6/27/23, 10:37 AM Amphotericin B nephrotoxicity - UpToDate

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Amphotericin B nephrotoxicity
AUTHOR: Mark A Perazella, MD, FACP
SECTION EDITOR: Michael Emmett, MD
DEPUTY EDITOR: Albert Q Lam, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2023.

This topic last updated: May 17, 2023.

INTRODUCTION

Amphotericin B is used in the treatment of often life-threatening fungal infections. Acute

kidney injury (AKI) is a relatively common complication of amphotericin B deoxycholate, as are
other kidney manifestations, including urinary potassium wasting and hypokalemia, urinary
magnesium wasting and hypomagnesemia, metabolic acidosis due to type 1 (or distal) renal
tubular acidosis (RTA), and polyuria due to arginine vasopressin resistance (AVP-R, previously
known as nephrogenic diabetes insipidus). Lipid-based formulations of amphotericin B have
reduced but not completely eliminated the risk of nephrotoxicity.

An overview of amphotericin B nephrotoxicity is presented here. The management of

hypokalemia, hypomagnesemia, distal RTA, and AVP-R is discussed in detail elsewhere:

● (See "Clinical manifestations and treatment of hypokalemia in adults", section on

'Treatment'.)
● (See "Hypomagnesemia: Evaluation and treatment".)
● (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on
'Distal (type 1) renal tubular acidosis'.)
● (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

ACUTE KIDNEY INJURY

Incidence and risk factors — Acute kidney injury (AKI) is a common complication of

conventional amphotericin B (ie, amphotericin B deoxycholate) [1-6]. In the two largest
reviews, a 50 percent or greater increase in serum creatinine was observed in 138 of 494 and
174 of 643 patients (28 and 27 percent, respectively) [4,5]. The incidence of nephrotoxicity is

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lower with lipid-based formulations of amphotericin B, as discussed below. (See 'Use of lipid-
based formulations' below.)

The risk of amphotericin-induced kidney injury is influenced by other factors:

● Concurrent therapy with other nephrotoxins, such as an aminoglycoside, cyclosporine,

or foscarnet, increases the risk of AKI [4-7]. In one report, the incidence of a twofold or
greater increase in serum creatinine was 15 percent in patients taking no or one
concurrent nephrotoxic drug and 41 percent in those taking two or more concurrent
nephrotoxic drugs [6].

● Chronic kidney disease (CKD) at baseline and the severity of the underlying illness also
increase the risk [4,5]. In one series, the incidence of moderate to severe nephrotoxicity
(defined as a doubling of the serum creatinine to a level greater than 2 mg/dL) was 4
percent in patients with no risk factors for AKI and 8 to 29 percent in those with CKD [4].

● The likelihood of kidney disease is also dose dependent, with the risk of kidney function
impairment being low at doses of less than 0.5 mg/kg per day and a cumulative dose of
less than 600 mg [4,5,7].

A prediction rule risk stratified patients based upon the following clinical data available during
the course of therapy: location of care (general medical unit versus intensive care unit),
concurrent use of cyclosporine, and maximum daily amphotericin B dose (<60 mg versus ≥60
mg daily). In the lowest risk group (12 percent of patients), the risk of nephrotoxicity was 4
percent, while in the highest risk group (10 percent of patients), the risk of AKI was 80 percent
[5].

Pathogenesis of AKI — The original formulation of amphotericin B contains sodium

deoxycholate to increase the solubility of amphotericin B in water. The hydrophobic part of
the molecule binds to ergosterol, the main sterol in the cytoplasmic membrane of fungi. This
forms pores and channels in the plasma membrane that allow the extravasation of
electrolytes from the intracellular medium (such as potassium, ammonium, and phosphate) in
addition to carbohydrate and proteins, thereby causing cell death. Besides its affinity for the
fungal ergosterol, amphotericin B deoxycholate also has affinity for cholesterol present in
mammalian cells. Thus, in addition to its antifungal activity, amphotericin B causes substantial
toxicity to mammalian cells, causing kidney, heart, and hematologic injury [8-11].

Proximal tubular cells and medullary interstitial cells respond with programmed cell death
when treated with therapeutic doses of amphotericin B. In animal models, the number of
apoptotic tubular cells correlates with the degree of hypokalemia and loss of renal
concentrating ability; administration of insulin-like growth factor-1, an antiapoptotic agent,
prevents hypokalemia and preserves concentrating ability [12]. In addition to this direct

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effect, in vitro studies suggest that approximately one-half of the tubular toxicity of
amphotericin B may be mediated by deoxycholate [8-11].

The reduction in glomerular filtration rate (GFR) associated with amphotericin B-induced
tubular toxicity may be mediated in part by the tubuloglomerular feedback (TGF) system
[1,13]. Normally, when sodium chloride delivery to the distal tubule increases, a greater
quantity of sodium chloride enters the macula densa cells located in the early portion of the
distal tubule. This results in activation of a feedback loop (TGF), which triggers afferent
arteriolar vasoconstriction and a fall in GFR [1,13]. Under most circumstances, this TGF
response is physiologically appropriate: high rates of sodium chloride delivery out of the
proximal tubule are restored to near normal levels by the appropriate reduction in GFR, and
this prevents excessive sodium chloride losses in the urine [14]. However, amphotericin B
nephrotoxicity increases the permeability of the macula densa cells. This may inappropriately
activate the TGF system and lead to excessive afferent arteriolar vasoconstriction and a fall in
GFR [1,13].

Alternatively, the renal vasoconstriction and fall in GFR may reflect a direct action of
amphotericin B on blood vessels, rather than TGF [15]. In experimental animals,
administration of a calcium channel blocker prevents amphotericin-induced vasoconstriction
and the resultant decline in GFR [16].

Clinical presentation — Amphotericin B-associated AKI generally manifests with an increase

in serum creatinine at four to five days following drug initiation, while hypokalemia and
hypomagnesemia develop within or slightly after (seven to eight days) that time frame.
However, these nephrotoxic events may occur before or after the noted times [17,18]. (See
'Electrolyte and acid-base disorders' below.)

In most cases, the serum creatinine increases by no more than 2.5 mg/dL (220 micromol/L)
above baseline [1,4,5,13]. More severe kidney injury due to amphotericin B alone is
uncommon but can occur with diuretic-induced volume depletion or the concurrent
administration of another nephrotoxin.

The nephrotoxicity associated with amphotericin B is usually reversible with discontinuation

of therapy [13,19]. However, recurrent AKI can occur if treatment is reinstituted [19]. There are
no data on the long-term clinical course of patients following amphotericin B-associated AKI.

Monitoring — All patients receiving amphotericin B should be monitored for nephrotoxicity

during therapy, particularly those with underlying risk factors. Electrolytes, blood urea
nitrogen (BUN), and serum creatinine along with serum magnesium concentrations should be
measured while on therapy with amphotericin B. (See 'Incidence and risk factors' above.)

Prevention — The risk of nephrotoxicity can be reduced by using lower doses of

amphotericin and by avoiding concurrent therapy with other nephrotoxins, such as an
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aminoglycoside or cyclosporine [4,5]. Two other preventive measures are salt loading and the
use of lipid formulations of amphotericin B. In addition, for some fungal infections, non-
amphotericin B agents are now available.

Salt loading — For patients who are going to receive amphotericin B (conventional or lipid-
based formulation) and who are not hypervolemic, we suggest volume expansion with
isotonic fluids (typically isotonic saline) rather than more dilute fluids or no volume expansion
to prevent the development of AKI. In patients who are euvolemic, a total of 500 mL of
isotonic saline is typically given immediately prior to the amphotericin B infusion or divided
before and after amphotericin B administration. Patients who are hypovolemic may require
additional isotonic saline for volume repletion, while those who are hypervolemic should not
receive isotonic saline prior to or after receiving amphotericin B.

The proposed importance of TGF in amphotericin B nephrotoxicity has led to the use of salt
loading since volume expansion has been shown to reduce the sensitivity of the TGF system.
Studies in both humans and animals have shown that saline administration can protect
against or ameliorate the amphotericin B-induced decline in GFR [1,2,13,20] but not the signs
of tubular dysfunction described above [20]. (See 'Pathogenesis of AKI' above.)

The beneficial effect of salt loading was best shown in a controlled study of patients with
mucocutaneous leishmaniasis who received a 10-week course of amphotericin B (average
dose 50 mg per day, given three times per week) [20]. The serum creatinine concentration
was stable with salt loading (1 liter of isotonic saline over the 60 minutes prior to
amphotericin B administration) but rose from 0.6 to 1 mg/dL (53 to 88 micromol/L) in patients
given only water. The minor degree of kidney function impairment in the relatively healthy
control group probably reflects in part the absence of potentiating factors, such as volume
depletion or concurrent aminoglycoside therapy.

However, this benefit of salt loading does not prove that TGF, rather than vasoconstriction, is
the major mechanism underlying the reduced GFR. Increases in the secretion of
vasoconstrictors (angiotensin II and norepinephrine) and decreases in the secretion of the
vasodilator atrial natriuretic peptide might modulate the constrictive effect of amphotericin B
[15]; volume expansion could prevent these hormonal changes.

Use of lipid-based formulations — Administering amphotericin B in a lipid-based

formulation can minimize, though not eliminate, the incidence and severity of nephrotoxicity.
Two lipid-based amphotericin B formulations are available: amphotericin B lipid complex
(ABLC) and liposomal amphotericin B (L-AMB). These formulations have largely supplanted
the use of amphotericin B deoxycholate in resource-abundant countries. L-AMB may be less
nephrotoxic than ABLC [21]. (See "Pharmacology of amphotericin B", section on 'Lipid-based
amphotericin B formulations'.)

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Data from randomized trials [22-24] and observational studies [25-28] suggest that
administering amphotericin B in a lipid-based formulation can minimize, though not
eliminate, the incidence and severity of nephrotoxicity. The best comparative data are
reported in a meta-analysis of randomized trials that compared conventional amphotericin B
with both liposomal amphotericin B (five trials, 1233 patients) and lipid emulsion
amphotericin B (nine trials, 459 patients) [22]. Compared with conventional amphotericin B,
the incidence of nephrotoxicity was reduced with the use of liposomal amphotericin B (15
versus 33 percent) or lipid emulsion amphotericin B (12 versus 31 percent).

The reason why lipid-based formulations are associated with less AKI is incompletely
understood. However, two possibilities have been proposed:

● The liposomal preparation does not contain deoxycholate, which (as noted above) has
direct tubular toxicity [8]. (See 'Pathogenesis of AKI' above.)

● The liposomes may be preferentially distributed to the reticuloendothelial system, where

amphotericin B can be transferred directly to trapped fungi with less delivery to other
cholesterol-containing cells, such as those in the kidney [9].

As with amphotericin B deoxycholate, the risk of nephrotoxicity with lipid-based formulations

is higher among patients concurrently treated with other potentially nephrotoxic drugs,
including aminoglycosides, cyclosporine, foscarnet, angiotensin-converting enzyme (ACE)
inhibitors, and angiotensin receptor blockers (ARBs) [6,27,29,30].

Preventive interventions of unclear benefit — N-acetylcysteine has been shown to protect

against amphotericin-induced nephrotoxicity in animal models, preserving GFR and reducing
apoptosis of renal tubular cells [31,32]. Evidence for a protective role in humans, however, has
been inconclusive [33].

Pentoxifylline and sodium bicarbonate have also been employed for prophylaxis without
success [17,34].

Continuous infusion of amphotericin B deoxycholate over 24 hours may help to minimize

potentially nephrotoxic peak concentrations and decrease nephrotoxicity when compared
with conventional infusion (over two to six hours) [35-37]. There are no studies comparing this
approach with the use of lipid-based formulations of amphotericin B.

Management of AKI — For patients with amphotericin B-associated AKI, discontinuing

amphotericin B and switching to another effective antifungal agent is appropriate. The
general approach to the management of AKI after amphotericin administration is the same as
that for other causes of AKI. These issues are discussed separately. (See "Overview of the
management of acute kidney injury (AKI) in adults" and "Prevention and management of
acute kidney injury (acute renal failure) in children".)

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ELECTROLYTE AND ACID-BASE DISORDERS

Amphotericin B has been associated with the following electrolyte and acid-base disorders:

● Urinary potassium wasting and hypokalemia

● Urinary magnesium wasting and hypomagnesemia
● Metabolic acidosis due to type 1 (or distal) renal tubular acidosis (RTA)
● Polyuria due to arginine vasopressin resistance (AVP-R, previously known as
nephrogenic diabetes insipidus)

Pathogenesis — The increase in membrane permeability caused by amphotericin B is also

thought to contribute to the electrolyte abnormalities that often occur. This defect results in
the reduction of ion concentration gradients, which normally exist between the cytoplasm of
distal tubule cells and the tubule lumen. In these cases, potassium leaks from the cytoplasm
down a favorable concentration gradient into the lumen. Similarly, hydrogen ions diffuse
down their gradient from the lumen into the cytoplasm of distal tubule cells [38]. Thus, an
increase in tubular permeability will promote the back-diffusion of secreted hydrogen ions (or
of carbonic acid formed by the combination of hydrogen with filtered bicarbonate), thereby
limiting acid excretion [39-41]. Hypomagnesemia and renal magnesium wasting also occur as
a result of amphotericin kidney toxicity [41,42].

The loss of magnesium and potassium may also be related in part to the systemic toxicity of
the amphotericin B that causes these intracellular ions to leak into the extracellular fluid
space and then be lost into the urine [2].

The net effect of these changes is that both hypokalemia due to potassium loss and a normal
anion gap metabolic acidosis (ie, a distal RTA) due to hydrogen retention are commonly seen
[2,6,38,40]. Hypomagnesemia, though somewhat less common, is also reported. The distal
RTA generated by amphotericin B, unlike most other forms of distal RTA, is associated with a
normal urine-blood partial pressure of carbon dioxide (PCO2) after alkaline loading [43,44].
This likely results from the previously mentioned back-diffusion of secreted hydrogen ions,
but a loss of polarity of the chloride-bicarbonate exchanger is also consistent with this finding
[43].

Amphotericin B may also cause resistance to antidiuretic hormone, leading to polyuria and
polydipsia [2,6,44,45]. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus):
Clinical manifestations and causes".)

Prevention and management

● Prevention – As with acute kidney injury (AKI), the use of liposomal amphotericin B may
help to prevent electrolyte abnormalities and AVP-R [6,46]. In one randomized trial,

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patients receiving liposomal amphotericin B had a significantly lower rate of

hypokalemia (serum potassium concentration ≤2.5 mEq/L) but no significant change in
the rate of hypomagnesemia (serum magnesium concentration ≤1.5 mg/dL [0.6
mmol/L]) [6]. (See 'Use of lipid-based formulations' above.)

If conventional amphotericin B is used, patients without significant kidney function

impairment should receive daily preemptive administration of potassium, which may
prevent serious hypokalemia due to urinary potassium wasting [47].

In contrast to AKI, amphotericin B-induced electrolyte and acid-base abnormalities do

not appear to be ameliorated by volume expansion [20]. (See 'Salt loading' above.)

● Management – In general, treatment of the hypokalemia and RTA consists of

administering alkali with potassium. Treatment of the magnesium wasting consists of
the administration of magnesium supplements. However, the efficacy of this regimen is
limited by the urinary excretion of most of the supplemental magnesium.

Management of the electrolyte and acid-base disorders associated with amphotericin B

is discussed in greater detail elsewhere:

• Hypokalemia (see "Clinical manifestations and treatment of hypokalemia in adults",

section on 'Treatment')

• Hypomagnesemia (see "Hypomagnesemia: Evaluation and treatment", section on

'Treatment')

• Distal RTA (see "Treatment of distal (type 1) and proximal (type 2) renal tubular
acidosis", section on 'Management of distal RTA')

• Polyuria due to arginine vasopressin resistance (see "Arginine vasopressin resistance

(nephrogenic diabetes insipidus): Treatment")

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Acute kidney injury in
adults" and "Society guideline links: Acute kidney injury in children".)

SUMMARY AND RECOMMENDATIONS

● Acute kidney injury – Conventional amphotericin B (ie, amphotericin B deoxycholate)

commonly causes acute kidney injury (AKI). Lipid-based formulations of amphotericin B

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have reduced but not completely eliminated the risk of nephrotoxicity. (See
'Introduction' above.)

• Risk factors – The risk of amphotericin B nephrotoxicity is increased by higher daily

doses, longer duration of therapy, and concurrent therapy with other nephrotoxins,
such as an aminoglycoside, cyclosporine, or foscarnet. (See 'Incidence and risk
factors' above.)

• Clinical presentation – Amphotericin B-associated AKI generally manifests with an

increase in serum creatinine at four to five days following drug initiation, while
hypokalemia and hypomagnesemia develop within or slightly after (seven to eight
days) that time frame. However, these nephrotoxic events may occur before or after
the noted times. The nephrotoxicity is usually reversible with discontinuation of
therapy. (See 'Clinical presentation' above.)

• Monitoring – All patients receiving amphotericin B should be monitored for

nephrotoxicity during therapy, particularly those with underlying risk factors.
Electrolytes, blood urea nitrogen (BUN), and serum creatinine along with serum
magnesium concentrations should be measured while on therapy with amphotericin
B. (See 'Monitoring' above.)

• Prevention – The risk of nephrotoxicity can be reduced by using lipid-based

formulations of amphotericin B, lower doses of amphotericin, and by avoiding
concurrent therapy with other nephrotoxins, such as an aminoglycoside or
cyclosporine. For patients who are going to receive amphotericin B (conventional or
lipid-based formulation) and who are not hypervolemic, we suggest volume
expansion with isotonic fluids (typically isotonic saline) rather than more dilute fluids
or no volume expansion to prevent the development of AKI (Grade 2C). (See 'Salt
loading' above and 'Use of lipid-based formulations' above.)

• Management – For patients with amphotericin B-associated AKI, discontinuing

amphotericin B and switching to another effective antifungal agent is appropriate.
The general approach to the management of AKI after amphotericin administration
is the same as that for other causes of AKI. (See "Overview of the management of
acute kidney injury (AKI) in adults" and "Prevention and management of acute kidney
injury (acute renal failure) in children".)

● Electrolyte and acid-base disorders – Amphotericin B can also cause urinary potassium
wasting and hypokalemia, urinary magnesium wasting and hypomagnesemia,
metabolic acidosis due to type 1 (or distal) renal tubular acidosis (RTA), and polyuria due
to arginine vasopressin resistance (AVP-R, previously known as nephrogenic diabetes
insipidus).

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• Prevention – As with AKI, the use of liposomal amphotericin B may help to prevent
amphotericin B-associated electrolyte abnormalities and AVP-R. However, these
abnormalities are not ameliorated by volume expansion. Patients without significant
kidney function impairment who are receiving conventional amphotericin B are
generally given daily potassium supplementation to prevent hypokalemia due to
urinary potassium wasting. (See 'Prevention and management' above.)

• Management – In general, treatment of the hypokalemia and RTA consists of

administering alkali with potassium. Treatment of the magnesium wasting consists of
the administration of magnesium supplements. However, the efficacy of this regimen
is limited by the urinary excretion of most of the supplemental magnesium. (See
'Prevention and management' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Richard Sterns, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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