05-02-2013, 03:21 PM
An overview of drug-induced acute kidney injury
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Mechanisms of Nephrotoxicity
Drugs with direct nephrotoxic effects
may induce renal injury by several mechanisms
(Table 1). Most commonly, renally
excreted drugs can exert direct toxic
effects on renal tubules, inducing cellular
injury and death in acute tubular necrosis,
or induce inflammation in the renal
interstitium in acute interstitial nephritis
(AIN).
Other types of nephrotoxic tubular injury
include osmotic nephrosis induced
by hypertonic solutions and tubular obstruction
by drug precipitation (e.g.,
crystalline nephropathy). Nephrotoxic
acute tubular necrosis is generally a dosedependent
phenomenon that predictably
occurs in patients at high risk for renal
injury (older patients, pre-existing renal
disease, multiple nephrotoxic agents
used) and is characteristically noninflammatory
in nature. In contrast, acute (allergic)
interstitial nephritis is an idiosyncratic
inflammatory response to drug
exposure. Drugs also may be indirectly
vnephrotoxic by modulating intrarenal
blood flow, thus rendering the kidneys vulnerable
to ischemia and injury in the case
of decreased renal blood flow. Therapeutic
agents have been associated with the development
of glomerular disease or vasculitis;
however, these are relatively rare complications
of medical therapy and will not be
discussed in detail in this review.
Drug-Induced Acute Tubular
Necrosis
Aminoglycosides. Aminoglycosides
(AGs) continue to be commonly used for
the management of severe Gram-negative
infections, despite well established ototoxicity
and nephrotoxicity. AKI as defined
by a 0.5–1 mg/dL increase in serum
creatinine values is a relatively common
complication of treatment with a reported
frequency ranging between 10%
and 20% (5, 6). Aminoglycosides are
non–protein bound drugs that are not
metabolized and are primarily excreted
by glomerular filtration. The cationic
properties of these agents facilitate binding
to the tubuloepithelial membrane in
the proximal tubule, resulting in rapid
intracellular transport (7, 8). The number
of cationic groups on the molecules determines
the facility with which these
drugs are transported across the cell
membrane and are an important determinant
of toxicity (5, 9). Neomycin is
associated with the most nephrotoxicity;
gentamicin, tobramycin, and amikacin
are intermediate, and streptomycin is the
least nephrotoxic (9 –12). Several hypotheses
have been proposed to explain the
nephrotoxic effects of these agents. Intracellular
accumulation of AG within lysosomes
is thought to interfere with normal
cellular function, such as protein
synthesis and mitochondrial function,
eventually leading to cell death (13).
Hemodynamically Mediated Nephrotoxic Acute Renal Failure
Angiotensin-Converting Enzyme Inhibitors
and Angiotensin Receptor Blockers.
Intraglomerular pressure and consequently
glomerular filtration rate (GFR)
are normally regulated by the vasomotor
tone of the afferent (preglomerular) and
the efferent (postglomerular) arterioles.
In situations of decreased renal blood
flow, intraglomerular pressures are
maintained by vasodilation of the afferent
arteriole and vasoconstriction of the efferent
arteriole. Medications that affect
the renin angiotensin system also have
the potential of causing or exacerbating
acute renal failure by modulating intrarenal
blood flow. Angiotensin-converting
enzyme inhibitors and angiotensin receptor
blockers decrease intraglomerular
pressure by selective inhibition of angiotensin
II–mediated vasoconstriction at
the efferent arteriole. As a consequence,
the serum creatinine may increase by as
much as 30% after initiating angiotensinconverting
enzyme inhibitors or angiotensin
receptor blockers without being a
cause for concern, a reflection of angiotensin
II inhibition (60, 61). This apparent
decline in GFR is seen 3–5 days after
initiating therapy and stabilizes within 7
days. This action is beneficial in proteinuric
renal disease or diabetic renal disease
in which high intraglomerular pressures
are associated with progression of
renal disease; however, in situations involving
a reduction in renal perfusion
(bilateral renal artery stenosis, shock of
any cause, or decreased intravascular volume)
these drugs will further decrease
intraglomerular pressure, precipitating
prerenal failure.