LIVER TRANSPLANTATION 21:300–307, 2015

ORIGINAL ARTICLE

Outcomes of Patients With Cirrhosis and

Hepatorenal Syndrome Type 1 Treated With
Liver Transplantation
Florence Wong,1 Wesley Leung,1 Mohammed Al Beshir,1 Max Marquez,2 and Eberhard L. Renner1,2
1
Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto,
Toronto, Canada; and 2Liver Transplant Program/Multiorgan Transplant Program, University Health
Network/Toronto General Hospital, Toronto, Canada

Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic
derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS)
reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to
assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver trans-
plant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was con-
ducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to
posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center’s transplant electronic database.
Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 6 1.2 years; mean
Model for End-Stage Liver Disease score, 35 6 1) with HRS1 (serum creatinine, 3.37 6 0.13 mg/dL) at liver transplant were
enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialy-
sis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients
(75.8%) at a mean time of 13 6 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine lev-
els (3.81 6 0.34 versus 3.23 6 0.14 mg/dL, P 5 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42
days] versus 10 days (95% CI, 10-18 days), P 5 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days)
versus 10 days (95% CI, 6-14 days), P 5 0.01], and increased posttransplant mortality (P 5 0.0045) in comparison with those
whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6%
increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1
should receive a timely liver transplant to improve their outcome. Liver Transpl 21:300-307, 2015. V C 2015 AASLD.

Received September 2, 2014; accepted November 16, 2014.

Hepatorenal syndrome type 1 (HRS1) is a functional onset renal failure.1 It is a condition induced by renal
renal disorder observed in patients with advanced cir- vasoconstriction, which occurs in the setting of a gen-
rhosis and ascites, and it is characterized by rapid- eral circulatory dysfunction of splanchnic and

Additional Supporting Information may be found in the online version of this article.

Abbreviations: CI, conftdence interval; CKD, chronic kidney disease; GI, gastrointestinal; HRS, hepatorenal syndrome; HRS–,
patients who experienced reversal of hepatorenal syndrome type 1; HRS 1, patients who did not experience reversal of hepatorenal
syndrome type 1; HRS1, hepatorenal syndrome type 1; LVP, large-volume paracentesis; SBP, spontaneous bacterial peritonitis; SD,
standard deviation; SEM, standard error of the mean; UTI, urinary tract infection.
Wesley Leung is currently afftliated with the Rough Valley Health System, Toronto, Canada.

Mohammad Al Beshir is currently afftliated with King Fahad Specialist Hospital, Dammam, Saudi Arabia.

Potential conflict of interest: Nothing to report.

Address reprint requests to Florence Wong, M.B.B.S., M.D., F.R.A.C.P., F.R.C.P.C., Division of Gastroenterology, Department of Medicine, Toronto
General Hospital, 200 Elizabeth Street, 9N/983, Toronto, Ontario M5G 2C4, Canada. Telephone: 416-340-4800; FAX: 416-340-5019; E-mail:
florence.wong@utoronto.ca

DOI 10.1002/lt.24049
View this article online at wileyonlinelibrary.com.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

V
C 2015 American Association for the Study of Liver Diseases.
LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015
systemic arterial vasodilatation. If left untreated, HRS1
carries a poor prognosis with a median survival of 7 to
10 days.2 Various pharmacological treatments aimed
at correcting the underlying pathophysiology of
splanchnic and systemic vasodilatation have met with
some success. For example, systemic vasoconstrictors
and volume expansion with colloid solutions have been
shown to improve renal function but not overall or
transplant-free survival in patients with cirrhosis and
HRS1,3-5 with approximately one-third of patients
responding with normalization of renal function.3-5 The
deftnitive treatment for HRS1 is liver transplanta- tion
because this eliminates liver dysfunction and portal
hypertension, the 2 main pathophysiological factors
that lead to the development of splanchnic and
systemic vasodilatation, which is central to the
pathogenesis of HRS1.6 Although we know that renal
function improves in many of these patients after liver
transplantation,7 up to 25% of patients remain
dialysis-dependent after liver transplantation.8 Persis-
tent ischemia from renal vasoconstriction with pro-
longed duration of HRS1 may lead to structural renal
damage9,10 and thereby prevent recovery of renal
function. This has led many to advocate combined
liver-kidney transplantation for patients whose HRS1
has lasted longer than 2 to 3 months11,12 because the
outcomes for patients who receive both organ trans-
plants seem to be better than those of patients who
receive a liver transplant alone.13 However, the poten-
tial for renal recovery in patients with HRS1 after liver
transplantation and a shortage of donor kidneys mean
that not every patient with HRS1 will be able to receive
combined liver-kidney transplantation, and individual
patient needs will have to be balanced against resource
allocation. Furthermore, it is not clear whether other
factors such as the etiology of cir- rhosis, the presence
of a bacterial infection as a pre- cipitant of HRS1, and
the extent of pretransplant renal dysfunction will also
influence renal recovery or patient outcomes.
Therefore, the aims of this study were (1) to assess the
clinical course of patients with cirrhosis and HRS1 who
received a liver transplant alone, especially with
respect to their renal outcomes, and (2) to determine
factors predicting HRS1 reversal.
PATIENTS AND METHODS
The Research Ethics Board of the University Health
Network (Toronto, Canada) approved this study.
This is a retrospective cohort study assessing the
time course of renal recovery after liver transplanta-
tion in patients who had HRS1 at the time of liver
transplantation. The liver transplant program at
Toronto General Hospital, a part of the University
Health Network, maintains a prospectively collected
electronic database of all patients who have ever
undergone a liver transplant at the institution. This
database contains information on patient demo-
graphics and laboratory test results. Enquiries were
made to the database for all patients who received a
liver transplant between 2001 and 2010. To identify
WONG ET AL. 301
eligible patients with HRS1, a pretransplant serum
creatinine level 2.5
≤ mg/dL (222 mmol/L) was used, and
all patients had to have follow-up for at least 12 months
after their liver transplant (or until death). These cases
were then reviewed to determine whether they, at the
time of liver transplantation, fulftlled the 2007
International Ascites Club diagnostic criteria for
HRS1, which is deftned as a doubling of the serum
≤ mmol/L in <2 weeks after
creatinine level to a value 222
the exclusion of organic renal disease and volume-
responsive prerenal renal failure.1 Patients could be
on dialysis at the time of transplantation
and be included. The exclusion criteria were patients
who had undergone combined liver-kidney transplan-
tation, patients who did not fulftll the diagnostic crite-
ria for HRS1, patients whose indication for liver
transplantation was hepatocellular carcinoma, and
patients who had undergone living donor liver
transplantation.
Collected clinical data included baseline parameters
such as patient demographics, the etiology of cirrho-
sis, and comorbid conditions as well as pretransplant,
peritransplant, and posttransplant variables. Pre-
transplant variables included the form of decompen-
sation, presence of infection, degree of liver dysfunction
as indicated by the Model for End-Stage Liver Disease
score, laboratory data (serum electro- lytes, serum
creatinine, complete blood count, inter- national
normalized ratio, liver enzymes, and liver function),
medications, treatment with vasoconstric- tors and
albumin, need for and duration of dialysis, and
duration of HRS1 before liver transplantation.
Peritransplant variables included the age and sex of the
donor and the cold ischemia time. Posttransplant
variables included the time to the reversal of hepato-
renal syndrome (HRS), the need for dialysis and its
duration, and mortality. Patients were assigned to
groups according to whether they had experienced an
HRS reversal [hepatorenal syndrome type 1–negative
(HRS–) group] or not [hepatorenal syndrome type 1–
positive (HRS1) group]. The reversal of HRS1 was
deftned as a reduction of serum creatinine to
<1.5 mg/dL (133 mmol/L) for more than 2 consecutive
days and being off dialysis 30 days after liver
transplantation.
The primary endpoint of the study was the reversal of
HRS1 in the posttransplant period as deftned previ-
ously. Secondary endpoints included the time to the
reversal of HRS1 and the predictors of HRS reversal.
Statistical Analysis
Descriptive statistics were applied to all parameters
collected. The chi-square test was used to analyze
nominal variables. Continuous data were compared
with the Student t test or an analysis of variance as
appropriate. The Mann-Whitney U test was used for
data that failed tests of normality. A logistic regres-
sion analysis with forward variable selection was per-
formed to determine those variables independently
predictive of renal recovery. A series of exact logistic
302 WONG ET AL.
regression models were implemented to obtain bivari-
ate estimates and conftdence intervals (CIs) with a
small sample. Variables with a correlation > 0.8 were
investigated, and only the variable that was more bio-
logically plausible was included to avoid issues of col-
linearity. Signiftcant predictors (P <0.05) were
included in subsequent multivariate model building
with adjustments for covariates. Kaplan-Meier curves
were constructed to determine survival. All results were
expressed as means and standard errors of the mean
(SEMs). All calculations were performed with PRISM 6
(GraphPad, La Jolla, CA) and IBM SPSS Sta- tistics 20
(IBM Corp., Armonk, NY); Stata Statistical Software 13
(StataCorp LP, College Station, TX) was used for exact
logistic regression modeling. A P val-
ue < 0.05 was regarded as statistically signiftcant.
RESULTS
For the 10-year period from 2001 to 2010, there were
1084 liver transplants performed at Toronto General
Hospital. One hundred twenty-four patients had a
serum creatinine level > 2.5 mg/dL before liver trans-
plantation; 62 of these patients had HRS1 as deftned
by the International Ascites Club1 and fulftlled all
inclusion and exclusion criteria. Among the remaining
62 patients, 13 had chronic kidney disease (CKD; as
deftned later) without any superimposed acute deteri-
oration. The other 49 patients had acute renal failure
that did not fulftll the diagnostic criteria of HRS1. The
enrolled patients included 36 males and 26 females
with a mean age of 54.7 6 1.2 years. The mean serum
creatinine level on the day of liver transplantation was
3.37 6 0.13 mg/dL, and the mean Model for End- Stage
Liver Disease score was 35 6 1. Forty-seven patients
(76%) ultimately had a reversal of HRS1 after liver
transplantation and were, therefore, placed in the
HRS– group, whereas the remaining 15 patients had
persistent renal dysfunction after liver transplan-
tation (the HRS1 group). Patient demographics and
baseline laboratory data for the 2 groups are pre-
sented in Table 1. The patients who did not recover
from HRS1 were signiftcantly older and were more
likely to have alcohol as an etiology of their liver cir-
rhosis. In addition, there were signiftcantly more
patients in the HRS1 group versus the HRS– group
(26.7% versus 4.3%, P 5 0.03) who had underlying
CKD, which was deftned as a glomerular ftltration
rate < 60 mL/minute for >3 months as calculated with
the Modiftcation of Diet in Renal Disease for-
mula, which uses 6 variables: serum creatinine, age,
sex, albumin, blood urea nitrogen, and African Ameri-
can status.15 The causes of CKD in the 2 groups were
similar, with diabetes and systemic hypertension being
the predominant etiologies. One patient in the HRS1
group had an unknown cause for his CKD. Notably, the
serum creatinine level 1 month before liver
transplantation was signiftcantly higher in the HRS1
group versus the HRS– group (1.30 6 0.10
versus 1.00 6 0.05 mg/dL, P 5 0.003). All other labo-
ratory parameters were similar between the 2 groups.
LIVER TRANSPLANTATION, March 2015
The serum albumin values were artiftcially high in both
groups because many patients received intrave- nous
albumin as part of their treatment for their HRS1 before
liver transplantation.
HRS1 Episode
The HRS1 episode occurred at a median time of 18 days
(95% CI, 13-22 days) before liver transplanta- tion, and
it was signiftcantly longer in the HRS 1 group (median,
25 days; 95% CI, 16-42 days) versus the
HRS– group (median, 10 days; 95% CI, 10-18 days; P
5 0.02). The majority of the HRS1 episodes were pre-
cipitated by infections (8/15 or 53% in the HRS1 group
and 34/47 or 72% in the HRS– group, P 5 0.21; Fig.
1A), with spontaneous bacterial peritonitis (SBP),
septicemia, and urinary tract infections (UTIs) being
the most common infections (Fig. 1B). Two of the 8
patients in the HRS1 group and 5 of the 34 patients in
the HRS– group had multiple infections. Pharmaco-
therapy consisting of midodrine and octreotide was
commenced in 38 patients (10 patients or 67% in the
HRS1 group and 28 patients or 60% in the HRS– group,
P 5 0.76) because terlipressin is not available in
Canada. Albumin was administered to only 6 patients
in the HRS1 group and 23 patients in the HRS– group
with median doses of 288 g (95% CI, 5- 805 g) and 175
g (95% CI, 155-291 g), respectively (P 5 0.22). None
of the patients responded to pharma- cotherapy, so
dialysis was started. One additional patient in the HRS1
group received dialysis without preceding
pharmacotherapy. Four patients in the HRS1 group and
19 patients in the HRS– group did not receive dialysis
before liver transplantation (P 5 0.38). Figure 2A,B
show that the HRS1 group had signiftcantly higher peak
serum creatinine levels before the commencement of
dialysis and on the day of liver transplantation. In
addition, the duration of HRS1 and the duration of
dialysis were also signift- cantly longer for the HRS1
group (Fig. 2C,D).
Peritransplant Period
All patients received a deceased donor liver trans-
plant. There was no difference in terms of the donor
age, cold ischemia time, or amount of blood products
used (Table 2). However, there were signiftcantly more
male donors for the HRS1 group (P 5 0.02; Table 2).
Immunosuppression after liver transplantation con-
sisted of a steroid and a calcineurin inhibitor. Seventy-
two percent of the patients with HRS1 rever- sal
received tacrolimus, whereas 66% of those without
HRS1 reversal did (P 5 0.75). Cyclosporine was used in
28% of the patients with HRS reversal versus 33% of
those without HRS1 reversal (P 5 0.75). A conver- sion
from cyclosporine to tacrolimus occurred in 11% and
13% of cases, respectively (P 5 0.85). Mycofeno- late
mofetil was used in half of the cases in both groups (P
5 1).
Eleven of the 15 HRS1 patients (73%) received post-
transplant dialysis for a median duration of 48 days
LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 WONG ET AL. 303

TABLE 1. Patient Demographics and Laboratory Data on the Day of Liver Transplantation

HRS– HRS1 P Value

Patients, n 47 15
Age, mean 6 SD, years 48.97 6 1.47 55.07 6 2.30 0.04
Sex: male/female, n/n 25/22 11/4 0.23
Etiology of cirrhosis, n 0.03
Alcohol 6 viral 5 7
Viral hepatitis 10 2
Nonalcoholic steatohepatitis 14 2
Cholestatic/autoimmune hepatitis 11 1
Other 7 3
Comorbid conditions, n 0.76
Systemic hypertension 6 diabetes 21 8
No systemic hypertension 6 diabetes 26 7
History of CKD: yes/no, n/n* 2/45 4/11 0.03
Duration of prior CKD, mean 6 SD, days 197.5 6 12.5 355.3 6 76.7 0.24
History of acute kidney injury: yes/no, n/n† 12/35 4/11 1.00
Duration of prior acute kidney injury, mean 6 SD, days 12.8 6 5.5 15.5 6 8.3 0.81
Laboratory data, mean 6 SD‡
Sodium, mmol/L (135-145 mmol/L) 142 6 1 143 6 1 0.34
Creatinine 1 month before, mg/dL (<1.2 mg/dL) 1.00 6 0.05 1.30 6 0.10 0.003
Creatinine, mg/dL (<1.2 mg/dL) 3.23 6 0.14 3.81 6 0.34 0.06
Aspartate aminotransferase, IU/L (<34 IU/L) 166 6 25 174 6 62 0.90
Alanine aminotransferase, IU/L (<40 IU/L) 103 6 21 119 6 62 0.75
Bilirubin, mg/dL (<1 mg/dL) 17.0 6 2.6 21.8 6 5.1 0.38
Albumin, g/L (35-47 g/L) 39 6 1 37 6 3 0.41
Hemoglobin, g/L (120-180 g/L) 97 6 1 100 6 3 0.14
White blood cell count, /L (4-11 3 106/L) 8.57 6 0.25 9.64 6 1.20 0.18
Platelets, /L (150-400 3 106/L) 87 6 4 138 6 31 0.008
International normalized ratio (1.0-1.2) 3.58 6 0.21 4.20 6 0.52 0.19
Model for End-Stage Liver Disease score 38 6 1 40 6 2 0.37

*CKD was deftned as a glomerular ftltration rate < 60 mL/minute for >3 months. The rate was calculated with the Modiftca-
tion of Diet in Renal Disease formula, which uses 6 variables: serum creatinine, age, sex, albumin, blood urea nitrogen,
and African American status.14
†
Acute kidney injury was deftned as an absolute increase in serum creatinine of 0.3 g/dL (26.4 mmol/L) from the baseline
within 48 hours or less or as an increase in the serum creatinine concentration 50% from a stable baseline reading within
a 6-month period.14
‡
Values in parentheses are normal ranges.

(95% CI, 259 to 430 days). This contrasts with 28 of
the 47 patients (60%) in the HRS– group (P 5 0.38), who
required posttransplant dialysis for a signift- cantly
shorter median duration of 5.5 days (95% CI, 5.4-13
days; P < 0.001 versus the HRS1 group). There were no
differences in the lengths of stay in the inten-
sive care unit or the hospital between the 2 groups
(Table 2).
HRS1 Reversal
Forty-seven of the 62 enrolled patients (75.8%) had a
reversal of their HRS1, which was deftned as a reduc-
tion of the serum creatinine level to <1.5 mg/dL for
more than 2 consecutive days and being off dialysis 30
days after liver transplantation (mean time, 13 6 2
days). Sixty percent of the HRS– group needed short-
term dialysis. The mean serum creatinine level at the
time of HRS reversal for the HRS– group was
1.21 6 0.03 mg/dL. In the HRS1 group, 11 of 15
patients remained on dialysis. The 4 patients in the
HRS1 group who did not receive posttransplant dialy-
sis died 1 to 206 days after their liver transplant. Fig-
ure 3 shows the mean serum creatinine levels for the
12 months after liver transplantation for both the HRS1
group and the HRS– group. An exact logistic regression
model was constructed to examine risk fac- tors
associated with the nonreversal of HRS1. A uni- variate
analysis showed that the recipient’s age (P 5 0.046),
alcoholic liver disease (P 5 0.008), and the duration of
pretransplant dialysis (P 5 0.008) were predictive of
HRS1 nonreversal. A multivariate analy- sis showed
that only the duration of pretransplant dialysis was
signiftcant for predicting HRS1 nonrever- sal after liver
transplantation with a hazard ratio of
1.59 (95% CI, 1.016-1.105); that is, for every day that
the patient received dialysis before transplanta- tion,
there was a 6% increase in the risk of HRS1
304 WONG ET AL.
Figure 1. (A) Frequencies of various precipitants for HRS1 in the
HRS– and HRS1 groups. (B) Frequencies of the various types of
infections as precipitants for HRS1 in the HRS– and HRS1 groups.
Some patients had more than 1 infection at the time of the HRS
diagnosis.
nonreversal after liver transplantation. When the data
were reanalyzed after the exclusion of 6 patients with
preexisting CKD, the duration of pretransplant dialy-
sis still remained a signiftcant predictor of posttrans-
plant HRS reversal (hazard ratio, 1.05; 95%CI, 1.01-
1.096; P 5 0.026).
According to univariate exact logistic regression
using dialysis before transplantation as a dichoto-
mous variable, a cutoff point of 14 days was signift-
cant (P 5 0.003) with a hazard ratio of 9.2 (95%CI, 2.2-
38.9). That is, a patient who required dialysis for more
than 14 days was 9.2 times more likely to not have a
reversal of HRS1.
Follow-Up and Survival
The follow-up period for the HRS– group (median, 77.2
months; 95% CI, 62.3-93.2 months) was signiftcantly
longer than the period for the HRS1 group (median,
50.5 months; 95% CI, 21.8-69.8 months; P 5 0.01)
because of the signiftcantly better survival of the HRS –
group (Fig. 4). The 1-year survival for the HRS– group
was 97%, whereas it was 60% for the HRS1 group (P
5 0.007). One patient in the HRS1 group received a
kidney transplant 74 months after her liver transplant.
All patients showed a signiftcant improvement in liver
function to nearly normal levels within the ftrst month
after transplantation. The HRS1 group had persistently
elevated serum creatinine levels throughout the study
in comparison with the HRS– group (Fig. 3). However,
LIVER TRANSPLANTATION, March 2015
the HRS– group had similar serum creatinine levels 1
year after transplantation (1.23 6 0.07 mg/dL) in com-
parison with the patients who underwent transplanta-
tion during the same period without HRS1 (1.02
6 0.02 mg/dL, P 5 0.80).
DISCUSSION
This study conftrms previous reports of HRS1 reversal
in the majority of patients receiving a liver transplant
as the deftnitive treatment for their HRS1.7,8,11 Patients
who recovered their kidney function with liver
transplantation were younger, were less likely to have
CKD, had HRS1 and pretransplant dialysis for shorter
durations, and had lower levels of serum creatinine at
the time of liver transplantation. The reversal of HRS1
was associated with an excellent survival rate of 97%
at 1 year together with maintenance of normal renal
function for the same period. Prolonged dialysis before
transplantation predicted nonreversal of HRS1 with
liver transplantation as well as signiftcant mortality
within the ftrst year after transplantation.
HRS1 arises as a result of hemodynamic changes
that occur in advanced cirrhosis. With the elimination
of liver dysfunction and portal hypertension after liver
transplantation, the stimulus of renal vasoconstric-
tion and hence renal underperfusion is removed, and
this leads to the recovery of renal function. Renal
recovery is independent of pre–liver transplant dialy-
sis. Continued dialysis may be temporarily required
after liver transplantation because the abnormal
hemodynamics characteristic of patients with
advanced liver failure may persist in the posttrans-
plant period.15 Further follow-up shows that as the
liver function of HRS– patients improves, normal renal
function is maintained despite the discontinuation of
dialysis. However, recovery from HRS1 is not univer-
sal among patients who receive a liver transplant. Our
results are consistent with a recent study reporting a
58% renal recovery rate after liver transplantation for
HRS1.8 Our ftndings contrast with most reports from
the earlier literature, which have documented almost
universal recovery of renal function.7,16-18 This may be
related to the fact that many of these earlier stud- ies
are from an era before HRS1 was formally deftned by
the International Ascites Club1; therefore, some of the
patients may not have had HRS1 before liver
transplantation. The presence of CKD in the current
study and Marik et al.’s study9 may have also contrib-
uted to the higher percentage of nonreversal of HRS1
after liver transplantation.
The strongest predictor of nonreversal of HRS1 is the
duration of dialysis before liver transplantation. The
majority of the patients who recovered their renal
function received 14 ≤ days of dialysis before their liver
transplant. Conversely, most of those patients who did
not have a reversal of their renal function had at least
13 days of dialysis. In fact, in our study, for every day
of dialysis received before liver transplan- tation, there
was an additional 6% risk of nonreversal of renal
function after liver transplantation. Even after
LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 WONG ET AL. 305

Figure 2. Pretransplant renal function in the HRS– and HRS1 groups: (A) peak serum creatinine during the HRS1 episode, (B) serum
creatinine on the day of liver transplantation, (C) duration of HRS1, and (D) duration of dialysis.

the removal of those patients who had underlying
chronic renal dysfunction, the duration of dialysis was
still signiftcant in the prediction of nonreversal of
HRS1. In fact, a duration of 14 days of pretransplant
dialysis provides a useful cutoff value for the prediction
of HRS1 nonreversal with liver transplantation. It is
possible that prolonged renal ischemia from HRS1 of
signiftcant duration can lead to renal tubular dam-
age.19 Indeed, in an animal model of renal ischemia,
chronic underperfusion of the kidneys beyond 8 weeks
was associated with a 30% to 50% reduction in peri-
tubular capillary density in the inner medulla, which
led to proteinuria, a urinary concentrating defect, and,
ultimately, tubulointerstitial ftbrosis.20 In patients with
HRS1 who did not respond to vasopressor therapy,
various biomarkers of renal tubular damage were
already evident on day 5 after the diagnosis of HRS1,
and their levels continued to rise on day 10; however,

HRS– HRS1 P Value

Patients, n 47 15
Donor age, mean 6 SD, years 42 6 2.7 50 6 4.0 0.16
Donor sex: male/female, n/n 21/26 12/3 0.02
Blood products used, mean 6 SD, U
Red blood cells 8.4 6 0.08 9.3 6 1.3 0.57
Fresh frozen plasma 12 6 1.1 11 6 1.4 0.61
Ischemic times, mean 6 SD, minutes
Cold 460 6 21 438 6 31 0.58
Warm 51 6 2.8 43 6 2.5 0.14
Intensive care unit stay, mean 6 SD, days 18.0 6 2.7 15.0 6 2.8 0.64
Hospital stay, mean 6 SD, days 58 6 5 54 6 9 0.68
306 WONG ET AL.
Figure 3. Serial serum creatinine levels in the HRS – and HRS1 groups from the baseline through the first 12 months after transplan-
tation. D and M indicate day and month, respectively. *P < 0.01 for the HRS– group versus the HRS1 group. §P < 0.05 for the HRS– group
versus the HRS1 group. ¶P < 0.001 for the HRS– group versus the HRS1 group.
in patients who responded to vasopressor therapy, the
levels of these biomarkers fell below the upper limit of
normal by day 10.21 This suggests that structural
injury to the renal tubules occurs early in the course of
HRS1, and this may explain the reasons for the non-
reversal of HRS1 in the patients who received dialysis
for more than 2 weeks. In another study assessing the
outcomes of patients who received a liver transplant
alone as a treatment for HRS1, Xu et al.22 showed that
when the mean period between the onset of HRS1 and
liver transplantation was less than 4 weeks, HRS1 was
resolved for 30 of 32 patients after liver transplanta-
tion; this once again suggests that a shorter duration
of HRS1 is crucial for renal recovery after liver trans-
Figure 4. Survival of the HRS– group versus the HRS1 group.
LIVER TRANSPLANTATION, March 2015
plantation. Current guidelines from the United Net-
work for Organ Sharing recommend that a dialysis
period longer than 8 weeks is an indication for com-
bined liver-kidney transplantation in patients with cir-
rhosis and HRS1.13 Future studies should assess
whether a shorter duration of dialysis should be set as
the benchmark for consideration of combined liver-
kidney transplantation because prolonged dialysis and
the associated nonreversal of HRS1 have a signiftcant
negative impact on post–liver transplant survival.
In contrast, the reversal of HRS1 after liver transplan-
tation is associated with an excellent survival rate of 97%
at 1 year. This is consistent with the ftndings of Boyer et
al.,23 who also described 97% survival at 6 months for
HRS1 patients after liver transplantation. Restuccia et
al.24 suggested that good outcomes can be achieved only
if the patients respond to treatment with
vasoconstrictors before liver transplantation. However,
their study included only 3 patients with HRS1 and 6
patients with HRS type 2. Our study and Boyer et al.’s
study suggest that a remarkable survival rate can be
achieved regardless of whether the patients receive
vasoconstrictor treatment for their HRS1, and this is
independent of the type of vasoconstrictor used. In
another series from the prevasoconstrictor era, patients
with HRS1 had a 1-year survival rate (76.6%) similar to
that of patients without HRS1 (87.2%) after liver trans-
plantation.7 Therefore, it is liver transplantation rather
than vasoconstrictor therapy that will improve patient
outcomes and should be the deftnitive treatment for
HRS1. Because prolonged dialysis is associated with
reduced posttransplant survival, patients with HRS1
should be offered liver transplantation as soon as pos-
sible if they have shown no response to vasoconstrictor
therapy, although a response to vasoconstrictors
LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015
without liver transplantation is associated with improved
survival.25 Whether pretreatment with vasopressors such
as terlipressin, independent of a response before liver
transplantation, contributes to improved survival is
unknown because terlipressin was not used in any of
these patients; a word of caution is given with respect to
the interpretation of our results, which may not be gen-
eralizable to all countries and especially not to those that
routinely use terlipressin as the ftrst-line treatment for
HRS1. The recent suggestion that living donor liver
transplantation for HRS1 yields excellent results at
experienced centers26 should allow more patients with
HRS1 to receive this deftnitive therapy.
In conclusion, patients with advanced cirrhosis and
HRS1 who receive a liver transplant as a deftnitive
treatment have a renal recovery rate of 76%. Those
patients who reverse their HRS1 have an excellent 1-
year survival rate of 97%. The only predictor of HRS
nonreversal is prolonged dialysis before transplanta-
tion. Therefore, patients who do not respond to vaso-
constrictor therapy for HRS1 should be offered liver
transplantation without delay; otherwise, the possible
evolution to structural renal damage may impede ulti-
mate renal recovery and patient survival.
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