Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease, occurring

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1 1310 RECENT ADVANCES IN CLINICAL PRACTICE DIAGNOSIS, PREVENTION AND TREATMENT OF HEPATORENAL SYNDROME IN CIRRHOSIS Franeso Salerno, Alexander Gerbes, Pere Ginès, Florene Wong, Viente Arroyo Gut 2007; 56: doi: /gut Hepatorenal syndrome (HRS) is a serious ompliation of end-stage liver disease, ourring mainly in patients with advaned irrhosis and asites, who have marked irulatory dysfuntion, 1 as well as in patients with aute liver failure. 2 In spite of its funtional nature, HRS is assoiated with a poor prognosis, 3 4 and the only effetive treatment is liver transplantation. During the 56th Meeting of the Amerian Assoiation for the Study of Liver Diseases, the International Asites Club held a Foused Study Group (FSG) on HRS for the purpose of reporting the results of an international workshop and to reah a onsensus on a new definition, riteria for diagnosis and reommendations on HRS treatment. A similar workshop was held in Chiago in 1994 in whih standardised nomenlature and diagnosti riteria for refratory asites and HRS were established. 5 The introdution of innovative treatments and improvements in our understanding of the pathogenesis of HRS during the previous deade led to an inreasing need to undertake a new onsensus meeting. This paper reports the sientifi rationale behind the new definitions and reommendations. The international workshop inluded four issues debated by four panels of experts (see Aknowledgements). The issues were: (1) evidene-based HRS pathogenesis; (2) treatment of HRS using vasoonstritors; (3) other HRS treatments using transjugular intrahepati portosystemi stent-shunt (TIPS) and extraorporeal albumin dialysis (ECAD); and (4) new definitions and diagnosti riteria for HRS and reommendations for its treatment. BACKGROUND The definition and diagnosti riteria for HRS established in were based on the following three onepts: (1) renal failure in HRS is funtional and aused by marked intrarenal arteriolar vasoonstrition; (2) HRS ours in patients with systemi irulatory dysfuntion aused by extra-renal vasodilatation; (3) plasma volume expansion does not improve renal failure. Four new onepts have emerged sine then, these are: (a) Extra-renal arterial vasodilatation ours mainly in the splanhni vasular bed, whereas other vasular beds, suh as those whih supply the brain and the liver, may be vasoonstrited. This may ontribute to the development of hepati enephalopathy and hepati failure, respetively. (b) Cardia output in patients with HRS may be low, normal or high, but it is insuffiient for the patient s needs beause of redued peripheral resistanes. () The most ommon trigger for the development of type-1 HRS is baterial infetion, mainly spontaneous baterial peritonitis (SBP). (d) Renal funtion an be improved by medial treatment in patients with HRS and is assoiated with improved survival. See end of artile for authors affiliations Correspondene to: Franeso Salerno, Department of Internal Mediine, Polilinio IRCCS San Donato, University of Milan, Via Morandi, 30, San Donato (MI), Italy; franeso.salerno@unimi.it Bakground for the new onepts The first of these onepts was formulated following investigation onduted using Doppler ultrasonography or plethysmography both before and after These studies were performed in patients with varying degrees of severity of irrhosis, and revealed arterial vasodilatation in the splanhni irulation as well as arterial vasoonstrition in other areas suh as the brain, kidneys and liver, 6 13 whereas the utaneous and musular blood flow has been reported as low, normal or inreased The dilatation of the splanhni vessels is mainly aused by loal release of potent vasodilators suh as nitri oxide (NO), 17 whih also render the splanhni irulation resistant to various vasopressors inluding angiotensin II, norepinephrine, vasopressin and endothelin The

2 Main pathophysiologial and linial aspets of HRS HRS is a funtional renal failure aused by intrarenal vasoonstrition whih ours in patiens with end-stage liver disease and irulatory dysfuntion. Cirulatory dysfuntion is haraterised by vasodilatation in the splanhni irulation with a relatively low and insuffiient ardia output, leading to effetive hypovolaemia. HRS may our spontaneously with worsening liver funtion, or seondary to a preipitating event suh as baterial infetion (eg, SBP). HRS an be improved by the administration of vasoonstritors and albumin, or by TIPS. resistane of the splanhni irulation to these vasopressor agents renders the ontrol of arterial pressure in irrhosis dependent on the extra-splanhni effets exerted by the endogenous vasoonstritor systems. As arterial vasodilatation inreases with progression of irrhosis, the role of vasoonstritors in maintaining haemodynami stability beomes ritial, and explains why irrhoti patients with HRS are predisposed to develop renal, hepati and erebral vasoonstrition. The seond new onept that is, that insuffiient ardia output ontributes to renal hypoperfusion in patients with HRS was first suggested by Tristani and Cohn, 25 but it is only reently that this has been onfirmed. The first study showed that the ardia output of irrhoti patients with SBP who developed progressive renal failure was relatively low, despite resolution of infetion, when ompared with a similar group of patients with SBP who did not develop renal failure. 26 The seond study ompared non-azotaemi irrhoti patients who developed HRS with similar patients who did not, and showed that low ardia output and high plasma renin ativity (PRA) were independent preditors of HRS. 27 Moreover, in patients developing HRS, the progression of irulatory dysfuntion leading to arterial hypotension and renal failure ourred in the setting of a ontinued derease in ardia output and inrease in PRA. These findings support the hypothesis that hyperdynami irulation is essential to maintain entral blood volume and renal perfusion in irrhosis. Therefore, when ardia output dereases, effetive hypovolaemia ours, leading to renal hypoperfusion and HRS. The mehanism leading to impaired or insuffient ardia output in patients developing HRS is unknown. In reent years, a speifi ardia abnormality, haraterised by attenuated systoli and diastoli responses to stimuli, hanges in repolarisation and hypertrophy of the ardia hambers, has beome inreasingly reognised the so-alled irrhoti ardiomyopathy. 28 A fall in ardia preload due to a derease in venous return is another hypothesis that might justify the effetiveness of albumin infusion. 27 HRS an be triggered by preipitating events. The most important of these are infetion, bleeding and large-volume paraentesis without albumin administration The role of SBP has reently been emphasised. Table 1 ompares the results of two studies assessing the prevalene of renal failure in irrhoti patients with SBP and in those with infetions unrelated to SBP, and shows that: (a) in spite of an effetive antibioti therapy, a signifiant proportion of irrhoti patients with baterial infetion develop progressive renal failure. This almost exlusively ours in patients with SBP; (b) in patients not responsive to antibioti therapy, progressive renal failure ours and is independent of the type of infetion. Furthermore, hanges in irulatory funtion, endogenous vasoative systems and renal funtion in patients developing renal failure triggered by SBP are idential to those observed in patients with HRS unrelated to infetion, suggesting that the pathogenesis of progressive renal failure in irrhoti patients with infetion is the same as that of HRS. The most important onept of HRS, however, arises from studies exploring new therapeuti strategies. 33 Sine type-1 HRS is often assoiated with a rapid deterioration of liver funtion with inreased levels of bilirubin and prothrombin time, it has traditionally been viewed as a manifestation of terminal hepati failure. The demonstration that type-1 HRS an be improved by vasoonstritors 34 or by TIPS, and that reversal of type-1 HRS may be assoiated with improved survival, represents a major hange in our understanding of the syndrome. In onlusion, the main pathogeni mehanism in type-1 HRS is a potentially reversible deterioration of systemi irulatory funtion, mostly due to splanhni vasodilatation and renal vasoonstrition and often triggered by a preipitating event (fig 1). In addition to renal failure, the syndrome may be assoiated with other organ dysfuntions, suh as dereased ardia output, hepati failure and enephalopathy. TREATMENT OF HRS New treatments of HRS are designed to expand the entral blood volume by simultaneously inreasing the total plasma volume and reduing intense peripheral vasodilatation. This strategy is not entirely new, as in 1967 Tristani and Cohn 25 showed that dextran infusion improved ardia output and 1311 Table 1 Inidene and ourse of renal failure in irrhoti patients with severe baterial infetions without shok aording to response to antibioti treatment and to type of infetion No response SBP (n = 21)* Response Sepsis unrelated to SBP (n = 9)À SBP (n = 231)* Sepsis unrelated to SBP (n = 98)À No renal failure 3 (14%) 2 (22%) 166 (71%) 77 (78%) Transient renal failure 0 (0%) 0 (0%) 21 (9%) 22 (22%) Steady renal failure 1 (5%) 2 (22%) 26 (11%) 0 (0%) Progressive renal failure 17 (81%) 5 (55%) 18 (7%) 1 (1%) *Data on spontaneous baterial peritonitis (SBP) are from Follo et al. 29 ÀData on sepsis unrelated to SBP are from Terra et al. 30

3 1312 Figure 1 Shemati view of the pathogeneti mehanisms of hepatorenal syndrome in irrhosis. Dotted arrows indiate that preipitating fators are frequent but not neessary. RAAS, renin angiotensin aldosterone system; SBP, spontaneous baterial peritonitis; SNS, sympatheti nervous system. renal perfusion in oliguri irrhoti patients, and 18 years later Shapiro et al 37 showed that the urine water and sodium exretion in irrhoti patients with asites was improved by the administration of norepinephrine ombined with head-out water immersion, a manoeuvre aimed at expanding entral blood volume. However, linially relevant results have only been obtained more reently with the use of albumin and various vasoonstritors. The mehanism by whih vasoonstritors and albumin improve the glomerular filtration rate (GFR) in patients with HRS is inompletely understood. Nevertheless, administration of terlipressin to patients with HRS inreases blood pressure and leads to a signifiant derease in PRA and inrease in GFR, 38 indiretly indiating orretion of irulatory dysfuntion. It is oneivable that vasopressin analogues ause vasoonstrition of the splanhni bed, thereby allowing redistribution of the blood volume to some of the extrasplanhni organs inluding the entral ompartment and the kidneys. Filling of the entral ompartment will lead to the inhibition of the sympatheti nervous and renin angiotensin systems, thereby shifting the autoregulatory urve to the left and making renal blood flow and GFR more responsive to hanges in blood pressure. Albumin is traditionally onsidered to improve irulatory funtion in irrhosis by expanding entral blood volume and inreasing ardia output. 41 Moreover, reent studies have shown that the administration of albumin to irrhoti patients with SBP auses arterial vasoonstrition and blood pressure inrease, 42 probably attributable to the ability of albumin to bind vasodilators. It is therefore oneivable that an improvement of renal funtion in patients with HRS treated with vasoonstritors and albumin is due to the additive effets that the two ompounds have on ardia funtion and peripheral arterial irulation. Prophylaxis of HRS One randomised ontrolled trial (RCT) showed that albumin prevented type-1 HRS in patients with SBP. 41 Patients reeiving albumin (1.5 g/kg body weight on the first day plus 1 g/kg body weight on the third day) showed a 66% redution in the inidene of HRS (10% vs 33%) and a signifiant redution of in-hospital and 3-month mortality rates (10% vs 29%, p,0.01, and 22% vs 41%, p,0.03, respetively,). The albumin effet was related to an improvement in systemi haemodynamis, as indiated by PRA suppression. Indeed, albumin infusion in irrhoti patients with SBP improves both ardia funtion and systemi vasular resistane. 43 As type-1 HRS almost exlusively ourred in patients with serum bilirubin.68 mmol/l (4 mg/dl) and serum reatinine.88.4 mmol/l (1 mg/dl), the prophylati use of albumin ould probably be restrited to these patients, but trials need to be onduted so that the optimum dosage to be used an be defined more preisely. New treatments of HRS Vasoonstritors and albumin The use of an analogue of vasopressin to improve renal blood flow in irrhoti patients was first proposed by Kew et al 35 years ago. 44 More reently, Lenz et al 45 showed that GFR may be moderately improved by ornipressin infusion in patients with HRS, but the drug was given for only 4 h, therefore preluding assessment of its long-term effets. Two more studies demonstrated that a long-term (1 2 weeks) infusion of ornipressin, ombined with albumin or dopamine, normalised serum reatinine onentrations in many patients with type-1 HRS Interestingly, reurrene of renal failure rarely ourred after treatment withdrawal, and in the few ases where it did reur a seond ourse of therapy was suessful. However, the drawbak with ornipressin was the frequent ourrene of ishaemi ompliations. Therefore, widespread use of vasoonstritors in patients with HRS has only beome linially feasible with the advent of safer ompounds suh as terlipressin, a vasopressin analogue with longer ativity, and the a 2 -agonist midodrine ombined with otreotide. Table 2 summarises the data

4 Table 2 Charateristis and results of studies reporting the effet of terlipressin in patients with irrhosis and type-1 HRS Author, year (referene) Type of study Suess rate of therapyà Dose (mg/ day) Duration (days) Survival at 4 weeks* Adverse events Ganne-Carrie, C 1/ Yes Yes Le Moine, C 1/ Yes No Duhamel, R 6/ /18 4/12 Colle, R 11/ (0.1) 9 (1) 1/16 0/18 Halimi, R 12/ /7 4/16 Moreau, R 53/ (1.2) 11 (12) 37/99 23/99 Danalioglu, R 3/ ND No Uriz, PU 4/ /6 1/6 Mulkay, PU 12/ /12 4/12 Angeli, PU 12/ (15 13/19 ND Ortega, PU T+A: 8/ /9 1/16 T: 1/7 1/7 Hadengue, RCT 6/9 2 2 ND 0/9 Solanki, RCT T: 5/ nd 5/12 P: 0/12 Sanyal, RCT T+A: 19/ /56À A: 7/56 27/56À Total 154/ /251 43/ C, ase report; R, retrospetive; PU, prospetive unontrolled; PC, prospetive ontrolled; RCT, randomised ontrolled trial; ND, not determined. *Suess rate of therapy means partial or omplete response in terms of renal funtion. T+A, terlipressin+albumin; T, terlipressin; P, plaebo; A, albumin. ÀSurvival was reported at 60 days. available on the use of terlipressin in type-1 HRS. They inlude four RCTs, and many pilot or retrospetive studies. These studies show that: (a) although GFR rarely reahes normal levels, a short period of treatment with terlipressin improves renal funtion in up to 65% of patients with type-1 HRS; (b) the effetiveness of terlipressin is probably enhaned by albumin; 49 () HRS reurs after treatment withdrawal in approximately 20% of patients, but re-treatment is often effetive; (d) in most ases, dilutional hyponatraemia assoiated with HRS improves with terlipressin treatment; (e) severe side effets of the treatment are unommon (5 10%). With regards to survival, patients who experiened a omplete reversal of type-1 HRS by terlipressin seem to have improved short-term survival, although the RCT of Sanyal 53 reported similar survival at 60 days of follow-up between patients treated with terlipressin plus albumin and those treated only with albumin. Therefore, the long-term survival of patients with type-1 HRS treated with terlipressin merits further investigation. Nevertheless, using terlipressin to improve renal funtion is an important support resoure for patients inluded on a liver transplant waiting list who develop type-1 HRS. 54 The initial dose of terlipressin in many studies ranged from 0.5 to 1 mg every 4 6 h. This regimen was maintained until reversal of HRS, whih usually ourred within the seond week of treatment In other studies, the initial dose in ases without an early response was inreased up to 2 mg every 4 6h. 49 The daily dose of albumin was generally g, preeded in some studies by a load of 1 g/kg body weight. Some refer to entral venous pressure to establish and titrate albumin doses and to prevent fluid overload. Experiene of using midodrine in patients with type-1 HRS is more limited. To date, there have been two pilot studies In both, midodrine was ombined with otreotide to enhane the effet of splanhni vasoonstrition, but doses and routes of administration were quite different. Angeli et al 50 used mg of oral or intravenous midodrine three times a day plus mg of subutaneous otreotide three times a day, whereas Wong et al 51 used 2.5 mg of oral midodrine three times a day plus an intravenous infusion of otreotide (25 mg/h after a bolus of 25 mg). The dose of midodrine was adjusted to inrease mean arterial pressure to 90 mm Hg. Albumin was also administered to patients in these studies. The results are similar to those observed with terlipressin, although the response was slower. Sine otreotide alone had no impat on GFR in patients with HRS, 55 it is likely that midodrine plays the main role in improving GFR. A pilot study has also explored the effet of norepinephrine infusion (0.5 3 mg/h) ombined with albumin and furosemide in type-1 HRS. 56 The doses were titrated to inrease mean arterial pressure by 10 mm Hg. Reversal of HRS was ahieved in 10 out of 12 ases and was assoiated with improvement in urinary sodium exretion and derease in PRA. Norepinephrine is heaper and more widely available than terlipressin, but it is thought to have a greater propensity to indue ardia arrhythmias. Therefore, the role of norepinephrine in patients with type-1 HRS still needs to be established on the basis of future omparisons with terlipressin or midodrine/otreotide. Only a few patients with type-2 HRS have been speifially treated using terlipressin and albumin. 33 In most ases, normalisation of serum reatinine was observed, but, in ontrast to type-1 HRS, renal failure invariably reurred after treatment withdrawal. Transjugular intrahepati portosystemi stent-shunt Only a few studies have assessed the role of TIPS in HRS 91 patients in total. Most were prospetive but unontrolled studies Three were performed in patients with type- 1 HRS, one in patients with type-1 or type-2 HRS, 57 and the last speifially investigated type-2 HRS. 58 The following an be observed: (a) signifiant suppression of the endogenous vasoative systems, partiularly the renin angiotensin system, 35 and a

5 1314 derease of reatinine levels were reorded after TIPS in most patients with type-1 HRS. The rate of the reatinine derease was slower than is usually obtained using terlipressin plus albumin; (b) reurrene of HRS was rare, provided that there was no shunt malfuntion; () hepati enephalopathy was a frequent ompliation of TIPS but was adequately managed by medial treatment; (d) TIPS almost always indued a redution of asites volume; (e) resolution of type-1 HRS by TIPS an improve survival; (f) sequential treatment with vasoonstritors and albumin followed by TIPS ould be used as an alternative approah to inreasing the probability of long-term suess; 51 (g) although TIPS may improve renal funtion and refratory asites in patients with type-2 HRS, its effet on survival is still undefined. However, sine almost all studies exluded patients with a history of severe enephalopathy, serum bilirubin levels.85 mmol/l (5 mg/dl), or Child Pugh sore.12, the appliability of TIPS may be rather limited in patients with HRS who frequently show jaundie, enephalopathy and high Child Pugh sores. 59 There has been little investigation into the mehanism through whih TIPS exerts benefiial effets in patients with HRS. Nevertheless, as TIPS funtions as a side-to-side portoaval shunt, it is expeted to relieve portal hypertension, whih plays a pivotal role in the pathogenesis of splanhni arterial vasodilatation. 60 Moreover, TIPS insertion is assoiated with an inrease in ardia output and an expansion in entral blood volume The simultaneous effets on the splanhni and systemi irulation may represent the mehanism by whih TIPS improves renal perfusion, GFR, urine sodium and water exretion, and hyponatraemia. 63 Extraorporeal albumin dialysis (ECAD) This proedure uses a ell-free albumin-ontaining dialysate that is re-irulated and perfused through haroal and anion exhange olumns (moleular adsorbent reyling system (MARS)). The system is also onneted to a haemodialysis or haemoperfusion apparatus. ECAD enables the removal of albumin-bound substanes, inluding bilirubin, bile aids, aromati amino aids, medium hain fatty aids and ytokines. 64 There are few data available for ECAD in irrhoti patients with HRS, and these data are ontroversial ECAD dereases serum reatinine levels, but it is not definitively known whether or not this effet is due to a true improvement of renal funtion or simply to the filtration proess. A few studies reported that systemi haemodynamis improved during ECAD, indiated by an inrease in arterial pressure and systemi vasular resistanes, and a derease in ardia output, PRA and norepinephrine levels. However, studies regarding the effet of ECAD on survival in patients with type-1 HRS inluded too few patients to draw any definite onlusions Moreover, ECAD is a very expensive proedure and should still therefore be onsidered experimental. Liver transplantation in patients with HRS Liver transplantation was the only effetive therapy for patients with HRS before the introdution of vasoonstritors and TIPS, and is still the treatment of hoie for these patients Further impairment in GFR may be observed immediately after liver transplantation, and many patients require long-term dialysis (35% of transplanted patients with HRS vs 5% of transplanted patients without HRS) As alineurin inhibitors (ilosporin and tarolimus) may ontribute to GFR impairment, it is suggested to delay their administration until a partial reovery of renal funtion is reorded, usually h after transplantation. After this early impairment, GFR starts to improve until an average value of ml/min is reahed 1 2 months postoperatively. This moderate renal failure persists during the follow-up and is probably due to an enhaned nephrotoxi effet of alineurin inhibitors in patients with pretransplant renal impairment. In fat, the haemodynami and neurohormonal abnormalities assoiated with HRS disappear within the first month after transplantation, and the patients regain their ability to exrete sodium and free water. 72 Patients with HRS who undergo liver transplantation tend to have more ompliations, spend more days in intensive are units and have higher in-hospital mortality rates than liver transplant patients without HRS. However, their 3-year probability of survival is aeptable (60% vs 70 80% in liver transplant patients without HRS). 70 The main limitation of liver transplantation is that due to the shortage of donor organs, and their extremely short survival, most patients with type-1 HRS die before transplantation. The introdution of the model of end-stage liver disease (MELD) for organ prioritisation has partially solved this problem, sine patients with HRS are generally given high priority on the waiting list. On the other hand, treatment of type-1 HRS with vasoonstritors and albumin (see above) an improve patient survival, and therefore improve their probability of being transplanted. In one non-randomised pilot study, reversal of type-1 HRS using terlipressin and albumin was assoiated with redution in early morbidity and mortality after liver transplantation. 54 CONCLUSIONS OF THE CONSENSUS WORKSHOP Improved knowledge of the mehanisms underlying HRS and the development of new treatment strategies are the reasons for Effetive treatments of type-1 HRS Albumin infusion may prevent HRS in patients with SBP. Vasoonstritors and albumin are reommended as the first line of treatment for type-1 HRS. Terlipressin is the most widely used vasoonstritor. Midodrine+otreotide and norepinephrine are two possible alternatives requiring further linial evaluation. With the use of terlipressin (2 12 mg/day) and albumin (20 40 g/day after 1 g/kg on the first day), about 60% of renal failure ases reover. The improvement of survival using only vasoonstritors and albumin seems rather limited. TIPS is an alternative treatment in suitable patients, espeially in those who do not show a omplete response to vasoonstritors, but it an also be used in patients who show a omplete serum reatinine response to eliminate asites and to maintain normal renal funtion. Liver transplantation is the only treatment that assures longterm survival. Pharmaologial treatment and TIPS an bridge the time to liver transplantation and improve post-transplant survival.

6 the new onsensus on definition, diagnosti riteria and HRS treatment modalities organised by the International Asites Club. New definition of HRS HRS is a potentially reversible syndrome that ours in patients with irrhosis, asites and liver failure, as well as in patients with aute liver failure or aloholi hepatitis. It is haraterised by impaired renal funtion, marked alterations in ardiovasular funtion and overativity of the sympatheti nervous and renin angiotensin systems. Severe renal vasoonstrition leads to a derease of GFR. There are two types of HRS. Type-2 HRS is haraterised by moderate renal failure (serum reatinine from 133 to 226 mmol/l or from 1.5 to 2.5 mg/dl), with a steady or slowly progressive ourse. It appears spontaneously, but an also follow a preipitating event. Type-2 HRS is typially assoiated with refratory asites. Survival of patients with type-2 HRS is shorter than that of non-azotaemi irrhoti patients with asites but better than that of patients with type-1 HRS (fig 2). 75 Type-1 HRS is haraterised by rapid progressive renal failure defined by doubling of the initial serum reatinine onentrations to a level greater than 226 mmol/l (2.5 mg/dl) in less than 2 weeks. It may appear spontaneously, but often develops after a preipitating event, partiularly SBP. Type-1 HRS usually ours within the setting of an aute deterioration of irulatory funtion haraterised by arterial hypotension and ativation of endogenous vasoonstritor systems, and may be assoiated with impaired ardia and liver funtions as well as enephalopathy. The natural prognosis of type-1 HRS is very poor (fig 2). The main differenes from the definition reported in are: (a) the potential reversibility of HRS without liver transplantation; (b) the dominant role of the splanhni bed in arterial vasodilatation; () the frequent role of SBP as an event preipitating type-1 HRS; (d) the onept that in addition to renal failure the funtion of other organs, partiularly the heart, is frequently impaired. Revised diagnosti riteria of HRS As there are no speifi hallmarks of HRS, the diagnosis is based on the exlusion of other types of renal failure. The riteria neessary to diagnose HRS are reported in the box below. The main differenes between these riteria and those previously established 5 are: (a) reatinine learane has been exluded beause it is more ompliated than simple serum reatinine for routine purposes, and it does not inrease the auray of renal funtion estimation in irrhoti patients; 76 (b) renal failure in the setting of ongoing baterial infetion, but in the absene of septi shok, is now onsidered HRS. This means treatment of HRS an be started without waiting for omplete reovery from the infetion; () plasma volume expansion should be performed with albumin rather than saline. Members of the panel agreed that albumin auses a greater and more sustained expansion than saline; (d) minor diagnosti riteria have been removed as they are not essential. Treatments of HRS Most data urrently available on HRS treatments ome from retrospetive analyses, pilot studies, non-randomised omparative studies and only a few RCTs. Furthermore, most studies have inluded too few patients. Therefore, onepts and pratial reommendations given in this part of the artile are based on both published data and the personal experiene of the panelists, and may be improved upon by further experiene gained in the future Prevention of HRS The inidene of HRS in patients with SBP may be redued by albumin administration, prevention whih was assoiated with improved survival. The suggested dose of albumin is 1.5 g/kg body weight on the first day and 1 g/kg body weight on the third day, up to a maximum of 150 and 100 g, respetively. Albumin administration is learly indiated for patients with SBP and serum bilirubin levels.68.4 mmol/l (4 mg/dl) or 1315 Figure 2 Atuarial probability to survive in irrhoti patients with different renal impairments: non-azotaemi patients (ontinuous line); patients with hepati renal syndrome (HRS) type-2 (dotted line) and patients with HRS type-1 (red line). Adapted from Alessandria et al 75. New diagnosti hepatorenal syndrome riteria in irrhosis Cirrhosis with asites. Serum reatinine.133 mmol/l (1.5 mg/dl). No improvement of serum reatinine (derease to a level of (133 mmol/l) after at least 2 days with diureti withdrawal and volume expansion with albumin. The reommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day. Absene of shok. No urrent or reent treatment with nephrotoxi drugs. Absene of parenhymal kidney disease as indiated by proteinuria.500 mg/day, mirohaematuria (.50 red blood ells per high power field) and/or abnormal renal ultrasonography.

7 1316 serum reatinine levels.88.4 mmol/l (1 mg/dl). Future studies are neessary to define better optimal doses of albumin and the subgroup of patients for whom treatment is highly indiated. Effetive treatments of HRS Liver transplantation This is the treatment of hoie for both type-1 and type-2 HRS. Morbidity after liver transplantation is higher in patients with HRS than in those without HRS, 74 although the long-term probability of survival is only slightly lower. Reversal of type-1 HRS by pharmaologial treatment before liver transplantation may improve survival after transplantation. The redution in serum reatinine levels after treatment and the related derease in the MELD sore should not hange the deision to perform liver transplantation sine the prognosis after reovering from type-1 HRS is still very poor. Pharmaologial treatment with vasoonstritors Studies on the pharmaologial treatment of HRS have mainly been performed in patients with type-1 HRS. Terlipressin is the most widely studied ompound. It should be started at mg every 4 6 h. If there is no early response (.25% derease in reatinine levels after 2 days), the dose an be doubled every 2 days up to a maximum of 12 mg/day. Treatment an be stopped if serum reatinine does not derease by at least 50% after 7 days of the highest dose, or if there is no redution after the first 3 days. In patients with early response, treatment should be extended until reversal of HRS (see text box) or for a maximum of 14 days. Terlipressin may indue ishaemi side effets and arrhythmias requiring drug disontinuation. 33 Other vasoonstritors tested in HRS are midodrine, in ombination with otreotide, or norepinephrine. The shedules for midodrine and otreotide and those of norepinephrine are reported above. In addition to reatinine levels being useful in adjusting the doses of these vasoonstritors, blood pressure, renal water and sodium exretion, and serum sodium levels may also be helpful. The administration of albumin may improve the effet of vasoonstritors. In the absene of dose/effet studies, the dose of albumin reommended is 1 g/kg of body weight on the first day, up to a maximum of 100 g, followed by g/day. Albumin may be disontinued if serum albumin onentration is.45 g/l and should be withdrawn in the ase of pulmonary oedema. Sine this ompliation is unommon, atheterisation to monitor entral venous pressure is not mandatory, but Types of response to treatment using vasoonstritors Complete response (reversal of HRS): derease of serum reatinine to below 133 mmol/l (1.5 mg/dl). Relapse of HRS: reurrene of renal failure (reatinine.133 mmol/l (1.5 mg/dl)) after disontinuation of therapy. Partial response: derease in serum reatinine to >50% of its pre-treatment value, without reahing a level below 133 mmol/l (1.5 mg/dl). No response: no derease of serum reatinine or derease to,50% of its pre-treatment value, with a final level above 133 mmol/l (1.5 mg/dl. areful physial and radiologial monitoring of the ardiopulmonary funtion is reommended. As reported in the text box, three types of response to treatment with vasoonstritors and albumin an be observed. Complete response ours in approximately 60% of patients treated with terlipressin and an improve survival. Renal failure may reur after disontinuation of therapy (relapse), but retreatment is usually effetive. In ontrast, partial response is frequently followed by a severe and irreversible relapse of renal failure. TIPS The small amount of data on the use of TIPS in HRS shows that it improves renal funtion and eliminates asites. In patients with type-1 HRS, TIPS may also improve survival, but this is debatable in patients with type-2 HRS. The major disadvantage of TIPS is its low appliability. Indeed, it should not be used in patients with serum bilirubin levels.85.5 mmol/l (5 mg/dl), severe enephalopathy or history of reurrent enephalopathy, severe baterial infetion, serious ardia or pulmonary dysfuntion or a Child Pugh sore.11. Final reommendations for the treatment of patients with HRS Type-1 HRS The first line of therapy is the use of vasoonstritors ombined with albumin. Patients with partial or no response to vasoonstritors may be treated with TIPS. If there are ontra-indiations to TIPS, ECAD ould be used in the setting of prospetive trials. The sequential use of vasoonstritors plus albumin and TIPS in suitable patients is an interesting idea deserving further investigation. Type-2 HRS There are no definite data to support the use of vasoonstritors in these patients. TIPS an be used to improve refratory asites, whih is often assoiated with type-2 HRS. Data on the effet of TIPS on survival are still insuffiient. ACKNOWLEDGEMENTS Experts who partiipated to the four panels for the preparation of the onsensus were the following: (a) Evidene-based pathogenesis of HRS: hairman: P Gines (Spain), panelists: G di Bona (USA), S Lee (Canada), J H Henriksen (Denmark), L Ruiz del Arbol (Spain), F Wong (Canada). (b) Treatment with vasoonstritors: hairman: A Gerbes (Germany), panelists: P Angeli (Italy), G Garia-Tsao (USA), V Gülberg (Germany), M Guevara (Spain), R Moreau (Frane), R Ortega (Colombia). () Treatment with other resoures: hairman: F Wong (Canada), panelists: P Kamath (USA), K Moore (UK), K Mullen (USA), F Salerno (Italy), A Sanyal (USA). (d) Definitions, diagnosti riteria and reommendations: hairman V Arroyo (Spain), panelists: M Bernardi (Italy), L Blendis (Israel), G Garia-Tsao (USA), R Terg (Argentina).... Authors affiliations Franeso Salerno, Department of Internal Mediine, Polilinio IRCCS San Donato, University of Milan, Via Morandi, 30, San Donato (MI), Italy Alexander Gerbes, Department of Internal Mediine II, Klinikum of the Ludwig-Maximilians-University/Großhadern, University of Munih, Germany Pere Ginès, Viente Arroyo, Liver Unit, Hospital Clini, University of Barelona, Spain

8 Florene Wong, Department of Mediine, Division of Gastroenterology, Toronto General Hospital, University of Toronto, Canada Funding: The work of P Ginès in this projet was supported by a grant from the Fondo de Investigaion sanitaria (Fis 05/246). The work of F Salerno in this projet was supported by a grant of Ministero della Università Italiana (FIRST 2005). Competing interests: None. REFERENCES 1 Ginès P, Guevara M, Arroyo V, et al. Hepatorenal syndrome. Lanet 2003;362: O Grady JG. Clinial disorders of renal funtion in aute liver failure. In: Gines P, Arroyo V, Rodes J, Shrier RW, eds. Asites and renal dysfuntion in liver disease.2nd edn. Oxford: Blakwell Publishing, 2005: Ginès A, Esorsell A, Ginès P, et al. Inidene, preditive fators, and prognosis of hepatorenal syndrome in irrhosis with asites. Gastroenterology 1993;105: Dagher L, Moore K. The hepatorenal syndrome. Gut 2001;49: Arroyo V, Gines P, Gerbes A, et al. 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Terlipressin and albumin ombination treatment in hepatorenal syndrome. Hepatogastroenterology. 2003;50: iii v, (Suppl 2). 83 Mulkay JP, Louis H, Donkier V, et al. Long-term terlipressin administration improves renal funtion in irrhoti patients with type 1 hepatorenal syndrome: a pilot study. Ata Gastroenterol Belg 2001;64: Angeli P, Guarda S, Fasolato S, et al. Swith therapy with iprofloxain vs. intravenous eftazidime in the treatment of spontaneous baterial peritonitis in patients with irrhosis: similar effiay at lower ost, Aliment Pharmaol Ther 2006;23: bmjupdates+ bmjupdates+ is a unique and free alerting servie, designed to keep you up to date with the medial literature that is truly important to your pratie. bmjupdates+ will alert you to important new researh and will provide you with the best new evidene onerning important advanes in health are, tailored to your medial interests and time demands. 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10 Diagnosis, prevention and treatment of hepatorenal syndrome in irrhosis Franeso Salerno, Alexander Gerbes, Pere Ginès, et al. Gut : originally published online Marh 27, 2007 doi: /gut Updated information and servies an be found at: Referenes alerting servie These inlude: This artile ites 80 artiles, 8 of whih an be aessed free at: Artile ited in: Reeive free alerts when new artiles ite this artile. Sign up in the box at the top right orner of the online artile. Topi Colletions Artiles on similar topis an be found in the following olletions GUT Reent advanes in linial pratie (47 artiles) Notes To request permissions go to: To order reprints go to: To subsribe to BMJ go to: