Curr Treat Options Gastro DOI 10.1007/s11938-015-0050-2

Liver (J Bajaj, Section Editor)

Treatment to Improve Acute Kidney Injury in Cirrhosis Florence Wong, MBBS, MD, FRACP, FRCPC Address Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada Email: [email protected]

* Springer Science+Business Media, LLC 2015

This article is part of the Topical Collection on Liver Keywords Albumin I Acute kidney injury I Hepatorenal syndrome I Liver transplantation I Terlipressin I Vasoconstrictors

Opinion statement Acute kidney injury (AKI) is an ominous complication of decompensated cirrhosis, which can be fatal if not treated promptly. It is important that clinicians recognize that AKI has occurred and institute timely treatment. Recent establishment of diagnostic criteria and treatment guidelines are most useful, and these will be further refined as treatments are being modified to improve patient outcome. To manage such a patient, firstly, the cause of the AKI needs to be identified and any precipitating factors corrected. Bacterial infections are a common cause of AKI in cirrhosis, and it is recommended to offer empirical antibiotics in cases of suspicious bacterial infection until all the cultures are negative. Patients should be given albumin infusion in doses of 1 g/kg of body weight for at least 2 days. This can improve the filling of the central circulation, and also absorb many of the bacterial products or inflammatory cytokines that play a role in mediating the renal dysfunction. Often, albumin infusion alone may be sufficient to reverse the AKI. For patients who have acute or type 1 hepatorenal syndrome (HRS1), which is a special form of AKI, pharmacotherapy in the form of vasoconstrictor will be needed. The vasoconstrictor can be terlipressin, norepinephrine, or midodrine, depending on the local availability of drugs or facilities. Currently, approximately 40 % of patients will respond to a combination of vasoconstrictor and albumin. All patients with HRS1 should be assessed for liver transplant. If accepted for liver transplantation, those patients who do not respond to vasocontrictors and albumin need to be started on renal replacement therapy, which otherwise has no place in the treatment of HRS1. Once listed, liver transplantation should occur promptly, preferable under 2 weeks. Otherwise, the chances for renal recovery after liver transplant are significantly reduced, necessitating a renal transplant at the future date.

Liver (J Bajaj, Section Editor)

Introduction Acute renal failure is a common complication of advanced liver cirrhosis, estimated to occur in 19 % of all hospitalized cirrhotic patients with decompensation [1]. The etiology of acute renal failure can be broadly divided into those resulting from structural renal diseases, such as acute tubular necrosis, glomerulo-nephritis, or interstitial nephritis and functional renal failure related to

hemodynamic changes particular to advanced cirrhosis. While the diagnosis and treatment of acute structural renal diseases are fairly standard, the diagnosis of acute functional renal failure has undergone considerable changes in recent times, and this has significant implications for the management of the condition in these patients.

The Diagnosis of Acute Kidney Injury and Hepatorenal Syndrome Hepatorenal syndrome (HRS) is perhaps the best known form of acute functional renal failure in cirrhosis. The diagnostic criteria of HRS were set down by the International Ascites Club (IAC) in 1996 [2] and then further modified in 2007 [3]. Acute or type 1 HRS (HRS1) is diagnosed when there has been an acute increase in the serum creatinine defined by a doubling of the serum creatinine in less than 2 weeks. Furthermore, the final serum creatinine has to be at least 2.5 mg/dL (226 μmol/L) [3]. However, with the recent advances in the understanding of the pathophysiology of HRS, and the improved treatments that have evolved from the new knowledge, many investigators have realized that patients with HRS1 are not well served by these rigid diagnostic criteria, as they have to delay treatment until these diagnostic criteria are met [4•]. Therefore, many academic organizations have begun to gather evidence to support redefining the diagnostic criteria for acute renal failure in cirrhosis, especially since smaller changes such as a 0.3 mg/dL (26.4 µmol/L) increase in serum creatinine have been associated with poorer clinical outcome in some patient populations [5]. Expertise is borrowed from the specialties of nephrology and intensive care and adapted for the use in the cirrhotic population. The term acute renal failure is also changed to acute kidney injury (AKI), in line with the nomenclature used in the nephrology community. Several sets of AKI diagnostic criteria have been assessed to determine their applicability to the cirrhotic population. These include the Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Renal Disease (RIFLE) criteria [6], the Acute Kidney Injury Network (AKIN) criteria [7], and the Kidney Disease, Improving Global Outcome (KDIGO) criteria [8]. All of these set forth the diagnostic criteria for AKI based on either a percentage change in the glomerular filtration rate [6], or an absolute or percentage change of the serum creatinine [7, 8], together with a change in the quantity of urine produced. In addition, staging of AKI is also defined, which allows the severity of the AKI to be described. However, all of these various criteria have their drawbacks. For example, a well-defined baseline serum creatinine is essential in order to calculate either a percentage change or an absolute change, and this is missing in all of these diagnostic criteria. Furthermore, the RIFLE criteria allow for the backcalculation of the baseline glomerular filtration rate, which has its own inherent errors. Therefore, the IAC and the Acute Dialysis Quality Initiative (ADQI) proposed to simplify the diagnosis of AKI in cirrhosis by just using the change in

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serum creatinine [9]. This is because decompensated cirrhotic patients who are predisposed to develop AKI usually have avid sodium and water retention, and hence reduced urine output. Therefore, the proposed AKI diagnostic criteria suggest that they should not incorporate measures of urine output, as this will be difficult in cirrhotic patients with baseline low urine output. Acute kidney injury as defined by IAC and ADQI requires an increase in serum creatinine by either 0.3 mg/dL (26.4 μmol/L) within 48 h or by 50 % from baseline, with the baseline creatinine defined as any stable serum creatinine within the previous 6 months [9]. No staging was proposed with these initial criteria. These diagnostic criteria therefore allow AKI to be diagnosed with a much smaller increase in serum creatinine, thereby allowing the institution of appropriate therapies before the renal dysfunction is too advanced. When applied to decompensated cirrhotic patients in both outpatient [10] and inpatient [11•] settings, these diagnostic criteria were able to predict patient outcome, especially with respect to survival. However, AKI may progress once established. Recognizing that the progression of AKI is associated with a worse prognosis [12•], the IAC further proposes to include staging as part of the diagnostic criteria of AKI in cirrhosis [13••]. Continued increase in serum creatinine by set amounts is defined as progression in AKI stages, while a reduction in serum creatinine with treatment is defined as regression in AKI stages (Table 1). These changes in stages of AKI therefore allow better prognostication of these patients.

Spectrum of Acute Kidney Injury in Cirrhosis The separation of various etiologies of AKI into structural and functional cases of AKI has helped to conceptualize these conditions as different entities with very different treatments. However, recent evidence suggests that the two categories of AKI may not be as discrete as previously represented. For example, although HRS is the prototype of functional AKI, the result of extreme renal vasoconstriction secondary to systemic arterial vasodilatation with consequent activation of various vasoconstrictor systems [14], prolonged duration of HRS has been associated with renal tubular damage [15]. The recognition that a significant proportion of patient with functional AKI also have the systemic inflammatory response syndrome (SIRS) [16] has led to the proposal that inflammatory mediators may be responsible for the renal structural damage observed in cases of functional AKI [17••]. The presence of a bacterial infection in decompensated cirrhosis often triggers the development of AKI. This is related to further disturbance of the tenuous hemodynamic status, causing further reduction in renal perfusion and renal ischemia, predisposing these patients to the development of AKI. Bacterial infections are also associated with an intense SIRS. Abundant inflammatory mediators derived from the bacteria and activated immune cells can also trigger changes in epithelial and parenchymal cells [18]. In the kidneys, these inflammatory mediators or damage/ pathogen associated molecular patterns (DAMPs/PAMPs) arrive via glomerular filtration as well as through the peritubular capillaries. Alterations in the microcirculation of the kidney means that the renal tubules have prolonged exposure to these DAMPs and PAMPs, which in turn cause oxidative stress and

Liver (J Bajaj, Section Editor)

Table 1. Proposed definitions when assessing patients with cirrhosis and acute kidney injury Definition Acute kidney injury (AKI) Baseline serum creatinine Staging of AKI Stage 1 Stage 2 Stage 3

Changing stages of AKI Progression Regression Response to treatment No response Partial response Complete response

Increase in serum creatinine by ≥0.3 mg/dL (26.4 μmol/L) in ≤48 h or an increase in serum creatinine by ≥50 % from its stable baseline value in the last 3 months A stable serum creatinine within the past 3 months (at least two similar readings are needed to ensure stability). If no historical serum creatinine is available, the serum creatinine on admission to hospital should be used Increase in serum creatinine ≥0.3 mg/dL (26.4 μmol/L) or an increase in serum creatinine by ≥1.5 to 2-fold from baseline Increase in serum creatinine by 92 to 3-fold from baseline Increase in serum creatinine by 93-fold from baseline; or a serum creatinine of 94 mg/dL (352 μmol/L) with an acute increase of 90.3 mg/dL; or the need to start renal replacement therapy Increase in AKI stage or need for renal replacement therapy Reduction of AKI stage No change in AKI stage Regression of AKI stage to a serum creatinine of 90.3 mg/dL (26.4 μmol/L) of baseline Regression of AKI stage to a serum creatinine of ≤0.3 mg/dL (26.4 μmol/L) of baseline

Modified from [13••] AKI acute kidney injury

tubular damage [19•]. Clinically, infection-associated AKI occurs more often than classical HRS [20]. The histological findings in the kidneys of infectionassociated AKI are also different from those of classical HRS [21]. However, progression of infection-associated AKI may make it indistinguishable from classical HRS clinically. Likewise, prolonged classical HRS with tubular damage may be difficult to differentiate from cases of acute tubular necrosis. Thus, blurring of these different causes of AKI will have some implications on how we approach the management of these conditions.

Treatment of Acute Kidney Injury in Cirrhosis General Measures As AKI in cirrhosis may have many causes, it is imperative that the etiology of AKI is clearly defined before appropriate treatment can be applied [22]. Therefore, one needs to exclude AKI due to parenchymal renal disease by assessing for proteinuria and hematuria. Nephrotoxic drugs or radiographic dye induced nephropathy also need to be ruled out. Once excluded, the cause of functional AKI needs to be identified. As functional AKI is frequently precipitated by an acute event that perturbs the hemodynamics of the patient with advanced cirrhosis, these need to be sought and corrected. Measures such as withdrawal of diuretics and appropriate fluid replacement will have to be given to patients with acute volume loss from over diuresis, large volume paracentesis without intravascular volume replacement, or gastrointestinal blood loss. An infection that causes worsening of the vasodilatory state of the systemic and splanchnic

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hemodynamics will need to be treated with the appropriate antibiotics. Frequently, the AKI will resolve once the precipitant is dealt with. For those AKI events that do not have a clear precipitant, or those with a precipitant that have not improved with corrective measures, the IAC recommends a volume challenge using colloid solutions such as albumin [3]. This may bring about an improvement of renal function. For those patients whose AKI does not reverse with the above measures, and structural renal diseases have been excluded, consideration will need to be given to administer vasoconstrictor therapy. The aim of AKI therapy is to return the renal function back to baseline level.

Albumin Albumin is frequently used in patients with decompensated cirrhosis and AKI. In healthy individuals, albumin constitutes about 60 % of the plasma proteins. It is a negatively charged molecule and therefore it attracts sodium and this in turn retains water, thereby providing the oncotic pressure [23]. In addition, albumin has a free cysteine moiety at position 34 (cys-34), which is responsible for the anti-oxidant and scavenging properties of albumin [24]. Thus, albumin is also useful in absorbing many unwanted molecules such as proinflammatory cytokines, bacterial products, and reactive oxygen species [25••], thereby reducing the potentially damaging effects of these molecules. In decompensated cirrhosis, both the metabolism and function of albumin are abnormal [25••]. Firstly, the synthesis of albumin in hepatocytes is reduced, partly related to liver dysfunction, and partly related to the presence of systemic inflammation, which is inherent in the decompensated state [26, 27]. Furthermore, the presence of various inflammatory cytokines, especially in those with infection, will increase the rate of albumin catabolism [23]. Therefore, hypoalbuminemia is not uncommon in patients with decompensated cirrhosis. In addition, the circulating albumin in these patients may not have full functional capabilities. The increased oxidative stress that is frequently observed in decompensated cirrhosis means that more of the circulating albumin exists in an oxidized rather than a reduced form, thereby reducing the ability of the albumin molecule to bind free radicals and perform its scavenger and detoxification functions [28, 29, 30•]. This has led to the concept that the Beffective albumin concentration^ is really less than the serum concentration of albumin [24], leaving the decompensated cirrhotic patient vulnerable to the potential damaging effects of systemic inflammation. Consequently, the concept of replenishing the circulating pool of albumin with infusions of human albumin to compensate for these deficiencies has attracted a lot of attention. In the assessment of patients with AKI, it is the volume expanding property of albumin that is used to determine whether the renal dysfunction is volume responsive or not. The IAC recommends that albumin should be given at a dose of 1 g/kg of body weight up to a maximum daily dose of 100 g for at least 2 days [3]. Patients who are volume responsive have pre-renal causes of AKI, while patients whose renal function does not improve with albumin infusion are likely to have HRS1 if their serum creatinine remains above 2.5 mg/dL (226 μmol/L) [3]. Although in HRS1, albumin alone does not seem to be able to improve renal function [31, 32], yet the addition of albumin enhances the beneficial effects of vasoconstrictor therapy [33]. This is likely related to the antioxidant, immune modulating and endothelial stabilizing effects of albumin. In

Liver (J Bajaj, Section Editor) patients with AKI related to acute-on-chronic liver failure (ACLF), some of whom did not quite fulfill the diagnosis of HRS1, the infusion of 40–60 g of human albumin/day for 3–4 days resulted in improvement of renal blood flow as well as renal function [34]. Interestingly, the increase in renal blood flow was not associated with any change in renal perfusion pressure. Rather, it was associated with a significant reduction in sympathetic activity as indicated by a marked decrease in plasma norepinephrine. Therefore, better filling of the intravascular volume as a result of albumin’s oncotic power has led to a suppression of the activity of the compensatory vasoconstrictor systems including the sympathetic nervous system. The fact that there was a significant correlation between the reduction in endothelial activation and improvement in renal blood flow [34] suggests that the endothelial stabilizing effect of albumin on the microcirculation [35] has also contributed to the improvement in renal blood flow. As we improve our understanding of the many functions of albumin, the role of albumin in the management of AKI may also expand.

Vasoconstrictors Vasoconstrictors are the mainstay of treatment for HRS1 in cirrhosis but have not been tried in other forms of functional AKI that do not fulfill the diagnostic criteria of HRS. Systemic vasoconstrictors such as midodrine and norepinephrine increase the mean arterial pressure and therefore will improve the renal perfusion pressure, whereas splanchnic vasoconstrictors such as terlipressin and other vasopressin analogs will transfer part of the splanchnic vascular volume to the central circulation, thereby improving the filling of the central compartment and reduce the compensatory activation of the systemic vasoconstrictors, which in turn will improve the renal perfusion and the renal circulation.

Terlipressin Three pivotal randomized control trials, two published as full papers [32, 36], and one in abstract form [37•] have assessed the effect of bolus doses of terlipressin plus albumin versus either albumin alone [32] or versus placebo with or without albumin [36, 37•] in the treatment of patients with HRS1. All three studies showed that terlipressin was able to significantly improve but not normalize renal function after treatment for up to 14 days. Reversal of HRS1 only occurred in 24–44 % of patients (Fig. 1). Despite the fact that improvement of renal function was associated with improved survival [37•], the overall survival of the terlipressin group was no different to that in the control group in all three studies, because many patients in the terlipressin group did not have reversal of their HRS1. However, when a meta-analysis was performed on all the published papers on the use of terlipressin as a treatment for HRS1, there was a significant reduction of mortality by 29 % [38]. More recently, terlipressin was administered to a specific group of patients with infection-associated AKI [39]. These patients were indistinguishable from those with classical HRS1 apart from the presence of an infection. Twelve of the eighteen patients responded with reduction of their serum creatinine falling below 1.5 mg/dL (133 μmol/L) by the latest on day 9 of treatment. Reversal of AKI was dependent on infection resolution, and an increase in mean arterial pressure with treatment, suggesting that reduction in inflammation and improvement in circulatory dysfunction are both important in contributing to renal recovery.

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Fig. 1. Frequency of reversal of hepatorenal syndrome type 1 with terlipressin plus albumin versus albumin alone [32] or versus placebo with or without albumin [36, 37•].

Although terlipressin is generally considered to be safe, it is after all a vasoconstrictor, and therefore its use is associated with vasoconstriction in many vascular territories. The overall incidence of side effects is approximately 30 % and these include abdominal cramps, diarrhea, possibly representing splanchnic ischemia, mild cyanosis in fingers and toes, and occasionally arrhythmia representing cardiac ischemia [40]. Therefore, some investigators prefer to use a continuous infusion rather than bolus doses of terlipressin, as this provides an overall lower daily dose with significantly less ischemic side effects, without compromising on efficacy [41, 42]. Given the fact that not all patients treated with terlipressin responded with a reduction in serum creatinine, various investigators explored the possibility of identifying biomarkers that could predict a renal response to terlipressin. Nazar et al. reported that a response to terlipressin with a reduction of serum creatinine to G1.5 mg/dL (133 μmol/L) was only observed in patients with a baseline serum bilirubin of G10 mg/dL (170 μmol/L), and a rise in mean arterial pressure by at least 5 mmHg on day 3 of treatment [43]. Boyer et al. also found that improvement in the systemic hemodynamics was an important predictive factor for the response to terlipressin [44]. In addition, patients whose baseline serum creatinine was ≥5 mg/dL (440 μmol/L) were unlikely to respond to terlipressin. All these suggest that pharmacological therapy for HRS1 should not be given to patients who have severe liver dysfunction as indicated by a high serum bilirubin or those with severe renal dysfunction, as their overall condition is so poor that they are unlikely to benefit from vasoconstrictor therapy.

Norepinephrine To date, there have been four studies assessing the efficacy of norepinephrine versus terlipressin in the treatment of patients with HRS1. However, only two of these studies included a homogenous population of HRS1 patients, totalling 86 patients [45, 46]. Despite the small number of patients, the authors from both studies were able to demonstrate that norepinephrine had the same efficacy and side effect profile as terlipressin. Furthermore, the 30-day mortality was similar between norepinephrine and terlipressin [47]. Therefore, in parts of the world

Liver (J Bajaj, Section Editor) such as North America, where terlipressin is not available, norepinephrine could be an alternative treatment for patients with HRS1. The authors of these two studies suggested that norepinephrine should be the preferred drug, as the treatment with norepinephrine only involves a fraction of the cost as that for terlipressin. However, the administration of norepinephrine requires cardiac monitoring in an intensive care setting, whereas that for terlipressin does not, thereby negative the economic advantage of using norepinephrine.

Midodrine Midodrine has gained popularity in North America as the treatment for HRS1 because terlipressin is not yet available. It can improve the mean arterial pressure through it alpha-adrenergic effects. It is actually indicated for the treatment for postural hypertension. It is usually used in combination with octreotide, which is a nonspecific antagonist to various splanchnic vasodilators, and albumin because of its volume expanding property. The combination has been evaluated in various prospective and retrospective studies [48–51]. The general consensus is that the combination does improve renal function, albeit rather slowly. The later studies also showed a significant increased survival compared with no treatment [48, 49]. The American Association for the Study of the Liver suggested the use of a combination of midodrine, octreotide, and albumin as the preferred treatment for HRS1 because of its convenience and minimal side effects [52]. But this combination is likely to be supplanted by terlipressin once it becomes commercially available in North America.

Nonpharmacotherapy Many other nonpharmacological based therapies have been tried as treatment for HRS1. These include the use of molecular adsorbent re-circulating system (MARS), the insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS), and renal replacement therapy (RRT). MARS is a form of dialysis which uses albumin to adsorb various cytokines and bacterial products which are thought to be responsible for maintaining the vasodilatory state of the splanchnic and systemic circulations of advanced cirrhosis. The albumin is cleaned and recycled to adsorb more unwanted molecules, therefore economizing on the use of albumin. Theoretically, by removing these substances, there should be an improvement in overall systemic hemodynamics, thereby leading to an improved renal circulation with consequent recovery of renal function [53]. Indeed, initial studies did show a reduction in serum creatinine with MARS [53, 54]. However, measurement of renal function using clearance techniques revealed that serum creatinine was just being dialyzed out without there being any actual improvement in renal function [55]. MARS is currently not a recommended treatment for HRS1. TIPS is a type of side-to-side portocaval shunt that is very effective in reducing portal hypertension, the initiator of the hemodynamic changes that lead to relative renal ischemia and hence decreased renal function. Therefore, it is not surprising that TIPS would be useful in the management of cirrhotic patients with HRS. Indeed, several studies from more than a decade ago reported on the efficacy of TIPS as a treatment for HRS [56]. Serum creatinine decreased, but it did not normalize in many patients. There was also a suggestion of improved survival compared with no treatment [57].

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However, there have been no reports on the use of TIPS as a treatment for type 1 HRS in recent years, suggesting that this may be a treatment option that is falling out of favor, especially since the use of TIPS is associated with its own set of complications [58]. One of the hemodynamic changes that occur after TIPS is worsening of the systemic arterial vasodilatation with lowering of the systemic arterial blood pressure and consequent reduction in renal perfusion pressure [59]. This has the potential for causing further deterioration of the renal function. Furthermore, TIPS cannot be applied to patients who have compromised liver function, as the relative hepatic ischemia immediately after TIPS insertion can actually precipitate liver failure in patients with baseline severe liver dysfunction. Therefore, the application of TIPS is limited in patients with HRS1. The best candidates for TIPS placement are those patients whose liver function is relatively preserved such as abstinent alcoholics and/or patients who have had their viral hepatitis treated. Pretreatment with pharmacotherapy to improve renal function before TIPS may provide better patient outcome [50]. Renal replacement therapy does not have a role in the management of patients with HRS1 unless there is a potentially reversible component of the underlying liver failure, or the patient is listed for liver transplant [60]. Otherwise, renal replacement therapy will only prolong the inevitable dismal outcome of the patient. Furthermore, patients with HRS1 are usually hemodynamically very unstable, making dialysis difficult.

Liver Transplantation The definitive treatment for HRS1 is liver transplantation, as this eliminates liver dysfunction and portal hypertension, the two main pathophysiological factors that underlie the pathogenesis of HRS1 [14, 17••, 61]. Indeed, many studies have reported the reversal of HRS1 with the serum creatinine falling to G1.5 mg/dL (133 μmol/L) at a period of several weeks after liver transplantation [62, 63, 64•]. Renal recovery is independent of pre-transplant pharmacotherapy [64•, 65, 66] or dialysis [64•, 66]. Older literature reported almost universal recovery of renal function post-transplant [63, 67, 68]. However, more recent literature suggests that the renal recovery rate is approximately 50–75 % [62, 64•]. This may be related to the fact that older studies were performed before the diagnostic criteria for HRS1 were defined [3], and therefore some of those patients might not have had HRS1. The factors predicting nonreversal of HRS1 post liver transplant are not clear, as studies that evaluate whether renal function will improve, stabilize or continue to progress following liver transplantation are few and far between. However, there appears to be a tendency for longer duration of pretransplant renal dysfunction to be predictive of post-transplant nonreversal of HRS [64•, 69, 70]. Current guidelines from The United Network for Organ Sharing have recommended that a dialysis period of more than 8 weeks is an indication for combined liver and kidney transplantation in patients with cirrhosis and HRS1 [71]. The ADQI and the IAC were the two organizations that suggested patients who had a pre-transplant dialysis period of ≥4 weeks should be offered combined

Liver (J Bajaj, Section Editor) liver–kidney transplant based on research of available literature [60]. However, a more recent retrospective study consisting of a homogeneous cohort of HRS1 patients showed that a pre-transplant dialysis period of 914 days was predictive of renal nonrecovery [64•]. In fact, for every day of dialysis received prior to their liver transplant, there is an additional 6 % risk of nonreversal of renal function post liver transplant. Therefore, a duration of 14 days of pre-transplant dialysis may provide a useful cut-off value for the prediction of HRS1 nonreversal with liver transplantation. Of course, this will need to be validated in a prospective study. This nonreversal of HRS may be related to structural changes consequent upon prolonged renal ischemia, as shown by the appearance of various biomarkers of renal tubular damage on day 5 after the diagnosis of HRS1 [72]. In patients who reverse their HRS1 with liver transplantation, their survival is excellent, reported as 990 % at 6 months to 1 year in recent series [64•, 65], and this is independent of whether the patients receive vasoconstrictor treatment for their HRS1 or not. This contrasts with patients who do not reverse their HRS1 post liver transplant, whose survival is significantly reduced to 60 % at 1 year [64•]. Since nonreversal is associated with prolonged dialysis pre-transplant, the onus is on the treating physician to offer liver transplantation as soon as possible if patients show no response to vasoconstrictor therapy. It appears that living donor liver transplant for HRS1 yields just as excellent results as cadaveric liver transplant in experienced centers [73]. This should allow more patients with HRS1 to receive this definitive therapy.

Conclusion Great strides have been made in the understanding and treatment of HRS1. What used to be a universally fatal disease is now very treatable. The currently available treatment options include the use of albumin, vasoconstrictors, and liver transplantation. As we gain more experience with these treatment modalities, we will be able to better select patients for the appropriate treatment. The recent efforts in modifying the definition of AKI means that patients with cirrhosis and ascites who develop acute renal dysfunction will be diagnosed earlier in the natural history of AKI, and therefore, treatment will be instituted earlier. It is anticipated that this will be translated into better patient outcomes.

Compliance with Ethics Guidelines Conflict of Interest Florence Wong has received consultancy fees and grants from Ikaria. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008;48(6):2064–77. 2. Arroyo V, Gines P, Gerbes A, Dudley FJ, Gentilini P, Laffi G, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology. 1996;23(1):164–76. 3. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56(9):1310–8. 4.• Angeli P, Sanyal A, Moller S, Alessandria C, Gadano A, Kim R, et al. Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. Liver Int. 2013;33D1]:16–23. This paper outlines the difficulty in coming to an agreement on how to define renal failure in cirrhosis, and lays the ground work for what needs to be done to come to a consensus definition of renal failure, so that we can set criteria for treatments. 5. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol. 2004;15(6):1597–605. 6. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute dialysis quality initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care. 2004;8(4):R204–12. 7. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. 8. KDIGO Clinical Practice Guideline for Acute Kidney Injury. AKI definition. Kidney Int. 2012; Suppl 2:19– 36. 9. Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, et al. Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut. 2011;60(5):702–9. 10. Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut. 2013;62(1):131–7. 11.• Wong F, O’Leary JG, Reddy KR, Patton H, Kamath PS, Fallon MB, et al. New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection. Gastroenterology. 2013;145D6]:1280–9. This paper evaluates the validity of the consensus definition of acute kidney injury in a cohort of infected cirrhotic patients

who were admitted into hospital. The authors found that the consensus definition of acute kidney injury accurately predicted the 30-day survival of these patients. This is one of the first papers that confirms that smaller changes in serum creatinine can have a negative impact on the outcome of these patients. 12.• Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al. Association of AKI With mortality and complications in hospitalized patients with cirrhosis. Hepatology. 2013;57D2]:753–62. This paper shows that not only is the diagnosis of acute kidney injury important in determining the prognosis of decompensated cirrhotic patients, progression of the acute kidney injury has an even more negative prognostic implication for these patients. 13.•• Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes AL, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club. Gut. 2015 (in press). This is the most recent effort of the International Ascites Club in trying to bring about a consensus definition and diagnostic criteria of acute kidney injury in cirrhosis, based on a combination of available data and expert opinions. This will set the platform for designing future studies to validate these criteria, and for finding the most appropriate treatment options. 14. Wong F. Recent advances in our understanding of hepatorenal syndrome. Nat Rev Gastroenterol Hepatol. 2012;9(7):382–91. 15. Mandal AK, Lansing M, Fahmy A. Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study. Am J Kidney Dis. 1982;2(3):363–74. 16. Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology. 2007;46(6):1872–82. 17.•• Adebayo D, Morabito V, Davenport A, Jalan R. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int. 2014. Oct 8. A very clear and concise review on the different types of renal failure in cirrhosis. 18. Fry DE. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am Surg. 2012;78(1):1–8. 19.• Gomez H, Ince C, De Backer D, Pickkers P, Payen D, Hotchkiss J, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014;41D1]:3–11.

Liver (J Bajaj, Section Editor) A good review on the most recent pathophysiology on inflammation, and how it relates to acute renal failure. This helps to explain the latest findings that inflammation plays an important role in the development of acute renal failure in cirrhosis. 20. Montoliu S, Ballesté B, Planas R, Alvarez MA, Rivera M, Miquel M, et al. Incidence and prognosis of different types of functional renal failure in cirrhotic patients with ascites. Clin Gastroenterol Hepatol. 2010;8(7):616–22. 21. Shah N, Mohamed FE, Jover-Cobos M, Macnaughtan J, Davies N, Moreau R, et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int. 2013;33(3):398– 409. 22. Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet. 2003;362(9398):1819–27. 23. Wong F. Drug insight: the role of albumin in the management of chronic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4(1):43–51. 24. Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology. 2013;58:1836–46. 25.•• Arroyo V, Garcia-Martinez R, Salvatella X. Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol. 2014;61D2]:396–407. An excellent review on the properties of albumin and its use in the many complications of cirrhosis. 26. Albillos A, Lario M, Alvarez-Mon M. Cirrhosisassociated immune dysfunction: distinctive features and clinical relevance. J Hepatol. 2014;61(6):1385–96. 27. Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44(12):1027–31. 28. Oettl K, Birner-Gruenberger R, Spindelboeck W, Stueger HP, Dorn L, Stadlbauer V, et al. Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. J Hepatol. 2013;59(5):978–83. 29. Jalan R, Schnurr K, Mookerjee RP, Sen S, Cheshire L, Hodges S, et al. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology. 2009;50(2):555–64. 30.• Domenicali M, Baldassarre M, Giannone FA, Naldi M, Mastroroberto M, Biselli M, et al. Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis. Hepatology. 2014;60D6]:1851–60. An interesting study that confirms that the circulating albumin in cirrhosis is abnormal in quantity and function, thereby providing the rationale for the use of albumin in decompensated cirrhosis. 31. Neri S, Pulvirenti D, Malaguarnera M, Cosimo BM, Bertino G, Ignaccolo L, et al. Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Dig Dis Sci. 2008;53(3):830–5.

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Treatment to improve acute kidney injury in cirrhosis.

Acute kidney injury (AKI) is an ominous complication of decompensated cirrhosis, which can be fatal if not treated promptly. It is important that clin...
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