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Hepatorenal Syndrome: Claire Francoz, Franc Ois Durand, Jeffrey A. Kahn, Yuri S. Genyk, and Mitra K. Nadim
Hepatorenal Syndrome: Claire Francoz, Franc Ois Durand, Jeffrey A. Kahn, Yuri S. Genyk, and Mitra K. Nadim
Hepatorenal Syndrome: Claire Francoz, Franc Ois Durand, Jeffrey A. Kahn, Yuri S. Genyk, and Mitra K. Nadim
12451018
Hepatorenal Syndrome
Claire Francoz,1,2 François 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 cirrhosis characterized by increased splanchnic
blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems,
and extreme kidney 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. 1
Hepatology and Liver
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,
Clichy, France;
hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) 2
INSERM 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. Liver transplantation is and 3Division of
the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal Gastrointestinal and
Liver Disease,
syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating Department of
hepatorenal syndrome from acute tubular necrosis (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
Abdominal Organ
and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the
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, portal hypertension, in- University of Southern
creased splanchnic blood volume, hyperdynamic California, Los
Definition of Hepatorenal Syndrome and
Angeles, California
state with increased cardiac output, systemic vasodi- AKI in Cirrhosis
latation, a state of decreased central blood volume, The definition of AKI in cirrhosis has undergone
Correspondence:
and systemic inflammatory response. AKI is one of significant 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 creatinine 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 Dialysis 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
Angeles, CA 90033.
volume expansion. Hepatorenal syndrome is asso- creatinine criteria to define AKI in this patient pop-
Email: mitra.nadim@
ciated with significant 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 Ascites (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 oliguria 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, urine output has been found to be a
drome with the use of vasoconstrictive agents in 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 vasodilation is
cirrhosis until proven otherwise. moderate and reduced systemic vascular resistance 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 hemodynamics 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 renin-angiotensin-aldosterone system, sym-
lar resistance due to splanchnic arterial vasodilation (6). pathetic nervous system, and arginine vasopressin) are
A B
Activation of Activation of
Proinflammatory Proinflammatory
vasoconstriction systems vasoconstriction systems
cytokines cytokines +++
RAAS, SNS, AVP RAAS, SNS, AVP Cirrhotic
cardiomyopathy
Non-selective
beta-blockers?
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 diarrhea), 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 peritonitis, 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-blockers is not associated with a significant 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. that the decrease in cardiac output caused by b-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 infections 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 0.5–1 mg every
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 intestinal ischemia. Baseline serum creatinine and acute-on-
on day 1 followed by 1 g/kg on day 3) (14) and patients chronic liver failure grade are associated with response to
undergoing large-volume paracentesis (.5 L) (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 octreotide/midodrine (maximum 3 days) can be attempted before initiation
of norepinephrine. ACS, abdominal compartment syndrome; AIN, acute interstitial nephritis; ATN, acute tubular 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 benefit in patients with
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).
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, %
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 diuretic 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, but also by the concern of lack of kidney
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 such as duration of AKI and 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
Early diagnosis and identification 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
Davis et al. (2007) (41) 1. CKD with CrCl#30 ml/min (preferentially iothalamate) for .3 mo
2. AKI and/or hepatorenal syndrome on hemodialysis for $6 wk
3. AKI with kidney biopsy showing fixed kidney damage
4. Simultaneous liver–kidney not recommended in AKI not requiring hemodialysis
5. 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
transplantation and is either on chronic hemodialysis or has an eGFR,20 ml/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
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