type II HRS [1]. Patients with advanced cirrhosis and ascites are at high risk for HRS, with 18% of patients developing hepatorenal syn- drome (HRS) within 1 year and up to 39% developing HRS by 5 years [2-4]. HRS is a unique renal dysfunction, because it is a functional renal failure that occurs in the absence of pa- renchymal kidney disease. Patients with cirrhosis have resistance to portal flow leading to changes in shear stress of the portal vessel wall. This resultant portal hy- pertension is the initiating factor for HRS resulting in the production of various vasodilators including nitric oxide, carbon monoxide, cysteinyl leukotrienes, thromboxane A2, endothelin-1, and others. As portal venous pressure is increased, shear stress on the splanchic vasculature re- sults in further release of vasodilators, causing develop- ment of splanchnic vasodilation and porto-systemic shunts reducing effective arterial blood volume and mean arteri- al pressure. Activation of several compensatory mechan- isms, including the sympathetic nervous system, the re- nin-angiotensin-aldosterone system (RAAS), and the re- lease of arginine vasopressin occurs to counteract the systemic vasodilation and increase sodium and water re-
Hepatorenal Syndrome
103 tention to increase intravascular blood volume. Cardiac output is increased in response to reduced effective ar- terial volume resulting in tachycardia and low systemic blood pressure. Ultimately, this cascade of events causes a shift in the renal autoregulation curve, making renal perfusion much more sensitive to changes in mean ar- terial pressure. As cirrhosis progresses, further renal va- soconstriction and sodium retention occurs as the splan- chnic and systemic vasodilation worsens leading to the development of a functional renal failure (
) [5,6].
Pathophysiology of hepatorenal syndrome. a: the development of splanchnic vasodilatation and b: the development of renal dysfunction. The solid arrows indicate a baseline condition, whereas the dotted arrows indicate hepatorenal syn- drome occurring in the event of a precipitating factor. Abbreviations: AVP, arginine vasopressin; CO, cardiac output; EABV, effective arterial blood volume; GFR, glomerular filtration rate; Na, sodium; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow; SNS, sympathetic nervous system; TNF, tumor necrosis factor. Reprinted with permission [6]. Hepatorenal Syndrome OPEN ACCESS IJCM 104
Frequently, the development of HRS is precipitated by an acute event. In patients with cirrhosis and ascites, bacterial infections appear to be the most important risk factor for the development of HRS. Infection results in circulatory dysfunction by releasing various cytokines, such as tumor necrosis factor and interleukin 6 in the splanchnic vasculature [5,6]. These inflammatory cyto- kines activate endothelial and inducible nitric oxide syn- thases increasing the production of nitric oxide [6]. As many 33% of patients who develop spontaneous bacterial peritonitis will develop HRS [7]. Other HRS triggering events include severe alcoholic hepatitis, hypovolemia as the result of excess diuresis or gastrointestinal losses (bleeding or diarrhea), large volume shifts between in- travascular and extravascular compartments, and use of medications that affect afferent or efferent arteriole con- striction or vasodilation in the kidney (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin-con- verting enzyme inhibitors [ACE-Is], angiotensin II re- ceptor blockers [ARBs]) [5]. Additionally, cirrhotic car- diomyopathy resulting in the inability to maintain the re- quired cardiac reserve may be an important contributor to HRS.
2. Diagnosis of HRS The assessment of HRS is daunting, because of the dif- ficulties in providing a definitive diagnosis and the poor overall response rate to currently available therapies. The diagnosis of HRS is made by excluding all other possible causes of renal failure and utilizing revised criteria pub- lished by the International Ascites Club in 2007 (
) [8,9]. These diagnostic criteria have been widely ac- cepted; however, they may be difficult to apply in the acute care setting. The major struggle within the diag- nostic criteria is the difficulty in fulfilling all of the di- agnostic criteria in patients who have a presentation sug- gestive of HRS. One of the major limitations in the clin- ical setting is the ability to rule out renal failure caused by other factors, because many patients with HRS physi- ology have bacterial infections with or without shock, are receiving diuretic therapy prior to their AKI, or may be receiving medications or undergoing procedures that are detrimental to renal blood flow or kidney function. Addi- tionally, patients with prolonged Type I HRS may even- tually develop acute tubular necrosis due to intense renal arteriole vasoconstrition. As a result of these limitations, several renal biomarkers are being studied to help deci- pher HRS from other causes of AKI in patients with cirrhosis; but further studies are required before they can be applied in clinical practice [10-12]. After establishing the diagnosis, HRS can be divided into one of two forms: Type I and Type II. Type I HRS is diagnosed when there is a doubling in SCr to a val- ue >2.5 mg/dL in a period of less than 2 weeks. Type I Table 1. Diagnostic criteria for hepatorenal syndrome. Diagnostic Criteria for Hepatorenal Syndrome Cirrhosis with ascites Serum creatinine (SCr) >1.5 mg/dL (>133 umol/L) No improvement in serum creatinine levels (decrease to of ≤1.5 mg/dL) after at least 2 days with diuretic withdrawal (if on diuretics) and volume expansion with 20% to 25% albumin. The recommended dose of albumin is 1 g/kg of body weight per day, up to a maximum of 100 g/day. Absence of shock No current or recent treatment with nephrotoxic medications Absence of parenchymal kidney disease as defined by proteinuria <500 mg/day, no microhematuria (<50 red blood cells per high power field), and normal renal ultrasonography) Classification of Hepatorenal Syndrome Type I — doubling in SCr to a value > 2.5 mg/dL in a period of less than 2 weeks Type II — stable or more slowly progressive renal dysfunction (SCr > 1.5 mg/dL) not meeting the criteria for Type I HRS Adapted from Solerno, et al. [9] and Gines, et al. [5].
HRS usually develops as a result of a triggering factor that causes acute deterioration of hepatic function to- gether with other organ dysfunctions. The most common triggers for Type I HRS are bacterial infections and se- vere alcoholic hepatitis. In contrast, Type II HRS occurs in patients with refractory ascites and involves renal dysfunction (SCr > 1.5 mg/dL) that is more slowly pro- gressive and does not meet the criteria for Type I HRS. It is common for patients with Type II HRS to eventually develop Type I HRS as the result of a precipitating event [4,12].
3. Prevention of HRS Prevention of Type I HRS involves appropriate identifi- cation and management of potential HRS precipitating events; whereas, prevention of Type II HRS commonly involves management of refractory ascites. In general, avoiding relative renal hypoperfusion is the key strategy for preventing HRS development. Avoiding hypovolemia by appropriately managing outpatient diuretic therapy and the discontinuation of diuretics at the first indication of AKI is extremely important. Fluid management is of critical importance and assessment of effective intravas- cular volume and renal perfusion pressure should be con- sidered in hospitalized patients at risk for HRS. Fluid overload, as the result of excessive intravenous fluid ad- ministration, should also be avoided because it can be equally detrimental, resulting in hyponatremia, increased ascites, and edema. When utilizing large-volume para- centesis for the management of ascites, administration of intravenous albumin 20% to 25% (at least 6 - 8 grams per
Hepatorenal Syndrome
105 liter of ascites removed) is necessary to avoid large vo- lume shifts from the intravascular space [13,14]. Addi- tionally, antibiotic prophylaxis in patients with a ga- strointestinal bleed can reduce the incidence of sponta- neous bacterial peritonitis and renal failure and pentox- ifylline therapy may reduce the incidence of HRS in pa- tients with acute alcoholic hepatitis [15,16]. 4. Treatment of HRS Liver transplantation is the optimal and definitive therapy for patients with HRS because it cures the underlying organ dysfunction responsible for the pathophysiologic pathway to HRS [17-19]. Liver transplantation drastical- ly improves mortality for patients with HRS, resulting in 5-year survival rates similar to patients without HRS who underwent liver transplantation (67.1% versus 70.1%, respectively; P = NS) [18]. Renal dysfunction can often be reversible and, therefore, patients with HRS are not frequently listed for combined liver-kidney transplants (LKTx); however, recommendations have been made to consider LKTx in HRS patients who have received he- modialysis (HD) for >8 weeks [14], with some groups advocating for a requirement of >12 weeks of HD prior to transplantation before consideration of LKTx [12]. Treatment of HRS with the intent to improve renal function and prolong survival long enough to allow for liver transplantation is the ultimate goal of pharmacolog- ic therapy for HRS. Vasoconstrictors are the mainstay of therapy for HRS due to their ability to improve the he- modynamic instability that is responsible for the de- creased renal perfusion pressure. The addition of albumin therapy to vasoconstrictors may further improve renal blood flow, glomerular filtration, and ultimately response rates to vasoconstrictor therapy [20]. If albumin is uti- lized, the admixture should provide a high concentration of albumin and the typical dose is 1 g/kg (up to 100 g) on day 1 or 2, then 25 to 50 g/day of 25% albumin (or 20 to 40 g/day of 20% albumin) thereafter [4]. Albumin thera- py is continued, along with vasoconstrictor therapy, until a complete response in SCr is realized or until futility of therapy is determined. The dose and duration of albumin therapy should be dictated by volume status; as albumin is initially effective at improving intravascular volume, but will eventually result in third space volume expan- sion. Volume status should be assessed by hemodynamic monitoring, although the optimal method for evaluating volume status is controversial and likely includes the interpretation of several possible measurements, includ- ing heart rate, mean arterial pressure (MAP), central ve- nous pressure, pulse pressure variation, stroke volume variation, echocardiography, urine output, ascites, and edema.
Terlipressin is a unique vasopressin analogue with po- tential advantages that make it the preferred vasocon- strictor for patients with HRS. The effects of vasopressin and vasopressin analogues on the V1 receptor are the predominate mechanism for treating the underlying splanchnic vasodilation present in those with HRS. There are a large number of V1 receptors in the splanchnic vasculature, making this area especially sensitive to the vasoconstrictive effects [21]. Vasoconstriction of the splanchnic vascular beds is believed to reverse HRS by increasing effective arterial blood volume, thereby sup- pressing activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, reversing compensatory renal vasoconstriction and ulti- mately increasing renal perfusion. Terlipressin reduces portal vein pressure and increases MAP in patients with cirrhosis and splanchnic vasodilation. It improves splan- chnic blood flow and down-regulates the excessive salt and water retention that leads to ascitic fluid accumula- tion [22]. These attributes have made terlipressin one of the most widely used agents for the treatment of Type I HRS outside of North America. Although the number of prospective controlled trials is small, terlipressin has been one of the most studied vaso- pressor agents for the treatment of HRS (
) [22].
A comprehensive review of the terlipressin literature for HRS through January 2012 can be found in the Cochrane Database [23]. Combined analysis of 6 prospective stu- dies demonstrates that terlipressin treatment improves renal function and mortality for patients with HRS. HRS reversal (reversal or complete response is defined as a decrease in SCr to a value ≤1.5 mg/dL) occurs in 25% to 50% of patients treated with terlipressin. Relapse rates after stopping therapy do occur and retreatment with va- soconstrictor therapy may be necessary. Adverse effects related to terlipressin include tachycardia, arrhythmias, chest pain, diarrhea, abdominal pain, bronchospasm, and peripheral ischemia [24]. Serious ischemic adverse events have required discontinuation of terlipressin ther- apy in a small percentage of patients (e.g., nonfatal myo- cardial infarction, livedo reticularis, and cyanosis of the fingers) [25]. The phase III Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucas- sin (Terlipressin) (REVERSE) trial [ClinicalTrials. gov identifier NCT01143246] with provide further evidence evaluating terlipressin therapy for the management of patients with HRS. Terlipressin dosing has ranged from 0.5 to 2 mg intra- venously every 4 to 12 hrs. Continuous infusion terli- pressin has also been utilized, but it does not appear to offer an efficacy or safety advantage over intermittent therapy and is less convenient. Terlipressin should be initiated at 0.5 mg every 4 to 6 hours. Stepwise titration in dose (e.g., 0.5 mg increments) should be done every 1 to 2 days as tolerated if the urine output (UOP) has not improved and the SCr has not decreased from baseline
Hepatorenal Syndrome OPEN ACCESS IJCM 106
Table 2. Selected clinical studies of vasoconstrictors in the treatment of HRS. Study Design No. of Patients Therapy Significant Outcomes Prospective, Randomized [40] N = 46 (35 Type I and 11 Type II HRS) Terlipressin + Albumin versus Albumin Renal function improvement more likely in terlipressin + albumin (43.5% versus 8.7%, P = 0.017) Prospective, observational[20] N = 21 (16 Type I and 5 Type II HRS) Terlipressin + Albumin versus Terlipressin Albumin administration found to predict renal function response (77% responders versus 25% responders, P = 0.03) Prospective, randomized [41] N = 24 (Type I HRS) Terlipressin versus Placebo Terlipressin significantly improved UOP, CrCl, MAP, and de- creased SCr compared with placebo. At day 15, 5 of 12 patients receiving terlipressin survived compared with 0 of 12 patients receiving placebo (P < 0.05). International, Multi-center, Randomized [25] N = 112
(Type I HRS) Terlipressin versus Placebo Treatment success: terlipressin 25% versus placebo 12.5%, P = 0.093. HRS reversal: terlipressin 34% versus 13%, P = 0.008. Related adverse effects: terlipressin 9% versus placebo 2%, P = NS Prospective, randomized [24] N = 52
(Type I HRS) Terlipressin + Albumin versus Albumin 80% complete response with terlipressin + albumin versus 19% response with albumin (p < 0.01). Improved survival at 180 days with terlipressin + albumin (p < 0.01) Retrospective [26]
N = 43 (32 Type I and 11 Type II HRS) Vasopressin + Octreotide versus Vasopressin versus Octreotide Complete response higher in patients receiving vasopressin or vasopressin + octreotide versus octreotide monotherapy (P = 0.01) Prospective, open label [29] N = 40 (Type I HRS) Norepinephrine versus Terlipressin Reversal of HRS occurred in 50% of patients in each treatment group (p = NS). Survival was similar between groups (p = 0.8). Baseline creatinine clearance, MAP, and plasma renin activity were independent predictors of response. UOP = urine output; CrCl = creatinine clearance; MAP = mean arterial pressure; SCr = serum creatinine; Adapted from Kiser et al. [22].
(
) [4]. It may take 2 to 3 days for a response in SCr to be observed, so early dosing titration decisions should focus on achieving a MAP increase of 10 mm Hg, UOP improvement, and avoidance of ischemic adverse effects. Therapy should be discontinued if patients dem- onstrate no response in SCr by day 4 of therapy, despite adequate titration and an increase in MAP, because a response to therapy at this point is unlikely. In countries where terlipressin is not commercially available, other vasoconstrictor treatment options (e.g., vasopressin or norepinephrine) must still be considered. Vasopressin is considered a reasonable alternative to terlipressin therapy because of its effects on the V1 re- ceptor; however, it is less selective than terlipressin and must be administered by a continuous infusion because of its shorter half-life. Evidence for vasopressin use in HRS comes from a retrospective study that evaluated 43 patients who had received vasopressin and/or octreotide for treatment of HRS. Response in SCr (SCR < 1.5 mg/dL) occured in 41% of the patients that received va- sopressin therapy. Therapy with vasopressin, either alone or in combination with octreotide, was an independent predictor of renal function recovery (odds ratio [OR] 6.4; 95% confidence interval [CI] 1.3 - 31.8). The mean va- sopressin dose in patients that responded to therapy was 0.23 ± 0.19 units/min, which is significantly higher than typically utilized in shock syndromes [26]. Although patients with cirrhosis and HRS appear to be more tole- rant to higher doses of vasopressin, caution and careful monitoring of serum lactate levels and the monitoring of extremities for ischemia should be maintained for pa- tients receiving vasopressin doses >0.1 units/min as ad- verse effects related to vasopressin are ischemic in nature and dose dependent [27]. Norepinephrine’s alpha-adrenergic agonist activity makes it a potent vasoconstrictor of both the venous and arterial vasculature. Similar to terlipressin, in patients with HRS, norepinephrine effectively improves UOP, sodium excretion, serum sodium concentration, creati- nine clearance (CrCl), MAP, plasma renin activity, and aldosterone activity. In small comparative studies, nore- pinephrine has demonstrated a similar rate of HRS re- versal and patient survival when compared with terli- pressin [28,29]. Adverse effects between norepinephrine and terlipressin are similar, with reversible cardiac and digital ischemia being the most common adverse events [29]. The cost of norepinephrine therapy is also signifi- cantly lower than terlipressin (107 ± 31 versus 1536 ± 40 Euros, P < 0.0001), making it an attractive alternative therapy [28]. However, the possibility of utilizing terli- pressin in patients outside of a monitored hospital setting may reduce the overall difference in cost between treat- ment options. Midodrine is frequently utilized for the treatment of Type II HRS patients in North America, because it is an orally administered alpha-adrenergic agonist medication that can be administered outside of the intensive care unit. When used in combination with octreotide ± albumin it may improve length of survival and transplantation rates, particularly for patients with Type II HRS [30]. The Hepatorenal Syndrome
107
Terlipressin 0.5 to 2 mg IV q4 to 6 hours; increase dose by 0.5 mg increments every 1 to 2 days if there is no improvement in SCr as long as no side effects are present. Goal MAP increase of 10 mm Hg from baseline. Maximum dose = 12 mg/day. Vasopressin 0.01 to 0.8 units/min continuous IV infusion. Increase dose by 0.05 units/min every 30 to 60 minutes to achieve a 10 mm Hg increase in MAP from baseline or a MAP > 70 mm Hg Norepinephrine 0.05 to 1 mcg/kg/min (5 to 75 mcg/min) continuous IV infusion. Titrate every 30 minutes to achieve a 10 mm Hg increase in MAP from baseline Midodrine + Octreotide Midodrine 5 to 15 mg PO TID. Titrate to achieve a 10 to 15 mm Hg increase in MAP from baseline. Octreotide: 100 to 200 mcg
SQ/IV
TID; or 25 to 50 mcg IV bolus, followed by 25 to 50 mcg/hour continuous infusion (no titration) SCr = serum creatinine; MAP = mean arterial pressure; IV = intravenous; 1) Adjunctive albumin administration is recommended: 1 g/kg (up to 100 g) on day 1 or 2, then 25 to 50 g/day of 25% albumin (or 20 to 40 g/day of 20% albumin) thereafter. 2) Therapy should be discontinued after 4 days if no response in SCr is observed, despite adequate dosage titration, because the likelihood of a response to therapy is low. 3) All patients should be monitored for signs of ischemia (i.e., visual evaluation of digits, distal pulses, abdominal pain, serum lactate, and/or troponin) at least every 12 hours and after any dosing titration. 4) In patients that demonstrate a complete response to therapy, dosage reduction or vaso- constrictor discontinuation should be attempted by day 14 of therapy to determine the sustainability of the response. Restarting therapy may be necessary if a relapse occurs; Adapted from Nadim et al. [4]
usual midodrine dosage range for the treatment of HRS is 5 to 15 mg orally TID. If goal MAP cannot be achieved and there is no response in UOP or SCr, despite titration to 15 mg orally TID, consideration of switching to a more potent intravenous vasoconstrictor may be neces- sary [4]. TIPS procedures can significantly decrease the porto- systemic pressure gradient. This leads to decreased plasma renin and sympathetic activity potentially im- proving or reversing HRS physiology [31]. Insertion of the shunt within 4 to 6 weeks of HRS onset may improve renal function recovery and survival [32]. Improvement in renal function after TIPS may take several weeks, so the use of other therapies for treating HRS is commonly required until the effect of TIPS placement is realized. TIPS can be beneficial for patients with both Type I and Type II HRS; however, many patients with Type I HRS cannot safely undergo the procedure due to their ad- vanced liver disease or other contraindications. Patients with lower bilirubin and those with Type II HRS are more likely to have prolonged survival post TIPS [32]. Artificial liver support therapies have been evaluated for the treatment of HRS; including molecular adsorbent recirculating system (MARS), Prometheus, single pass albumin dialysis (SPAD), and single pass albumin ex- tended dialysis (SPAED) [33-37]. These extracorporeal systems provide combined hepatic and renal support by removing water-soluble and albumin-bound toxins re- sulting in improved serum bilirubin, creatinine, and other laboratory measurements. Unfortunately, these artificial support systems do not provide sustained responses in kidney function after discontinuation and laboratory val- ues commonly return to pretreatment levels after discon- tinuation [33]. In addition to the inability to produce meaningful outcomes, other challenges to artificial liver support systems include hypotension, blood loss each time the circuit is replaced, and the frequent need for anticoagulant administration into the extracorporeal cir- cuit to prevent clotting of the circuit. Therefore, use of these systems for the management of patients with HRS are not recommended at this time [4,6]. Few studies have evaluated renal replacement therapy (RRT) for the treatment of HRS [38,39]. The use of RRT can improve short-term survival for patients with HRS and may be helpful with bridging patients to transplant or treating patients who have an acute reversible cause of hepatic decompensation. Use by patients who are not transplant candidates and those without an acute reversi- ble component is unlikely to change a patient’s disease course and merely results in resource overutilization and substantial costs to the health care system [39]. Therefore, the initiation of continuous or intermittent RRT for pa- tients with HRS is generally reserved until a significant indication for dialysis arises (e.g., severe hyperkalemia, metabolic acidosis, or volume overload). Individual pa- tient selection, according to the severity of illness, Child- Pugh and MELD scores, and the potential for liver trans- plantation should all be considered prior to the initiation of RRT.
5. Conclusions HRS is the most significant disease within the spectrum of hepatorenal disorders and is associated with a substan- tial mortality rate. HRS physiology is characterized by splanchnic arterial vasodilation causing reduced effective arterial volume, renal vasoconstriction as a result of ac- tivation of the sympathetic nervous system and the RAAS, reduced cardiac output as the result of cirrhotic cardiomyopathy, and release of vasoactive mediators that affect renal blood flow and glomerular microcirculatory hemodynamics. Patients with Type 1 HRS have a more acute rise in their SCr values and shorter survival times as compared to patients with Type II HRS. Early identification and management of HRS is critical to the success of the chosen treatment. The only defini- tive treatment established for HRS is liver transplantation. Hepatorenal Syndrome OPEN ACCESS IJCM 108
The goal of all other pharmacologic and nonpharmaco- logic therapies is to prolong survival time enough to al- low for liver transplantation. Several small studies have attempted to evaluate various pharmacologic agents for the treatment of HRS, but only vasoconstrictors com- bined with albumin therapy have emerged as a preferred initial treatment option. Terlipressin, in combination with albumin volume expansion, is the preferred pharmaco- logic therapy for the management of patients with HRS. Norepinephrine and vasopressin are alternatives if terli- pressin is unavailable. Midodrine with octreotide appears to be an effective pharmacologic regimen in patients with Type II HRS and those who require an alternative to intravenous therapy. Although TIPS is effective for both Type I and II HRS, it is less commonly employed in Type I HRS patients due to the presence of contraindica- tions to the procedure. Artificial hepatic support devices and renal replacement therapy are effective for correcting abnormal laboratory values, but have not demonstrated the ability to reverse HRS. The decision to deliver these therapies should be limited to patients who have an indi- cation for dialysis and are high on the liver transplant list. Substantial advances in understanding the pathophysi- ology and management of HRS has improved the recog- nition and treatment of HRS patients. However, several questions still remain regarding how best to optimize current treatment options. Given the substantial morbidi- ty, mortality, and cost associated with HRS management; more studies are urgently needed to help improve patient outcomes in this difficult population. REFERENCES [1]
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