ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No.

1
Copyright 1982, Institute for Clinical Science, Inc.

Mechanisms of Antibiotic-Induced
Nephrotoxicity
THOMAS W. SEALE, Ph .D. and OWEN M. RENNERT, M.D.
Departments of Pediatrics and Biochemistry and Molecular Biology,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK 73190

ABSTRACT
Each of the major classes of clinically useful antibiotics can cause neph
rotoxicity. Major differences exist among classes, and these are reviewed
with regard to the frequency of occurrence of nephrotoxicity, the direct or
indirect toxic effects of the drugs, their site(s) of action within the kidney,
current views of their pathophysiological effects and observations which
provide clues to the biochemical mechanisms underlying their adverse
effects on kidney structure and function. Even for a single abnormal kidney
function, such as non-oliguric reduction of glomerular filtration rate by
gentamicin, the physiological and biochemical mechanisms may be com
plex. In no instance has the biochemical mechanism underlying antibioticinduced nephrotoxicity been definitely established.
Introduction
Nephrotoxicity has long been recog
nized as a serious complication resulting
from antibiotic administration. The vast
array of antibiotic types and derivatives
available to the clinician and the in
creased monitoring for early signs of renal
impairment have reduced the risk of kid
ney damage compared to the early days of
sulfonam ide and neom ycin therapy.
However, the improved technical capac
ity to maintain the severely debilitated
patient who is markedly more susceptible
to a variety of opportunistic pathogens and
the increasing incidence of microbial
drug resistance often necessitate the use

of antibiotics w ith relatively low

therapeutic indices and significant neph
rotoxic potential. In addition, some
widely employed antibiotics with low po
tential for inducing renal disease will in
frequently have significant detrimental
effects on the kidneys of certain patients.
These idiosyncratic drug responses may
reflect intrinsic or environm entallyinduced changes in renal function or drug
metabolism. The intent of this paper is to
review concisely current insights into the
mechanisms underlying the most fre
quently encountered types of antibioticinduced nephrotoxicity. The aminoglyco
sides, amphotericin, and the polymixins

0091-7370/82/0100-0001 $01.50 Institute for Clinical Science, Inc.

SEALE AND RENNERT

As shown in table I, these antibiotics

are reviewed in detail based on a litera
ture search complete through December, include a diverse group of chemically dis
1980. Additional aspects of this topic can sim ilar com pounds which exert their
be found in excellent reviews by Appel antimicrobial effects through site-specific
action on several distinct biological
and Neu1 and Sanders and Sanders.56
targets. The structural and functional dis
sim ilarities among these agents, e.g.,
General Features of Antibioticpolymyxin
and penicillin, suggested the
Induced Nephrotoxicity
likelihood
that
differences would occur in
Several general considerations help to their target sites
the kidney, in
provide an overview of the patho their biochemical within
mechanisms
of action
physiological effects of antibiotics on on renal tissue, and in their frequencies
of
the kidney. (1) Toxicity has been doc inducing renal damages. The order of ar
umented to occur upon administration of rangement of the antibiotics listed in table
the major classes of therapeutically use I reflects in general their propensity for
ful antibiotics. (2) The frequency of occur impairing renal function. Thus, most pa
rence of antibiotic-induced nephrotox tients receiving am photericin B have
icity varies greatly and depends upon the evidence of some degree of nephrotox
class of antibiotic, the properties of par icity.7,13,68 The high frequency (approxi
ticular derivatives within one antibiotic mately 20 percent) of occurrence of renal
class, and the physiological status of the damage associated with colistimethate
patient. (3) Several anatomically and func (polymyxin E)35 and other polymyxins51
tionally distinct kidney sites are suscep limits their clinical application to situa
tible targets for the adverse effects of tions in which other antibiotics cannot be
antibiotics. (4) Antibiotic-induced nephro
ployed. N ephrotoxicity associated
toxicity may be indirectly or directly em
with
the aminoglycosides ranges from 2 to
mediated.
25 percent of treated patients, depending
upon the specific aminoglycoside ad
m inistered, the criteria for defining
toxicity, and the patient population.9,15,59
The remaining classes of antibiotics
listed in table I are much less frequently
associated with untoward renal effects.
From the search for improved therapeutic
indices and more useful antimicrobial ac
tion spectra, many analogs of classic an
tibiotic types have become available.
These derivatives often differ markedly
in their renal effects. For example, the
aminoglycosides, tobramycin and amika
cin, are markedly less nephrotoxic than
gentamicin in both animal models20,31,42
and in man.59,60,61 The relationship be
tween empirically determined nephrotox
icity and chemical modifications of the
parent antibiotic can help to identify par
ticular portions of the antibiotic molecule
which function in the induction of renal
dam age and may suggest possible
TABLE I

Commonly Employed Antibiotics

Causing Nephrotoxicity

Antibiotic Class

Chemical Structure

Microbial Target

Amphotericin

Large double bonded

ring structure
(polyene)-amino
sugar conjugate

Membrane
permeability
(fungal)

Polymyxins

Small cationic
polypeptides

Membrane
permeability

Aminoglycosides

Three covalently
bonded amino sugars

Protein
synthesis

Sulfonamides

Derivatives of
p-aminobenzenesulfonic acid

Folic acid
synthesis

Rifampicin

Complex double
bonded ring
structure

Ribonucleic acid
synthesis

Penicillins

Thiazolide (five
membered) 0-lactam ring
conjugates

Cell wall
synthesis

Cephalosporins

Thiazolide (six
membered) 3-lactam ring
conjugates

Cell wall
synthesis

MECHANISMS OF ANTIBIOTIC-INDUCED NEPHROTOXICITY

physiological mechanisms of action of

these drugs.
In addition to the intrinsic toxicity of an
antibiotic, its nephrotoxicity depends
upon physiological influences and phar
macokinetic considerations, such as the
maximum concentration achieved and the
duration of significant levels of the an
tibiotic. Pre-existing renal dysfunction,
the disease process rendering the indi
vidual susceptible to infection, changes in
renal blood flow, electrolyte imbalance
and pre- or concomitant administration of
other nephrotoxic drugs, increases the
likelihood of deleterious effects of an
tibiotics on the kidney. These factors and
the problem of distinguishing between
the patients underlying illness and druginduced nephrotoxicity make difficult the
determ ination of the incidence of
antibiotic-induced renal disease in pa
tients. Such factors further complicate the
determination of the mechanisms respon
sible for the deleterious action of antibio
tics on the kidney.
With the possible exception of the Loop
of Henle, each region of the nephron can
be damaged by one or more antibiotic
classes. The proximal tubule, site of the
quantitatively most significant reabsorptive functions, is particularly vulnerable.
If generalized effects, such as phenomena
related to hypersensitivity, are excluded,
most antibiotics affect only one or a few
targets. For example, the major site of ac
tion of the aminoglycosides is the proxi
mal tubule,2,16,32 the site of potential toxic
action of the currently used sulfonamides
is the collecting duct. Site specificity of
antibiotic-induced nephropathy implies
several possibilities: (1) there exist cell
types with distinctly susceptible targets
for the deleterious effects of certain
specific antibiotics; (2) the drug may
achieve toxic concentrations in only cer
tain kidney regions; and (3) toxic metabo
lites may be generated in only certain
kidney cells. However, in addition to the
apparently direct deleterious action of

many antibiotics on renal functions, cer

tain antibiotics may act indirectly.
In table II is indicated the association of
each of the major classes of antibiotics
with either immunity-mediated phenom
ena or direct toxic action. In general, the
immunity-related nephrotoxic activities
of antibiotics occur infrequently. Intersti
tial nephritis brought about by methicillin
is a rare complication that appears to be
associated with prolonged exposure to
high levels of antibiotic.310 Fever,
eosinophilia, and rash, indicators of an
immune reaction, often precede or occur
concom itantly w ith the penicillininduced renal lesion.3 Penicillins, serving
as haptens, produce allergic reactions
through their ability to stimulate anti
body production and to initiate haptenantibody reactions. In patients, circulat
ing antibodies to penicillins are not di
rected to the intact penicillin molecule
but to its degradation products, e.g., the
penicilloyl group, that can form covalent
bonds to proteins.4050
Target organ specificity, as for example
might be suggested to explain the occur
rence of interstitial nephritis, could result
from at least four biochemical factors. (1)
The intrinsic activity of the metabolic
pathway converting the antibiotic to the
activated hapten may be restricted to a
specific tissue and thereby elevate its
local concentration. (2) Conjugation of the
TABLE I I
Antibiotic - Induced Nephrotoxicity Arises
By Two Different Mechanisms

Indirect Action (Immunity-Medicated)

Penicillins (expecially methicillin)
Cephalosporins (espec ially cephaloth in)
Sulfonamides
Rifampicin
Direct Action
Amphotericin
Polymyxins
Aminoglycosides
Sulfonamides

SEALE AND RENNERT

hapten to a particular tissue-specific pro

tein may generate antibodies which react
with the protein directly. This may lead to
localized autoimmune disease. (3) One
tissue may possess the ability to concen
trate the antibiotic to levels sufficient for
the generation of significant quantities of
the hapten. (4) The specific capacity of a
tissue to bind antigen-antibody com
plexes formed elsewhere may predispose
it to immunologically-mediated damage.49
It is unlikely that an interstitial concen
trating mechanism contributes to the oc
currence of interstitial nephritis induced
by penicillins because immune-mediated
nephrotoxicity occurs with penicillins
that differ from one another markedly
with regard to protein binding and serum
half life.1,12,63 The kidney is one of the
target organs in drug-induced serum sick
ness, the glomerulus being an especially
frequent site of non-specific localization
of antigen-antibody complexes. Although
this phenomenon would seem to be a log
ical consequence in many penicillin re
cipients who possess antibodies to the
drug, the absence of the characteristic
glomerular lesion seen in other immune
complex disease and the extreme rarity of
penicillin-induced glomerulitis suggest
that immune mechanisms account for
penicillin-induced nephrotoxicity.4 Cer
tain cephalosporins also act indirectly on
the kidney. Some instances of cephalothin
nephropathy have a strong resemblance to
penicillin-induced nephropathy.4 Neph
rotoxicity associated with cephalothin is
uncommon even with large doses of this
antibiotic. It too is frequently charac
terized by signs of hypersensitivity in
cluding rash, eosinophilia, and interstitial
nephritis. In neither penicillin-induced
nor cephalosporin-induced renal lesions
is the exact m echanism of im m unemediation established.
With this general background, the di
rect toxic actions of antibiotics as they per
tain to the kidney will be discussed.

Mechanisms of Nephrotoxic
Antibiotics
Consideration of the spectrum of chem
ical structures, the known mechanisms of
antimicrobial actions (table I), and the di
verse sites of action of the nephrotoxic
antibiotics suggests that a variety of dis
tinctly different mechanisms must ac
count for their direct toxic action on renal
structure and function. Although much
progress has been made in identifying the
anatomical sites which are the targets for
renal damage by antibiotics, there cur
rently exists only a partial description of
the physiological events that are as
sociated with the derangement of renal
functions by antibiotics. In no case has the
biochem ical m echanism underlying
specific renal physiological alterations
been established. For certain antibiotics,
however, descriptions of their action are
sufficiently detailed that one may begin to
predict their probable mechanism(s) of ac
tion. The known nephrotoxic actions of
several antibiotic classes are summarized
in the following sections.
A m p h o t e r ic in B

Nephrotoxicity is the most serious side

effect of am photericin B, a polyene
macrolide antifungal agent. Most patients
receiving the drug demonstrate some
degree of dose-dependent nephrotox
icity.7,13 Urinalysis reveals hematuria,
pyuria, presence of tubular cells, and
cylindruria but little proteinuria.8,33 His
tologic changes in blood vessels and glo
meruli occur infrequently and are not
specific for the drug.13,33 In animals, am
photericin causes intratubular calcium
deposits accompanied by necrosis of the
proximal and distal convoluted tubules
and thickening of the tubular basement
membranes.65,66 Much of the effect of
amphotericin on the kidney involves its
action on the distal tubule. The drug
causes a distal tubular acidosis charac

MECHANISMS OF ANTIBIOTIC-INDUCED NEPHROTOXICITY

terized by net acid excretion and reduced

acidification of urine in response to an
acid load.11,18 Kaliuresis and resultant
potassium deficiency also frequently oc
cur.7,11 Both inulin and p-aminohippuric
acid clearance decrease during acute ad
ministration of amphotericin. Decreased
glomerular filtration rate and ischemic
damage appear to be secondary to drugmediated renal vasoconstriction.54 These
effects are probably the result of the action
of amphotericin on the distal tubule. It has
been established that an increased deliv
ery of chloride ion to the distal tubule can
lead to a profound decrease in the glo
merular filtration rate of the nephron.58
This suppression of glomerular function
by the distal tubule is called tubulo-glomerular feedback. Both this tubulo-glomerular feedback mechanism and the
acute ischemic change caused by am
photericin are attenuated by preloading
animals with sodium or by pre-treating
them with furosemide.27 These findings
are consistent with the hypothesis that the
acute amphotericin-mediated response
includes an increased chloride permea
bility of the distal tubule followed by acti
vation of tubulo-glomerular feedback.
How can this site-specific action be
reconciled with the known biochemical
activities of amphotericin? Polyene macrolide antibiotic toxicity toward eukary
otic cells in generally attributed to mem
brane perm eability changes resulting
from polyene macrolide-sterol interac
tions.17 Amphotericin is slowly excreted
and has a half life of about 24 hours.24 It is
almost completely protein bound; im
paired renal function does not signifi
cantly alter the serum concentration.24
Thus, generalized cellular toxicity result
ing from membrane alterations might be
expected in the kidney. However, under
certain circumstances it is possible to dis
sociate toxicity and permeability changes.
In some in vitro experimental systems,
cell toxicity has been demonstrated at

polyene macrolide concentrations that do

not elicit changes in membrane permea
bility. Alternatively, immediate mem
brane damage may occur in the absence of
cell lethality.25 It appears, then, that the
acute effect of amphotericin B on the dis
tal tubule is a reflection of a rapid per
meability change to chloride ions. With
extended therapy, this may be accom
panied by a more generalized cellular
toxicity which results from continued ex
posure to the drug or from exposure to an
increased concentration of this drug.
T h e P o l y m y x in s

The polymyxinspolymyxin B, colistin, and colistimethateare basic, cyclic

polypeptide antibiotics with a broad
range of activity against Gram-negative
bacteria. All are associated with signifi
cant nephrotoxicity typically charac
terized by decreased creatinine clear
ance, proteinuria and cellular casts in the
urine.35,47,55 In fatal cases, histological
studies have established proximal tubular
damage and acute tubular necro
sis.53, 55PhysiologicaI evidence for the ac
tion of polymixins on the proximal convo
luted tubule has been obtained from in
vitro studies employing hippurate uptake
by rabbit renal cortical slices.46 (Hippu
rate transport is a biochemical marker of
proximal tubule function.) In man, the de
gree of inhibition of this organic acid
transport system by the polymyxins is
well correlated with their relative ability
to induce nephrotoxicity.46 While the ori
gin of the relatively specific effects of
polymyxins on the proximal tubule may in
some manner relate directly to the proxi
mal tubule organic base transport sys
tem ,39 this hypothesis rem ains to be
verified.
It seems reasonable to assume that the
kidney is susceptible to the surfactant ac
tion of the polymyxins through which
their antibacterial action is mediated.23,48

SEALE AND RENNERT

The interaction of these compounds with

the phospholipid component of bacterial
cell m em branes, especially phosphatidylethanolam ine groups, leads to
changes in membrane permeability and
cell death.23 Polymyxins bind to the cellu
lar com ponents of the kidney,37 and
polymyxin B accumulates intracellularly
to high levels in the kidney.34 The drug is
retained for an extended period in an un
metabolized form. With regard to the
chemical structure of the polymyxins, the
degree of tissue binding, nephrotoxicity,
inhibitory action on proximal tubular hippurate transport, and antibacterial activity
are directly related to the number of free
amino groups in this antibiotic.46,48,52,64 It
has been suggested that a balance be
tw een protonated and unprotonated
amino groups in the molecule is important
in both antibacterial and nephrotoxic ef
fects since there is a pH optimum for hippurate transport inhibition and phos
pholipid binding by polymyxins.23,46
From these observations it can be conjec
tured that proximal tubular damage by
polymyxins may result from their rela
tively selective accumulation in cells of
the proximal tubule where their concen
tration becomes sufficient to produce di
rectly significant membrane damage.
T h e A m in o g l y c o s id e s

Nephrotoxicity and ototoxicity are major

factors lim iting the clinical utility of
the aminoglycosides. Included among the
group of clinically useful aminoglycosides
are neomycin, gentamicin, kanamycin,
tobramycin, netilm icin, amikacin, and
streptomycin. The preceeding list is given
in order of decreasing nephrotoxicity and is
based upon a composite of data derived
from experiments in animal models19,20,22,
32,42,44an(j clin jcal observations.9,59,60,61
Neomycin, sometimes employed orally to
reduce the gut flora, is not administered
intravenously because of its high fre
quency of nephrotoxic complications. The

problems of extrapolating to man conclu

sions based on observations in animal
models are numerous, but the agreement
is surprisingly good for those am ino
glycosides rigorously evaluated in man
(e.g., comparing nephrotoxicity of gen
tamicin and tobramycin).44,60
Clinical observations and animal exper
iments demonstrate that aminoglycosides
can induce both structural and functional
kidney damage.2,26,32,36 Typical findings
include proteinuria, enzymuria (derived
from proxim al tubule lysosom al en
zymes), hematuria, cylindruria, elevated
blood urea nitrogen, reduced glomerular
filtration rate and impaired urinary con
centrating ability.1,2,16 These abnor
malities may or may not be associated
with oliguria, although the disease may
progress to oliguric renal failure should
aminoglycoside administration be con
tinued. Proximal tubule damage progress
ing to acute tubular necrosis typifies the
histological picture associated w ith
am inoglycoside-induced renal dam
age.14,32,36 The glomeruli and blood ves
sels are not histologically altered.
Myeloid body formation is a prominent
feature of aminoglycoside nephrotoxicity
and occurs most prom inently in lysosomes of proxim al tubule epithelial
cells.20,32,36
Aminoglycosides are not metabolized
to a significant extent, and the major route
of excretion is by glom erular filtra
tion.1,2,32 In patients with severely im
paired renal function, the serum half life
of these drugs increases to 25 to 40 times
that of the two hours28,38'41 seen in normal
individuals. One feature of am ino
glycoside antibiotics which distinguishes
them from most other antibiotics is their
accumulation in the renal cortex42,43,44,67
(consistent with the tubular action of
aminoglycosides since the tubules are lo
cated in the renal cortex). The ratio of
cortex-bound to serum aminoglycoside
concentration ranges from 5 to 20, de
pending on experim ental conditions.

MECHANISMS OF ANTIBIOTIC-INDUCED NEPHROTOXICITY

Other classes of antibiotics, e.g., penicil

lins or cephalosporins, have cortical to
serum ratios ranging from one to three.
The capacity of the kidney to accumulate
aminoglycosides is large, and repeated in
jections result in progressively increased
cortical levels.
In dogs, at stable therapeutic serum
levels, the aminoglycosides can be se
quentially ordered with regard to their
levels of cortical accumulation. From
highest to lowest these areneomycin >
gentamicin > kanamycin > tobramycin >
streptomycinan order which bears a
remarkable similarity to their relative
nephrotoxic potencies.67 Streptomycin is
not accumulated to a significant extent
and is the least toxic. Results generally
similar to those in the dog are found in the
rat model. One exception, netilmicin, an
aminoglycoside with low nephrotoxicity,
accumulates to an extent similar to highly
toxic gentamicin.42,4345 The toxic effects
of all aminoglycosides are known to be
both dose- and duration-dependent. In
addition to being concentrated in the
renal cortex, these antibiotics also are re
tained there in chemically unmodified
form for an extended period of
time.2943,4467 In the rat, for example, the
half-time of gentamycin in serum is 0.5
hours, whereas in the renal cortex the
half-time is 109 hours. A single dose may
persist for days and, after cessation of drug
administration following repeated doses,
aminoglycoside may be detectable in
urine for weeks. These results may ex
plain delayed nephrotoxicity and de
velopment of nephrotoxicity in patients
receiving a second course of therapy
within a few weeks of previous drug
therapy.67
There is no definitely known mecha
nism explaining how these antibiotics
cause their deleterious effect on cells
of the proxim al tubule. The am ino
glycosides exert their effect on bacteria by
binding to specific protein components of
the small (30S) ribosomal subunit. This

binding results in inhibition of protein

synthesis and m is-translation during
polypeptide chain elongation. Although
these effects usually have not been dem
onstrated to occur with eukaryotic cyto
plasmic ribosomes, there are reports that
in eukaryotes inhibition of protein syn
thesis and messenger RNA misreading
can occur in vitro. The proximal tubule
specificity observed in vivo may result
from the unusually high levels of amino
glycoside achieved and intrinsic or en
vironmentally induced factors. Such fac
tors appear to make certain tubular cells
sensitive to the drug, perhaps at the level
of the protein synthesis. Other mecha
nisms may, however, be involved. For
example, neom ycin has major effects
upon polyphosphoinositide metabolism
in guinea pig kidney both in vivo and in
vitro.57 In view of the probable function of
polyphosphoinositides in m em brane
permeability and ion transport,30,57 altera
tion of their metabolism could have prpfound effects on the cell. Finally, there
may be unexpected effects of am ino
glycosides on particular metabolic func
tions, for example, the inhibition of the
Embden-Meyerhof pathway by kanamy
cin has been shown in the guinea pig.62
A less generally appreciated second
target for am inoglycosides is the
glomerulus. Reduction of glomerular fil
tration rate often occurs after am ino
glycoside adm inistration and is fre
quently of the non-oliguric type.60 Baylis
has investigated the mechanisms respon
sible for the impairment of glomerular fil
tration by gentamicin in the rat.5,6 Several
factors alone or in combination could
cause a fall in glomerular filtration rate. (1)
There is a major and directly proportional
dependence on the renal plasma flow rate.
(2) Reduction of the hydrostatic pressure
difference across the capillary wall has an
important effect. (3) An increase in plasma
protein concentration leading to elevated
plasma oncotic pressure will decrease fil
tration rate. (4) Reduction in capillary

SEALE AND RENNERT

water permeability and/or effective sur

face area in the glomerulus will reduce
the glomerular filtration rate. At low to
moderate concentrations of gentamicin,
micropuncture studies establish the sig
nificant alteration of the last pair of pa
rameters. At high concentrations of the
antibiotic, the reduction in glomerular
filtration rate is multifactorial.5,6 The de
tailed molecular mechanisms accounting
for any of these physiological changes by
gentamicin are completely unknown.
Conclusions
Among nephrotoxic agents, the most
common offenders are drugs prescribed
for the treatment of clinical conditions not
directly concerned with the kidney. In
this category, antibiotics are major induc
ers of kidney disease. While the incidence
of nephrotoxicity mediated by allergic re
sponses is uncommon, high frequencies
of renal impairment occur with the admin
istration of the major antibiotic used to
combat systemic fungal infections, am
photericin B, and the aminoglycosides
used to combat broadly antibiotic resis
tant organisms such as Pseudomonas
aeruginosa. A detailed picture is begin
ning to be established of the pathological
alterations which arise in the kidney upon
antibiotic administration. A few of the
circum stances w hich may potentiate
antibiotic-induced nephrotoxicity are
known, but it is unclear why in the same
kidney some nephrons are damaged while
others are not when presumably exposed
to similar local concentrations of the drug.
In no case has the underlying biochemical
mechanism been definitively established
for antibiotic-induced nephrotoxicity.
Further clarification of the underlying
mechanisms of toxicity could have major
impact upon the design of new antibiotic
analogs with reduced nephrotoxic proper
ties and for the establishment of therapeu
tic regim ens w hich am eliorate the
nephrotoxic effects of antibiotics without
impairing their antimicrobial activity.

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