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Home , Hepatorenal syndrome

CJASN ePress. Published on April 17, 2019 as doi: 10.2215/CJN.12451018

Hepatorenal Syndrome

Claire Francoz,1,2 Franc¸ois Durand,1,2 Jeffrey A. Kahn,3 Yuri S. Genyk,4 and Mitra K. Nadim5

Abstract Hepatorenal syndrome is a severe complication of end-stage characterized by increased splanchnic flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. 1Hepatology and The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal Intensive Care Unit, syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of Hospital Beaujon, hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents ( in particular) Clichy, France; 2INSERM U1149, and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective University Paris at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even Diderot, Paris, France; in responders, early mortality rates are very high in the absence of . Liver transplantation is and 3Division of the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal Gastrointestinal and , syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating Department of hepatorenal syndrome from (ATN) is often a challenging yet important step because Medicine, 4Division of vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered Hepatobiliary, as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions Pancreas, and and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the Abdominal Organ Transplant, decision for simultaneous liver–kidney transplantation. Department of Clin J Am Soc Nephrol 14: ccc–ccc, 2019. doi: https://doi.org/10.2215/CJN.12451018 Surgery, and 5Division of Nephrology and Hypertension, Department of Introduction will focus on the definitions, mechanisms, and man- Medicine, Keck Advanced cirrhosis is a condition characterized by agement of hepatorenal syndrome. School of Medicine, impaired liver function, , in- University of Southern creased splanchnic blood volume, hyperdynamic Definition of Hepatorenal Syndrome and California, Los Angeles, California state with increased , systemic vasodi- AKI in Cirrhosis latation, a state of decreased central blood volume, The definition of AKI in cirrhosis has undergone fl fi Correspondence: and systemic in ammatory response. AKI is one of signi cant changes over the past several years. The Dr. Mitra K. Nadim, the most severe complications of cirrhosis, occurring common theme among the definitions is use of relative Division of in up to 50% of hospitalized patients, and has been changes in serum instead of absolute cut- Nephrology and associated with higher mortality, which increases offs (e.g., .1.5 mg/dl) and identifying patients at Hypertension, Department of with severity of AKI (1). Hepatorenal syndrome is highest risk for short- and long-term mortality on the Medicine, University of one of the phenotypes of AKI that occurs in patients basis of the escalating stages within each criterion (3,4). Southern California, with advanced cirrhosis and is characterized by In 2012, the Acute Quality Initiative (ADQI) 1520 San Pablo Street, decreased kidney blood flow that is unresponsive to recommended adaptation of the AKI Network serum Suite 4300, Los volume expansion. Hepatorenal syndrome is asso- creatinine criteria to define AKI in this patient pop- Angeles, CA 90033. fi Email: mitra.nadim@ ciated with signi cant health care resource utiliza- ulation (3). These criteria were irrespective of the cause med.usc.edu tion, with an estimated annual total direct medical of AKI and as such, hepatorenal syndrome type 1 was cost in the United States of approximately $4 billion categorized as a specific type of AKI and hepatorenal dollars (2). Refinements in the definitions have helped syndrome type 2 was categorized as a form of CKD. in the diagnosis of hepatorenal syndrome at an earlier The International Club of (ICA) further mod- stage during the course of cirrhosis. Recent advances in ified the definition of AKI on the basis of the Kidney our understanding of the pathophysiology of hepa- Disease Improving Global Outcomes serum creati- torenal syndrome suggest the involvement of systemic nine criteria, using a baseline serum creatinine within inflammation and circulatory changes in the kidney the previous 3 months (1,4). Although is not in parallel with systemic and splanchnic circulatory included in the current definition of AKI in patients changes. Although treatment of hepatorenal syn- with cirrhosis, output has been found to be a dromewiththeuseofvasoconstrictiveagentsin sensitive and early marker for AKI in critically ill combination with albumin has improved outcomes, patients with cirrhosis and is associated with adverse prognosis remains poor without liver transplanta- outcomes (5). Therefore, regardless of any rise in serum tion. This review, using the most recent literature, creatinine, decrease in urine output or development www.cjasn.org Vol 14 May, 2019 Copyright © 2019 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

of anuria should be considered as AKI in patients with In early stages of the disease, splanchnic is cirrhosis until proven otherwise. moderate and reduced systemic is balanced Changes in the definition of AKI in patients with cirrhosis by increased cardiac output. In advanced stages, vasodilation has led to changes in the definition of hepatorenal syndrome is more pronounced because of increased synthesis of such that the cut-off value of serum creatinine was removed vasodilator factors, and cannot be balanced by the increase and replaced with ICA AKI criteria, allowing for earlier in cardiac output (Figure 1) (7). As a result, there is an effective diagnosis and treatment of patients with hepatorenal syn- arterial hypovolemia as a consequence of the disparity drome (4). A major limitation of the hepatorenal syndrome between the intravascular blood volume and the mark- criteria is that it does not allow for the coexistence of other edly dilated arterial circulation. Cirrhotic cardiomyopathy forms of acute or CKD, such as underlying diabetic ne- is a condition combining diastolic dysfunction, blunted phropathy or glomerular diseases often associated in patients increase in cardiac output after stimulations, and electro- with liver disease. Patients with underlying kidney disease mechanical abnormalities (7). Inflammatory response dur- can still develop “hepatorenal physiology”; thus the term ing cirrhosis with increased circulating levels of TNF-a may “hepatorenal disorders” has been proposed by ADQI to contribute to blunted cardiac response (8). In advanced stages describe all patients with advanced cirrhosis and concurrent of cirrhosis with ascites, decreased cardiac output seems to kidney dysfunction, which would allow these patients to be precede the occurrence of hepatorenal syndrome (9). De- properly classified and treated while maintaining the term creased cardiac output may precipitate the decline in kidney hepatorenal syndrome (3). blood flow. Eventually, changes in in the kidney and altered autoregulation of kidney blood flow contribute to decreased GFR. Pathogenesis of Hepatorenal Syndrome To maintain arterial pressure, systemic vasoconstrictor Cirrhosis is characterized by reduced systemic vascu- systems (the -angiotensin- system, sym- lar resistance due to splanchnic arterial vasodilation (6). pathetic nervous system, and arginine ) are

A B

Cirrhosis and Portal Hypertension Advanced Cirrhosis and Portal Hypertension

Vasodilation theory Inflammatory theory Vasodilation theory Inflammatory theory

Bleeding or any other cause reducing effective volemia (, lactulose- induceddiarrhea)

Splanchnic vasodilation Splanchnic vasodilation +++ Bacterial translocation Bacterial translocation +++ Effective hypovolemia Effective hypovolemia

Activation of Activation of Proinflammatory Proinflammatory vasoconstriction systems vasoconstriction systems cytokines cytokines +++ RAAS, SNS, AVP RAAS, SNS, AVP Cirrhotic cardiomyopathy Non-selective beta-blockers?

Arterial vasoconstriction +++, Arterial vasoconstriction, Compensatory increase Insufficient increase inflammation, microvascular changes +++ inflammation, and microvascular in cardiac output in cardiac output and impaired autoregulation changes in the kidney

High cardiac output Normal or low cardiac output Ascites Ascites Increased kidney susceptibility to but normal GFR Decreased GFR, AKI

Figure 1. | Mechanisms involved in AKI in decompensated cirrhosis. (A) In decompensated cirrhosis, both vasodilation secondary to portal hypertension and systemic inflammation induced by gut bacterial translocation tend to induce kidney arterial vasoconstriction because of the activation of vasoconstrictive systems in response to decreased effective blood volume and inflammation in the kidney inducing microvascular changes. These changes result in a hyperdynamic state characterized by increased cardiac output, ascites, and normal GFR, but increase susceptibility of the kidney to AKI. (B) The onset of hepatorenal syndrome corresponds to the most advanced stages of these changes, with an intense kidney vasoconstriction and impaired kidney autoregulation leading to a decrease in GFR. Any event further decreasing hypovolemia (bleeding, diuretics overdose, lactulose-induced ), decreased cardiac output (e.g., cirrhotic cardiomyopathy, nonselective b-blockers) or systemic inflammation, with or without over sepsis, can precipitate hepatorenal syndrome. AVP, arginine vasopressin; RAAS, renin-an- giotensin-aldosterone system; SNS, sympathetic nervous system. Clin J Am Soc Nephrol 14: ccc–ccc, May, 2019 Hepatorenal Syndrome, Francoz et al. 3

activated, which, along with increased cardiac output related bacterial , hepatorenal syndrome, and improved to hyperdynamic state, help to preserve kidney blood flow. survival (16). Although activation of these systems has positive effects by b-Blockers are very effective at preventing variceal bleeding increasing arterial pressure, they result in kidney vasocon- and are widely used in patients with cirrhosis and significant striction, sodium retention leading to edema and ascites, portal hypertension. A recent meta-analysis suggests that the and solute-free water excretion leading to hyponatremia use of b-blockersisnotassociatedwithasignificant increase and decreased GFR. In the most advanced stages of cirrhosis in mortality in patients with ascites or refractory ascites (17). intense kidney vasoconstriction occurs and kidney perfu- However, in some series increased mortality has been observed sion is no longer compensated by increased cardiac output in patients with refractory ascites receiving b-blockers com- and GFR decreases, ultimately leading to the development pared with patients without b-blockers. It has been suggested of hepatorenal syndrome. thatthedecreaseincardiacoutputcausedbyb-blockers could Recently, the concept of systemic inflammatory disease in precipitate AKI (18). Clinicians should weigh the risks and cirrhosis has emerged, with growing evidence that inflam- benefits of continuation of nonselective b-blockers on an mation plays a role in hepatorenal syndrome (10). Cirrhosis individual basis in patients with refractory ascites. is associated with systemic inflammation, which correlates to the severity of liver disease and portal hypertension. The main mechanism is the translocation of bacteria and/or Management and Treatment of pathogen-associated molecular patterns from the gut due Hepatorenal Syndrome to altered intestinal permeability. Translocation induces a The etiology of AKI should be investigated quickly to prevent wide spectrum of genes encoding molecules responsible for further worsening of AKI, because progression to advanced inflammatory response via specific receptors called pattern stage AKI has been associated with a higher mortality rate recognition receptors (11). Toll-like receptor 4 (TLR4) is the (Figure 2) (1,5). This is particularly important in those with main pattern recognition receptor that has been studied in this hepatorenal syndrome because early initiation of treatment context. Overexpression of tubular TLR4 has been described in may increase the likelihood of hepatorenal syndrome patients with cirrhosis and kidney dysfunction (12). A subset resolution, possibly improving short-term survival. Albu- of patients with a diagnosis of hepatorenal syndrome showed min is an important step in the treatment and diagnosis of both overexpression of TLR4 in tubular cells and evidence hepatorenal syndrome; however, it is important to exercise of tubular cell damage, suggesting that a diagnosis of caution when administrating fluids in patients with AKI so hepatorenal syndrome does not exclude some degree of as to avoid development of significant fluid retention and structural changes (12). Inflammatory components may extend pulmonary edema, given the presence of reduced kidney to the systemic circulation and peripheral organs leading sodium and water excretion in patients with cirrhosis. to extra hepatic organ dysfunction, including the kidney. Inflammation may contribute to systemic circulatory changes Pharmacologic Therapy and compromised kidney perfusion. Patients with bacterial Vasoconstrictive agents in combination with albumin translocation have increased levels of proinflammatory cyto- represent the first-line option to treat hepatorenal syn- kines (TNF-a and IL-6) as well as increased level of vasodilating drome (Table 1) (19–23). Terlipressin is the most com- factors (such as nitric oxide) (13). Bacterial represent a monly used vasopressin analog; however, it has not been typical trigger of hepatorenal syndrome; however, about 30% approved in all countries. The efficacy of terlipressin plus of patients with hepatorenal syndrome have systemic inflam- albumin in the treatment of hepatorenal syndrome has been matory response syndrome without documented bacterial proven in a large number of studies, with a response rate infection (10). ranging from 25% to 75%. Terlipressin can be administered by intravenous boluses at starting dose of 0.5–1mgevery 4–6 hours, with a progressive increase to a maximum dose Prevention of Hepatorenal Syndrome of 2 mg every 4 hours in cases of nonresponse, namely a Strategies to prevent the development of hepatorenal reduction of baseline serum creatinine of ,25%. Treatment syndrome include preventing progression of liver disease should be maintained until complete response or for a max- in the well compensated patient, reversing decompensation imum of 14 days in cases of partial response or nonresponse. in patients who have advanced cirrhosis, avoiding agents Continuous infusion of terlipressin at a dose of 2–12 mg/d has known to exacerbate AKI, and preventing factors that been shown in a single study to be as efficacious as bolus further impair circulatory status and reduce kidney perfu- administration but with lower rates of adverse events (24). sion. Prophylactic antibiotics to prevent spontaneous bacte- The most serious side effects of terlipressin are related to rial peritonitis and, after variceal bleed, intravenous albumin vasoconstriction with a risk of myocardial infarction and in patients with spontaneous bacterial peritonitis (1.5 g/kg . Baseline serum creatinine and acute-on- on day 1 followed by 1 g/kg on day 3) (14) and patients chronic grade are associated with response to undergoing large-volume (.5L)(15)have terlipressin (25,26). However, studies in the use of vaso- been shown to decrease the incidence of hepatorenal syn- constrictors with lower serum creatinine and in early stages drome (14). There is no evidence that albumin in addition of hepatorenal syndrome are lacking. to antibiotics reduces the incidence of AKI in patients Other vasoconstrictive agents in combination with albu- with bacterial infection other than spontaneous bacterial min have been proposed (Table 1). Norepinephrine (given peritonitis (14). In a controlled trial, long-term admin- intravenously at a dose of 0.5–3 mg/h) is an alternative istration of albumin in patients with decompensated agent that has been shown in small studies to be effec- cirrhosis was associated with reduced rates of spontaneous tive in increasing arterial pressure and reversal of kidney 4 Clinical Journal of the American Society of Nephrology

Figure 2. | Algorithm for workup and management of AKI. *A trial of / (maximum 3 days) can be attempted before initiation of norepinephrine. ACS,abdominal compartment syndrome; AIN, acuteinterstitial nephritis; ATN, acutetubular necrosis; BPH, benign prostatic hypertrophy. impairment in patients with hepatorenal syndrome (27–29); reversing the circulatory changes (and possibly systemic however, a recent controlled trial suggests that norepi- inflammation) that precipitate hepatorenal syndrome. Small nephrine is inferior to terlipressin in reversal of hepatorenal studies have shown that a transjugular intrahepatic por- syndrome, kidney replacement therapy (KRT) requirement, tosystemic shunt is associated with a decrease in serum and overall survival (22). The combination of midodrine creatinine, with possible survival benefitinpatientswith plus octreotide, used in countries where terlipressin is not hepatorenal syndrome, but with high incidence of hepatic yet available, has been shown in a single-center study to be encephalopathy and further deterioration in patients with less effective than terlipressin (19). advanced liver disease (30).

Transjugular Intrahepatic Portosystemic Shunt Kidney Replacement Therapy Theoretically, a transjugular intrahepatic portosystemic Initiation of KRT in patients with hepatorenal syndrome shunt may improve kidney function in hepatorenal syn- is controversial and has typically been viewed as a bridge drome by decreasing portal hypertension and reducing and to transplantation in listed patients. Recent studies have Clin J Am Soc Nephrol 14: ccc–ccc, May, 2019 Hepatorenal Syndrome, Francoz et al. 5

Table 1. Summary of randomized, controlled studies of vasoconstrictor therapy in patients with type 1 hepatorenal syndrome

Hepatorenal Mortality without Author Year Treatment Patients Syndrome Transplantation, % Transplantation, % Reversal, %

Alessandria et al. (27) 2007 Terlipressin 12 83 90 66 Norepinephrine 10 70 100 70 Sharma et al. (28) 2008 Terlipressin 20 50 45 — Norepinephrine 20 50 45 — Sanyal et al. (21) 2008 Terlipressin 56 34 87 — Placebo 56 13 91 — Martin-Llahí et al. (20) 2008 Terlipressin 23 44 73 0 Albumin 23 9 81 4 Singh et al. (29) 2012 Terlipressin 23 39 61 0 Norepinephrine 23 43 52 0 Cavallin et al. (19) 2015 Terlipressin 27 70 41 0 Midodrine 22 29 57 4 Boyer et al. (23) 2016 Terlipressin 97 24 42 — Albumin 99 15 46 — Arora et al. (22) 2018 Terlipressin 60 40 52 — Noradrenaline 60 17 80 —

All treatment arms included albumin. —, not available.

demonstrated that the severity of illness and number of (34,35). Using the Scientific Registry of Transplant Recip- organ failure in patients with acute-on-chronic liver failure ients, in a Centers for Medicare and Medicaid Services is more predictive of 28-day mortality than cause of AKI ESKD program cohort of 2112 liver transplant recipients who (31,32). Therefore, it seems reasonable to consider a trial of received acute KRT for #90 days before liver transplantation, KRT in select patients regardless of transplant candidacy. only 9% had kidney nonrecovery and needed chronic KRT The ideal timing for initiation of KRT has not been studied within 6 months after liver transplantation; however, the in patients with cirrhosis and so should be individualized postliver-transplantation mortality was high in this cohort and made on clinical grounds, such as worsening kidney (36). The treatment of choice for patients with hepatorenal function coupled with electrolyte disturbances not re- syndrome is liver transplantation, and in theory, kidney sponding to medical management, or intolerance/ function is fully reversible post-transplant. Kidney recovery resistance. KRT should also be considered if the daily fluid and patient survival after liver transplantation in patients balance cannot be maintained or is negative, regardless of with hepatorenal syndrome was shown in a single-center their urine output, to prevent fluid accumulation. study to be significantly higher than patients with acute tubular necrosis and comparable with those with no AKI Liver Support System or stage 1 AKI regardless of their dialysis status before Although preliminary results suggested that albumin transplantation (35). dialysis with the molecular adsorbent recirculating system The introduction of organ allocation on the basis of the could improve the outcome of patients with hepatorenal Model for End-Stage Liver Disease in 2002 resulted in a syndrome, this has not been confirmed in larger random- dramatic increase in the number of simultaneous liver– ized trials. In a randomized trial of patients with acute on kidney transplantations because of priority in allocation chronic liver failure, there was no significant difference in to liver transplantation candidates with kidney dysfunc- 28-day mortality between patients with hepatorenal syndrome tion (37). Simultaneous liver–kidney transplantation now who underwent molecular adsorbent recirculating system represents 10% of all liver transplants in the United States, therapy compared with standard medical therapy (33). At with approximately 5% of transplanted deceased donor this time, there is no evidence that albumin dialysis is superior kidneys drawn away from kidney-transplant-only candi- to conventional filtration in patients requiring KRT. dates, raising concern in the kidney transplant community, especially given the uncertain benefit of simultaneous liver– Liver versus Simultaneous Liver–Kidney Transplantation kidney transplantation (38). The decision to perform simulta- Predicting the recovery of impaired kidney function and neous liver–kidney transplantation versus liver transplantation the extent of that recovery after liver transplantation is alone is driven not only by the concern of increased mortality challenging because of difficulties in delineating the relative post-transplant,butalsobytheconcernoflackofkidney contribution of preexisting comorbidities, unrecognized intrin- recovery, which is felt to contribute to the increased mortality. sic kidney disease, perioperative events, and post-transplant Studies have shown that postliver-transplantation patients immunosuppression to kidney dysfunction after liver trans- on the kidney waitlist have a higher mortality compared plant. The development of AKI before liver transplantation with patients waiting for kidney transplant only (39). Recently, has been shown to be associated with higher risk of CKD listing criteria for simultaneous liver-kidney transplantation and ESKD in the long-term after liver transplantation, but were developed by the Organ Procurement and Transplanta- has also been associated with increased risk of mortality tion Network on the basis of prior consensus recommendations, 6 Clinical Journal of the American Society of Nephrology

which include factors suchasdurationofAKIand clear cut-off value separates hepatorenal syndrome from dialysis and evidence of CKD (Table 2) (40–42). Factors acute tubular necrosis. Biomarkers predictive of recov- such as age, comorbidities, or cause of AKI, which could ery from AKI after liver transplantation could enhance affect kidney recovery, are currently not included in the decision algorithms regarding the need for liver–kidney criteria. transplant or kidney-sparing regimens (46). Tissue inhibitor of metalloproteinase-1 and osteopontin, along with patient characteristics (e.g., age, diabetes), have been shown in a Biomarkers single-center study to differentiate between recipients that fi Early diagnosis and identi cation of the phenotype of developed reversible versus irreversible AKI after liver AKI is crucial as management differs according to different transplantation (46). causes. Conventional tools such as urine output or fractional excretion of sodium or urea have been shown to have significant limitation in patients with advanced cirrhosis Imaging Studies and poor correlation with biopsy findings (43). Recently, Kidney ultrasonography is a useful noninvasive test to several innovative biomarkers have been studied, with help exclude structural causes of AKI, such as obstruc- neutrophil gelatinase-associated lipocalin, kidney injury tive uropathy and intrinsic parenchymal kidney disease, molecule-1, liver fatty acid-binding protein, and IL-18 be- which would rule out the diagnosis of hepatorenal syn- ing the most extensively studied. These specific biomarkers drome. Assessment of arterial kidney-resistive indexes by typically reflect the earliest markers of ischemia-related events Doppler ultrasonography (47,48), contrast-enhanced ultra- and may play a role in the diagnosis of AKI before liver sonography (49), and magnetic resonance elastography (50) transplantation (44,45). These biomarkers are not specific have been shown in very small studies to be associated with to kidney injury, may be influenced by inflammation or the development of hepatorenal syndrome. Whether these infection, do not comprehensively discriminate dichoto- techniques help in early diagnosis of hepatorenal syndrome, mous outcomes, and have not been validated using kidney differentiation of hepatorenal syndrome from other pheno- biopsy as a gold standard. In addition, substantial overlap types of AKI, or prediction of response to vasoconstrictors has been observed between different phenotypes and no needs to be further explored in larger trials.

Table 2. Previously proposed and existing Organ Procurement and Transplantation Network selection criteria for simultaneous liver and kidney transplantation

Author (yr) Eligibility Criteria for Simultaneous Liver–Kidney Transplantation

Davis et al. (2007) (41) 1. CKD with CrCl#30 ml/min (preferentially iothalamate) for .3mo 2. AKI and/or hepatorenal syndrome on for $6wk 3. AKI with kidney biopsy showing fixed kidney damage 4. Simultaneous liver–kidney not recommended in AKI not requiring hemodialysis 5. Metabolic diseases

Eason et al. (2008) (40) 1. CKD with GFR#30 ml/min for .3mo 2. AKI with serum creatinine $2 and on hemodialysis for $8wk 3. Kidney biopsy with .30% glomerulosclerosis or 30% fibrosis 4. Metabolic diseases c Criteria recommended to be considered: diabetes, hypertension, age .65 yr, kidney size, and duration of serum creatinine $2mg/dl

Nadim et al. (2012) (42) 1. AKI $ 4 wk with one of the following: c Stage 3 AKI: three times the baseline serum creatinine or on KRT c eGFR#35 ml/min (MDRD-6) or GFR#25 ml/min (iothalamate) 2. CKD with one of the following: c eGFR#40 ml/min (MDRD-6) or GFR#30 ml/min (iothalamate) c $2g/d c Kidney biopsy .30% glomerulosclerosis and/or .30% interstitial fibrosis 3. Metabolic diseases

Organ Procurement and Transplantation 1. AKI for $6 consecutive wk with one or a combination of both Network (2017) (37) (weekly documentation) c Dialysis c eGFR/CrCl #25 ml/min 2. CKD with eGFR#60 ml/min for .90 d with one of the following: c ESKD c eGFR/CrCl #30 ml/min at the time or after registration on kidney waiting list 3. Metabolic diseases 4. Safety net: c Any patient who is registered on the kidney waitlist between 60–365 d after liver transplantationandiseitheronchronichemodialysis orhasaneGFR,20ml/min will qualify for increased priority c Documentation required by transplant nephrologist

CrCl, creatinine clearance; KRT, kidney replacement therapy; MDRD, Modification of Diet in Renal Disease. Clin J Am Soc Nephrol 14: ccc–ccc, May, 2019 Hepatorenal Syndrome, Francoz et al. 7

Conclusion and Perspectives 11. Albillos A, Lario M, A´ lvarez-Mon M: Cirrhosis-associated Significant improvements have been achieved in the immune dysfunction: Distinctive features and clinical relevance. J Hepatol 61: 1385–1396, 2014 diagnosis and management of hepatorenal syndrome in 12. Shah N, Mohamed FE, Jover-Cobos M, Macnaughtan J, Davies N, recent years. Even with the use of vasoconstrictive agents Moreau R, Paradis V, Moore K, Mookerjee R, Jalan R: Increased and albumin, 3-month mortality rates remain especially renal expression and urinary excretion of TLR4 in acute kidney high in the absence of liver transplantation. In addition to injury associated with cirrhosis. Liver Int 33: 398–409, 2013 splanchnic and systemic circulatory changes, inflamma- 13. Du Plessis J, Vanheel H, Janssen CE, Roos L, Slavik T, Stivaktas PI, Nieuwoudt M, van Wyk SG, Vieira W, Pretorius E, Beukes M, tion may play an important role in the development of Farre´ R, Tack J, Laleman W, Fevery J, Nevens F, Roskams T, Van hepatorenal syndrome. Therapeutic interventions aimed at der Merwe SW: Activated intestinal macrophages in patients controlling inflammation may help prevent or reverse with cirrhosis release NO and IL-6 that may disrupt intestinal hepatorenal syndrome. Novel biomarker in combination barrier function. J Hepatol 58: 1125–1132, 2013 14. Ferna´ndez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano with imaging studies may improve diagnostic perfor- G, Vila C, Pardo A, Quintero E, Vargas V,Such J, Gine`s P,Arroyo V: mance of AKI in patients with cirrhosis. Irreversible Primary prophylaxis of spontaneous bacterial peritonitis delays kidney changes are probably underestimated; in the future, hepatorenal syndrome and improves survival in cirrhosis. novel biomarkers and imaging studies may provide 133: 818–824, 2007 further information on the potential of kidney recovery 15. Bernardi M, Caraceni P, Navickis RJ, Wilkes MM: Albumin infusion in patients undergoing large-volume paracentesis: A after liver transplantation (along with cause), and po- meta-analysis of randomized trials. 55: 1172–1181, tentially affect the decision to allocate a simultaneous 2012 liver–kidney transplantation. 16. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, Levantesi F, Airoldi A, Boccia S, Svegliati-Baroni G, Fagiuoli S, Disclosures Romanelli RG, Cozzolongo R, Di Marco V, Sangiovanni V, Dr. Nadim reports receiving personal fees from Mallinckrodt Morisco F, Toniutto P, Tortora A, De Marco R, Angelico M, and Baxter, outside the submitted work. 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