The Use of Albumin for the Prevention of Hepatorenal ...sites.utexas.edu/pharmacotherapy-rounds/files/2015/09/giddings10... · 2 Hepatorenal Syndrome Introduction1 Renal failure in

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The Use of Albumin for the Prevention of Hepatorenal

Syndrome in Patients with Spontaneous Bacterial Peritonitis

and Cirrhosis

http://www.funnyjunk.com/funny_pictures/1743659/Enlarged/

Daniel Giddings, PharmD

PGY-1 Pharmacy Practice Resident

St. David's South Austin Medical Center

October 4, 2013

Learning Objectives:

1. Describe the diagnostic criteria, pathogenesis and epidemiology of hepatorenal syndrome and

spontaneous bacterial peritonitis (SBP).

2. Compare treatment guidelines for the use of albumin for the prevention of hepatorenal syndrome in

SBP.

3. Examine the evidence base for use of albumin in these patients.

4. Determine albumin's role in the prevention of hepatorenal syndrome in SBP patients.

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Hepatorenal Syndrome

Introduction

1

Renal failure in patients with cirrhosis is relatively common, and can be attributed in some to dehydration or

intrinsic renal parenchymal disease such as glomerulonephritis. In other cases, however, renal failure is not

accompanied by any underlying renal pathology and cannot be attributed to other factors; this is known as

hepatorenal syndrome.

Diagnosis

1

Entirely a diagnosis of exclusion in patients with cirrhosis and ascites with associated renal impairment

Treatment guidelines both reference diagnostic criteria put out by the International Ascites Club,

updated last in 2007

The six criteria are:

o Presence of cirrhosis with ascites

o Renal impairment, as indicated by a serum creatinine of greater than 1.5mg/dL

o No improvement in renal impairment (reduction in serum creatinine to < 1.5mg/dL) despite

diuretic withdrawal and volume expansion with albumin (1g/kg actual body weight up to 100g)

for 2 days

o Absence of shock

o No current or recent treatment with nephrotoxic drugs, such as aminoglycosides

o Absence of parenchymal kidney disease as indicated by proteinuria of more than 500mg/day,

microhematuria (> 50 RBC/hpf), and/or abnormal renal ultrasound

Can be separated into two dynamic classes

o Type 1 - A doubling in serum creatinine that reaches at least 2.5mg/dL over the course of at least

two weeks

o Type 2 - Cases that meet diagnostic criteria without meeting the criteria for Type 1 hepatorenal

syndrome

Pathogenesis1,2

Centers around extreme renal vasoconstriction as a result of pathological splanchnic vasodilation

The underlying cirrhotic process causes increased splanchnic vascular resistance and portal hypertension

This leads to a decrease in systemic vascular resistance (SVR) through local release of vasodilators,

including nitric oxide (NO), carbon monoxide, and endogenous cannabanoids

o Bacterial translocation from the intestines may also play a role through the inflammatory

response (could explain the relationship to SBP)

Initially, cardiac output is increased to compensate for this decrease in vascular resistance (recall the

formula: BP = SVR x CO)

As portal hypertension and decrease in SVR progress, vasoconstrictor systems activate to keep blood

pressure normal, including the RAAS system, the sympathetic nervous system, and the release of ADH

These systems cause intense vasoconstriction in the renal arteries, leading to renal hypoperfusion, salt

and water retention, and renal failure

3

Precipitating Factors1

Bacterial infection, including spontaneous bacterial peritonitis (SBP)

o SBP is the only infection with a clearly demonstrated relationship to hepatorenal syndrome

Large-volume paracentesis without volume repletion

Gastrointestinal bleeding

Hypovolemic shock

Over-diuresis (no study evidence for this)

Epidemiology and Prognosis

Overall incidence of hepatorenal syndrome was estimated to be 40% at 5 years in one study

Renal failure in patients with cirrhosis and ascites is associated with a poor prognosis, but the

development of hepatorenal syndrome indicates an even poorer one

• Portal Hypertension

• Caused by underlying cirrhosis, leads to increased vascular resistance in splanchnic system

• Splanchnic Vasodilation

• Reponse to underlying cirrhosis and portal hypertension

• Compensatory Response

• Includes increased cardiac output and activation of vasoconstricting systems, including RAAS, ADH, and sympathetic nervous system activation

• Renal failure and Hepatorenal Syndrome

• Due to extreme vasoconstriction of the renal arteries mediated by the compensatory response

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Probability of survivial in cirrhotic patients with different renal impairments.

SBP Diagnosis

3,4,5,6

Presentation is variable, and may include fever (mostly commonly), abdominal pain, altered mental

status, diarrhea, or paralytic ileus

Patients may be asymptomatic; thus diagnostic paracentesis should be performed in all patients who:

o Have new-onset ascites

o Develop symptoms such as unexplained encephalopathy or renal failure

o Are stable, but suddenly deteriorate

A PMN count > 250 cells/mm3 is diagnostic of SBP

Pathogenesis3,4

Still unclear, but thought to be due to the translocation of bacteria from the intestinal lumen to the

mesenteric lymph nodes, and thus to the peritoneum

o Intestinal dysmotility and subsequent bacterial overgrowth may contribute

o Oxidative stress and decreased bile acid synthesis may lead to increased permeability of the

intestinal walls to bacteria and bacterial products (endotoxin, bacterial DNA)

Could also be due to bacteremia from urinary or respiratory tract infections

Cirrhotic patients are generally more susceptible to infections

Risk Factors3,4

GI bleeding

Prior episode of SBP

Ascitic fluid albumin concentrations of less than 1g/dL

5

Epidemiology and Mortality3,4,5,6

Prevalence studies from the 1970's showed a prevalence of 5-10%, but newer studies using modern

diagnostic criteria show a prevalence of roughly 10-30% of patients admitted to hospitals with cirrhosis

In-hospital mortality rates have fallen from 90% to around 10-30%

o Renal impairment is a strong predictor of mortality; progressive renal failure was associated with

an in-hospital mortality of 100% in one study, with stable renal impairment being associated

with a 31% mortality rate and no renal impairment only 7%

o Other predictors of mortality include elevated BUN and serum bilirubin, positive ascitic fluid

cultures, and age

Treatment Guidelines5,6

Two regularly updated guidelines that address the treatment and prevention of hepatorenal syndrome:

o The American Association for the Study of Liver Diseases (AASLD)

o The European Association for the Study of the Liver (EASL)

AASLD Guidelines

Class IIa, Level B

EASL Guidelines

Class I, Level B

Patients with ascitic fluid PMN counts greater than or

equal to 250 cells/mm3 (0.25 x 10

9/L) and clinical

suspicion of SBP, who also have a serum creatinine

>1 mg/dL, blood urea nitrogen >30 mg/dL, or total

bilirubin >4 mg/dL should receive 1.5 g albumin per

kg body weight within 6 hours of detection and 1.0

g/kg on day 3.

Until more information is available, we recommend

that all patients who develop SBP should be treated

with broad spectrum antibiotics and intravenous

albumin (1.5 g/kg at diagnosis and 1g/kg on day 3).

Albumin7,8

Overview

Albumin is an endogenous protein 66,500 kDa in molecular weight that exerts most (70-80%) of the

colloid oncotic pressure in blood plasma

Derived for pharmaceutical use from pooled human plasma

Distributes widely in the vasculature and extravascular space

Acts as a transport molecule for a variety of endogenous substances and drugs, including:

o Nitric oxide

o Fatty acids

o Metals

o Cholesterol

o Phenytoin (recall corrected phenytoin level in hypoalbuminemia)

o Digoxin

Exerts a strong oncotic pressure and can serve as a vascular volume expander (this is its FDA labeled

indication)

Serves as a thiol sink and is the major contributor of extracellular thiols, which are scavengers of

reactive oxygen and nitrogen species

Available in the US as a 5% and 25% solution

Mechanism of Action in the Prevention of Hepatorenal Syndrome

6

Albumin's function as a plasma volume expander may serve to compensate for the decrease in SVR

caused by cirrhosis and portal hypertension (this is likely the primary mechanism of action in the

prevention of hepatorenal syndrome)

Antioxidant effects may play a role by decreasing the release of vasodilators from cirrhotic liver tissue

Albumin may bind bacterial endotoxins and DNA fragments that contribute to hepatorenal syndrome via

bacterial translocation

As discussed in guidelines, albumin must be combined with a vasoconstrictor to maximize effectiveness

in the treatment of SBP

Costs and Adverse Effects

Available as a generic: AWP for 25g of 25% albumin is $64.50

For reference, a guideline-recommended course of albumin in a 70kg SBP patient would cost roughly

$450 at AWP

Contraindications and Precautions

o Contraindicated in cardiac failure: leads to circulatory overload

o Use with caution in patients with renal or hepatic impairment, as protein load may precipitate

azotemia or encephalopathy

o Pulmonary or peripheral edema may result from overly rapid infusion

o Hypersensitivity reactions have occurred

o Blood product: though pasteurized, cannot rule out transmission of infective agents

Literature Review

Effect of intravenous albumin on renal impairment and mortality in patients with

cirrhosis and spontaneous bacterial peritonitis9

Objective: To determine whether plasma volume expansion with albumin could prevent the impairment of

renal function and reduce mortality in patients with SBP.

Methods

Multicenter, randomized, controlled trial

Inclusion and exclusion criteria (notice parallels to hepatorenal syndrome and SBP diagnostic criteria)

o Ascitic fluid PMN count > 250 cells/mm3

o Absence of findings suggestive of secondary peritonitis

o Absence of shock, GI bleed, grade 3 or 4 hepatic encephalopathy, HIV infection, cardiac failure,

and other infections

o Serum creatinine no more than 3 mg/dL

o Severe dehydration within one week of diagnosis of peritonitis, as evaluated clinically or by

CVP < 4

199 patients were evaluated, 126 were included

Patients were randomized to either renally adjusted cefotaxime or renally adjusted cefotaxime plus 20%

albumin 1.5g/kg on day 1 and 1g/kg on day 3 of enrollment

Follow-up lasted 90 days from the enrollment period

Renal impairment at the time of enrollment was defined as a BUN of > 40 mg/dL or a serum creatinine

of > 1.5 mg/dL

In patients without renal impairment at baseline, a 50% increase in BUN or serum creatinine to levels

above 40 mg/dL and 1.5 mg/dL respectively was diagnostic for renal impairment during treatment

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For patients with renal impairment at baseline, simply a 50% increase in BUN or serum creatinine was

diagnostic for worsening renal failure

50 patients in each group were required for an 80% power to detect a 25% difference in the rate of renal

failure

Results

Clinical outcome according to assigned treatment.

Outcome Variable

Cefotaxime

(n = 63)

Cefotaxime

plus albumin

(n = 63) p Value

Resolution of infection - No. (%) 59 (94) 62 (98) 0.36

Duration of antibiotic therapy - days 6±1 5±1 .48

Paracentesis for ascites after resolution of infection -

no. (%) 16 (25) 14 (22) .83

Hospital stay - days 13±1 14±1 .48

Renal impairment - no. (%) 21 (33) 6 (10) 0.01

Death - no (%)

In hospitals

At three months

18 (29)

26 (41)

6 (10)

14 (22)

0.01

0.03

In-hospital mortality according to variables with independent predictive value.

Variable

Cefotaxime

(n = 63)

Cefotaxime plus albumin

(n = 63)

BUN

<30 mg/dL

BUN

≥30 mg/dL

BUN

<30 mg/dL

BUN

≥30 mg/dL

no. of patients who died/total no. (%)

Bilirubin <4 mg/dL

Prothrombin time ≥60% of control

Prothrombin time < 60% of control

0/13

0/7

3/6 (50)

2/8 (25)

0/10

0/14

1/10 (10)

2/5 (40)

Bilirubin ≥4 mg/dL

Prothrombin time ≥60% of control

Prothrombin time < 60% of control

1/3 (33)

4/12 (33)

1/5 (20)

7/9 (78)

0/0

0/16

0/1

3/7 (43)

Total 5/35 (14) 13/28 (46) 0/40 6/23(26)

Mortality and progression to renal failure were significantly reduced in the cefotaxime plus albumin

group

Importantly, BUN > 30 mg/dL, bilirubin > 4mg/dL, and prothrombin time > the control group were

independent predictors of mortality

All patients in the trial had a baseline serum creatinine of 1.1±0.1 (control group) or 1.2±0.1 (treatment

group)

89% of patients who developed renal failure and 16% of patients who did not develop renal failure had

died at 3-month followup

Discussion and Conclusions

8

The authors conclude that albumin plus empiric antibiotic treatment is more effective at reducing

mortality and progression to renal failure in patients with SBP than empiric antibiotics alone

The trial helps confirm that progressive renal failure and hepatorenal syndrome are indicative of a poor

prognosis

Trial strengths

o Randomized and adequately controlled

o Endpoints and inclusion criteria consistent with the disease states being studied (PMN count in

ascitic fluid, serum creatinine cutoffs, etc.)

o Demonstrated a mortality benefit

o Appropriate statistical analysis

Trial weaknesses

o Benefit was most apparent in patients with BUN > 30 mg/dL and bilirubin > 4mg/dL, and only

patients with a serum creatinine above 1.0 were included in the trial

o Does not shed light on whether albumin is unique or other plasma volume expanders would be

effective for the same purpose (the authors address this in their discussion)

o Control patients may have been sicker

Restricted use of albumin for spontaneous bacterial peritonitis10

Objective: To assess whether albumin treatment is needed in all cases of SBP or whether a risk stratification

strategy is desirable.

Methods

A 28 patient prospective case series in two medical centers

Patients with a bilirubin > 4 or a serum creatinine > 1.0 were treated with albumin 1.5g/kg on day 1 and

1g/kg on day 3 of treatment along with empiric antibiotics

Low-risk patients (serum creatnine < 1.0 and bilirubin < 4) were treated only with empiric antibiotic

therapy

Results

Selected clinical characteristics of patients at diagnosis of spontaneous bacterial peritonitis episodes who did

receive (A) and who did not receive (B) albumin.

A

(n = 26)

B

(n = 18) p Value

Total bilirubin(mmol/L) 115 (12-395) 39 (14-67) <0.001

BUN (mg/dL) 28.5 (7-74) 18(5-48) 0.003

Creatinine (mmol/L) 124 (35-327) 80 (53-106) 0.001

In the low-risk group, SBP resolved in all patients and no patients developed renal impairment.

In the high-risk group, 12 patients developed renal impairment and five patients died.

Discussion and Conclusions

The authors conclude that albumin is not needed in all SBP patients

Strengths

o Used parameters based on the single randomized, controlled trial performed for this intervention

o Used established guidelines for diagnosis and treatment of SBP and hepatorenal syndrome

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o Calculated p values

Weaknesses

o No control group

o Small case series

Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a

meta-analysis of randomized trials11

Objective: To quantify the effect of albumin infusion on renal impairment and mortality in patients with SBP.

Methods

A meta-analysis limited to only randomized, controlled trials evaluation albumin in SBP patients

o No language or time period restrictions

All three investigators independently determined trial inclusion eligibility

Endpoints of the analysis were renal impairment (as defined by the included trials) and mortality

Heterogeneity was judged using the Cochran Q test and the I2 test

Results of the trials were combined under a fixed-effects model

Results

Renal impairment. Confidence interval (CI) is shown by error bars. Data points for individual trials scaled

accordingly to meta-analytic weight.

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Improvement in the incidence of renal impairment and mortality were shown

o Removing either of the two most heavily weighted studies did not change the overall conclusion

No differences shown between subgroups, however, a non-significant increase was seen in the incidence

of renal impairment and mortality in patients with BUN > 30 mg/dL and/or bilirubin > 4

Discussion and Conclusions

The authors conclude that albumin is effective for prevention of renal failure and mortality in SBP

patients with cirrhosis.

Strengths

o Relied only on randomized, controlled trials

o Appropriate statistical analysis

o Robust results

Weaknesses

o Small sample size

o 3 out of the 4 trials were not blinded

Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis.

A randomized, controlled study12

Objective: To determine if albumin has beneficial effects outside of patients with cirrhosis that develop SBP.

Methods

Single center, randomized, controlled trial

Inclusion criteria

o Cirrhosis, diagnosed by liver biopsy or by clinical findings according to published guildelines

o Presence of infection, diagnosed by cultures or clinical suspicion with at least one of the

following:

PMN count > 10,000 cells/mm3 or 50% increase from baseline with a final value above

8,000 cells/mm3

5% or greater bands

Temperature > 37.5 C

Exclusion criteria

o GI bleed

o Previous antibiotic treatment

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o Malignancy

o HIV infection

o Presence of shock

51 patients were randomized to each group (control and treatment)

Control group received only empiric antibiotic treatment with:

o IV ceftriaxone for UTI, sepsis of unknown origin, or spontaneous bacteremia

o IV ceftriaxone plus cloxacillin or Augmentin for SSTI

o IV ceftriaxone and a macrolide or levofloxacin (with clindamycin for aspiration) for CAP

o IV ceftazadime plus ciprofloxacin for HAP

o IV vancomycin and ceftazadime for catheter-related infections

Intervention group received empiric antibiotic therapy plus albumin 1.5g/kg on day 1 and 1g/kg on day

3

Primary endpoint was 3-month mortality

Secondary endpoints were the effects on serum creatinine, percentage of patients who developed renal

failure, and effects on circulatory and vasoactive variables

Study sized for an 80% power to detect a 30% difference in survival rates

Results

Three-month probability of survival.

Univariate analysis of the 3-month survival according to baseline variables, characteristics of infection, and

occurrence of renal failure.

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Variable

Alive

(n = 79)

Death

(n = 18) p Value

Age (yr) 55 ± 11 60 ± 12 0.158

Ascites at inclusion 54 (68%) 17 (94%) 0.036

Hepatic encephalopathy at inclusion 24 (30%) 11 (61%) 0.027

Nosocomial infection 11 (14%) 10 (56%) <0.0001

Serum bilirubin (mg/dL) 3.5 ± 3.3 9.8 ± 8.6 0.007

Serum albumin (mg/dL) 29 ± 6 26 ± 4 0.024

Serum creatinine (mg/dL) 1.2 ± 0.6 1.3 ± 0.6 0.258

BUN (mg/dL) 24 ± 19 37 ± 21 0.010

Renal failure during infection 15 (19%) 10 (56%) 0.006

Overall, there were no significant differences in the unadjusted 3-month mortality rates between the

control and intervention groups (80% survival in the control group vs. 82.6% survival in the intervention

group)

Significance was shown when the results were adjusted for variables shown in univariate analysis to

have independent predictive value

Differences in the incidence of renal failure and in serum creatnine concentrations between the control

and intervention groups did not reach statistical significance

o Compared to SBP patients, renal failure did not occur as often in the control group of this study

o Mortality was also lower in the control group compared to SBP patients not treated with albumin

Discussion and Conclusions

The authors conclude that albumin treatment in patients with bacterial infections other than SBP is not

associated with a significant decrease in either 3 month mortality or the incidence of renal failure

The overall incidence of renal failure and mortality in the trial's control group reveals that the overall

difference in prognosis between SBP and other bacterial infections may help explain the negative results

of this trial

Strengths

o Randomized and controlled

o Used mortality as an endpoint

o Statistical analysis appropriate, including power calculation, and did not overstep with

conclusions based on post-hoc adjustment of results

Weaknesses

o Power estimate greatly overstated the actual effect size

o Needed to adjust results for statistical significance

Conclusions

Albumin is effective for the prevention of progression to hepatorenal syndrome and renal

failure in SBP patients

There is a small body of evidence that suggests that albumin is not needed in all SBP

patients, but more study is needed

No evidence to suggest that albumin is effective in other bacterial infections in cirrhotic

patients

More evidence is needed to inform about the optimal dose of albumin in SBP patients

o Trials underway (ClinicalTrials.gov: NCT00761098)

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References

1. Diagnosis, prevention, and treatment of hepatorenal syndrome in cirrhosis. Salerno F, Gerbes A, Gines

P, et al. Gut. 2007;56:1310-1308.

2. Mechanisms promoting bacterial translocation from the gastrointestinal tract. Berg RD. Adv Exp Med

Biol 1999;473:11-30

3. Spontaneous bacterial peritonitis: recent data on incidence and treatment. Mansour PA, Atreja A, Zein

NN. Cleve Clin J Med. 2004;71(7):569-76.

4. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: Incidence, clinical course,

predictive factors and prognosis. Follo A, Llovet JM, Navasa M, et al. Hepatology 1994;20:1495–1501.

5. Management of adult patients with ascites due to cirrhosis: update 2012. Runyon, BA for the AASLD.

Hepatology 2013;57(4):1651-3.

6. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and

hepatorenal syndrome in cirrhosis. EASL. Hepatology 2010;53:397-417.

7. Albumin. Lexi-Comp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; Accessed September 22,

2013.

8. Albumin for end-stage liver disease. Lee JS. Korean J Intern Med 2012(27):13-19

9. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and

spontaneous bacterial peritonitis. Sort P, Navasa M, Arroyo V, et al. N Engl J Med 1999;341:403-409.

10. Restricted use of albumin for spontaneous bacterial peritonitis. Sigal SH, Stanca SM, Fernandez J, et al.

Gut 2007;56(4):597-599

11. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis

of randomized trials. Salerno F, Navickis RJ, Wilkes MM. Clin Gastroenterol Hepatol 2013;11(2):123-

130

12. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized,

controlled study. Guevara M, Terra C, Nazar A, et al. Hepatology 2012;57:759-765

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Appendix A: Included Trials in the Meta-analysis from Salerno et al.

Table 1.

Included Trials

Trial N Age

(SD)

Male, % Ethnicity Etiology Treatment regimen

Sort et al,

1999

126 61.0

(7.9)

64.3 Caucasian 29.4% alcohol,

70.6% other

Cefotaxime intravenously dosed

according to creatinine without vs

with 1.5g/kg 20% albumin within

first 6 h plus 1.0 g/kg on day 3

Xue et al,

2002

112 22-70 - Chinese - Ceftriaxone intravenously dosed

according to creatinine without vs

with 0.5-1.0 g/kg 20% albumin

within first 6 h and every third

day for 21 days

Fernandez

et al, 2005

20 61.0

(9.5)

55 Caucasian 60.0% HCV,

40.0% other

Ceftriaxone intravenously 2 g at

diagnosis and then 1 g/d plus 1.5

g/kg at baseline and 1.0g/kg on

day 3 of 20% albumin vs 6% HES

200/0.5

Chen et al,

2009

30 56.5

(11.5)

60 Chinese 60.0%

HBV<comma>

23.3%

HCV<comma>

16.7% alcohol

Cephalosporins without vs with

50 mL 20% albumin (0.14

g/kg−1 for a 70-kg patient) on

days 1–3