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CHAPTER
17
Hepatorenal syndrome and acute kidney injury
in cirrhosis
Florence Wong
Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto General
Hospital, Toronto, ON, Canada
Introduction
Renal dysfunction is a common complication of cirrhosis with ascites, occurring in approximately 50% of
patients admitted into hospital
[1,2], associated with significant morbidity and negatively impacts patient sur-
vival
[3]. Renal dysfunction can be broadly divided into either acute or chronic. Acut e renal dysfunction, or more
commonly known as acute kidney injury (AKI), describes a sudden deterioration in renal function usually over
days, while chronic renal failure evolves over weeks to months. AKI can also occur in patients with chronic kid-
ney disease (CKD), the so-called acute-on-chronic renal failure
[4].
AKI is a syndrome that describes a heterogeneous group of conditions. It encompasses both functional renal
diseases and structural renal damage that occur acutely (
Fig. 17.1). It usually occurs in patients who do not have
any previous renal disease but may have some underlying condition that predisposes to the development of
AKI. Functional AKI includes prerenal azotemia and type 1 hepatorenal syndrome (HRS1), while structural AKI
includes conditio ns such as acute tubular necrosis (ATN), acute glomerulonephritis, and interstitial nephritis.
CKD can also be related to either functional abnormalities or structural changes in the kidneys. Typical example
of functional CKD would be type 2 HRS related to the presence of refractory ascites in cirrhosis, while structural
CKD can result from diabetic or hypertensive nephropathy (
Fig. 17.1). In patients with cirrhosis, AKI occurs
more commonly than CKD. However, the prevalence of CKD in cirrhosis will rise in the future, as the prevalence
of nonalcoholic steatohepatitis is increasing rapidly, associated with a corresponding rise in the prevalence of
diabetes and diabetic nephropathy. However, this chapter will concentrate on functional AKI in cirrhosis and
its prototype HRS1, and will discuss the diagnosis, its pathophysiology, management, prevention, and future
directions
[5].
The evolving concept of renal dysfunction in cirrhosis
For several decades, acute renal dysfunction in cirrhosis has always been diagnosed as HRS1, which was first
defined by the International Ascites Club (IAC) in the 1990s
[6]. Clinicians caring for patients with cirrhosis, asci-
tes, and renal dysfunction soon recognized that the threshold serum creatinine (sCr) of 2.5 mg/dL (233 μ mol/L)
required for the diagnosis of HRS1 in patients with decompensated cirrhosis and sarcopenia represented very
advanced renal failure. This is because creatinine is derived from creatine, and in cachectic patients with
decreased muscle bulk, the sCr is often significantly lower compared to the reduction in glomerular filtration
rate (GFR)
[7]. Thus sCr can still be within the normal laboratory range despite significant renal dysfunction [8] .
Therefore the IAC, in collaboration with other subspecialty organizations, adopted an acute change in sCr as a
275
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00003-6 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
means of diagnosing acute renal dysfunction in cirrhosis [9], especially when other patient populations had
shown that a small change in sCr had a negative impact on patient outcomes
[10]. The term AKI was also
adopted to describe the condition in line with the nephrology and intensive care subspecialties.
While the nephrology and intensive care subspecialties were refining their definition of AKI
[1113], the IAC
was also adapting the definition of AKI to suit the cirrhotic patients. The Kidney Disease Improving Global
Outcome’s definition of AKI is the latest reiteration
[13], which was modified in 2015 by the IAC to accept only the
sCr changes without taking into consideration the urine volume changes for the diagnosis of AKI in cirrhosis
[4].
This is because patients with decompensated cirrhosis and ascites frequently only make approximately 500 mL of
urine per day due to severe renal water retention, without any evidence of reduction in GFR. Accepting the urine
output reduction as a definition for AKI would place the majority of patients with decompensated cirrhosis and
ascites as having AKI which would not be appropriate. Indeed, a retrospective study using intensive care admis-
sion database from a single center identified AKI in 84.6% of cirrhotic patients admitted into intensive care unit
[14]. The results of this study are also not representative of the cirrhotic population as a whole and therefore hepa-
tologists have continued to not adopt the urine output criteria in the diagnosis of AKI in cirrhosis.
Fig. 17.2 shows
the evolution of the concept of renal dysfunction in cirrhosis over the past three decades.
FIGURE 17.2 The evolving concept of renal dysfunction in cirrhosis. ADQI, Acute Dialysis Quality Initiative; AKI, acute kidney injury;
AKIN, Acute Kidney Injury Network; HRS1, hepatorenal syndrome type 1; IAC, International Ascites Club; KDIGO, Kidney Disease
Improving Global Outcome; RIFLE, Risk, Injury, Failure, Loss of function, End-stage renal disease.
FIGURE 17.1 Different phenotypes of renal disease
in patients with cirrhosis. AKI, acute kidney injury;
ATN, acute tubular necrosis; CKD, chronic kidney dis-
ease; GN, glomerulonephritis; HRS, hepatorenal syn-
drome; AKI-nonHRS, AKI episodes that do not fulfill all
the diagnostic criteria for AKI-HRS and are not respon-
sive to fluid challenge. Source: Adapted with permission
from N. Jagarlamudi, F. Wong. Acute kidney injury: predic-
tion, prognostication and optimisation for liver transplant.
Hepatol Int. 2020;14:167179.
276 17. Hepatorenal syndrome and acute kidney injury in cirrhosis
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Definition and diagnostic criteria of acute kidney injury in cirrhosis
AKI is defined when there is either an acute increase in sCr of at least 0.3 mg/dL (26.4 μmol/L) in ,48 hours
or a 50% increase in sCr from a stable baseline within the previous 3 months. If no such value exists, the closest
available stable sCr is used. If no previous sCr is available, the admission sCr is used. A new baseline may then
be established during the admission
[4] (Table 17.1). Once AKI is diagnosed, its severity is described in stages,
with stage 1 representing minimal change, stage 2 a twofold increase, and stage 3 a threefold increase in the sCr.
The initiation of renal replacement therapy (RRT) irrespective of the fold increase in sCr is also classified as stage
3 AKI. The European Association for the Study of the Liver recognizes the subdivision of stages 1a and 1b
depending on whether the sCr at AKI diagnosis is below or above 1.5 mg/dL (133 μmol/L), respectively
[15].
The reason for separating stage 1 AKI into the a and b substages is because studies from Europe have reported
quite different clinical outcomes for these subgroups of patients, with the prognosis of stage 1b AKI approaching
that of stage 2 AKI
[16,17].
However, the IAC and the American Association for the Study of Liver Diseases have not endorsed the separation
of stage 1 AKI into the a and b subgroups
[4,18]. HRS1 is a special form of AKI. It has now been renamed HRS-AKI
and is defined by an acute sCr change that is stage 2 or higher AKI, while fulfilling all the other diagnostic criteria of
HRS (
Table 17.2) [19]. However, the latest proposal is to assess whether a urine output of # 0.5 mL/kg of body weight
in $ 6 hours with or without the sCr change could define HRS-AKI
[20]. This will have to await future studies.
Progression or regression of AKI is defined as upgrading or downgrading of AKI stage with treatment, respectively,
TABLE 17.1 Diagnostic criteria of acute kidney injury in cirrhosis.
Parameter Definition
Baseline sCr Stable sCr in # 3 months
If not available, a stable sCr closest to the current one
If no previous sCr at all, use admission sCr
Definition of AKI Increase in sCr by $ 0.3 mg/dL (26.4 μmol/L) in ,48 h, or 50% increase in sCr from baseline
Staging:
Stage 1
Stage 2
Stage 3
Increase in sCr by $ 0.3 mg/dL (26.4 μmol/L) in ,48 h, or increase in sCr $ 1.52.0 times from baseline
Increase in sCr .2.03.0 times from baseline
Increase in sCr .3.0 times from baseline, or sCr .4 mg/dL (352 μmol/L) with an acute increase of $ 0.3 mg/dL
(26.4 μmol/L), or the initiation of renal replacement therapy
Course of AKI:
Progression
Regression
Progression of AKI to a higher stage or need for renal replacement therapy
Regression of AKI to a lower stage
Response to Rx:
None
Partial
Complete
No regression of AKI
Regression of AKI stage with final sCr $ 0.3 mg/dL (26.4 μmol/L) from baseline
Regression of AKI stage with final sCr , 0.3mg/dL (26.4 μmol/L) from baseline
AKI, acute kidney injury; Rx, treatment; sCr, serum creatinine.
Adapted with permission from Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients
with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64:531537.
TABLE 17.2 Diagnostic criteria for HRS-AKI.
• Cirrhosis with ascites
• Diagnosis of $ stage 2 AKI according to IAC-AKI criteria
• No response after two consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg of body weight to a
maximum of 100 g/day
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal kidney disease as indicated by: absence of proteinuria .500 mg/day, microhaematuria ( . 50 red blood cells per
high power field), and normal renal ultrasonography
AKI, acute kidney injury; IAC, International Ascites Club; HRS, hepatorenal syndrome.
Adapted with permission from Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients
with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64:531537.
277Definition and diagnostic criteria of acute kidney injury in cirrhosis
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and with a corresponding worsening or improvement in prognosis [21]. Treatment response can be partial or complete
when the improvement in sCr is either above or below 0.3 mg/dL (26.4 μmol/L) from baseline, respectively.
More recently, the IAC proposed to add another category or renal dysfunction in cirrhosis. It is termed HRS-
acute kidney disease, defined as a percent increase in sCr of ,50% or as an estimated GFR , 60 min/mL/1.73m
2
for less than 3 months while fulfilling the IAC criteria for HRS [20]. The natural history and outcomes of this sub-
category of HRS are yet unknown and await further studies.
Epidemiology
AKI can occur in both outpatients and hospitalized patients with cirrhosis. Among outpatients with cirrhosis
having baseline sCr within the normal laboratory range, AKI has been reported to occur in 37%54%
[22,23] of
patients; the higher the baseline sCr, even when it is within the normal range, the higher the likelihood of devel-
oping AKI. Among inpatients, a retrospective study using International Classification of Diseases codes to iden-
tify admitted patients with cirrhosis in the province of Alberta, Canada reported that 39% of patients experienced
at least one episode of AKI, with the majority (92%) having had the AKI episode within 30 days of admission
[24]. In another retrospective study using the National Inpatient Sample of the United States which contains data
from 44 states, the incidence of AKI was 14.9% in patients with cirrhosis
[25]. However, in a prospective cohort
of admitted patients with cirrhosis and a bacterial infection, the incidence of AKI of any severity was as high as
49%
[26].
HRS1 is a special type of AKI. Older literature have reported an annual incidence of 18%
[27] among patients
with cirrhosis and ascites during follow-up. Further assessment of inpatients with cirrhosis and ascites showed
an incidence of 6.9% for HRS1 among all admitted cirrhotic patients and 17% among patients with functional
renal failure
[1]. With the use of the newer diagnostic criteria for AKI in cirrhosis [4], the incidence of HRS-AKI
or stages 2 and 3 AKI has been reported to be 12%15% of all admitted cirrhotic patients
[28,29] but 43%45%
among admitted patients with AKI
[29,30].
The typical patient who develops AKI is a middle-age man with either alcoholic live r disease or viral hepatitis
as the etiology of cirrhosis, who has had some past history of cirrho tic complications unrelated to ascites and
some degree of liver dysfunction, and who is admitted into hospital because of infection
[2830]. However, all
cirrhotic patients with ascites are at risk for the development of AKI and therefore all of these patients need to be
monitored regularly for the development of AKI, as early diagnosis could potentially be lifesaving in these
patients.
Pathophysiology
The pathophysiology of functional AKI is complex (Fig. 17.3). Several mechanisms involving multiple organ
systems interact to produce the pathophysiological changes that lead to AKI in cirrhosis. These patients are sus-
ceptible to the development of AKI bec ause of circulatory dysfunction that occurs in decompensated cirrhosis
and a maladaptive renal perfusion response. Other contributing factors include abnormal cardiac function pecu-
liar to cirrhosis, known as cirrhotic cardiomyopathy, systemic inflammation, infection, or any other event that
can disturb the circulatory dysfunction. All of these processes can occur independently of each other but can aug-
ment the deleterious effects of the other
[31].
Hemodynamic changes in cirrhosis
The distortion of liver architecture with the development of cirrhosis leads to increased resistance to portal
flow and the development of portal hypertension (see Chapter 14: Peripheral Vasculature in Portal
Hypertension). This leads to additional shear stress on the splanchnic vessels with resultant increased production
of local vasodilators. The most abundant vasodilator is nitric oxide, although others such as carbon monoxide,
adrenomedullin, and glucagon are also present in significant amounts
[32]. The presence of portal hypertension
also increases bacterial translocation across the gut wall
[33]. Some of the bacterial products also have vasodila-
tory properties. The end result is splanchnic vasodilatation. The presence of portal hypertension also stimulates
local angiogenesis, thereby greatly increasing the capacitance of the splanchnic circulation. The resultant increase
278 17. Hepatorenal syndrome and acute kidney injury in cirrhosis
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in portal inflow perpetuates the portal hypertension. The opening of preexisting portal systemic connections or
collateral vessels allows some of the splanchnic vasodilators to be transferred to the systemic circulation resulting
in systemic vasodilatation. The circulatory volume then becomes relatively inadequate to fill the expanded circu-
latory capacitance, a condition known as a reduction in the effective arterial blood volume (EABV)
[34].
Several physiological compensatory mechanisms are recruited to replenish the EABV. These include the acti-
vation of vasoconstrictor systems including the sympathetic nervous system, the renin-angiotensin-aldosterone
system, and the nonosmotic release of vasopressin to reduce the extent of splanchnic and systemic vasodilatation.
The renal circulation also undergoes renal vasoconstriction to retain sodium and water to increase the circulatory
volume. Thus the scene is set for re nal dysf unction and any further event that exaggerates the reduction of EABV
will precipitate AKI.
Cardiac dysfunction in cirrhosis
In the early stages of cirrhosis, hemodynamic stability in the presence of splanchnic and systemic vasodilata-
tion is maintained by a hyperdynamic circulation characterized by increased cardiac output, heart rate, and
plasma volume. However, this hyperdynamic circulation occurs at the expense of a diminished cardiac reserve.
As the vasodilatation progresses, the gradual reduction in afterload is no longer followed by an appropriate
increase in cardiac output
[35]. This inability to increase cardiac output in the presence of a physiological stress is
known as systolic incompetence, which is part of a syndrome known as cirrhotic cardiomyopathy
[36] (see
Chapter 15). In a longitudinal study on cirrhotic patients with refractory ascites, cardiac output was noted to
be significantly lower in patients who subsequently developed HRS1 and that it became further decreased at the
onset of HRS1
[37]. Indeed, impaired cardiac reserve has been identified as a predictive factor for HRS develop-
ment
[38]. In another cohort of cirrhotic patients with ascites and spontaneous bacterial peritonitis (SBP), those
who developed HRS1 had a significant lower cardiac output at SBP diagnosis, which declined even further after
the resolution of the SBP
[39]. It is postulated that this systolic incompetence is eliciting an even higher vasocon-
strictor response contributing to the renal failure
[40]. Furthermore, diastolic dysfunction, which is another com-
ponent of cirrhotic cardiomyopathy [36], if present, can lead to high right-sided cardiac pressures, which could
result in renal venous congestion, further compromising renal hemodynamics and function
[41].
FIGURE 17.3 Pathophysiology of acute kidney injury in cirrhosis. DAMPs, damage-associated molecular patterns; DILI, drug induced
liver failure; GFR, glomerular filtration rate; NO, nitric oxide; PAMPs, pathogen associated molecular patterns; RAAS, renin angiotensin aldo-
sterone system; SNS, sympathetic nervous system.
279Cardiac dysfunction in cirrhosis
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The role of inflammation
The immune surveillance function of the liver in patients with cirrhosis is constantly challenged by the pres-
ence of excess inflammation, related to increased translocation of bacteria and bacterial products across the gut
wall as a result of portal hypertension. In patients with ongoing liver cell damage, such as those with alcoholic
hepatitis or viral hepatitis, hepatocyte death further adds to the inflammation. The respective by-products are
pathogen-associated molecular patterns and damage-associated molecular patterns, which incite an immune
response with a downstream effect of activation of the inflammatory cascade
[42]. Increased levels of various
proinflammatory cytokines, particularly interleukin-6 (IL-6) and tumor necrosis factor alpha, reported in decom-
pensated cirrhosis support this contention
[33]. These inflammatory cytokines may also stimulate the production
of nitric oxide [43], a potent systemic vasodilator, thereby adding to the systemic vasodilatation, exaggerating the
extent of reduction in EABV, and causing further reflex renal vasoconstriction. In addition, endotoxemia in
decompensated cirrhosis has been shown to be involved in promoting endothelial dysfunction
[44]. This has the
effects of stagnation of the microcirculation in various organs including the kidneys, thereby exposing the tissues
to oxidative stress-related injuries
[4547]. It has been noted that at least one-third of patients with HRS-AKI
have evidence of inflammation without any documented infection
[48], confirming the role of inflammation in
the pathogenesis of HRS-AKI.
Predictive factors for the development of hepatorenal syndrome-acute kidney injury
While the hemodynamic changes and the proinflammatory milieu are inducive to the development of HRS-
AKI in decompensated cirrhosis, usually there is a precipitating event that either disturbs the hemodynamics fur-
ther or exacerbates the inflammatory state that will trigger the development of HRS-AKI. This is well exemplified
in a cohort of 58 patients who developed HRS-AKI, whose inflammatory cytokine levels were significantly higher
than those in patients without HRS-AKI
[49].
The most common precipitating event for HRS-AKI is bacterial infection, accounting for two-thirds of the cases
[50], with SBP being the most frequent precipitant followed by urinary tract infection (UTI), pneumonia, cellulitis,
and bacteremia
[51]. In patients with cirrhosis admitted with a bacterial infection or who developed a nosocomial
infection, AKI of any severity occurred in 49% of patients following an episode of SBP or UTI, and in 37% of
patients with other bacterial infections, HRS-AKI was diagnosed in 9% of patients
[52]. Once AKI occurred, the
patients with endocarditis, secondary peritonitis, pneumonia, and bacteraemia had the worst prognosis
[53].
Patients with sterile inflammation such as those with alcoholic hepatitis or viral hepatitis are also at risk for
the development of AKI. In patients admitted with alcoholic hepatitis, especially those with a higher Model of
End-Stage Liver Disease (MELD) score, the incidence of AKI was 32%
[52]. In another study including patients
with cirrhosis admitted mostly with viral hepatitis B flare, acute renal failure as defined by a sCr of $ 2 mg/dL
occurred in 29.2% of all patients who developed at least one organ failure
[54].
Other less-common precipitants of HRS-AKI include events that can further perturb the volume statu s of thes e
patients. These include large-volume paracentesis without adequate volume replacement, excessive diuretic
doses, or intravascular volume depletion with gastrointestinal blee d or vomiting and diarrhea
[50]. Patients who
have gastrointestinal bleeds are also at risk for the devel opment of bacterial infection related to increased bacte-
rial translocation, complement deficiency, and aspiration pneumonia
[55], further adding to their risk for the
development of AKI.
Diagnosis
The diagnosis of HRS-AKI is one of exclusion (Fig. 17.4). The differential diagnoses of HRS-AKI include struc-
tural cause of AKI, renal injury from nephrotoxic drugs, and prerenal azotemia. A history of excess fluid loss
and dry mucous membranes on examination suggests the presence of prerenal azotemia. Improvement of sCr
after fluid challenge confirms the diagnosis of prerenal azotemia. A history of nephrotoxic drug use or the
administration of radiographic dye suggests renal injury from these agents. A history of hypotension or septic
shock suggests the presence of ATN, especially in patients admitted into intensive care units. These patients also
have various casts, such as granular or epithelial cell casts, and occasionally even free epithelial cells. Patients
280 17. Hepatorenal syndrome and acute kidney injury in cirrhosis
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with significant proteinuria or hematuria are likely to have parenchymal renal disease such as glomerulonephri-
tis. If the abdominal ultrasound shows small echogenic kidneys, the patient is likely to have CKD. Therefore
HRS-AKI can only be diagnosed after all the above causes of renal dysfunction have been excluded
[56].Itis
worthy to note that patients with CKD can also develop AKI superimposed on their CKD. Such patients are said
to have acute-on-CKD and tend to have a worse prognosis when compared to patients with AKI
[2].
Biomarkers
It is sometimes difficult to differentiate clinically the various etiologies of AKI. For example, patients who
have had a prolonged course of HRS-AKI may develop ATN as a result of renal ischemia
[57]. Patients with
severe liver dysfunction and therefore high levels of serum bilirubin are at risk of developing HRS-AKI, and yet
they are not responsive to vasoconstric tor therapy
[58], the mainstay of treatment for HRS-AKI (see further). This
is because these patients may have developed tubular damage from the high bilirubin levels, the so-called chole-
mic nephropathy
[59]. Therefore various biomarkers have been developed which try to differentiate the various
types of AKI. Biomarkers are molecules or substances that can be objectively measured and evaluated as an indi-
cator of biological functions or pathogenic processes. In the presence of either functional changes, such as alter-
ation in glomerular filtration or tubular reabsorption, or renal tubular damage, the appropriate biomarkers
should increase propor tionally. Sometimes the increases can precede the rise in sCr
[60]. Therefore they have
emerged as potentially useful tools in the prediction for the development and differential diagnosis of AKI.
Cystatin C is a low molecular weight molecule produced by all nucleated cells. Like creatinine, it is filtered by
the glomeruli and reabsorbed by the proximal tubules where it is catabolized
[61]. That is, it is handled by the
kidney in a similar fashion as creatinine and therefore can be used as a marker of renal dysfunct ion. It is a better
index of glomerular filtration than sCr as its level is not confounded by age, gender, and muscle mass
[62]. The
detection of elevated levels could herald the onset of renal dysfunction and therefore could be used as a tool for
the prediction of AKI development. It is commercially available but has not been implemented into clinical
practice.
Biomarkers that can differentiate between the various causes of AKI are neutrophil gelatinase-associated lipo-
calin (NGAL), IL-18, kidney injury molecule-1, and liver-type fatty acid-binding protein
[63]. These are tubular
injury markers and therefore elevated levels can be detected in both serum and urine within hours of renal tubu-
lar damage. The best-studied biomarker in cirrhosis is NGAL. Patients with ATN as a cause of AKI had NGAL
levels at least 10-fold higher than those with prerenal azotemia, while those with HRS1 had NGAL levels
FIGURE 17.4 Hepatorenal syndrome type 1 as a diagnosis of exclusion. ATN, acute tubular necrosis; GI, gastrointestinal; HRS1, type 1
hepatorenal syndrome; LVP, large-volume paracentesis; sCr, serum creatinine.
281Biomarkers
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intermediate between the other two groups [6467]. However, NGAL is also expressed in neutrophils, in the
liver and the gastrointestinal tract. Therefore, serum and urinary NGAL levels can also be increased in the pres-
ence of liver injury or UTI, respectively. Despite this, NGAL has been shown to perform well in the differentia-
tion of various types of AKI in situations without these confounding factors
[68].
When a panel of renal tubular damage biomarkers including urinary NGAL, IL-18, kidney injury molecule-1,
and liver-type fatty acid-binding protein were employed in patients with cirrhosis, the diagnosis of ATN as a
cause of the renal dysfu nction was more accurate
[69]. Patients with ATN consistently had higher levels of all
four biomarkers compared to those with non-ATN causes of AKI. Cut-off levels were identified for all four bio-
markers and the relative risk for the presence of ATN increased in proportion to the number of biomarkers being
above the cut-off values. When four biomarkers were present above their cut-off levels, there was a . 90% chance
of accuracy for the patient to have ATN as a cause of AKI
[69].
Despite their promise as a useful tool in the differential diagnosis of AKI, none of the tubular injury markers
is currently approved for clinical use. As new biomarkers are being developed, the ones that are described today
may be superseded tomorrow. In the future, as the demarcation between functional and structural causes of AKI
become blurred, it may be a panel of biomarkers that will be employed to best identify the cause of AKI and
assist in the management of these patients.
Management
The goals of management of HRS-AKI are several fold: (1) to correctly diagnose the AKI phenotype; (2) to
institute treatment as soon as possible to improve the chances of HRS-AKI reversal; and (3) to optimize the
patient for liver transplant if needed (
Fig. 17.5).
General measures
A careful history and physical examination might provide some clues as to whether the patient has prerenal azo-
temia, structural renal disease, or HRS-AKI. A bland urine microscopic examination suggests functional renal fail-
ure while the presence of casts in the urine suggests structural renal disease, and the presence of small-sized
echogenic kidneys on abdominal ultrasound suggests the presence of chronic parenchymal renal disease (
Fig. 17.4).
FIGURE 17.5 Suggested algorithm for
the management of hepatorenal syndrome.
AKI, acute kidney injury; HRS-AKI, hepa-
torenal syndrome-acute kidney injury; Rx,
treatment; sCr, serum creatinine. The sym-
bol “#” represents diagnosis of HRS-AKI
as per reference
[4].
282 17. Hepatorenal syndrome and acute kidney injury in cirrhosis
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Once structural renal diseases have been excluded, the main differential diagnoses are prerenal azotemia and
HRS-AKI. The next step is optimization of the patient’s fluid status by withdrawing diuretics and fluid resuscitation.
This should be packed red blood cells in situations of blood loss or colloids in case of fluid loss. Crystalloids such as
normal saline is discouraged, as it is isotonic to plasma, and therefore tends to be pushed into the peritoneal cavity
as ascites due to the presence of portal hypertension. Patients should undergo a septic work-up culturing from all
possible sites and then commence on empirical antibiotics until the culture results are available
[70].
Albumin
Albumin is the most abundant plasma protein produced by the liver, constituting 50%60% of protein in the
circulation in healthy individuals. In patients with cirrhosis, the production of albumin is reduced and whatever
is produced is functionally impaired
[71]. Therefore, external albumin is the preferred resuscitation solution, not
only for its oncotic properties but also for its antiinflammatory, antioxidant, and scavenger qualities
[72]. The
multiple binding sites of albumin are important in binding toxic metabolites and inflammatory mediators,
thereby reducing the extent of inflammation and toxic tissue damage. Albumin also reduces the oxidative stress
by circulating mainly in the reduced state and acting as a free radical scavenger for reactive oxygen and nitroge n
species. Because albumin is an effective volume expander, it prevents the decrease in cardiac output and the con-
sequent increase in plasma renin activity. An improvement in cardiac contractility is also attained by albumin
infusion, by reversing the negative effects of oxidative stress
[73], with overall improvement in cardiovascular
function and renal perfusion. It appears that only high doses of albumin are effective in suppressing the inflam-
matory mediators in cirrhosis
[74], although a formal dose-response study has never been done. This may also
explain why in patients with HRS-AKI, the survival was proportional to the doses of albumin given
[75].
Therefore, the use of albumin is now recommended by practice guidelines as part of the treatment for HRS-AKI
[15,18]. The recommended dose of albumin is 1 g/kg of body weight up to maximum of 100 g/day. This can be
used to diagnose HRS-AKI as well as the definitive treatment for prerenal azotemia.
Vasoconstrictors
Albumin alone is usually ineffective in reversing HRS-AKI and vasoconstrictor is needed to improve renal
function. This is because improvement of hemodynamics is needed to correct the pathophysiological abnormali-
ties that underly the pathogenesis of HRS-AKI. The vasoconstrictors that have been studied so far include terli-
pressin, norepinephrine, a combination of midodrine and octreotide, and dopamine with furosemide
[76].To
date, all the publ ished literature have reported on results of vasoconstrictor use on patients who fulfilled the tra-
ditional definition of HRS1. Whether the results in patients who fulfill the revised definition of HRS-AKI will be
the same still awaits future studies. Although terlipressin is the vasoconstrictor that has been most frequently
reported in the literature and is widely used in many countries around the world, many physicians in North
America still use the combination of midodrine and octreotide, as terlipressin is still not yet licenced in the
United States or Canada.
Terlipressin
Terlipressin is a vasopressin analog. It acts on the vascular smooth muscle cells causing vasoconstriction. In
the splanchnic circulation, it reduces portal inflow and therefore decreases portal pressure
[77], as portal hyper-
tension is the initiator of the pathogenetic processes that lead to renal vasoconstriction. Simultaneously, terlipres-
sin also induces a reduction of intrahepatic resistance, resulting in an increase in intrahepatic blood volume. This
when transferred to the pulmonary circulation improves the central blood volume, with improved EABV
[78].In
the systemic circulation, terlipressin increases the blood pressure and therefore the renal perfusion pressure. It
has also been postulated that by reducing the portal pressure, terlipressin can redu ce the extent of bacterial trans-
location in the gut of patients with advanced cirrhosis, potentially reducing the extent of inflammation in these
patients
[79]. There is evidence that terlipressin may also reduce the extent of vasodilatation in the presence of
infection
[80]. Therefore terlipressin targets many aspects of the pathophysiology of HRS-AKI.
283Vasoconstrictors
III. Cardiovascular system in liver failure
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