|
7.1 Introduction
Acute kidney injury is an independent risk factor
for patient mortality, even with small decrements in kidney
function. In addition, it increases length of stay in the hospital
and increases cost of treatment. Renal injury is often
multifactorial, with drugs being only one of the factors in its
pathogenesis. Hence, it is often difficult to estimate involvement
of drugs as a cause of acute kidney injury. However, some data
shows that in almost one quarter of cases of severe acute kidney
injury nephrotoxic drugs are signifficant contributors. Renal
handling of drugs involves glomerular filtration, excretion through
transcellular transport into tubular fluid and reabsorbtion from
the tubular fluid. High renal blood flow and process of
concentration of drugs and their metabolites during formation of
urine predisposes kidneys to toxic drug injury. From the pathogenic
(pathophysiologic) perspective drug-induced kidney injury can be
devided into hemodynamic, intrinsic (injury to renal tissue) and
intrarenal obstruction (obstruction of tubule fluid flow). From
didactical point of view kidney histology can be divided into four
compartments: glomeruli, tubules, interstitium and vasculature.
Each of these compartments can be target of drug-induced injury,
with clinical and laboratory manifestations being dependent on
which of them is predominantly involved. It is important to
appreciate that a single drug renal toxicity can involve multiple
pathophysiologic pathways and that predisposing factors are common
to virtually all causative agents mediating kidney injury.
Dehydration, hypotension, preexisting kidney disease, advanced age,
diabetes and simultaneous use of multiple nephrotoxic drugs all
greatly increase risk for any nephrotoxic drug to exert its
nephrotoxic effect. At an increased risk are particularly patients
in intensive care units.
7.2 Hemodynamic kidney injury
7.2.1 Non-steroidal antiinflammatory drugs and
drugs that inhibit renin-angiotensin system
Renal blood flow and glomerular filtration
normaly depend on renal perfusion pressure (determined by the mean
arterial pressure) and on tonus of the afferent and efferent
arteriole. In the setting of decreased perfusion pressure
glomerular filtration is maintained by the afferent arteriole
dilatation, mediated in part by vasodilatory prostaglandins and by
the efferent arteriole vasoconstriction mediated partly by
angiotensin II. Therefore, it is not surprising that inhibition of
prostaglandin synthesis by the non-steroidal antiinflammatory drugs
(NSAID) may precipitate kidney dysfunction. Renal microvasculature
expresses both isoforms of cyclooxygenase (COX), COX-1 and COX-2.
In conditions where renal blood flow is impaired, such as
congestive heart failure, liver cirrhosis, dehydration and chronic
kidney disease vasodilatory prostaglandins help to maintain renal
blood flow and glomerular filtration. Both, selective (COX-2) and
non-selective COX inhibitors impair synthesis of vasodilatory
prostaglandins in the kidney and are associated with development of
intrarenal vasoconstriction and renal function impairment. Other
forms of kidney injury by the NSAID are acute tubulointerstitial
nephritis, chronic interstitial nephritis and glomerulopathy
(usually minimal change disease).
Similarly, in the setting of effective blood volume depletion
(decompensated heart failure, decompenstaed cirrhosis, systemic
hypotension), or renal hypoperfusion due to bilateral renal artery
stenosis, administration of drugs that block synthesis of
angiotensin II (angiotensin-converting enzyme inhibitors), or its
binding to type I receptors (AT1 receptor antagonists) reverses
efferent arteriole vasoconstriction and decreases intraglomerular
pressure, which reduces glomerular filtration rate.
Both NSAID-induced or anti-angiotensin
drug-induced kidney injury is functional and quickly resolves upon
withdrawal of a causative drug. Diagnosis relies on clinical
judgement. Urinalysis reveals blank sediment. Hemodynamic kidney
injury is treated by withdrawal of causative drug. Renal
replacement therapy is rarely needed.
Other drugs that may cause kidney injury by
intrarenal vasoconstriction are vasopressors, calcineurin
inhibitors (cyclosporine and tacrolimus) and amphotericin B.
7.2.2 Contrast-induced nephropathy
Contrast-induced nephropathy (CIN) is a form of
acute kidney injury that occurs after intravenous administration of
iodine-based radiocontrast agents for radiologic examinations. At
particular risk for CIN are diabetics, volume-depleted patients,
older patients and patients with preexistant kidney injury. Acute
worsening of glomerular filtration occurs within several days of
radiologic procedure (usually after 48-72 hrs). Decrease in
glomerular filtration is usually small or moderate and renal
function returns to baseline level within several days. However,
sometimes hemodialysis is needed to bridge period to recovery. Even
small decrements in kidney function have been linked to increased
mortality in patients with CIN, although it is not clear whether
CIN is an independent risk factor for mortality. Because of this
potential effect on patient survival, and increased costs of care
for patients with CIN, great effort should be put to prevention of
CIN in patients at risk. Preventive measures include adequate
hydration of patients prior to and after procedure, use of
low-osmolar or iso-osmolar contrast agents and limiting ammount of
agent used. Role of particular agents such as bicarbonate and
N-acetyl cystein, as well as continuous venovenous hemofiltration
in prevention of CIN is not clearly established.
7.3 Intrinsic kidney injury
7.3.1 Tubulointerstitial injury
Acute tubulointerstitial injury can be caused by
two mechanisms: by the hypersensitive idiosyncratic reaction that
is dose-independent and is reffered to as acute hypersensitive
tubulointerstitial nephritis and by the toxic acute kidney injury
characterized by acute tubular necrosis. Acute tubular necrosis is
dose-dependent. Chronic form of tubulointerstitial nephritis is
seen with long-term use of NSAID, usually in combination and is
reffered to as analgesic nephropathy.
7.3.2 Acute hypersensitive interstitial
nephritis
It is an idiosyncratic fenomenon, caused by the
allergic reaction to variety of drugs. Characteristically,
reexposure to the same drug causes recidive of the disease. Many
drugs have been implicated in inducing tubulointerstitial nephritis
(TIN). Among them are beta-lactam antibiotics (penicillins and
cephalosporins), quinolone antibiotics (ciprofloxacin), NSAID,
proton pump inhibitors (e.g. omeprazole), sulfonamides,
allopurinol, etc. Histologicaly, interstitial inflammatory
infiltrate consisting of T and B lymphocytes, with frequently
prominent eosinophils is found in renal tissue obtained by biopsy.
Accordingly, sterile leucocyturia with eosinophyluria is found on
urinalysis. Acute interstitial nephritis causes acute kidney
injury, characterized by an increase in serum creatinine levels,
which is reversible upon discontinuation of the offending drug.
Corticosteroids may foster resolution of kidney inflammation and
recovery of renal function.
7.3.3 Acute tubular necrosis
Prototype class of agents that induces acute
tubular necrosis (ATN) are aminoglycoside antibiotics. These drugs
are freely filtrable by the glomerulus. Their nephrotoxic potential
is dependent on the number of cationic groups on the molecule.
Aminoglycosides bind to acidic phospholipids and megalin on the
apical membrane of proximal tubule cells, and after uptake into the
cells by endocytosis they accumulate in lysosomes causing their
rupture. They are also thought to interfere with cellular functions
such as protein synthesis and mitochondrial function. Ultimately,
proximal tubule cell apoptosis and necrosis occurs, leading to
acute kidney injury. In addition, there is some evidence that
aminoglycosides may potentiate nephrotoxicity of gramm-negative
bacterial endotoxin. Acute kidney injury caused by aminoglycosides
is frequently non-oliguric, with increases in serum urea and
creatinine within days of initiation of antibiotic therapy. Kidney
injury may be severe enough to require renal replacement therapy.
Urinalysis shows mild proteinuria with hyaline and granular casts
in the sediment. After stopping the drug renal function returns to
baseline values usually within weeks. To prevent
aminoglycoside-induced acute kidney injury it is important to
identify patients at risk, as stipulated in the introduction
section. In patients with reduced kidney function, it is of
paramount importance to adjust the dose according to glomerular
filtration rate. Also, it seems that once-daily dosing of
aminoglycosides decreases incidence of acute kidney injury
(although this is a metter of some controversy). The role of
therapeutic drug monitoring, usually by measuring trough plasma
concentration is helpful in determination of appropriate dose, but
its role in preventing kidney injury is not clearly
established.
Other agents that may cause acute tubular
necrosis are chemotherapeutics such as platinum derivatives,
amphotericin B, foscarnet, cidofovir and statins (by causing
rhabdomyolysis and myoglobinuria).
7.3.4 Osmotic nephrosis
Osmotic nephrosis is a form of acute kidney
injury caused by a high-dose intravenous immunoglobuline, or
osmotic diuretics such as mannitol and plasma expanders, such as
hydroxiethylstarch. Histologicaly, it is characterized by isometric
vacuolization of proximal tubules. It is thought that proximal
tubule cell injury occurs after uptake of either osmotic agent
itself, or its vehicle (such as sucrose in case of intravenous
immunoglobuline) with consequent tubule cell swelling and
injury.
7.3.5 Analgesic nephropathy
Analgesic nephropathy was a relatively frequent
cause of chronic kidney disease in the past. It is characterised by
the chronic interstitial nephritis, often with papillary necrosis.
First manifestation is mildly decreased glomerular filtration and
decreased urinary concentration capability. Later, interstitial
fibrosis, especially in the medulla, with papillary necrosis
occurs. Unless analgesic abuse is stopped, renal injury is
progressive and leads to end-stage kidney disease. Responsible
agents are analgesics in combinations. The most important causative
drug was phenacetin, often in mixtures with acethylsalicilic acid,
codeine or caffeine. A metabolite of phenacetin, acetaminophen,
which is a very frequently used analgesic may be also associated
with nephrotoxicity, although the risk is lower compared to
phenacetin. Similarly, consummation of other NSAID may be related
to development of chronic kidney disease. However, large quantities
of these drugs is required over many years to induce chronic kidney
disease. Mechanisms by which these drugs induce kidney damage
include oxidative stress and chronic inhibition of synthesis of
vasodilatory prostaglandins with consequent chronic renal ischemic
injury. Diagnosis relies on careful history taking, urinalysis
showing sterile leucocyturia and mild or moderate (usually
subnephrotic) proteinuria, with or without erythrocyturia. Urinary
infections are frequent in patients with analgesic nephropathy.
Hallmark of analgesic nephropathy, papillary necrosis can be
diagnosed by intravenous urography, CT scan, or by the ultrasound.
Other suggestive features on imaging procedures are shrunken
kidneys, nephrocalcinosis and kidneys with bumpy contours.
7.4 Intrarenal obstruction
Drug-induced intrarenal obstruction is mainly due
to antiviral drug precipitation. It is observed sometimes with use
of acyclovir. Risk factors are rapid bolus administration in a
volume-depleted patient. Crystaline nephropathy has also been a
complication of antiretroviral drugs such as indinavir or
tenofovir, especially in patients with high urinary pH values (pH
>6). Toxicity of these drugs is potentiated by concomitant use
of sulfometoxazole. Another drug which may precipitate in kidney
tubules is methotrexate used in high doses, in the setting of
dehydration and/or low urine pH (pH < 7). Crystal-induced tubule
obstruction is accompanied with crystaluria, which helps
establishing diagnosis. Kidney injury caused by drug precipitation
may be severe and hemodialysis is frequently needed to treat renal
failure and decrease drug burden.
7.5 Conclusion
Drug-induced kidney injury is a frequent, and
probably underappreciated causative or contributory event in
pathogenesis of acute or chronic kidney injury. At the same time,
it is often preventable and easily treatable if diagnosed early.
Diagnosis of drug-induced kidney injury requires vigilance and
knowledge of drug pharmacokinetics and pharmacodynamics. It is a
multidisciplinary task involving clinicians, pharmacists and
clinical chemists.
Recommended literature:
- Pannu N, Nadim M. An Overview of Drug-Induced
Acute Kidney Injury. Crit Care Med 2008;36(Suppl.):S216.
- Markowitz G S, Perazella M.A. Drug-Induced Renal
Failure: A Focus on Tubulointerstitial Disease. Clin Chim Acta
2005;351:31.
- Perazella M.A. Crystal-Induced Acute Renal
Failure. Am J Med 1999;106:459.
- Launay-Vacher V, Izzedine H, Karie S, Hulot J S,
Baumelou A, Deray G. Renal Tubular Drug Transporters. Nephron
Physiol 2006;103:97.
|