POSTGRADUATE CLINIC

* Professor, Department of Nephrol ogy, ** Resi dent, Department of Medi ci ne,

Dayanand Medi cal Col l ege and Hospi tal , Ludhi ana - 141 001, Punj ab.
Aminoglycoside Nephrotoxicity Revisited
J S Sandhu*, A Sehgal **, OGupta**, A Si ngh**
Abstract
Ami nogl ycosi des remai n dependabl e anti bacteri ci dal agents for severe Gram-negati ve i nfecti on. Ami nogl ycosi des are potenti al l y
nephrotoxi c. Ri sk factors for ami nogl ycosi de-i nducedrenal i nj ury have beeni denti fi ed. Aj udi ci ous use of ami nogl ycosi des, especi al l y
i nhi gh-ri sk i ndi vi dual s hel ps i npreventi ngnephrotoxi ci ty.
J I ACM2007; 8(4): 331-3
Clinical features of aminoglycoside induced
nephrotoxicity
The most common clinical presentation is non-oliguric
acute renal failure. The earliest urinary manifestations are
an increase in urine output and the appearance of
enzymuria. Enzymuria represents the elimination in the
urine of fragments of brush border membrane or
lysosomal enzymes. Measuring enzymuria as an early
marker of tubular damage is of unproven efficacy and is
impractical. The onset of renal failure is usually slower and
the daily rise of serum creatinine tends to be lower than
other causes of acute renal failure. Serum creatinine and
blood urea nitrogen characteristically increase 7 to 10 days
after initiation of aminoglycoside therapy. In more than
half of the cases with nephrotoxicity, the decline in renal
function occurs only after the therapy has been
completed
7
. Recovery from aminoglycoside nephrotoxicity
is usually slow, often taking 4 - 6 weeks time, particularly
in elderly individuals. Although the vast majority of patients
do recover, the presence of several risk factors may alter
the clinical presentation or the course, resulting in the
early appearance of acute renal failure as well as a
protracted course. In patients with underlying chronic
kidney disease, recovery in renal function may be
incomplete in some
8
. In addition, various tubular
dysfunction and electrolyte abnormalities may also
occur
9,10
(Table I).
Pathophysiology
Proximal tubule injury leading to cell necrosis underlines
aminoglycoside nephrotoxicity. Aminoglycosides, which
are strongly cationic drugs, bind to the negatively charged
Introduction
Streptomycin was the first aminoglycoside introduced
in 1944, followed by neomycin (1949), kanamycin (1957),
gentamicin (1963), tobramycin (1968), amikacin (1972),
and netilmicin in 1975
1
. Tobramycin, gentamicin,
amikacin and netilmicin are used in Gram-negative
bacteraemic patients, while streptomycin is used as a
mycobactericidal agent.
The incidence of nephrotoxicity from aminoglycosides
has increased from 2 to 3% in 1969 to 20% in the past
decade
2
. Despite nephrotoxicity and ototoxicity, the
aminoglycosides are continuously being used in clinical
practice because of their bactericidal efficacy, synergism
with -lactam agents, low cost, limited bacterial resistance,
and a post-antibiotic effect.
Renal handling of aminoglycosides
Aminoglycosides are polycationic, a property that is
responsible for their poor oral absorption, a poor
penetration into CSF, and a rapid renal clearance. The
polycationic charge also appears to contribute to
nephrotoxicity.
Aminoglycosides have molecular weight of approximately
500 Dalton and are water-soluble and minimally protein-
bound. The primary route of elimination from the body is
glomerular filtration, which is nearly equal to inulin
clearance. A small percentage (approximately 5) of the
filtered aminoglycoside gets actively reabsorbed in the
proximal tubule. The serum half-life of aminoglycosides is
a few hours as compared to 4 to 5 days in proximal tubule
cells
3 - 6
.
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October-December, 2007
acidic phosphoinositide components of the brush border
membrane of the proximal tubule. At this site, they reach
the cationic drug receptor megalin (gp330) located deep
at the base of the brush border villi. This receptor-drug
complex is rapidly internalised by pinocytosis and taken-
up by the lysosomes, where a process of lysosomal
phospholipidosis occurs, resulting in the formation of
typical morphologic myeloid bodies. After uptake into
proximal tubule cells in the S
1
and S
2
segments, a number
of intracellular processes are disrupted by the presence
of aminoglycoside
7, 11, 12
.
The nephrotoxic potential of various aminoglycosides
depends upon the number of free amino groups on their
surface. The nephrotoxicity of various aminoglycosides in
the decreasing order is neomycin > gentamicin ?
tobramycin ? amikacin ? netilmicin > streptomycin
13, 14
.
Various risk factors predisposing to aminoglycoside
nephrotoxicity
15
are depicted in Table II.
Table I: Clinical features of aminoglycoside induced
nephrotoxicity.
? Non-oliguric acute renal failure; slow recovery over
several weeks
? Proximal tubular dysfunction
? Hypomagnesaemia
? Hypocalcaemia
? Hypokalaemia
Table II: Risk factors for aminoglycoside induced
nephrotoxicity.
Increased risk Decreased risk
Fluid depletion Organic polycations
Potassium and magnesium deficiency Urinary alkalinisation
Endotoxaemia Thyroid hormone
Pre-existing renal disease Potassium loading
Advanced age Experimental diabetes
Co-administration of other nephrotoxins
Lengthy duration of treatment
Repeated courses of aminoglycosides
Liver disease
Obesity/male sex
Treatment
The initial therapy of aminoglycoside-induced acute
tubular necrosis is basically supportive, i.e., discontinuation
of the aminoglycoside and other nephrotoxic agents,
maintaining fluid and electrolyte balance, and controlling
sepsis. Some of the patients may need dialysis
15
.
Prevention
While the molecular mechanisms of toxicity themselves
are still unclear, it remains that the drugs must somehow
physically

interact with one or several cellular constituents
to initiate

the cascade of events leading to toxicity.
Approaches aimed at

reducing aminoglycoside toxicity
should therefore preferably be

targeted at preventing or
modulating these early interactions.

Two phenomena
appear to be essential in this context, namely,

the uptake of
aminoglycosides into proximal tubular cells and

their
interactions with phospholipids in cells.
To prevent aminoglycoside-induced nephrotoxicity in
clinical practice, the following points need emphasis
2, 15-18
.
? Aminoglycoside nephrotoxicity is directly dependent
on the dose and duration of therapy. Thus,
nephrotoxicity is more likely to occur if large doses
are given over prolonged periods, or usual doses are
given to patients with underlying renal disease. Hence
use the lowest dose and shortest possible course of
therapy.
? Use aminoglycosides as an once daily dose rather than
divided dose especially in high-risk individuals.
? Serial monitoring of renal function (serum creatinine
every other day) should be carried-out for early
detection of nephrotoxicity.
? Avoid combination of aminoglycosides with other
potential nephrotoxins (amphotericin, cisplatin,
diuretics, contrast material, etc.).
? During aminoglycoside therapy, ensure adequate
hydration especially in the elderly.
? Modify the dose according to GFR.
? Avoid aminoglycosides in a patient with liver disease.
Experimental nephroprotection
In experimental animals, various aminoglycoside
nephroprotective measures have been reported. These
include:
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October-December, 2007 333
? Pre-treatment with potassium chloride and high
calcium diets
19
.
? Co-administration of different polyanions and
polyamines (?-lipoic acid, daptomycin, inositol
hexasulfate, polyasparagine, polyglutamic and
polyaspartic acid) with aminoglycosides
16, 20, 21
.
? Concurrent penicillin therapy, e.g., tobramycin and
ticarcillin
22
.
Conclusion
More than 50 years since their introduction,
aminoglycosides continue to represent highly effective
antimicrobial agents especially in Gram-negative
infections. Aminoglycosides should be carefully used to
prevent nephrotoxicity especially in high-risk patients.
Monitor renal function frequently during their use. Use
single dose rather than divided doses. Critically ill patients
are not ideal candidates for aminoglycoside therapy,
though the clinician may not have a choice in patients
with life-threatening sepsis.
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