TY - JOUR
AU - Nadim, Mitra, K.
AB - Abstract Hepatorenal syndrome (HRS) is defined as the occurrence of renal dysfunction in a patient with end-stage liver cirrhosis in the absence of another identifiable cause of renal failure. The prognosis of HRS remains poor, with a median survival without liver transplantation of <6 months. However, understanding the pathogenesis of HRS has led to the introduction of treatments designed to increase renal perfusion and mean arterial blood pressure using vasopressors and albumin, which has led to improvement in renal function in ∼50% of patients. albumin, ascites, hepatorenal, vasopressors Introduction Hepatorenal syndrome (HRS) is currently defined as the occurrence of acute kidney injury (AKI) in patients with end-stage liver cirrhosis in the absence of another identifiable cause. The International Ascites Club defined HRS in 1996 [ 1 , 2 ], on the basis of a series of major inclusion criteria which were later revised in 2007 [ 3 ] and subdivided into Types 1 and 2 ( Table 1 ) [ 4 , 5 ]. Untreated, median survival is 2 weeks for patients with Type 1 HRS and 4–6 months in patients with Type 2 HRS [ 4 ]. Since the original diagnostic criteria for HRS, there have been major advances in the understanding of the pathogenesis of HRS, which have led to developments in medical management. A consensus conference under the auspices of the Acute Dialysis Quality Initiative (ADQI) was held in 2010 to appraise the existing evidence and develop a set of consensus recommendations to standardize care and direct further research for patients with liver cirrhosis and renal dysfunction. This review will focus on the medical management of patients with Type 1 HRS. Table 1. Criteria for diagnosis of HRS in cirrhosis (modified from references [ 4 , 5 ]) a Cirrhosis with ascites Serum creatinine >1.5 mg/dL (133 μmol/L) Absence of shock Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics) and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day No current or recent treatment with nephrotoxic drugs Cirrhosis with ascites Serum creatinine >1.5 mg/dL (133 μmol/L) Absence of shock Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics) and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day No current or recent treatment with nephrotoxic drugs a Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no microhaematuria (<50 red cells/high-powered field) and normal renal ultrasonography. Type 1 HRS characterized by a rapid and progressive impairment in renal function (increase in serum creatinine of ≥100% compared to baseline to a level >2.5 mg/dL in <2 weeks), and Type 2 HRS characterized by a stable or less progressive impairment in renal function. Open in new tab Table 1. Criteria for diagnosis of HRS in cirrhosis (modified from references [ 4 , 5 ]) a Cirrhosis with ascites Serum creatinine >1.5 mg/dL (133 μmol/L) Absence of shock Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics) and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day No current or recent treatment with nephrotoxic drugs Cirrhosis with ascites Serum creatinine >1.5 mg/dL (133 μmol/L) Absence of shock Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics) and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day No current or recent treatment with nephrotoxic drugs a Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no microhaematuria (<50 red cells/high-powered field) and normal renal ultrasonography. Type 1 HRS characterized by a rapid and progressive impairment in renal function (increase in serum creatinine of ≥100% compared to baseline to a level >2.5 mg/dL in <2 weeks), and Type 2 HRS characterized by a stable or less progressive impairment in renal function. Open in new tab Materials and methods ADQI ( www.adqi.net ) is an ongoing process that seeks to produce evidence-based recommendations for the prevention and management of AKI and on different issues concerning acute dialysis. It reviews the literature and provides expert-based statements and interpretation of current knowledge for use by clinicians according to professional judgment. The ADQI methods comprise (i) systemic search for evidence with review and evaluation of the available literature, (ii) the establishment of clinical and physiologic outcomes as well as measures to be used for comparison of different treatments, (iii) the description of the current practice and the rationale for the use of current techniques and (iv) the analysis of areas in which evidence is lacking and future research is required to obtain new information. Prior to the conference, the organizing committee of ADQI VIII (M.K.N., J.A.K. and Y.S.G.) identified five topics relevant to the field of HRS. We selected these topics based on (i) prevalence of the associated clinical problem; (ii) known variation in clinical practice; (iii) availability of scientific evidence; (iv) potential importance for clinical outcome and (v) development of evidence-based medicine guidelines. For each topic, we outlined a preliminary set of key questions and then assembled a diverse international panel representing multiple relevant disciplines (nephrology, hepatology, transplant surgery and critical care), representing various countries and both national and international scientific societies, based on their expertise in AKI and HRS. Work groups comprising four to five members, with one acting as group facilitator, were convened with each work group addressing one key topic. Systematic review of the literature For each topic, the systematic review included the development of well-specified research questions, literature searches, data extraction of primary studies and existing systematic reviews, tabulation of data, assessment of the quality of individual studies and assessment of the overall quality of the literature and summary conclusions. Literature review was applied using key terms relevant to the topic and electronic reference libraries with focus on human studies and limited to English language articles published between January 1960 and December 2009. Study eligibility was based on population, intervention, comparator, outcome and study design relevant to each clinical question. Although nonrandomized studies were reviewed, the majority of the work group resources were devoted to review of randomized trials, as these were deemed to be most likely to provide data to support Level 1 recommendations with very high- or high-quality (A or B) evidence. Exceptions were made for topics with sparse evidence. Each work group conducted literature searches related to their topic questions via MEDLINE, PubMed and bibliographies of key reviews and of all articles that met the search criteria. Decisions to restrict the topics were made to focus the systematic reviews on those topics in which existing evidence was thought to be likely to provide support for the guideline. Evaluation of studies A three-phase approach was used to construct the evidence-based recommendations. The phases included a systematic literature review of studies in HRS and AKI in patients with cirrhosis, a comprehensive appraisal of prior studies and convening an expert panel to synthesize this information and develop consensus-based recommendations. The quality of the overall evidence and the strength of recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system ( Table 2 ) [ 6–8 ]. There were four categories for the quality of overall evidence, ranging from A to D. The strength of a recommendation was determined by the quality of the evidence and was graded Level 1, 2 or ‘not graded’. Recommendations were marked as ungraded to provide guidance where the topic did not allow adequate application of evidence. Recommendation statements were developed from the systematic review, existing guidelines identified in the supplemental literature review and expert opinion. Recommendations were developed by incorporating the best available evidence and expert opinion. Expert opinion was used when evidence in the literature did not exist to inform the decision. Recommendation statements were incorporated when they met one of two criteria: if there was strong literature-based evidence or if the expert panel voted that the recommendation was appropriate. Table 2. Grading evidence and recommendations (adapted from the GRADE system) Notes Symbol Quality of evidence     High Large, high-quality randomized control trials A     Moderate Limited or conflicting data from randomized control trials B     Low Observational studies or very small randomized control trials C     Very low Expert opinion D Grading recommendation     Strong Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful and effective 1     Weak Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment 2 Notes Symbol Quality of evidence     High Large, high-quality randomized control trials A     Moderate Limited or conflicting data from randomized control trials B     Low Observational studies or very small randomized control trials C     Very low Expert opinion D Grading recommendation     Strong Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful and effective 1     Weak Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment 2 Open in new tab Table 2. Grading evidence and recommendations (adapted from the GRADE system) Notes Symbol Quality of evidence     High Large, high-quality randomized control trials A     Moderate Limited or conflicting data from randomized control trials B     Low Observational studies or very small randomized control trials C     Very low Expert opinion D Grading recommendation     Strong Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful and effective 1     Weak Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment 2 Notes Symbol Quality of evidence     High Large, high-quality randomized control trials A     Moderate Limited or conflicting data from randomized control trials B     Low Observational studies or very small randomized control trials C     Very low Expert opinion D Grading recommendation     Strong Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful and effective 1     Weak Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment 2 Open in new tab ADQI process ADQI activities were divided into a pre-conference, conference and post-conference phase. During the pre-conference phase, topics were selected, work groups assembled and assigned to specific topics. Each group identified a list of key questions, conducted a systematic literature search and generated a bibliography of key studies. Literature review was applied using key terms relevant to the topic and electronic reference libraries with focus on human studies and limited to English language articles. Each work group conducted literature searches related to their topic questions via MEDLINE, PubMed and bibliographies of review articles. During this stage, the scope of the conference was also defined and some topics were excluded. We then conducted a 2½-day conference. Our consensus process relied on evidence where available and, in the absence of evidence, consensus expert opinion where possible. The quality of the overall evidence and the strengths of the recommendations were graded using the GRADE system ( Table 2 ) [ 8 ]. There were four categories for the quality of overall evidence, ranging from A to D. The strength of a recommendation was determined by the quality of the evidence and was graded Level 1, 2 or ‘not graded’. Recommendations were ungraded if they were not based on systematic evidence to provide guidance where the topic did not allow adequate application of evidence. During the conference, work groups assembled in breakout sessions, as well as plenary sessions where their findings were presented, debated and refined. In each breakout session, the work groups refined the key questions, identified the supporting evidence and generated practice guidelines and/or directions for future research as appropriate. A series of summary statements were developed during the breakout sessions and presented to the entire group, revising each statement as needed until a final version was agreed. Directives for future research were achieved by asking the participants to identify deficiencies in the literature, determine if more evidence was necessary and if so, to articulate general research questions. When possible, pertinent study design issues were also considered. Post-conference reports were produced from each working group and emailed to each participant for comment and revision. Final reports were summarized into a final conference document by a writing committee. Results General management strategies Prevention of HRS. Cirrhotic patients with ascites at risk for HRS should be carefully assessed, closely monitored and potential precipitating factors actively excluded and appropriately treated as HRS more commonly develops in patients with greater systemic inflammatory response [ 9 ]. Patients with cirrhosis who are hypotensive may have a reduced cortisol response (hepatoadrenal syndrome) and thus covert hypoadrenalism should be considered and treated appropriately to improve response not only to vasopressors but also survival [ 10 ]. Drugs which reduce renal perfusion and those causing nephrotoxicity have been reported to precipitate HRS and should be avoided ( Table 3 ) [ 11–16 ]. Radiocontrast media, however, have not been established as causing AKI in cirrhotics despite being a known cause of AKI in the general population [ 17 ]. Following the introduction of antibiotic prophylaxis to reduce spontaneous bacterial peritonitis (SBP), studies using norfloxacin have reported not only a reduction in SBP (7 versus 61%) but also a reduction in the incidence of HRS (28 versus 41%) [ 18 ]. More recently, prophylactic oxypentifyllin, a tumor necrosis factor-α antagonist, reduced complications in patients with advanced cirrhosis, including renal dysfunction [ 19 ]. Albumin infusions have been reported to decrease the incidence of HRS in patients with SBP [ 20 ]. However, whether this is a specific effect of albumin or due to better volume resuscitation remains to be determined. Table 3. Drugs reported to precipitate HRS in patients with cirrhosis Renal insult Mechanism Drug 1. Reduced systemic blood pressure Reduced intra-renal perfusion pressure Alpha blockers Angiotensin-converting enzyme inhibitors 2. Reduced glomerular perfusion Inhibition vasodilatory renal prostanoids Non-steroidal anti-inflammatories COX 2 inhibitors Glomerular vasoconstriction Dipyridamole 3. Nephrotoxicity Renal tubular toxicity Aminoglycosides Amphotericin Renal insult Mechanism Drug 1. Reduced systemic blood pressure Reduced intra-renal perfusion pressure Alpha blockers Angiotensin-converting enzyme inhibitors 2. Reduced glomerular perfusion Inhibition vasodilatory renal prostanoids Non-steroidal anti-inflammatories COX 2 inhibitors Glomerular vasoconstriction Dipyridamole 3. Nephrotoxicity Renal tubular toxicity Aminoglycosides Amphotericin Open in new tab Table 3. Drugs reported to precipitate HRS in patients with cirrhosis Renal insult Mechanism Drug 1. Reduced systemic blood pressure Reduced intra-renal perfusion pressure Alpha blockers Angiotensin-converting enzyme inhibitors 2. Reduced glomerular perfusion Inhibition vasodilatory renal prostanoids Non-steroidal anti-inflammatories COX 2 inhibitors Glomerular vasoconstriction Dipyridamole 3. Nephrotoxicity Renal tubular toxicity Aminoglycosides Amphotericin Renal insult Mechanism Drug 1. Reduced systemic blood pressure Reduced intra-renal perfusion pressure Alpha blockers Angiotensin-converting enzyme inhibitors 2. Reduced glomerular perfusion Inhibition vasodilatory renal prostanoids Non-steroidal anti-inflammatories COX 2 inhibitors Glomerular vasoconstriction Dipyridamole 3. Nephrotoxicity Renal tubular toxicity Aminoglycosides Amphotericin Open in new tab Recommendations for clinical practice. Type 1 HRS patients should be closely monitored and precipitating factors including bacterial infection should be actively sought and treated (not graded). Drugs reducing renal perfusion or directly causing nephrotoxicity should be avoided when possible in patients with or at risk of developing HRS (1C). Exposure to contrast should be minimized to reduce contrast-induced kidney injury (1D). Assessment of intravascular volume in patients with cirrhosis. Cirrhotic patients often have a hyperdynamic circulation characterized by increased cardiac output, systemic hypotension and reduced peripheral vascular resistance [ 21 ]. Optimizing intravascular volume is essential in managing patients with HRS or at risk of developing HRS. However, intravascular volume expansion, which is often necessary to treat HRS, can potentially lead to worsening of ascites, pleural effusion or heart failure. Assessment of intravascular volume in HRS is difficult as the standard static hemodynamics measurements of central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) are not reliable markers of circulatory volume [ 22 , 23 ]. Goal-directed therapy for guiding fluid management has been investigated in patients with HRS with an infusion of 20% albumin significantly increasing central blood volume and cardiac index, without changes in CVP [ 24 ]. Pulse pressure variation derived from the arterial waveform and stroke volume variation from the pulse contour, as with other dynamic methods, are predictive of fluid responsiveness during volume-controlled mechanical ventilation [ 25 ] but are not as reliable in septic patients on pressure support ventilation [ 26 ]. The response to a fluid challenge in cirrhotics, however, is likely to be abnormal, as any fluid bolus which initially expands the intravascular space, will subsequently expand the ‘third space’. Other potential techniques include esophageal doppler, inferior vena caval diameter, right ventricular end-diastolic volume index, left ventricular end-diastolic area index and the global end-diastolic volume index, however, experience with these techniques in patients with cirrhosis remains limited [ 27–31 ]. Recommendations for clinical practice. Excessive administration of fluids should be avoided to prevent volume overload due to the presence of kidney injury and development or progression of dilutional hyponatremia (1D). Traditional methods based on clinical examination and static measurements of CVP and PCWP are of questionable accuracy in predicting volume responsiveness and should not be relied on (1C). Functional hemodynamic monitoring should be used where possible to assess the dynamic response to a fluid volume bolus (2D). Recommendation for future research. Prospective studies, specifically of volume assessment with hemodynamic monitoring tools in patients with HRS, are recommended as future research areas. Fluid resuscitation in HRS. Although albumin infusion was reported to reduce the incidence of HRS Type 1 in patients with SBP [ 20 ], there are few studies investigating the effect of fluid management in patients with cirrhosis. In advanced liver disease, volume expansion does not always resolve hypotension, most likely due to the increased vascular compliance in cirrhotics [ 32 ]. To date, the choice of intravenous fluids used in cirrhotics remains controversial. In severely ill patients with cirrhosis, volume expansion with albumin has been shown to reduce plasma renin, suggesting an improvement in the effective circulating volume. In randomized controlled clinical trials, albumin infusions reduced both the incidence of HRS and mortality [ 20 , 33 ]. Studies have shown that the use of vasopressors (octreotide with midodrine, norepinephrine and terlipressin) with albumin improves renal function and mortality compared to vasopressors alone [ 34–37 ]. The question arises as to whether the beneficial effect observed with albumin is primarily due to volume expansion or whether albumin has additional effects compared to other colloids [ 38–41 ]. In one randomized study in patients with SBP, albumin significantly increased mean arterial pressure (MAP) and suppressed plasma renin activity, compared to hetastarch, and albumin significantly caused less neurohumeral activation compared to other colloids or volume expanders post-large-volume paracentesis [ 38 ]. In addition, plasma von Willebrand-related antigen fell significantly in the albumin-treated group, but not in those treated with hetastarch, whereas serum nitrates increased with hetastarch but not with albumin suggesting additional beneficial effects with albumin [ 38 ]. Recommendations for clinical practice. Patients with HRS should be optimally resuscitated, with intravenous administration of albumin (initially 1 g of albumin/kg of body weight, up to a maximum of 100 g, followed by 20–40 g/day) in combination with vasopressor therapy (1A), for up to 14 days (2D). Paracentesis. AKI due to abdominal compartment syndrome is well recognized with intra-abdominal pressures (IAP) typically >18 mmHg [ 42 ], although AKI can develop with lower pressures [ 43 ]. In cirrhotics, paracentesis is typically performed for symptomatic relief. Uncontrolled studies have reported an improvement in renal function in patients with HRS following paracentesis for raised IAP [ 24 , 44 ]. Color Doppler studies have shown reduced intra-renal pressure with improved diastolic perfusion following paracentesis [ 42 , 45 ]. Recommendation for future research. Prospective studies are required to investigate the effect of reducing IAP on renal function in patients at risk of developing or with established HRS. Pharmacological treatment of HRS As splanchnic vasodilatation plays a key role in the pathogenesis of HRS, the focus of trials on the treatment of Type 1 HRS has been on the use of vasoconstrictors ( Table 4 ) [ 64–67 ]. Although the majority of these studies have been retrospective, more recently, several prospective trials have reported an improvement in renal function (but not a survival benefit). Hence, pharmacological treatment is often perceived as a bridge to liver transplantation [ 60 ]. Table 4. Clinical trials on vasocontrictor drugs for HRS a Author Study design N (% HRS Type 1) Comparative group Albumin administration HRS reversal ( n ) Terlipressin b Year Survival ( n ) Hadengue [ 46 ] 1998 RCT c 9 (100%) Albumin Initial volume expansion only NA T: 89%, C: 100% Uriz [ 47 ] 2000 P 9 (100%) No control group 1 g/kg then 20–40 g/day 78% 33% Duhamel [ 48 ] d 2000 P 12 (100%) No control group No information 50% 33% Mulkay [ 49 ] 2001 P 12 (100%) No control group 0.5–1.0 g/kg/day NA 25% Ortega [ 37 ] 2002 P 21 (76%) Terlipressin 1 g/kg then 20–40 g/day T + A: 77%, T: 25% T + A: 52%, T: 14% Colle [ 50 ] 2002 R 18 (100%) No control group Mean 21 g/day d 61% 17% Moreau [ 51 ] 2002 R 99 No control group Mean 38 g/day d NA 24% Halimi [ 52 ] d 2002 R 18 (88.8%) No control group No information 44% 11% Danalioglu [ 53 ] 2003 R 22 (68.2%) No control group 40 g/day NA 64% Solanki [ 54 ] 2003 RCT e 24 (100%) Albumin 40 g/day to keep CVP 10–12 T + A: 42%, A: 0% T: 42%, C: 0% Alessandria [ 55 ] 2007 RCT f 22 (41%) Noradrenaline To keep CVP 10–15 N: 70%, T: 83% N: 80%, T: 92% Sharma [ 56 ] 2008 RCT f 40 (100%) Noradrenaline To keep CVP 10–12 N: 50%, T: 40% N: 55%, T: 55% Neri [ 57 ] 2008 RCT f 52 (100%) Albumin 1 g/kg then 20–40 g/day T + A: 81%, A: 5/26 T: 42%, C: 15% Sanyal [ 58 ] 2008 RCT c 112 (100%) Albumin 1 g/kg then 25 g/day T + A: 34%, A: 13% T: 18%, C: 13% Martin-llahi [ 59 ] 2008 RCT e 46 (76%) Albumin 1 g/kg then 20 g/day T + A: 43%, A: 9% T: 26%, C: 17% Testro [ 60 ] 2008 R 69 (71%) No control group daily albumin—no dose specified 59% 30% Noradrenaline g Duvoux [ 36 ] 2002 P 12 (100%) No control group To keep CVP 4–8 10/12 7/12 Octreotide plus midodrine h Angeli [ 34 ] 1999 P 13 (100%) Dopamine + albumin 10–20 g/day NA OCT + M: 80%, dopamine: 12% Wong [ 61 ] 2004 P 14 (100%) No control group 50 g/day for 5 days 71% NA Esrailian [ 35 ] d 2007 R 81 (100%) No intervention 120 g initial dose NA OCT + M: 43%control: 71% Skagen [ 62 ] 2009 R 162 (63%) No intervention (Historical cohort) Mean 44 g/day (50–100) NA OCT + M: 73%, control: 39% Vasopressin i Kiser [ 63 ] 2005 R 43 (74%) AVP + OCT and OCT alone Responders mean 59 g/day + others mean 76 g/day AVP: 37%, AVP + OCT: 42%, OCT: 0% AVP: 37%, AVP + OCT: 42%, OCT: 56% Author Study design N (% HRS Type 1) Comparative group Albumin administration HRS reversal ( n ) Terlipressin b Year Survival ( n ) Hadengue [ 46 ] 1998 RCT c 9 (100%) Albumin Initial volume expansion only NA T: 89%, C: 100% Uriz [ 47 ] 2000 P 9 (100%) No control group 1 g/kg then 20–40 g/day 78% 33% Duhamel [ 48 ] d 2000 P 12 (100%) No control group No information 50% 33% Mulkay [ 49 ] 2001 P 12 (100%) No control group 0.5–1.0 g/kg/day NA 25% Ortega [ 37 ] 2002 P 21 (76%) Terlipressin 1 g/kg then 20–40 g/day T + A: 77%, T: 25% T + A: 52%, T: 14% Colle [ 50 ] 2002 R 18 (100%) No control group Mean 21 g/day d 61% 17% Moreau [ 51 ] 2002 R 99 No control group Mean 38 g/day d NA 24% Halimi [ 52 ] d 2002 R 18 (88.8%) No control group No information 44% 11% Danalioglu [ 53 ] 2003 R 22 (68.2%) No control group 40 g/day NA 64% Solanki [ 54 ] 2003 RCT e 24 (100%) Albumin 40 g/day to keep CVP 10–12 T + A: 42%, A: 0% T: 42%, C: 0% Alessandria [ 55 ] 2007 RCT f 22 (41%) Noradrenaline To keep CVP 10–15 N: 70%, T: 83% N: 80%, T: 92% Sharma [ 56 ] 2008 RCT f 40 (100%) Noradrenaline To keep CVP 10–12 N: 50%, T: 40% N: 55%, T: 55% Neri [ 57 ] 2008 RCT f 52 (100%) Albumin 1 g/kg then 20–40 g/day T + A: 81%, A: 5/26 T: 42%, C: 15% Sanyal [ 58 ] 2008 RCT c 112 (100%) Albumin 1 g/kg then 25 g/day T + A: 34%, A: 13% T: 18%, C: 13% Martin-llahi [ 59 ] 2008 RCT e 46 (76%) Albumin 1 g/kg then 20 g/day T + A: 43%, A: 9% T: 26%, C: 17% Testro [ 60 ] 2008 R 69 (71%) No control group daily albumin—no dose specified 59% 30% Noradrenaline g Duvoux [ 36 ] 2002 P 12 (100%) No control group To keep CVP 4–8 10/12 7/12 Octreotide plus midodrine h Angeli [ 34 ] 1999 P 13 (100%) Dopamine + albumin 10–20 g/day NA OCT + M: 80%, dopamine: 12% Wong [ 61 ] 2004 P 14 (100%) No control group 50 g/day for 5 days 71% NA Esrailian [ 35 ] d 2007 R 81 (100%) No intervention 120 g initial dose NA OCT + M: 43%control: 71% Skagen [ 62 ] 2009 R 162 (63%) No intervention (Historical cohort) Mean 44 g/day (50–100) NA OCT + M: 73%, control: 39% Vasopressin i Kiser [ 63 ] 2005 R 43 (74%) AVP + OCT and OCT alone Responders mean 59 g/day + others mean 76 g/day AVP: 37%, AVP + OCT: 42%, OCT: 0% AVP: 37%, AVP + OCT: 42%, OCT: 56% a AVP, vasopressin; OCT, octreotide; T, terlipressin; N, noradrenaline; A, albumin; M, midodrine; NA, not available; R, retrospective; RCT, randomized control trial; P, prospective. b 0.5–2.0 mg intravenously every 4–6 h; with stepwise dose increments every few days if there is no improvement in serum creatinine, up to a maximum dose of 12 mg/day as long as there are no side effects. Maximal treatment 14 days. c Double blind. d Mean daily dose of albumin, studies typically reported large SD (>20 g/day). e Single blind. f Unblinded. g 0.5–3.0 mg/h (continuous infusion), titrate dose to achieve increase in MAP by 10 mmHg. h Midodrine: 7.5–12.5 mg orally three times daily, octreotide: 100–200 μg subcutaneously three times daily or 25 μg bolus, followed by intravenous infusion of 25 μg/h to increase MAP by 15 mmHg. i 0.01–0.8 U/min (continuous infusion, titrate dose to achieve a 10 mmHg increase in MAP from baseline or MAP >70 mmHg. Open in new tab Table 4. Clinical trials on vasocontrictor drugs for HRS a Author Study design N (% HRS Type 1) Comparative group Albumin administration HRS reversal ( n ) Terlipressin b Year Survival ( n ) Hadengue [ 46 ] 1998 RCT c 9 (100%) Albumin Initial volume expansion only NA T: 89%, C: 100% Uriz [ 47 ] 2000 P 9 (100%) No control group 1 g/kg then 20–40 g/day 78% 33% Duhamel [ 48 ] d 2000 P 12 (100%) No control group No information 50% 33% Mulkay [ 49 ] 2001 P 12 (100%) No control group 0.5–1.0 g/kg/day NA 25% Ortega [ 37 ] 2002 P 21 (76%) Terlipressin 1 g/kg then 20–40 g/day T + A: 77%, T: 25% T + A: 52%, T: 14% Colle [ 50 ] 2002 R 18 (100%) No control group Mean 21 g/day d 61% 17% Moreau [ 51 ] 2002 R 99 No control group Mean 38 g/day d NA 24% Halimi [ 52 ] d 2002 R 18 (88.8%) No control group No information 44% 11% Danalioglu [ 53 ] 2003 R 22 (68.2%) No control group 40 g/day NA 64% Solanki [ 54 ] 2003 RCT e 24 (100%) Albumin 40 g/day to keep CVP 10–12 T + A: 42%, A: 0% T: 42%, C: 0% Alessandria [ 55 ] 2007 RCT f 22 (41%) Noradrenaline To keep CVP 10–15 N: 70%, T: 83% N: 80%, T: 92% Sharma [ 56 ] 2008 RCT f 40 (100%) Noradrenaline To keep CVP 10–12 N: 50%, T: 40% N: 55%, T: 55% Neri [ 57 ] 2008 RCT f 52 (100%) Albumin 1 g/kg then 20–40 g/day T + A: 81%, A: 5/26 T: 42%, C: 15% Sanyal [ 58 ] 2008 RCT c 112 (100%) Albumin 1 g/kg then 25 g/day T + A: 34%, A: 13% T: 18%, C: 13% Martin-llahi [ 59 ] 2008 RCT e 46 (76%) Albumin 1 g/kg then 20 g/day T + A: 43%, A: 9% T: 26%, C: 17% Testro [ 60 ] 2008 R 69 (71%) No control group daily albumin—no dose specified 59% 30% Noradrenaline g Duvoux [ 36 ] 2002 P 12 (100%) No control group To keep CVP 4–8 10/12 7/12 Octreotide plus midodrine h Angeli [ 34 ] 1999 P 13 (100%) Dopamine + albumin 10–20 g/day NA OCT + M: 80%, dopamine: 12% Wong [ 61 ] 2004 P 14 (100%) No control group 50 g/day for 5 days 71% NA Esrailian [ 35 ] d 2007 R 81 (100%) No intervention 120 g initial dose NA OCT + M: 43%control: 71% Skagen [ 62 ] 2009 R 162 (63%) No intervention (Historical cohort) Mean 44 g/day (50–100) NA OCT + M: 73%, control: 39% Vasopressin i Kiser [ 63 ] 2005 R 43 (74%) AVP + OCT and OCT alone Responders mean 59 g/day + others mean 76 g/day AVP: 37%, AVP + OCT: 42%, OCT: 0% AVP: 37%, AVP + OCT: 42%, OCT: 56% Author Study design N (% HRS Type 1) Comparative group Albumin administration HRS reversal ( n ) Terlipressin b Year Survival ( n ) Hadengue [ 46 ] 1998 RCT c 9 (100%) Albumin Initial volume expansion only NA T: 89%, C: 100% Uriz [ 47 ] 2000 P 9 (100%) No control group 1 g/kg then 20–40 g/day 78% 33% Duhamel [ 48 ] d 2000 P 12 (100%) No control group No information 50% 33% Mulkay [ 49 ] 2001 P 12 (100%) No control group 0.5–1.0 g/kg/day NA 25% Ortega [ 37 ] 2002 P 21 (76%) Terlipressin 1 g/kg then 20–40 g/day T + A: 77%, T: 25% T + A: 52%, T: 14% Colle [ 50 ] 2002 R 18 (100%) No control group Mean 21 g/day d 61% 17% Moreau [ 51 ] 2002 R 99 No control group Mean 38 g/day d NA 24% Halimi [ 52 ] d 2002 R 18 (88.8%) No control group No information 44% 11% Danalioglu [ 53 ] 2003 R 22 (68.2%) No control group 40 g/day NA 64% Solanki [ 54 ] 2003 RCT e 24 (100%) Albumin 40 g/day to keep CVP 10–12 T + A: 42%, A: 0% T: 42%, C: 0% Alessandria [ 55 ] 2007 RCT f 22 (41%) Noradrenaline To keep CVP 10–15 N: 70%, T: 83% N: 80%, T: 92% Sharma [ 56 ] 2008 RCT f 40 (100%) Noradrenaline To keep CVP 10–12 N: 50%, T: 40% N: 55%, T: 55% Neri [ 57 ] 2008 RCT f 52 (100%) Albumin 1 g/kg then 20–40 g/day T + A: 81%, A: 5/26 T: 42%, C: 15% Sanyal [ 58 ] 2008 RCT c 112 (100%) Albumin 1 g/kg then 25 g/day T + A: 34%, A: 13% T: 18%, C: 13% Martin-llahi [ 59 ] 2008 RCT e 46 (76%) Albumin 1 g/kg then 20 g/day T + A: 43%, A: 9% T: 26%, C: 17% Testro [ 60 ] 2008 R 69 (71%) No control group daily albumin—no dose specified 59% 30% Noradrenaline g Duvoux [ 36 ] 2002 P 12 (100%) No control group To keep CVP 4–8 10/12 7/12 Octreotide plus midodrine h Angeli [ 34 ] 1999 P 13 (100%) Dopamine + albumin 10–20 g/day NA OCT + M: 80%, dopamine: 12% Wong [ 61 ] 2004 P 14 (100%) No control group 50 g/day for 5 days 71% NA Esrailian [ 35 ] d 2007 R 81 (100%) No intervention 120 g initial dose NA OCT + M: 43%control: 71% Skagen [ 62 ] 2009 R 162 (63%) No intervention (Historical cohort) Mean 44 g/day (50–100) NA OCT + M: 73%, control: 39% Vasopressin i Kiser [ 63 ] 2005 R 43 (74%) AVP + OCT and OCT alone Responders mean 59 g/day + others mean 76 g/day AVP: 37%, AVP + OCT: 42%, OCT: 0% AVP: 37%, AVP + OCT: 42%, OCT: 56% a AVP, vasopressin; OCT, octreotide; T, terlipressin; N, noradrenaline; A, albumin; M, midodrine; NA, not available; R, retrospective; RCT, randomized control trial; P, prospective. b 0.5–2.0 mg intravenously every 4–6 h; with stepwise dose increments every few days if there is no improvement in serum creatinine, up to a maximum dose of 12 mg/day as long as there are no side effects. Maximal treatment 14 days. c Double blind. d Mean daily dose of albumin, studies typically reported large SD (>20 g/day). e Single blind. f Unblinded. g 0.5–3.0 mg/h (continuous infusion), titrate dose to achieve increase in MAP by 10 mmHg. h Midodrine: 7.5–12.5 mg orally three times daily, octreotide: 100–200 μg subcutaneously three times daily or 25 μg bolus, followed by intravenous infusion of 25 μg/h to increase MAP by 15 mmHg. i 0.01–0.8 U/min (continuous infusion, titrate dose to achieve a 10 mmHg increase in MAP from baseline or MAP >70 mmHg. Open in new tab Vasopressin. Vasopressin exerts its action through vasopressin receptors (V1, V2 and V3) [ 68 ]. V1 receptor activation leads to vascular smooth muscle contraction and the high density of V1 receptors in the splanchnic bed make this vasculature especially responsive to vasopressin [ 63 ]. There are limited data on the efficacy of vasopressin in HRS compared to the newer analogs ( Table 4 ). Terlipressin. Terlipressin is a distinctive vasopressin analog with preferential effects on the V1 receptor and a lower rate of ischemic complications compared to vasopressin. Although not currently commercially available in the USA, it is the most widely studied agent for Type 1 HRS. Currently, the data on terlipressin are predominantly from patients with Type 1 HRS, with studies varying in dosage, route of administration (subcutaneous infusion versus bolus) and duration of therapy [ 5 , 46 , 53–59 ]. Several small studies have demonstrated that terlipressin significantly decreases plasma renin and aldosterone, with an improvement in glomerular filtration rate (GFR) in patients with Type 1 HRS [ 46–50 , 52 , 57 ]. A larger European consortium confirmed these findings in a retrospective study of Type 1 HRS and also demonstrated a survival benefit, particularly as a bridge to liver transplantation [ 51 ]. The importance of albumin infusion to terlipressin therapy [ 47 ] was emphasized in a prospective study of predominantly Type 1 HRS. Terlipressin administration alone did not increase MAP or suppress renin–aldosterone, whereas the addition of albumin improved these parameters and was the only factor predictive of complete response [ 37 ]. These preliminary studies lead to three randomized prospective trials that established that terlipressin (in combination with albumin) improved renal function in patients with Type 1 HRS [ 54 , 58 , 59 ]. Terlipressin dosages ranged from 2 to 12 mg/day in divided doses and 20–40 g/day of albumin. However, in most studies, there were no overall survival benefits ( Table 4 ). The duration of terlipressin therapy is usually ≤2 weeks, with stepwise dose increments every few days, provided there is no improvement in serum creatinine (Scr) or adverse effects. The aim is to improve renal function sufficiently to decrease the Scr <1.5 mg/dL (complete response). For patients with a partial response (Scr improves, but does not decrease <1.5 mg/dL) or in those who exhibit no improvement of renal function (no reduction of Scr), then continued treatment should be avoided, and the consensus is to discontinue terlipressin within 14 days. There are no studies on how best to discontinue terlipressin therapy, and whether this affects HRS recurrence. Similarly, studies have focused on changes in Scr rather than titrating terlipressin to achieve a target MAP. More recent studies have focused on early predictors of response with a baseline serum bilirubin (<10 mg/dL) and an increase in MAP of ≥5 mmHg by Day 3 predicting response [ 51 ]. In addition, terlipressin may be beneficial in cirrhotics with ascites and renal impairment before they fulfill the diagnostic criteria for HRS, by decreasing plasma renin and norepinephrine and increasing GFR and natriuresis [ 69 ]. Compared to other V1 receptor agonists, terlipressin has a favorable adverse effect profile, but terlipressin can cause ischemia [ 5 ], and patients with additional comorbidities such as ischemic heart and peripheral vascular disease have typically been excluded from studies. Concerns had been raised about terlipressin increasing intracranial hypertension in patients with acute liver failure, but this has not been borne out with more recent studies [ 70 ]. Norepinephrine (noradrenaline). Norepinephrine is a catecholamine but its alpha-adrenergic activity makes it a potent vasoconstrictor of both the venous and arterial vasculature and therefore a potential agent for reversing HRS. A pilot study Type 1 HRS used norepinephrine at a dose titrated to achieve an increase in MAP of ≥10 mmHg or an increase in 4-h urine output to >200 mL [ 36 ]. Twelve patients were treated for a median of 10 days with a mean of 13 μg/min and albumin. Reversal of HRS occurred in 83%, with improvement in urine output, sodium excretion, serum sodium concentration, creatinine clearance, MAP, plasma renin activity and aldosterone. Two subsequent small studies have shown similar efficacy of norepinephrine to terlipressin in Type 1 HRS with a similar adverse effect profile but significant cost advantage [ 55 , 56 ]. Baseline creatinine clearance, MAP and plasma renin activity were independent predictors of response. Unfortunately, the number of patients prospectively treated with noradrenaline is small and no randomized comparative studies have been performed to evaluate its efficacy. Octreotide and midodrine. Both octreotide and midodrine have been tried alone or in combination in HRS with some beneficial effects. Oral midodrine, an alpha-adrenergic receptor agonist, causes vascular smooth muscle vasoconstriction, and subcutaneous octreotide, a long-acting somatostatin analogue, which is used to reduce portal hypertension after variceal hemorrhage. Early studies in Type 2 HRS demonstrated no improvement in renal function with midodrine [ 55 ] or octreotide [ 34 , 71 ]. However, the combination of thrice daily midodrine 7.5–12.5 mg and octreotide 100–200 μg, and albumin, improved renal plasma flow, GFR and urinary sodium excretion with reduction in plasma renin activity, vasopressin and glucagon levels in Type 1 HRS after 3 weeks of treatment. Survival was higher compared to Type 1 HRS patients treated with albumin and dopamine [ 71 ]. Additional studies reported improvement in renal function in HRS using the combination of octreotide and midodrine [ 35 , 62 ]. A longer acting version of octreotide (given monthly) has also been studied [ 61 ], as has the use of transjugular portosystemic shunting after the control of Type 1 HRS using octreotide and midodrine combination [ 72 ], with some encouraging results. Other agents. Ornipressin, a vaspressin analogue, has been associated with a high rate of ischemic complications (including ischemic colitis and tongue ischemia) requiring ornipressin withdrawal [ 73 , 74 ]. Dopamine and dopamine agonists [ 75 ], vasodilatory prostanoids [ 76 ], natriuretic peptides [ 77 , 78 ] and endothelin antagonists [ 79 ] have not been shown to be effective in clinical studies of HRS. N -acetyl cysteine used in the management of acetaminophen poisoning has been reported to help reverse HRS in case reports, but awaits confirmation [ 80 , 81 ]. Oxypentifylline, used in alcoholic hepatitis, has been reported to reduce the incidence of HRS [ 19 ], but has not been shown to improve renal function in established HRS [ 82 , 83 ]. Recommendations for clinical practice. We recommend that patients with Type 1 HRS be optimally resuscitated with albumin (initially 1 g of albumin/kg of body weight for 2 days, up to a maximum of 100 g/day, followed by 20–40 g/day) in combination with a vasoconstrictor (1A), preferentially terlipressin (2C). If terlipressin is unavailable, alternative vasoconstrictors, such as norepinephrine or combination octreotide/midodrine, together with albumin should be considered (2C). Therapy should be discontinued after 14 days in non-responders and only continued thereafter in partial responders while awaiting the outcome of salvage techniques (2D). Recommendation for future research Prospective trials are required to determine the optimum mode of delivery of terlipressin (bolus versus infusion). Comparative trials of vasoconstrictors are required to determine the merits of vasopressin analogs against norepinephrine. Conclusions Although the introduction of terlipressin and albumin has improved the outlook for patients with HRS, only ∼50% of patients respond to therapy [ 84 ]. Questions remain both as to whether earlier introduction of this therapy would help prevent the development of HRS, and also in patients with established HRS how best to both administer terlipressin and if targeting vasoconstrictor dosage to an absolute or relative increase in MAP improves response. In addition, the effects of changes in IAP on renal function in patients with HRS have not been explored and may need to be considered in terms of renal perfusion pressure, along with MAP. For those patients who fail medical therapy, further investigations regarding the use of extracorporeal systems are needed to help bridge patients to liver transplantation. The authors wish to acknowledge the University of Southern California for organization of ADQI 8th International Consensus Conference. This conference was supported by unrestricted educational grants from Ikaria, Gambro Renal Care, Otsuka Pharmaceutical, Nx-Stage Medical, IV League Inc. and Baxter Inc. ADQI is supported by a group of sponsors and no funding is accepted for the development of specific guidelines. None of the companies that provided financial support for this meeting were involved in any way in the organization of the meeting, the decision regarding invited faculty, the design and contents of the meeting, the collection, management, analysis and interpretation of the data and preparation, review or approval of the manuscript. ADQI 8th International Consensus Conference Participants: J.A., MD, Mount Sinai Hospital, USA; A.A.-K., MD, University of Pittsburgh School of Medicine, USA; Paolo Angeli, MD, University of Padova, Italy; Rinaldo Bellomo, MD, Melbourne University, Australia; Pat Brophy, MD, University of Iowa, USA; Jorge Cerda, MD, Albany Medical College, USA; Lakhmir S. 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TI - Medical management of hepatorenal syndrome
JF - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfr736
DA - 2012-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/medical-management-of-hepatorenal-syndrome-U2gbus2KAn
SP - 34
EP - 41
VL - 27
IS - 1
DP - DeepDyve
ER -