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

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

Splanchnic vasodilation Splanchnic vasodilation +++

Bacterial translocation Bacterial translocation +++
Effective hypovolemia Effective hypovolemia
Infection

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

High cardiac output Normal or low cardiac output

Ascites Ascites
Increased kidney susceptibility to ischemia 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 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
activated, which, along with increased cardiac output related
to hyperdynamic state, help to preserve kidney blood flow.
Although activation of these systems has positive effects by
increasing arterial pressure, they result in kidney vasocon-
striction, sodium retention leading to edema and ascites,
and solute-free water excretion leading to hyponatremia
and decreased GFR. In the most advanced stages of cirrhosis
intense kidney vasoconstriction occurs and kidney perfu-
sion is no longer compensated by increased cardiac output
and GFR decreases, ultimately leading to the development
of hepatorenal syndrome.
Recently, the concept of systemic inflammatory disease in
cirrhosis has emerged, with growing evidence that inflam-
mation plays a role in hepatorenal syndrome (10). Cirrhosis
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
pathogen-associated molecular patterns from the gut due
to altered intestinal permeability. Translocation induces a
wide spectrum of genes encoding molecules responsible for
inflammatory response via specific receptors called pattern
recognition receptors (11). Toll-like receptor 4 (TLR4) is the
main pattern recognition receptor that has been studied in this
context. Overexpression of tubular TLR4 has been described in
patients with cirrhosis and kidney dysfunction (12). A subset
of patients with a diagnosis of hepatorenal syndrome showed
both overexpression of TLR4 in tubular cells and evidence
of tubular cell damage, suggesting that a diagnosis of
hepatorenal syndrome does not exclude some degree of
structural changes (12). Inflammatory components may extend
to the systemic circulation and peripheral organs leading
to extra hepatic organ dysfunction, including the kidney.
Inflammation may contribute to systemic circulatory changes
and compromised kidney perfusion. Patients with bacterial
translocation have increased levels of proinflammatory cyto-
kines (TNF-a and IL-6) as well as increased level of vasodilating
factors (such as nitric oxide) (13). Bacterial infections represent a
typical trigger of hepatorenal syndrome; however, about 30%
of patients with hepatorenal syndrome have systemic inflam-
matory response syndrome without documented bacterial
infection (10).
Prevention of Hepatorenal Syndrome
Strategies to prevent the development of hepatorenal
syndrome include preventing progression of liver disease
in the well compensated patient, reversing decompensation
in patients who have advanced cirrhosis, avoiding agents
known to exacerbate AKI, and preventing factors that
further impair circulatory status and reduce kidney perfu-
sion. Prophylactic antibiotics to prevent spontaneous bacte-
rial peritonitis and, after variceal bleed, intravenous albumin
in patients with spontaneous bacterial peritonitis (1.5 g/kg
on day 1 followed by 1 g/kg on day 3) (14) and patients
undergoing large-volume paracentesis (.5 L) (15) have
been shown to decrease the incidence of hepatorenal syn-
drome (14). There is no evidence that albumin in addition
to antibiotics reduces the incidence of AKI in patients
with bacterial infection other than spontaneous bacterial
peritonitis (14). In a controlled trial, long-term admin-
istration of albumin in patients with decompensated
cirrhosis was associated with reduced rates of spontaneous
Hepatorenal Syndrome, Francoz et al. 3
bacterial peritonitis, hepatorenal syndrome, and improved
survival (16).
b-Blockers are very effective at preventing variceal bleeding
and are widely used in patients with cirrhosis and significant
portal hypertension. A recent meta-analysis suggests that the
use of b-blockers is not associated with a significant increase
in mortality in patients with ascites or refractory ascites (17).
However, in some series increased mortality has been observed
in patients with refractory ascites receiving b-blockers com-
pared with patients without b-blockers. It has been suggested
that the decrease in cardiac output caused by b-blockers could
precipitate AKI (18). Clinicians should weigh the risks and
benefits of continuation of nonselective b-blockers on an
individual basis in patients with refractory ascites.
Management and Treatment of
Hepatorenal Syndrome
The etiology of AKI should be investigated quickly to prevent
further worsening of AKI, because progression to advanced
stage AKI has been associated with a higher mortality rate
(Figure 2) (1,5). This is particularly important in those with
hepatorenal syndrome because early initiation of treatment
may increase the likelihood of hepatorenal syndrome
resolution, possibly improving short-term survival. Albu-
min is an important step in the treatment and diagnosis of
hepatorenal syndrome; however, it is important to exercise
caution when administrating fluids in patients with AKI so
as to avoid development of significant fluid retention and
pulmonary edema, given the presence of reduced kidney
sodium and water excretion in patients with cirrhosis.
Pharmacologic Therapy
Vasoconstrictive agents in combination with albumin
represent the first-line option to treat hepatorenal syn-
drome (Table 1) (19–23). Terlipressin is the most com-
monly used vasopressin analog; however, it has not been
approved in all countries. The efficacy of terlipressin plus
albumin in the treatment of hepatorenal syndrome has been
proven in a large number of studies, with a response rate
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
of 2 mg every 4 hours in cases of nonresponse, namely a
reduction of baseline serum creatinine of ,25%. Treatment
should be maintained until complete response or for a max-
imum of 14 days in cases of partial response or nonresponse.
Continuous infusion of terlipressin at a dose of 2–12 mg/d has
been shown in a single study to be as efficacious as bolus
administration but with lower rates of adverse events (24).
The most serious side effects of terlipressin are related to
vasoconstriction with a risk of myocardial infarction and
intestinal ischemia. Baseline serum creatinine and acute-on-
chronic liver failure grade are associated with response to
terlipressin (25,26). However, studies in the use of vaso-
constrictors with lower serum creatinine and in early stages
of hepatorenal syndrome are lacking.
Other vasoconstrictive agents in combination with albu-
min have been proposed (Table 1). Norepinephrine (given
intravenously at a dose of 0.5–3 mg/h) is an alternative
agent that has been shown in small studies to be effec-
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);
however, a recent controlled trial suggests that norepi-
nephrine is inferior to terlipressin in reversal of hepatorenal
syndrome, kidney replacement therapy (KRT) requirement,
and overall survival (22). The combination of midodrine
plus octreotide, used in countries where terlipressin is not
yet available, has been shown in a single-center study to be
less effective than terlipressin (19).
reversing the circulatory changes (and possibly systemic
inflammation) that precipitate hepatorenal syndrome. Small
studies have shown that a transjugular intrahepatic por-
tosystemic shunt is associated with a decrease in serum
creatinine, with possible survival benefit in patients with
hepatorenal syndrome, but with high incidence of hepatic
encephalopathy and further deterioration in patients with
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
organ failure in patients with acute-on-chronic liver failure
is more predictive of 28-day mortality than cause of AKI
(31,32). Therefore, it seems reasonable to consider a trial of
KRT in select patients regardless of transplant candidacy.
The ideal timing for initiation of KRT has not been studied
in patients with cirrhosis and so should be individualized
and made on clinical grounds, such as worsening kidney
function coupled with electrolyte disturbances not re-
sponding to medical management, or diuretic intolerance/
resistance. KRT should also be considered if the daily fluid
balance cannot be maintained or is negative, regardless of
their urine output, to prevent fluid accumulation.
Liver Support System
Although preliminary results suggested that albumin
dialysis with the molecular adsorbent recirculating system
could improve the outcome of patients with hepatorenal
syndrome, this has not been confirmed in larger random-
ized trials. In a randomized trial of patients with acute on
chronic liver failure, there was no significant difference in
28-day mortality between patients with hepatorenal syndrome
who underwent molecular adsorbent recirculating system
therapy compared with standard medical therapy (33). At
this time, there is no evidence that albumin dialysis is superior
to conventional filtration in patients requiring KRT.
Liver versus Simultaneous Liver–Kidney Transplantation
Predicting the recovery of impaired kidney function and
the extent of that recovery after liver transplantation is
challenging because of difficulties in delineating the relative
contribution of preexisting comorbidities, unrecognized intrin-
sic kidney disease, perioperative events, and post-transplant
immunosuppression to kidney dysfunction after liver trans-
plant. The development of AKI before liver transplantation
has been shown to be associated with higher risk of CKD
and ESKD in the long-term after liver transplantation, but
has also been associated with increased risk of mortality
(34,35). Using the Scientific Registry of Transplant Recip-
ients, in a Centers for Medicare and Medicaid Services
ESKD program cohort of 2112 liver transplant recipients who
received acute KRT for #90 days before liver transplantation,
only 9% had kidney nonrecovery and needed chronic KRT
within 6 months after liver transplantation; however, the
postliver-transplantation mortality was high in this cohort
(36). The treatment of choice for patients with hepatorenal
syndrome is liver transplantation, and in theory, kidney
function is fully reversible post-transplant. Kidney recovery
and patient survival after liver transplantation in patients
with hepatorenal syndrome was shown in a single-center
study to be significantly higher than patients with acute
tubular necrosis and comparable with those with no AKI
or stage 1 AKI regardless of their dialysis status before
transplantation (35).
The introduction of organ allocation on the basis of the
Model for End-Stage Liver Disease in 2002 resulted in a
dramatic increase in the number of simultaneous liver–
kidney transplantations because of priority in allocation
to liver transplantation candidates with kidney dysfunc-
tion (37). Simultaneous liver–kidney transplantation now
represents 10% of all liver transplants in the United States,
with approximately 5% of transplanted deceased donor
kidneys drawn away from kidney-transplant-only candi-
dates, raising concern in the kidney transplant community,
especially given the uncertain benefit of simultaneous liver–
kidney transplantation (38). The decision to perform simulta-
neous liver–kidney transplantation versus liver transplantation
alone is driven not only by the concern of increased mortality
post-transplant, but also by the concern of lack of kidney
recovery, which is felt to contribute to the increased mortality.
Studies have shown that postliver-transplantation patients
on the kidney waitlist have a higher mortality compared
with patients waiting for kidney transplant only (39). Recently,
listing criteria for simultaneous liver-kidney transplantation
were developed by the Organ Procurement and Transplanta-
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
dialysis and evidence of CKD (Table 2) (40–42). Factors
such as age, comorbidities, or cause of AKI, which could
affect kidney recovery, are currently not included in the
criteria.
Biomarkers
Early diagnosis and identification of the phenotype of
AKI is crucial as management differs according to different
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
and poor correlation with biopsy findings (43). Recently,
several innovative biomarkers have been studied, with
neutrophil gelatinase-associated lipocalin, kidney injury
molecule-1, liver fatty acid-binding protein, and IL-18 be-
ing the most extensively studied. These specific biomarkers
typically reflect the earliest markers of ischemia-related events
and may play a role in the diagnosis of AKI before liver
transplantation (44,45). These biomarkers are not specific
to kidney injury, may be influenced by inflammation or
infection, do not comprehensively discriminate dichoto-
mous outcomes, and have not been validated using kidney
biopsy as a gold standard. In addition, substantial overlap
has been observed between different phenotypes and no
Table 2. Previously proposed and existing Organ Procurement and Transplantation Network selection criteria for simultaneous liver
and kidney transplantation
Author (yr)
Davis et al. (2007) (41)
Eason et al. (2008) (40)
Nadim et al. (2012) (42)
Organ Procurement and Transplantation
Network (2017) (37)
CrCl, creatinine clearance; KRT, kidney replacement therapy; MDRD, Modification of Diet in Renal Disease.
clear cut-off value separates hepatorenal syndrome from
acute tubular necrosis. Biomarkers predictive of recov-
ery from AKI after liver transplantation could enhance
decision algorithms regarding the need for liver–kidney
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
single-center study to differentiate between recipients that
developed reversible versus irreversible AKI after liver
transplantation (46).
Imaging Studies
Kidney ultrasonography is a useful noninvasive test to
help exclude structural causes of AKI, such as obstruc-
tive uropathy and intrinsic parenchymal kidney disease,
which would rule out the diagnosis of hepatorenal syn-
drome. Assessment of arterial kidney-resistive indexes by
Doppler ultrasonography (47,48), contrast-enhanced ultra-
sonography (49), and magnetic resonance elastography (50)
have been shown in very small studies to be associated with
the development of hepatorenal syndrome. Whether these
techniques help in early diagnosis of hepatorenal syndrome,
differentiation of hepatorenal syndrome from other pheno-
types of AKI, or prediction of response to vasoconstrictors
needs to be further explored in larger trials.
Eligibility Criteria for Simultaneous Liver–Kidney Transplantation
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
1. CKD with GFR#30 ml/min for .3 mo
2. AKI with serum creatinine $2 and on hemodialysis for $8 wk
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 $2 mg/dl
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 Proteinuria $2 g/d
c Kidney biopsy .30% glomerulosclerosis and/or .30% interstitial fibrosis
3. Metabolic diseases
1. AKI for $6 consecutive wk with one or a combination of both
(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
Clin J Am Soc Nephrol 14: ccc–ccc, May, 2019
Conclusion and Perspectives
Significant improvements have been achieved in the
diagnosis and management of hepatorenal syndrome in
recent years. Even with the use of vasoconstrictive agents
and albumin, 3-month mortality rates remain especially
high in the absence of liver transplantation. In addition to
splanchnic and systemic circulatory changes, inflamma-
tion may play an important role in the development of
hepatorenal syndrome. Therapeutic interventions aimed at
controlling inflammation may help prevent or reverse
hepatorenal syndrome. Novel biomarker in combination
with imaging studies may improve diagnostic perfor-
mance of AKI in patients with cirrhosis. Irreversible
kidney changes are probably underestimated; in the future,
novel biomarkers and imaging studies may provide
further information on the potential of kidney recovery
after liver transplantation (along with cause), and po-
tentially affect the decision to allocate a simultaneous
liver–kidney transplantation.
Disclosures
Dr. Nadim reports receiving personal fees from Mallinckrodt
and Baxter, outside the submitted work. Dr. Durand, Dr. Francoz,
Dr. Genyk, and Dr. Kahn have nothing to disclose.
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