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REVIEW
Preventing and Treating Acute Kidney Injury
Among Hospitalized Patients with Cirrhosis and
Ascites: A Narrative Review
Elliot B. Tapper, MD,a Alan Bonder, MD,a Andres Cardenas, MD, MMSc, PhDb
a
Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, Mass; bGI/Liver Unit, Hospital Clinic, Institut de Malalties Digestives i Metaboliques, University of Barcelona, Spain.
ABSTRACT
Acute kidney injury in the setting of ascites and cirrhosis is a medical emergency characterized by
significant morbidity and mortality. Clinicians other than gastroenterologists are often the front line against
acute kidney injury for patients with ascites. Owing to the specifics of cirrhotic physiology, the treatment
and prevention of acute kidney injury in the setting of ascites has unique features, widespread knowledge of
which will benefit our patients with cirrhosis. Early detection and treatment of infection, maximization of
cardiac output, and avoidance of medications that limit cardiorenal adaptations to arterial underfilling are
part of a multipronged strategy to protect the renal function of our patients with cirrhosis and ascites.
Ó 2016 Elsevier Inc. All rights reserved. The American Journal of Medicine (2016) 129, 461-467
KEYWORDS: Hepatorenal syndrome; Hospitalist; Liver disease; Paracentesis; Spontaneous bacterial peritonitis
Cirrhosis is a common comorbidity among hospitalized
patients in the US. As up to 50% of patients with cirrhosis
develop ascites,1 it is, unsurprisingly, a common factor in
many admissions. In 2012 alone, there were more than
380,000 hospital discharges for patients with cirrhosis and
ascites at American hospitals.2 Owing to unique aspects of
cirrhotic hemodynamics and renal physiology, patients with
ascites are highly vulnerable to acute kidney injury.
Importantly, the definition of renal injury in the setting of
cirrhosis and ascites is based largely on changes relative to
the patient’s baseline. Given the frequency of sarcopenia in
this population, relying on serum creatinine levels alone
may overestimate renal function.3,4
Funding: EBT was supported by a grant from the Carl J. Shapiro
Institute for Education and Research. No other authors received any
financial support for this study.
Conflict of Interest: No author has any conflicts of interest to disclose.
Authorship: EBT is the guarantor of this article. Concept and writing:
EBT; acquisition of data: EBT, AB, AC; critical revision: AB, AC. All
authors approved this manuscript.
Requests for reprints should be addressed to Elliot B. Tapper, MD,
Division of Gastroenterology/Hepatology, Department of Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline
Ave, Boston, MA 02115.
E-mail address: [email protected]
0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2015.12.006
The most devastating complication of ascites is an
extreme form of renal injury termed “type 1 hepatorenal
syndrome.” Type 1 hepatorenal syndrome occurs with an
8% annual incidence among patients with ascites and heralds a median survival of 2 weeks without treatment.5 It is
defined in part by recently adjusted criteria that include an
acute increase in the serum creatinine by at least 0.3 mg/dL
or a 50% increase from the patient’s baseline (ie, stage 1
acute kidney injury) that is unresponsive to standard therapy
for prerenal azotemia.3 The rapidity and severity of type 1
hepatorenal syndrome is contrasted with the so-called type 2
hepatorenal syndrome, which is felt to reflect the same underlying physiology but is characterized by a slower, lower
increase in creatinine and increased risk for type 1 hepatorenal syndrome6,7 (Table). Compared to patients with
ascites without renal injury, those with type 2 hepatorenal
syndrome have reduced overall survival (6 months).6
In many hospitals, nongastroenterologists admit the
majority of patients with ascites and are therefore the front
line against renal injury.8 What transpires for these patients
early in their hospital course may prove critical to their renal
function. Early detection and treatment of infection, maintaining a balanced hyperdynamic circulation, and avoidance
of medications that limit cardiorenal adaptations to arterial
underfilling are part of a multipronged strategy to protect the
462
The American Journal of Medicine, Vol 129, No 5, May 2016
renal function of patients with cirrhosis and ascites. Herein,
we will review a physiology-driven approach to the prevention and treatment of renal injury in patients with
cirrhosis and ascites.
Diminished venous return results in an instantaneous
decrease in stroke volume that is addressed immediately
through 3 coordinated cardiorenal mechanisms (Figure 1).
First, carotid baroreceptors fire in response to volume/
pressure changes, causing catecholamine release to
compensate via chronotropic and inotropic adaptations.13
FROM PHYSIOLOGY TO
Indeed, even at rest, the heart of
THERAPY
a patient with cirrhosis is hyperCLINICAL SIGNIFICANCE
dynamic,14 often at a rate
Progressive hepatic injury and
exceeding that of noncirrhotic
fibrosis leads to cirrhosis, which is
Patients with cirrhosis complicated by
controls.15 Second, the same
broadly characterized by 2 feaascites are at markedly increased risk of
baroreceptor reflex leads to a
tures: architectural disruption with
renal failure.
nonosmotic release of antidiuretic
resultant interference with intra All patients with ascites must be
hormone to facilitate water recaphepatic blood flow (portal hyperture in the kidney as well as peassessed for spontaneous bacterial
tension) and diminished metabolic
ripheral vasoconstriction.16,17 The
capacity of the liver. Resistance to
peritonitis with a paracentesis immediresult is increased plasma volume
intrahepatic blood flow caused by
ately upon admission.
even while arteries remain underfibrosis and intrahepatic endothe The new definition of acute renal failure
filled.6 Third, a lower sensed
lial dysfunction,9 in turn, leads to
in
patients
with
cirrhosis
is
an
increase
arterial volume leads to the actiportal hypertension and the forin serum creatinine 0.3 mg/dL within
vation of the renin-angiotensin
mation of varices with portosys48 hours or 50% from baseline.
system to induce further renal
temic shunting and therefore,
salt avidity and peripheral vasodecreased delivery of blood to the
Hold beta-blockers if a patient with
constriction, which is active prevena cava.10 Portal hypertension
cirrhosis and ascites develops kidney
dominantly in the efferent
also leads to gut-barrier dysfuncinjury.
glomerular arterioles, thereby
tion complicated by the transmaintaining
intraglomerular
location of bacterial products into
perfusion pressures.6
the splanchnic vasculature11 with consequent production of
This balance between cardiac stimulation and vasoconinflammatory cytokines and splanchnic nitric oxide.12
striction is precarious. Many patients do well without
Additionally, abnormal liver metabolism leads to increased
complications. Over time, however, cardiac reserve fades or
splanchnic concentrations of vasodilatory neurotransmitters
vasodilation progresses and the result is an inability to
derived from the enteric nervous system.6 This cirrhotic
maintain sufficient cardiac output. Peripheral water retention
double hit produces one immediate consequence: decreased
progresses, and chronic renal insufficiency ensues, typified
venous return.
Table
Definition of Terms
Term
Definition
Acute kidney
injury (AKI)*
Stage 1
Stage 2
Stage 3
Type 1 hepatorenal
syndrome (HRS)*
Type 2 hepatorenal
syndrome
Spontaneous bacterial
peritonitis
a.
b.
c.
d.
e.
Increase in serum creatinine 0.3 mg/dL within 48 hours or 50% from
baseline
Increase in serum creatinine two- to threefold from baseline
Increase in serum creatinine > threefold from baseline or 4 mg/dL
Cirrhosis and ascites are present
AKI, as above
No creatinine response after 2 days of held diuretics and albumin challenge
Absence of shock, no recent nephrotoxins (eg, nonsteroidal antiinflammatory drugs, iodinated contrast)
Exclusion of structural renal disease: tubular necrosis, glomerulonephritis, proteinuria, or obstructive
nephropathy (could all be seen in or comorbid with HRS)
a. Cirrhosis and ascites are present
b. Limited response to diuretics (refractory ascites)
c. Moderate, steady decrease in renal function, typically occurring over months with creatinine <2.5 mg/dL
Paracentesis with a neutrocytic ascites (cell count >250 neutrophils/mm3) or ascitic fluid culture positive.
*New definitions as of 2015: see reference.3
Tapper et al
Protecting Cirrhotic Kidneys
Figure 1
463
Cirrhotic hemodynamics and the response to arterial underfilling.
by diuretic resistant or refractory ascites and the slow increase in serum creatinine described as Type 2 hepatorenal
syndrome.1 Type 1 hepatorenal syndrome, on the other
hand, is a rapid injury that reflects a catastrophically upset
hemodynamic balance.5,6 Spontaneous bacterial peritonitis
is a frequent inciting event.7,18 A common infection among
patients with cirrhosis, spontaneous bacterial peritonitis induces profound splanchnic and peripheral vasodilation,
further exacerbating deficits in venous return. Inotropic
stimulation cannot compensate for such deficits in preload.
When sudden arterial underfilling is addressed through
further vasoconstriction, the result is a rapid and severe renal
injury.
Leveraging the pathophysiology of renal injury in this
setting allows the clinician to quickly and, it is hoped,
effectively address it. To maintain renal perfusion, one must
ensure adequate circulating blood volume with a favorable
balance between cardiac output and vasoconstriction.
APPLYING THE THEORY
When hospitalized, patients with ascites either have or are at
risk for acute kidney injury. There are multiple generic ways
in which one can forestall the development of renal injury
by maintaining the patient’s effective circulating volume
(Figure 2). First and foremost, all patients with ascites
should have a paracentesis on admission to exclude
spontaneous bacterial peritonitis.19-22 Spontaneous bacterial peritonitis can present very subtly and often asymptomatically.1,23 Furthermore, prompt recognition and
therapy is critical to prevent hepatorenal syndrome and
shock—a delay in diagnosis by as little as 12 hours is
associated with a 2.7-fold increased risk of in-hospital
death.24 When spontaneous bacterial peritonitis is diagnosed, whether by neutrocytic ascites (> 250 neutrophils
per cubic millimeter) or culture positivity, immediate provision of appropriate antibiotics is essential (eg, 2 grams of
ceftriaxone daily for empiric treatment of communityacquired spontaneous bacterial peritonitis).25 Beyond that,
while those with jaundice will benefit most, all patients at
present should receive albumin for hepatorenal syndrome
prophylaxis using 1.5 g/kg on day 1 and 1 g/kg on day 3 of
diagnosis.26 Second, patients with cirrhosis and ascites are
at increased risk of contrast nephropathy and therefore,
benefit from efforts to prevent exposure to or reduce the
volume of iodinated contrast exposure.27 Third, routine
monitoring of urine output and temporary withholding of
diuretics during times of low oral intake are generally
indicated. Fourth, prevention of spontaneous bacterial
peritonitis can help patients avoid hepatorenal syndrome.
Although somewhat controversial given the risk for developing resistant organisms, well-selected patients with
elevated bilirubin (> 3 mg/dL) and low ascitic total protein
(< 1.5 g/dL) may benefit from antibiotic prophylaxis, usually with a fluoroquinolone.28,29
When a patient with ascites presents with acute kidney
injury, multiple maneuvers are needed (Figure 2). First,
consideration of the broader differential diagnosis is
crucial.30 Evaluation of the urine sediment and withholding potentially nephrotoxic agents should be routine.
464
The American Journal of Medicine, Vol 129, No 5, May 2016
Figure 2 A therapeutic approach to the patient with ascites. ACE ¼ angiotensin-converting enzyme;
ARB ¼ angiotensin receptor blocker; g/kg ¼ grams per kilogram; GI/Liver ¼ Gastroenterology;
NGAL ¼ neutrophil gelatinase-associated lipocalin; NSAIDS ¼ nonsteroidal antiinflammatory drugs.
Nonhepatorenal syndrome acute kidney injury has a more
favorable outcome.31 However, the distinction between
hepatorenal syndrome or prerenal azotemia and acute
tubular necrosis can be difficult. Unfortunately, urine microscopy is often inconclusive or nonspecific.32 There is
considerable interest and promise in urinary biomarkers
such as neutrophil gelatinase-associated lipocalin, a protease
expressed in the distal convoluted tubule. Fagundes et al33
demonstrated that patients with tubular necrosis had urinary neutrophil gelatinase-associated lipocalin concentrations that were several-fold higher than those with
hepatorenal syndrome. Patients with tubular necrosis had a
median of 417 mg/g creatinine, compared with 30 mg/g in
volume-depletion-related azotemia and 76 mg/g in patients
with hepatorenal syndrome. Further research is needed to
confirm the optimal cutoffs in the setting of changing definitions of acute kidney injury and heterogeneous populations, particularly in view of frequent concentration
overlap between etiologies.3,31,33,34
Second, it is critical to distinguish between simple prerenal azotemia and hepatorenal syndrome. Functionally, this
distinction is based on the outcome of volume expansion.
An “albumin challenge” is therefore recommended. Common scenarios prompting this presentation include largevolume paracentesis (particularly without prophylactic
albumin infusion), complications of diuresis, infection, and
resolved gastrointestinal bleeding. Recently revised recommendations from the International Club of Ascites suggest
as initial therapy the withholding of diuretics and 2 days of
albumin infusion at 1 g/kg.3 Given the risk of pulmonary
edema and respiratory failure after albumin infusion,35,36
caution is warranted. We recommend serial cardiopulmonary examinations and consideration of albumin dosereductions patients with known cardiomyopathy and
significant renal failure. The magnitude of creatinine
elevation at the time of presentation is associated directly
with the odds of renal injury resolution and survival,
implying that pretreatment factors partially determine patient outcomes.37 Specifically, the prehospital duration of
renal injury is prognostic, as are baseline creatinine levels.37
Additionally, there is no incremental survival benefit to
earlier albumin infusion within the first 48 hours.36 Therefore, with sufficient time for a thorough evaluation and
careful exclusion of other causes, a deliberate approach to
renal injury is safe and effective.
Third, a thoughtful examination of the medication list on
admission is essential to be sure to hold diuretics, discontinue
angiotensin-converting enzyme inhibitors, alpha-antagonists
(eg, tamsulosin), and avoid nonsteroidal antiinflammatories
(NSAIDs).1 Pain should never be treated with NSAIDs in
patients with ascites. Renal prostaglandin production may be the
only counterbalance to catecholamine- and angiotensin-induced
Tapper et al
Protecting Cirrhotic Kidneys
glomerular vasoconstriction in the afferent arteriole; NSAIDs
reduce prostaglandin production, which, for patients with ascites, will reduce glomerular filtration rate.38,39
Finally, cardiac compensation may be essential to renal
recovery. For example, the purpose of albumin infusion is
the preservation of cardiac output by supporting stroke
volume in the setting of arterial underfilling, especially in
the setting of infections.10,26 Beta-blockade, however, limits
chronotropic and inotropic cardiac compensation and may,
therefore, defeat the purpose of volume expansion.
Increasingly, beta-blockade is viewed as possessing a therapeutic index.40 Eventually, the benefits, be it primary
prophylaxis of variceal hemorrhage or prevention of spontaneous bacterial peritonitis, are outweighed by the risks of
decreased cardiac output, particularly acute kidney injury.40-42
The development of spontaneous bacterial peritonitis is
likely the most clear-cut example of an event that heralds
diminishing returns and increased risks of beta-blockade.
Indeed, as shown by Mandorfer et al,43 beta-blockers increase transplant-free survival in patients with a history of
ascites but not spontaneous bacterial peritonitis, while the
risk of death is increased for patients who continue betablockers after a first episode of spontaneous bacterial peritonitis. In order to maximize cardiac output and mean
arterial pressure during renal failure, beta-blockers,
including those prescribed for variceal bleeding prophylaxis, should be held at least temporarily.40,42,44,45
TREATMENT OF HEPATORENAL SYNDROME
A failure to respond to volume expansion and exclusion of
nephrotoxic agents and other causes of renal injury merits
initiation vasoconstrictor therapy (Table).1,3 The underlying
premise of vasoconstrictor therapy is that splanchnic vasodilation prevents the intended improvements in effective
arterial volume related to albumin infusion. In this setting,
agents that constrict the splanchnic vasculature augment
cardiac output by enhancing cardiac venous return and
improve renal perfusion.46 Vasoconstrictor therapies include
midodrine (an oral alpha-agonist and vasopressor) and
octreotide (a serotonin antagonist that likely reverses some
splanchnic vasodilation), norepinephrine (a vasopressor), or
terlipressin (a vasopressor) where available with additional
volume expansion.29 All vasoconstrictors should include cotherapy with 10-20 grams of albumin daily.1
Terlipressin delivered in a continuous infusion without a
bolus at 3 mg/24 hours up-titrated to 12 mg/24 hours if the
serum creatinine failed to decrease by > 25% of the initial
value provides significant benefit to patients with hepatorenal syndrome, with a superior rate of renal recovery in
a randomized trial compared with midodrine and octreotide.35 This study was stopped early for efficacy when 48
Italian patients with mean model for end-stage liver disease
scores of roughly 30 were enrolled; 55.5% of patients
receiving terlipressin achieved reversal of renal failure,
compared with 4.8% on midodrine/octreotide. As nonresponders were offered a rescue therapy, many patients
465
randomized to midodrine/octreotide ultimately received
terlipressin. In general, the factors associated with poor
response include total bilirubin 10 mg/dL, failure to increase mean arterial pressure > 5 mm Hg, or lack of an
absolute serum creatinine reduction > 0.5 mg/dL by the
third day of therapy.47
Terlipressin, however, is not approved for use in the US.
This is partly because a randomized, double-blind, placebocontrolled trial that employed bolus dosing with 1 mg of
terlipressin administered by slow intravenous push every 6
hours or matching placebo failed to achieve a survival
advantage over albumin monotherapy in this population.48
Furthermore, while early trials were suggestive of significant benefits,49,50 they also highlighted the risk of side
effects on treatment, including abdominal cramps and
ischemic extremities. These risks may be more likely in the
setting of bolus delivery, as opposed to continuous
infusions, as continuous terlipressin use was not associated
with risks over octreotide/midodrine.35 Side effects leading
to treatment discontinuation occur in roughly 7% of cases.
Nevertheless, a meta-analysis of prior trials including bolus
therapy still demonstrated a mortality benefit over albumin
monotherapy or no intervention (relative risk 0.76; 96%
confidence interval, 0.63-0.91).51
Three studies have evaluated the role for norepinephrine
infusions in the treatment of hepatorenal syndrome,52-54 2 in
comparison with terlipressin in randomized controlled trials.52,54 In the largest study, 46 patients were randomized to
receive terlipressin or norepinephrine (with albumin).54
Norepinephrine was provided in continuous infusion, 0.5
mg/h initially, with stepwise increases every 4 hours up to a
maximum of 3 mg/h, with the goal of a 10-mm Hg increase
in mean arterial pressure or a 200-mL increase in the
4-hour urine output. Responses were achieved in 39.1% and
43.4% of patients receiving terlipressin and norepinephrine,
respectively. Unfortunately, terlipressin may have been
under-dosed, limiting the interpretation of the data. Boluses
were given at initial doses of 0.5 mg/6 hours, with stepwise
increases every 3 days if a 1 mg/dL reduction in serum
creatinine was not achieved. Additionally, norepinephrine
use generally is restricted to the intensive care unit,
increasing its cost and limiting its application.
In general, patients on vasoconstrictor therapy must be
monitored closely. This includes serial blood pressure and
heart rate checks, particularly in view of a risk of bradycardia as well as extremity examinations. Response to
treatment via serum creatinine levels should be assessed at
least every 48 hours and continued for 24 hours beyond the
point of a complete response or for a maximum of 14
days.35 Finally, particularly if renal function deteriorates, the
risk of pulmonary edema with ongoing albumin infusions
and, as such, rigorous cardiopulmonary examinations
should be performed routinely.36
For centers without access to terlipressin, the standard
therapy for hepatorenal syndrome should include daily
infusions of albumin (10-20 grams), midodrine at doses up
to 12.5 mg 3 times per day to achieve an increase in mean
466
systolic blood pressure of 15 mm Hg, and octreotide titrated
from 100 to 200 mg subcutaneously 3 times daily.1
Octreotide alone is ineffective.55 As above, the expected
outcomes are somewhat poor.35 However, there is still a
small benefit. In a study of 87 patients with type 1 hepatorenal syndrome, 21 of whom received no intervention (66
who received midodrine/octreotide), sustained reductions in
serum creatinine were observed in 40% of patients on
therapy, compared with 5% of those without.56 Ultimately,
for poor outcomes, hemodialysis is the major salvage therapy, particularly for patients who are transplant candidates.
Beyond that, there is ongoing study about the role of a
transjugular intrahepatic portosystemic shunt for highly
selected patients with largely preserved hepatic function.
CONCLUSION
Acute kidney injury in the setting of ascites and cirrhosis is a
medical emergency characterized by significant morbidity
and mortality. Owing to the specifics of cirrhotic physiology, the treatment of acute kidney injury in the setting of
ascites has unique features, widespread knowledge of which
will benefit our patients with cirrhosis. The basic principles
of cirrhotic hemodynamics inform an effective approach to
the diagnosis and treatment of patients with ascites.
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