Drug-induced nephrotoxicity caused by amphotericin B lipid complex and liposomal amphotericin B: a review and meta-analysis.

Abstract

Lipid preparations of amphotericin B, commonly used to treat fungal infections, have been demonstrated to have reduced nephrotoxicity compared to conventional amphotericin B. However, to our knowledge, a comprehensive comparison of nephrotoxicity induced by different lipid preparations of amphotericin B has not been performed. We conducted a meta-analysis to evaluate nephrotoxicity associated with amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AmB). We searched the PubMed MEDLINE database and abstracts presented at key scientific meetings, and identified 11 studies reported between 1995 and 2008 that compared nephrotoxicity resulting from the use of these agents. Eight of the 11 studies were included in the meta-analysis. The Cochran-Mantel-Haenszel test was used to determine odds ratio (OR) and relative risk (RR), and the Breslow-Day test was used to analyze homogeneity of ORs across different studies. Analysis of all 8 studies (n = 1160) included in the meta-analysis showed an increased probability of nephrotoxicity in patients treated with ABLC versus L-AmB (OR, 1.75; RR, 1.55), but there was a significant lack of homogeneity across these studies (p < 0.001). After excluding the study by Wingard et al, the probability of experiencing nephrotoxicity was more similar between the 2 AmB lipid preparations (OR, 1.31; RR, 1.24; n = 916), particularly when the analysis included only the salvage patient population reported by Hachem et al (OR, 1.12; RR, 1.09; n = 839); the 7 remaining studies were more homogenous by Breslow-Day test (p = 0.054). Our results suggest that nephrotoxicity is generally similar for ABLC and L-AmB in patients receiving antifungal therapy and prophylaxis.

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Drug-Induced Nephrotoxicity Caused by Amphotericin B
Lipid Complex and Liposomal Amphotericin B
A Review and Meta-Analysis
Amar Safdar, MD, Jonathan Ma, PhD, Fouzi Saliba, MD, Bertrand Dupont, MD, John R. Wingard, MD,
Ray Y. Hachem, MD, Gloria N. Mattiuzzi, MD, Pranatharthi H. Chandrasekar, MD,
Dimitrios P. Kontoyiannis, MD, Kenneth V. Rolston, MD, Thomas J. Walsh, MD,
Richard E. Champlin, MD, and Issam I. Raad, MD
Abstract: Lipid preparations of amphotericin B, commonly used to
treat fungal infections, have been demonstrated to have reduced neph-
rotoxicity compared to conventional amphotericin B. However, to our
knowledge, a comprehensive comparison of nephrotoxicity induced by
different lipid preparations of amphotericin B has not been performed.
We conducted a meta-analysis to evaluate nephrotoxicity associated with
amphotericin B lipid complex (ABLC) and liposomal amphotericin B
(L-AmB).
We searched the PubMed MEDLINE database and abstracts pre-
sented at key scientific meetings, and identified 11 studies reported
between 1995 and 2008 that compared nephrotoxicity resulting from
the use of these agents. Eight of the 11 studies were included in the
meta-analysis. The Cochran-Mantel-Haenszel test was used to deter-
mine odds ratio (OR) and relative risk (RR), and the Breslow-Day test
was used to analyze homogeneity of ORs across different studies.
Analysis of all 8 studies (n = 1160) included in the meta-analysis
showed an increased probability of nephrotoxicity in patients treated
with ABLC versus L-AmB (OR, 1.75; RR, 1.55), but there was a sig-
nificant lack of homogeneity across these studies (p G 0.001). After
excluding the study by Wingard et al, the probability of experiencing
nephrotoxicity was more similar between the 2 AmB lipid preparations
(OR, 1.31; RR, 1.24; n = 916), particularly when the analysis included
only the salvage patient population reported by Hachem et al (OR,
1.12; RR, 1.09; n = 839); the 7 remaining studies were more homoge-
nous by Breslow-Day test (p = 0.054).
Our results suggest that nephrotoxicity is generally similar for ABLC
and L-AmB in patients receiving antifungal therapy and prophylaxis.
(Medicine 2010;89: 236Y244)
Abbreviations: ABLC = amphotericin B lipid complex, L-AmB =
liposomal amphotericin B, NCI = National Cancer Institute, NS =
not significant, OR = odds ratio, RR = relative risk, sCr = serum
creatinine.
INTRODUCTION
T
used commonly in immunosuppressed cancer and transplant
patients.2,19,22,25,27A rise in systemic zygomycosis among
patients who have received Aspergillus active triazoles has redi-
rected the focus on polyene-based antifungal therapy in neu-
tropenic cancer patients and stem cell transplant recipients with
graft-versus-host disease.13,26The oldestdruginthe polyeneclass
of antifungal agents is amphotericin B-deoxycholate, which has
been a mainstay of therapy for systemic fungal infections since its
release in the late 1950s7,23but is associated with many adverse
effects that limit its clinical utility, including acute renal failure.
During the 1990s, newer lipid preparations of amphotericin B
were developed to alleviate drug toxicity.
The reported frequency of acute renal failure associated
with amphotericin B-deoxycholate varies widely with the defi-
nition used and increases with cumulative dose delivered.12,24A
measurable decline in renal function has been reported to occur
in up to 80% of patients who receive the drug.24Acute renal
failure associated with amphotericin B-deoxycholate may be
dose-limiting and can prolong length of stay and increase treat-
ment costs.3An analysis of 707 adult patients at a tertiary-care
center, conducted by Bates and colleagues,3found that when
renal failure develops, patients_ stay in the hospital increases by
8.2 days, and total cost per patient increases by $29,823. In ad-
dition, the mortality rate was higher when renal failure occurred:
54% versus 16% in patients without renal complications.3
he spectrum of fungal infection continues to change as
newer drugs against Aspergillus and Candida species are
236
www.md-journal.com Medicine & Volume 89, Number 4, July 2010
From M. D. Anderson Cancer Center (AS, RYH, GNM, DPK, KVR, REC,
IIR), Houston, Texas; Columbia University (JM), New York, New York;
Assistance Publique-Ho ˆpitaux de Paris (AP-HP), Ho ˆpital Paul Brousse,
Centre He ´pato-Biliaire, Universite ´ Paris-Sud (FS), Villejuif, France; Assis-
tance Publique-Ho ˆpitaux de Paris (AP-HP), Hopital Necker-Enfants Malades
(BD), Paris, France; University of Florida College of Medicine (JRW),
Gainesville, Florida; Wayne State University, Harper Hospital (PHC), Detroit,
Michigan; and National Cancer Institute (TJW), Bethesda, Maryland.
Funding for this study was provided by Enzon Pharmaceuticals, Inc.,
Bridgewater, NJ. Editorial support was provided by Kakuri Omari, PhD,
Phase Five Communications Inc. (New York, NY) with funding from
Enzon Pharmaceuticals, Inc.
Conflicts of interest: Dr. Chandrasekar has been a member of the speaker_s
bureau and a consultant for Enzon Pharmaceuticals Inc. and Astellas
Pharmaceuticals, Inc.; Dr. Hachem has received research or educational
grants from Enzon Pharmaceuticals Inc.; Dr. Kontoyiannis has been a
member of the speaker_s bureau and received research or education
grants from Enzon Pharmaceuticals Inc.; Dr. Mattiuzzi has been a
member of the speaker_s bureau for Pfizer Inc. and Migenix Inc. and
has received research grants from Pfizer Inc., Merck & Co., Inc.,
Schering-Plough Corporation, and Migenix Inc.; Dr. Raad has been a
member of the speaker_s bureau for Merck & Co., Inc., Pfizer Inc.,
and Schering-Plough Corporation and has received research or
education grants from Enzon Pharmaceuticals Inc., Pfizer Inc., and
Schering-Plough Corporation; Dr. Rolston has been on advisory boards
for Enzon Pharmaceuticals Inc.; Dr. Safdar has been a member of the
speaker_s bureau and received research or education grants from Enzon
Pharmaceuticals Inc.; Dr. Wingard has been a member of the speaker_s
bureau and a consultant for Pfizer Inc., Merck & Co., Inc., and Astellas
Pharmaceuticals, Inc.; Drs. Champlin, Dupont, Ma, Saliba, and Walsh
have no conflicts of interest to disclose related to this manuscript.
Reprints: Amar Safdar, MD, Associate Professor of Medicine, Director
Immunology Research Program, Department of Infectious Diseases,
Infection Control and Employee Health, The University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Blvd, Unit 402, Houston,
TX 77030 (e-mail: asafdar)mdanderson.org).
Copyright * 2010 by Lippincott Williams & Wilkins
ISSN: 0025-7974
DOI: 10.1097/MD.0b013e3181e9441b

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Patients receiving low cumulative doses of amphotericin B-
deoxycholate (G1.0 g) have been reported to develop renal
failure less often.24
Therapeutic advantages of using amphotericin B in a lipid
delivery system have allowed increased delivery of amphotericin
B to sites of infection with less toxicity. These systems have
significantly improved tolerability of this drug, as patients ex-
perience fewer infusion-associated adverse reactions and a con-
siderably improved nephrotoxicity profile. The 2 commonly
used lipid formulations of amphotericin B, amphotericin B lipid
complex (ABLC) and liposomal amphotericin B (L-AmB),
are both associated with reduced renal toxicity compared with
conventional amphotericin B.8,23However, in a randomized trial
by Wingard et al,34in which 244 patients received empiric anti-
fungal therapy for febrile neutropenia, 166 patients who re-
ceived L-AmB had significantly lower rates of renal dysfunction
compared with 78 patients who received ABLC. Since that
time, new information, much of it from animal models, has be-
come available concerning the differing pharmacokinetics of
amphotericin B lipid formulations and the interaction with
the immune system.1,10,14Y16,30For instance, 2 recent studies by
Lewis et al15,16demonstrate early fungal clearance following ad-
ministration of ABLC compared with L-AmB in murine models
of invasive pulmonary aspergillosis and zygomycosis. The clin-
icalsignificanceofthesefindingsisyettobedetermined.Whether
there are differences in renal safety among the 2 commonly used
lipid formulations of amphotericin B remains controversial. We
sought to analyze the existing data for nephrotoxicity associated
with ABLC and L-AmB in adults who received these agents
for the treatment and prophylaxis of fungal infection.
LITERATURE SEARCH METHODS AND
CONSIDERATIONS FOR STUDY INCLUSION
We searched the PubMed MEDLINE database (National
Library of Medicine, Bethesda, MD) for studies comparing
nephrotoxicity between ABLC and L-AmB published between
1995 and 2008. Searches with terms ‘‘Amphotericin B and
Nephrotoxicity’’ yielded more than 280 abstracts, which were
further refined by including the search terms ‘‘Abelcet, ampho-
tericin B lipid complex, ABLC, AmBisome, liposomal ampho-
tericin B or L-AmB.’’ Only primary reports, in the English
language, of patient studies that directly compared nephrotoxi-
city associated with ABLC and L-AmB treatment were con-
sidered for inclusion in the meta-analysis. Reviews were not
included in the meta-analysis; however primary reports cited in
reviews were retrieved and evaluated for possible inclusion.
No other databases were searched in addition to PubMed
for journal articles, however, abstracts presented at key scienti-
fic meetings were researched. Meetings with an emphasis on
topics including infectious diseases, microbiology, fungal in-
fections, and pharmacy/pharmacology were prioritized for the
likelihood of containing studies comparing ABLC and L-AmB.
We searched more than 10 annual meeting programs for rele-
vant study data using similar search terms as in the PubMed
searches.MeetingprogramssearchedincludetheFocusonFungal
Infections (FOFI), Advances Against Aspergillosis (AAA), Infec-
tious Diseases Society of America (IDSA) Annual Meeting,
Interscience Conference on Antimicrobial Agents and Chemo-
therapy (ICAAC), American College of Clinical Pharmacology,
the American College of Clinical Pharmacy, and the American
Society of Health-System Pharmacists meetings.
PubMed results and abstracts were reviewed by 2 indivi-
duals. In total, 11 studies were identified that compared neph-
rotoxicity between ABLC and L-AmB; 3 were excluded because
ofthe lackofa comparisongroup,31incompletedata,5and avery
young neonatal population compared with other studies (average
age e1 mo)17(Figure 1).
There is no harmonized definition for nephrotoxicity re-
sulting from amphotericin B and the lipid formulations of am-
photericin B. Serum creatinine (sCr) increases Q1.5 mg/dL or
920% higher than baseline values represent clinically relevant
decreases in kidney function.29Studies included in this review
reported established standard definitions of nephrotoxicity that
are well accepted in peer-reviewed journals. We also reviewed
information regarding concomitant nephrotoxic drugs or agents,
prehydration (saline loading), comorbidities (for example, dia-
betes, hypertension, peripheral vascular disease), age of patient
populations, and average daily dose between the studies. In all
8 studies analyzed, ABLC and L-AmB were administered at
recommended doses (5 mg/kg and 3Y5 mg/kg, respectively),
with the exception of the study by Fleming et al,9in which the
daily dose of ABLC was lower than that of L-AmB; in the report
by Mattiuzzi et al,20in which the daily dose of ABLC was also
lower butsimilar to the L-AmB arm; and inthe study by Hachem
et al,11where patients received doses of ABLC or L-AmB up to
10 mg/kg. See Table 1 for a summary of the characteristics of
the 8 studies included in the meta-analysis.4,9,11,18,20,21,28,34
REVIEW OF STUDIES COMPARING
NEPHROTOXICITY ASSOCIATED WITH
ABLC AND L-AMB
Wingard et al34conducted a double-blind, randomized
study involving 18 centers in the United States between October
1997 and August 1998. The study directly compared ABLC and
L-AmB, administered empirically to febrile neutropenic patients
aged 2 years or older, who had persistent fever lasting at least
72 hours during broad-spectrum antibiotic treatment. Compar-
isons of the drugs were made for a number of safety parameters,
including the frequencyofchills/rigors,thefrequencyof infusion-
related reactions, and the frequency of nephrotoxicity. Two
hundred forty-four patients were randomized (1:1:1) to receive
ABLC at a dose of 5 mg/kg per day (n = 78), L-AmB at a dose
of 3 mg/kg per day (n = 85), or L-AmB at a dose of 5 mg/kg per
day (n = 81). Nephrotoxicity in this study was defined as an in-
crease in sCr greater than 100% above baseline value (2 ? base-
line); for patients aged more than 16 years, the post-baseline peak
sCr value also had to be greater than 1.2 mg/dL. The study also
evaluated increases in sCr by greater than 50% and 200% above
baseline value (1.5 ? and 3 ? baseline, respectively).
Significantly lessnephrotoxicity wasobserved amongpatients
treated with L-AmB (3 mg/kg per day and 5 mg/kg/d) compared
with ABLC (5 mg/kg/d), 14.1% and 14.8% versus 42.3%, re-
spectively (p = 0.01). This lower frequency of nephrotoxicity was
evident regardless of age, receipt of a bone marrow transplant,
transplant type, or use of immunosuppressive drugs. Adminis-
tration of concomitant nephrotoxic medications was similar among
the3treatmentgroups.ApeaksCRvalue93mg/dLwasobserved
in 7.1% of the 3-mg/kg L-AmB group, 1.2% of the 5-mg/kg
L-AmB group, and 12.8% of the ABLC group; the difference
was statistically significant between the 5-mg/kg per day L-AmB
groupandtheABLCgroup(pG0.01)butnotbetweenthe3mg/kg
per day L-AmB group and the ABLC group. The increase in sCr
levelwas significantly greater in the group of patients treated with
ABLC (mean sCr change [mg/dL T SD]: 0.5 T 0.8 for 3 mg/kg
L-AmB; 0.4 T 0.4 for 5 mg/kg L-AmB; 1.0 T 1.0 for 5 mg/kg
ABLC; p e 0.001, L-AmB vs. ABLC). The peak sCr level was
also higher with ABLC (peak sCr value [mg/dL TSD]: 1.3 T1.0
for 3 mg/kg L-AmB; 1.2T0.6 for 5 mg/kg L-AmB; 1.8 T1.2for
Medicine & Volume 89, Number 4, July 2010 Meta-Analysis: ABLC vs. L-AMB Nephrotoxicity
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5 mg/kg ABLC; p e 0.001, L-AmB vs. ABLC). There were
no statistical differences in nephrotoxicity between high- and
low-risk patients in the L-AmB group (15.4% vs. 13.9%) or
the ABLC group (45.5% vs. 41.8%).
Fleming et al9conducted a randomized study at the Uni-
versity of Texas, M.D. Anderson Cancer Center between August
and December 1997. Seventy-five consecutive patients with
leukemia developed 82 infectious episodes and were assigned
to receive ABLC (n = 43 episodes) or L-AmB (n = 39 episodes).
Patients with fever of unknown origin received 3 mg/kg study
drug daily, and those with pneumonia, sinusitis, and cellulitis
received a daily dose of 4Y5 mg/kg. The daily drug dose was
escalated to 5 mg/kg in patients with documented fungal infec-
tions. Infusion-related adverse events were evaluated following
the first administration of ABLC or L-AmB. Renal and liver
function were monitored twice a week by monitoring sCr and
bilirubin levels, respectively, beginning on the first day of ther-
apy until the end of treatment. Nephrotoxicity was defined as
an increase in sCr greater than 50% above baseline value (1.5 ?
baseline) that persisted until the end of treatment or discon-
tinuation of study drug. The authors reported a higher rate of
nephrotoxicity in patients who received ABLC (16/40, 40%)
compared with L-AmB (10/36, 28%), but this difference was
not statistically significant (p = 0.26). In contrast, the incidence
of hepatotoxicity was lower in the ABLC treatment arm (38%)
than in the L-AmB treatment group (59%; p = 0.05). Almost
all patients in both groups received concomitant nephrotoxic
drugs (98% ABLC, 92% L-AmB).
Cannon et al4carried out a single-center prospective and
retrospective observational study between 1996 and 1999, which
compared ABLC and L-AmB at a 350Ybed teaching hospital.
Of the 67 patients enrolled in the study, 46 received ABLC, and
21 received L-AmB. Twenty-six of the 46 (56%) patients re-
ceiving ABLC and 15 of the 21 (71%) patients receivingL-AmB
wererefractorytoapriorcourseofantifungaltherapy.Dosageand
duration of ABLC and L-AmB, and underlying conditions, were
similar in both treatment groups. Oncology patients accounted for
mostofthosetreatedwithABLC(70%)andL-AmB(90%).Inthis
study, nephrotoxicity was defined as 9100% increase in baseline
sCr. A higher incidence of nephrotoxicity was observed in patients
receiving L-AmB (4 of 19 patients) than ABLC (2 of 46 patients),
but this was not statistically significant. Analysis of nephrotoxi-
city may have been affected by a significant difference in baseline
sCr levels (1.77 mg/dL ABLC vs. 1.0 mg/dL L-AmB; p = 0.003).
All these patients were treated simultaneously with known neph-
rotoxic drugs such as vancomycin, aminoglycosides, acyclovir,
and tacrolimus. However, nephrotoxicity was not statistically dif-
ferent, regardless of baseline sCr levels. One patient receiving
L-AmB developed pulmonary Zygomycetes after 15 days of ther-
apy.Thispatientdiedafter receivingapproximately13gofL-AmB.
The McKechnie et al study21was a prospective and retro-
spective observational multicenter study at 11 tertiary care centers
and 1 community hospital in Canada that evaluated differences
in nephrotoxicity caused by ABLC (n = 150) and L-AmB (n =
104). Patients aged 2 years or older who received a minimum of
4 doses of ABLC or L-AmB and were not receiving dialysis
were enrolled. Nephrotoxicity was defined as at least a 1.5 ? in-
crease in baseline sCr levels. No significant differences were de-
tected between ABLC and L-AmB in any of the renal parameters
analyzed in the study. Patients in the 2 groups were comparable
FIGURE 1. Study search strategy flow chart.
Safdar et al
Medicine & Volume 89, Number 4, July 2010
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with respect to baseline sCr levels, prior therapy with amphoteri-
cin B-deoxycholate, saline loading, and number of concurrent
nephrotoxins. An average net change in sCr level (baseline to
peak) of 46.7 Kmol/L was observed in patients treated with
ABLC,and42.8Kmol/Lfor patientstreatedwithL-AmB(p=not
significant [NS]). Patients treated with ABLC and L-AmB ex-
perienced the same amount of change in sCr from baseline to end
of therapyV9 Kmol/L. An increase of at least 50% in sCr was
experienced by 30.7% of ABLC-treated patients and 28.4%
of patients in the L-AmB group; 13.6% of ABLC and 12.7%
of L-AmB patients had a doubling in sCr, and 2.1% of ABLC
and 3.9% of L-AmB patients had a tripling of baseline sCr
(p = NS).
Mattiuzzi et al20conducted an open-label, prospective,
single-institution study with historical controls between April
1998 and May 1999. The study compared ABLC (n = 131) with
L-AmB (n = 70) as antifungal prophylaxis in patients with acute
myelogenous leukemia and high-risk myelodysplastic syndrome
who were undergoing induction chemotherapy. Patients who
received at least 4 days of antifungal prophylaxis were eligi-
ble for enrollment. National Cancer Institute (NCI) toxicity
grades 0 to 4 were used to define nephrotoxicity in this study.
The study did not find significant differences in nephrotoxi-
city between patients receiving ABLC and L-AmB for antifun-
gal prophylaxis. Eighteen percent of patients receiving ABLC
therapy and 15% of L-AmB-treated patients withdrew from the
study because of probable drug-related adverse effects. Sixteen
patients (12.2%) receiving ABLC and 14 patients (20%) treated
with L-AmB experienced grade 1 or 2 nephrotoxicity, categorized
as probable or possibly related to therapy, but no patients in either
ofthe 2 treatmentgroupsexperienced grade 3 or 4 nephrotoxicity,
and no deaths were related to study drug administration.
TABLE 1. Summary of Studies Analyzed in the Meta-Analysis
Study
First Author
Year (ref.)
Wingard 200034
Study Type
(Yr)
Mean/Median
Age (TSD, yr),
Patient Population
ABLC
No. Patients,
Mean Daily Dose,
Duration (TSD)
L-AmB
No. Patients,
Mean Daily Dose,
Duration (TSD)
Nephrotoxicity*
ABLC vs. L-AmB
(P Value)
Randomized,
double-blind,
multicenter
(1997Y1998)
Randomized,
double-blind,
single-center
(1997)
Retrospective and
prospective,
observational
(1996Y1999)
Retrospective and
prospective,
observational,
multicenter (NA)
Prospective with
historical controls
(1997Y2000)
Retrospective
(1997Y2002)
Mean age: 42.0 T 20.4,
minimum age: Q2 yr;
Hematologic malignancies:
42%, HSCT: 49%
Median age: 57 (ABLC), 59
(L-AmB) AML/MDS: 65%,
ALL: 15%, CML/CLL: 11%
n = 78
5 mg/kg
8 d
n = 166
3Y5 mg/kg
8 d
42.3% vs. 14.5%
(p e 0.01)
Fleming† 20019
n = 40
3 mg/kg
10 d
n = 36
4 mg/kg
15 d
40% vs. 28%
(p = 0.26)
Cannon 20014
Mean age: 50 (ABLC),
55 (L-AmB), minimum age:
Q4 yr; Cancer: È73%, HSCT:
È24%, non-hemodialysis
Mean age: NA, minimum
age: Q2 yr; Hematologic
malignancies: È65%, HSCT:
È26%, non-hemodialysis
Median age: 65 (ABLC),
63 (L-AmB), minimum age:
Q15yr;AML:60%,MDS:40%
Mean age: 40.5 T 21.8,
minimum age: Q2 mo;
Hematologic malignancies:
È49%, HSCT: È27%,
renal insufficiency: È21%
Mean age: 49.6 T 14;
Neutropenic: 44%
n = 46
5.3 mg/kg
15 d
n = 21
4.8 mg/kg
16 d
4.3% vs. 19%
(p = NS)
McKechnie 200321
(Abstract)
n = 150
4 mg/kg
16 d
n = 104
3.3 mg/kg
19 d
13.6% vs. 12.7%
(p = NS)
Mattiuzzi 200420
n = 131
2.5 mg/kg
17 d
n = 31
4.5 mg/kg
38 d
n = 70
3 mg/kg
14 d
n = 41
4 mg/kg
31 d
12.2% vs. 20%
(p = NS)
Malani 200518
45% vs. 32%
(p = 0.36)
Saliba‡ 200628
(Abstract)
Prospective,
multicenter
(2003Y2004)
n = 60 [37]
4.8 mg/kg
13.5 T 8 d
n = 28 [19]
3.3 mg/kg
15.0 T 11 d
23.3% vs. 7.1%
(p = 0.067)
[10.8% vs. 5.3%]
[p = 0.067]
21.2% vs. 2.8%
p G 0.001
[10% vs. 5.9%]
[p = 0.67]
Hachem§ 200811
Retrospective,
single-center
(1993Y2005)
Mean age: 46.5 T 14.3 (ABLC),
48.1 T 15.1 (L-AmB); Acute
leukemia: È50%, chronic
leukemia: È20%, lymphoma:
È22%, myeloma: È4%
n = 52 [30]
5Y10 mg/kg
12.9 T 9.8 d
n = 106 [51]
5Y10 mg/kg
13.6 T 14.4 d
Abbreviations: ALL = acute lymphocytic leukemia, AML = acute myelogenous leukemia, CLL = chronic lymphocytic leukemia, CML = chronic
myelogenous leukemia, HSCT = hematopoietic stem cell transplant, MDS = myelodysplastic syndrome, NA = not available, NS = not significant.
*Nephrotoxicity defined as at least 1.5? baseline serum creatinine except for Mattiuzzi et al, where nephrotoxicity was defined as National Cancer
Institute grade 0Y4.
†Only patients assessed for renal impairment in this study are included in the meta-analysis.
‡Data for the subgroup of patients who received ABLC and L-AmB treatment for 10 days are presented in brackets.
§Data for patients who received ABLC and L-AmB as salvage therapy are presented in brackets.
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The study by Malani et al18was a retrospective review of
medical records from an outpatient clinic at a tertiary care center
performed between January 1997 and July 2002. The authors
evaluated the types and frequencies of adverse events associated
with home infusion ofamphotericin B-D, and the3 amphotericin
B lipid formulations (ABLC, L-AmB, amphotericin B colloidal
dispersion). Most if not all of the patients had fungal infections,
and nephrotoxicity was defined as 91 mg/dL or 2 ? increase in
baseline sCr. Significant rates of 4 types of adverse events oc-
curred: nephrotoxicity was associated with 46/113 courses of
therapy (41%), electrolyte abnormalities with 40/113 courses
(35%), infusion reactions with 13/113 courses (12%), and ve-
nous access device complications with 13/113 courses (12%).
Nephrotoxicity was noted in 45% of courses of ABLC, com-
pared with 32% courses of L-AmB, but the difference was not
significant (p = 0.36). In this study, the time interval between ad-
ministration of the antifungal agents and development of neph-
rotoxicity was also evaluated; for ABLC-treated patients, it was
19 T 19 days, and for L-AmB, it was 23 T 19 days (p = 0.43). In
general, nephrotoxicity was significantly lower in children aged
younger than 13 years (12%) compared with patients aged
60 years or older (67%) (p = 0.002).
Saliba et al28reported a prospective multicenter survey
conducted in France between April 2003 and December 2004 to
assess renal safety of ABLC and L-AmB. Eighty-eight patients
with a mean age of 49.6 T 14 years were enrolled; 60 patients
were treated with ABLC and 28 patients with L-AmB. Sixty-
eight percent of the patients received 2 or more nephrotoxic
drugs (72% for ABLC, 61% for L-AmB). The study also ana-
lyzed a subset of patients who received treatment for at least
10 days with ABLC (n = 37) or L-AmB (n = 19). Nephrotoxicity
was defined as a doubling in sCr levels from baseline to end of
study; changes in creatinine clearance were also measured. No
significant difference between ABLC and L-AmB was reported
in the change in sCr from baseline to end of therapy (ABLC:
baseline 81.3 Kmol/L, end of therapy 115.0 Kmol/L; L-AmB:
baseline 88.8 Kmol/L, end of therapy 106.0 Kmol/L). In addi-
tion, there was no significant difference in the change in creati-
nine clearance from baseline between the 2 lipid formulations
(ABLC: baseline 94.6 mL/min, end of therapy 89.5 mL/min;
L-AmB: baseline 85.2 mL/min, end of therapy 71.6 mL/min).
Fourteen patients on ABLC and 2 patients on L-AmB developed
elevations of sCr 2 ? normal levels. In the subset of patients who
received treatment for at least 10 days, 4 patients on ABLC and 1
patient on L-AmB developed elevations of sCr 2 ? normal levels.
Nephrotoxicity was reported in a larger proportion of patients in
the ABLC treatment group than in the L-AmB group, but this
was not statistically significant (p = 0.067 for both the entire
populationandthesubgroupofpatientsthatreceivedtreatmentfor
10 days). Forty percent of patients in the ABLC treatment group
received 3 or more concomitant nephrotoxic drugs or agents,
compared with 21% of patients receiving L-AmB.
In 2008, Hachem et al11published results of a retrospective
single-centerstudyperformedbetweenJune 1993andDecember
2005 in adults with advanced hematologic malignancy and
proven or probable invasive aspergillosis. The study compared
the safety of ABLC and L-AmB, used as either primary or sal-
vage therapy, in 381 consecutive patients. Of these patients, 158
received primary antifungal therapy with either ABLC (n = 52) or
L-AmB (n = 106), and 30 ABLC and 51 L-AmB salvage reg-
imenswereadministered.Patientsevaluatedinthisstudyhadbeen
assessed weekly for hepatotoxicity, definedasa 2 ? increasefrom
baseline in sCr levels. The results of this study are similar to those
reported by Wingard et al,34in that the use of ABLC as primary
antifungal therapy was associated with significantly more adverse
events and nephrotoxicity than L-AmB (p G 0.001). However,
adverse events and nephrotoxicity were not significantly different
between the 2 amphotericin B lipid formulations in patients
receiving salvage therapy (p = 0.67).11Of note, this report eval-
uated a group of patients that was not typical of the hematologic
cancer population with invasive aspergillosis; individuals in the
study had advanced-stage hematologic malignancy or were
severely ill, probably resulting in reduced renal reserves.
META-ANALYSIS OF DRUG-INDUCED
NEPHROTOXICITY
We used the Cochran-Mantel-Haenszel test to compare and
determine the odds ratio (OR) and relative risk (RR) of neph-
rotoxicity between ABLC and L-AmB. Data from the 8 studies
were pooled into the meta-analysis with study as the stratifica-
tion variable. Common OR and RR were generated to measure
the association between the rate of nephrotoxicity and ampho-
tericin B lipid formulations. An OR and/or RR closer to unity
indicates a similarity between the 2 formulations. The further
away the OR and RR are from unity, the stronger the evidence
that the 2 formulations are different in terms of nephrotoxicity.
The Cochran-Mantel-Haenszel method assumes that the studies
are homogeneous. We used the Breslow-Day test for homo-
geneity of the ORs to test the hypothesis that these studies
were homogeneous and had similar ORs. A significant p value
(p G 0.05) indicates that the assumption of homogeneity of the
ORs may have been violated and that there was statistical evi-
dence that at least 1 of the ORs from the studies was very dif-
ferent from the rest. In such a case, it is important to look into
the possible underlying reasons, revalidate which studies should
be included in the meta-analysis, and carefully interpret the
results accordingly. Statistical analyses were performed using
SAS version 9.1.3 (SAS Institute, Inc., Cary, NC).
The 8 studies identified were used in different combinations
to generate 8 different analyses (Figure 2), and homogeneity of
the ORs across the studies was assessed. The meta-analysis of
all 8 studies (n = 1160) evaluating nephrotoxicity showed an
increased probability of nephrotoxicity in patients treated with
ABLC (n = 588) compared with those treated with L-AmB (n =
572). The Cochran-Mantel-Haenszel OR and RR were 1.75 and
1.55, respectively, and were slightly lower when the analysis was
performed with the salvage patient population reported in the
Hachem11study (OR, 1.59; RR, 1.44; n = 1083). However, there
was a significant lack of homogeneity across these studies (p G
0.001 and p = 0.003, respectively, by Breslow-Day test). The
same analysis conducted with a subset of patients in the Saliba
study28who received treatment for 10 days (n = 1128) yielded
similar results. Patients receiving ABLC had an increased prob-
ability of developing nephrotoxicity compared with those re-
ceiving L-AmB (OR, 1.68; RR, 1.50); analysis with the salvage
patient population reported in the Hachem study11yielded lower
OR and RR (OR, 1.52; RR, 1.39; n = 1051). Breslow-Day anal-
ysis continuedtoshowa lackofhomogeneityinthese studies (p G
0.0001 and p = 0.0005, respectively). The lack of homogeneity
indicates that the increased OR and risk of developing nephro-
toxicity associated with ABLC should be interpreted cautiously.
We tested various permutations of the 8 studies by re-
evaluating the statistical analysis while excluding 1 study at a
time. We found that when the trial by Wingard et al34was
omitted (n = 916), the probability of nephrotoxicity was simi-
lar between patients treated with ABLC (n = 510) versus those
treated with L-AmB (n = 406) (OR, 1.31; RR, 1.24); the 7
studies included in this subanalysis were not homogenous by
Breslow-Day test (p = 0.0023). No differences in nephrotoxicity
Safdar et al
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were found between the 2 lipid formulations when the Wingard
study34was excluded from the analysis with the salvage
patient population from the Hachem study11(OR, 1.12; RR,
1.09; n = 839), and the subset of studies was more homogenous
(p = 0.054).
Additionally,the probabilityofexperiencingnephrotoxicity
was similar between ABLC and L-AmB in analyses excluding
the Wingard study,34using the subpopulation of patients treated
for 10 days in the Saliba study28(OR, 1.22; RR, 1.17; n = 884),
although these studies were not homogeneous based on results
of the Breslow-Day test (p = 0.0055). The same analysis per-
formed with patients treated for 10 days in the Saliba study and
the salvage population of patients in the Hachem study11also
showed no differences in the probability of nephrotoxicity be-
tween the 2 lipid formulations (OR, 1.02; RR, 1.02; n = 807).
Breslow-Day analysis indicated that this subset of studies was
homogeneous (p = 0.1430). Results from these analyses sug-
gest that there is no difference in nephrotoxicity between ABLC
and L-AmB when the Wingard study is excluded from the meta-
analysis, especially when data from the salvage patient popula-
tion reported by Hachem et al were analyzed (Figure 2).
We conducted additional subanalyses using various factors
that were most commonly reported in the studies to define sub-
groups summarized in Table 2.4,9,11,18,20,21,28,34The 8 studies
were grouped by study design (randomized vs. non-randomized),
mean/median age of patients (Q50 yr), percentage of bone mar-
row transfusion recipients (925% of patients), and the proportion
of patients receiving concomitant nephrotoxic drugs (Q80% of
patients). Similar to the overall meta-analysis, the probability of
patients experiencing nephrotoxicity was not related to the sub-
analyses. Higher rates of renal toxicity were observed in patients
TABLE 2. Factors Reported in the Studies Used to Define
Meta-Analysis Subgroups
Study
First Author
(ref.)
Wingard34
Fleming9
Cannon4
McKechnie21
Mattiuzzi20
Malani18
Saliba28
Hachem11
Number of patients:
Yes subgroup
No subgroup
Total
Randomized
Study
Age
(Q50 yr)
BMT
(925% of
Patients)
Nephrotoxins
(Q80% of
Patients)
Yes
Yes
No
No
No
No
No
No
No
Yes
Yes
NA
Yes
No
No
No
Yes
No
Yes
No
No
Yes
NA
Yes
No
Yes
Yes
NA
NA
NA
No
No
320
840
1160
344
562
906
541
531
1072
143
490
633
Abbreviations: BMT = bone marrow transplantation, NA = not
available.
FIGURE 2. Meta-analysis comparing nephrotoxicity between ABLC and L-AmB. Results indicate that there is no difference in
nephrotoxicity between ABLC and L-AmB when the Wingard study34is excluded from the meta-analysis, particularly when the analysis
was performed with the salvage patient population reported in the study by Hachem et al.11Cochran-Mantel-Haenszel odds ratios
and relative risks with their associated 95% confidence intervals are given.
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treated with ABLC than L-AmB only in subgroup analyses that
include the Wingard study.34Results from the subgroup analyses
are represented in Figure 3.
DISCUSSION
Differences in drug-induced nephrotoxicity between lipid
formulations of amphotericin B have been a subject of debate.
We analyzed 8 studies by the Cochran-Mantel-Haenszel method
that directly compared nephrotoxicity between ABLC and L-AmB;
only 2 of the studies evaluated, those by Wingard et al34and
Fleming et al,9were randomized. With the exception of meta-
analyses that included the Wingard study, our results demonstrate
that the rate of nephrotoxicity is not significantly different in pa-
tients treated with ABLC versus L-AmB. Additional subanalyses
revealed that, except for subgroups that included the Wingard
study, no other factors, including randomization, age, percentage
of bone marrow transfusion recipients, or the proportion of
patients receiving concomitant nephrotoxic drugs, are associated
with higher rates of nephrotoxicity in patients treated with ABLC
compared with L-AmB.
Ever since its introduction, amphotericin B has been a
mainstay in the treatment of invasive fungal infections because
of its activity against a broad spectrum of fungal pathogens and
rare cases of resistance. The use of conventional amphotericin B
is associated with high rates of infusion-related reactions and
adverse events, especially nephrotoxicity, which have hampered
its clinical utility. Lipid formulations of amphotericin B have
the same spectrum of activity but generally cause fewer adverse
events and are associated with decreasedrenal toxicity compared
with amphotericin B-deoxycholate, even when administered at
higher doses.6,8,23Both ABLC and L-AmB appear to be equally
effective in treating fungal infections and are considered ther-
apeutically equivalent for most fungal infections, as was the case
in the studies analyzed in this meta-analysis that provided ef-
ficacy data.4,9,20,34The 2008 study by Hachem et al11also
demonstrates that efficacy is comparable for both lipid formu-
lations of amphotericin B in the treatment of invasive aspergil-
losis in patients with underlying hematologic malignancy.
Excluding the study by Wingard et al,34the current meta-
analysis suggests a lack of clinically relevant differences be-
tween ABLC and L-AmB with regard to nephrotoxicity. It is
unclear why there was such a large difference in nephrotoxi-
city in the earlier trial by Wingard et al. One plausible expla-
nation could be the way nephrotoxicity and infusion reactions
were measured in the groups of heterogeneous patients in
regard to severity of their underlying clinical conditions and
the toxicity of concomitant treatments. Another explanation
could be when nephrotoxicity was assessed, from day 1 through
the7-dayfollow-up evaluation. The average duration of therapy
was shorter in that trial than the other studies. In a study by
Walsh et al,33creatinine levels were measured over a longer
time course and suggested improvement with time; among 162
patients with elevated baseline sCr values at the start of ABLC
therapy, the mean sCr values decreased significantly from the
first week through the sixth week (p e 0.0003). Improvements
in renal function during therapy with ABLC were similar for
all patient riskgroups.Thus,nephrotoxicityduringtreatmentwith
FIGURE 3. Subgroup meta-analyses evaluating nephrotoxicity between ABLC and L-AmB. Studies were grouped by study design,
mean/median age of patients, percentage of bone marrow transplantation recipients, and the proportion of patients receiving
concomitant nephrotoxic drugs. Results demonstrate that the probability of nephrotoxicity was similar in patients treated with ABLC
compared with L-AmB, except in the subgroups that include the Wingard study.34Cochran-Mantel-Haenszel odds ratios and relative
risks with their associated 95% confidence intervals are given.
Safdar et al
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amphotericin B lipid formulations may be transient. These re-
sults suggest that the time point when nephrotoxicity is as-
sessed during treatment is critical, the duration of therapy is
important, and these issues should be taken into account when
evaluating studies investigating renal toxicity of lipid forms of
amphotericin B. Of course, an alternative interpretation is that
there is more nephrotoxicity with ABLC, as shown by the
Wingard trial, and there may have been unrecognized reasons for
the lack of differences noted in the other studies. For example, the
studies by McKechnie et al21and Mattiuzzi et al20required a
minimal duration of therapy for inclusion that may have excluded
those patients removed from therapy due to early nephrotoxi-
city; thus, early nephrotoxicity differences would not have been
detected.
Results from the study by Hachem et al11are similar to
those reported by Wingard et al,34in that the use of ABLC as
primary antifungal therapy was associated with significantly
more nephrotoxicity than L-AmB. However, this difference was
not observed in patients receiving salvage therapy. In addition,
although meta-analysis results showed an increased probability
of developing nephrotoxicity when the primary treatment arm
was included in the analyses, the OR and RR were considerably
less than those observed with the Wingard study. As indicated
earlier, the Hachem study looked at severely ill patients with
advanced hematologic malignancies, who may have had reduced
renal function, confounding the nephrotoxicity analysis between
ABLC and L-AmB.
Despite reduced rates of adverse reactions compared with
conventional amphotericin B, patients receiving antifungal
therapy with ABLC and L-AmB still experience few infusion
reactions and renal toxicity.8,23,29Using a murine candidiasis
model, Andes et al1found that lipid formulations of amphoter-
icin B distribute preferentially to the mononuclear phagocytic
system. The interaction of free amphotericin B drug released
from lipid vehicles with macrophages may be responsible for
observed infusion reactions.1However, macrophage nitric oxide
synthase expression and tumor necrosis factor-> production is
reduced by lipid formulations of amphotericin B.14In addition,
ABLC and L-AmB appear to downregulate or have no effect on
genes coding for proinflammatory cytokines, which could ex-
plain the lower levels of infusion-related reactions compared
with conventional amphotericin B.30Lipid formulations of am-
photericin B may have reduced nephrotoxicity because the
drug is distributed to tissues of the reticulo-endothelial system,
sparing the kidneys. Furthermore, in the kidneys, less ampho-
tericin B is released from the lipid carrier, because the synthetic
phospholipids have a greater affinity for amphotericin B than
does cholesterol in renal epithelial cell membranes.32Toxic
effects and vasoconstriction associated with conventional am-
photericin B are diminished as a result of lower amounts of
amphotericin B reaching kidney cells.
Conclusions
Renal failure associated with the use of conventional
amphotericin B results in longer hospital stays, increased treat-
mentcosts, andhigher mortality rates.3Thedevelopmentoflipid
formulations of amphotericin B has improved delivery of the
drug and decreased the incidence of adverse reactions and
nephrotoxicity associated with conventional amphotericin B. A
comprehensive review and analysis of studies comparing am-
photericin B formulations demonstrate that lipid forms help pre-
serve renal function and improve survival in patients critically ill
from invasive fungal infections.29Considering the costs associ-
ated with renal failure, the ability to use lipid formulations of
amphotericin B becomes increasingly important in patients re-
quiring broad-spectrum antifungal therapy. Our meta-analysis
raises questions about the previously known relative nephrotoxi-
city of ABLC or L-AmB. In addition, no conclusive differences
in response and outcome have been reported in patients with
invasive fungal infections treated with ABLC or L-AmB. There-
fore, cumulative evidence suggests that ABLC or L-AmB can be
administered to immunocompromised individuals for the treat-
ment or prophylaxis of invasive mycoses, with comparable effi-
cacy and safety.
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