DRUGS INDUCED NEPHROTOXICITY

INTRODUCTION
Nephrotoxicity can be defined as renal disease or dysfunction that arises as a direct or indirect
result of exposure to medicines, and industrial or environmental chemicals. Drug nephrotoxicity
is therefore any renal dysfunction attributable to drugs.
Drug nephropathies are not restricted to a single type of renal injury. Drugs target one or more
discrete anatomical regions of the kidney and may affect only one cell type. The resulting insult
to the kidney may result in a spectrum of nephropathies that are indistinguishable from those that
do not have a chemical etiology.

HISTOLOGY AND PHYSIOLOGY

The nephron is the functional unit of the kidney and consists of a continuous tube of highly
specialized heterogeneous cells, which show sub-specialization along the length of nephrons and
between them. It is the major organ of excretion and homeostasis for water-soluble molecules;
because it is a metabolically active organ, it can concentrate certain substances actively. In
addition, its cells have the potential to bio-convert chemicals and metabolically activate a variety
of compounds.
Since the kidney excretes many drugs, it is routinely exposed to high concentrations of these
drugs or their metabolites or both. Furthermore, the kidney has several features that allow
nephrotoxins to accumulate. It is highly vascular, receiving about 25% of the resting cardiac
output. The proximal renal tubule presents a large area for nephrotoxin binding and transport into
the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intraluminal
nephrotoxin concentrations, while specific transport pathways in the kidney may engender sitespecific toxicity.

MECHANISMS OF TOXICITY
Many drugs can injure the kidney but they cause renal injury via only a few mechanism. Renal
injury can be in the form of:
acute renal failure
nephrotic syndrome
chronic renal failure.

ACUTE RENAL FAILURE

Acute renal failure (ARF), characterized by sudden loss of the ability of the kidneys to excrete
wastes, concentrate urine, conserve electrolytes, and maintain fluid balance, is a frequent clinical
problem.

NEPHROTIC SYNDROME
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria.
Drugs implicated include gold, NSAIDs, penicillamine, interferon, and captopril. Patients may
present with edema, proteinuria, and hypoalbuminemia.
Membranous nephropathy is the most common form reported, though minimal change
nephropathy has also been seen with NSAIDs, as discussed below. Treatment is by stopping the
drug and this often leads to resolution of nephrotic syndrome. However, irreversible injury has
also been described.

CHRONIC RENAL INSUFFICIENCY

Chronic renal insufficiency caused by drugs generally presents as tubulointerstitial disease. It is
important to note that for some drugs (e.g., cyclosporine, lithium), the mechanism of acute renal
toxicity may be different from that of chronic renal injury. Patients may present with slowly
progressive elevation of creatinine, with or without renal tubular dysfunction syndromes.
These syndromes may manifest as renal tubular acidosis, renal potassium wasting, concentration
defects, and tubular proteinuria. These syndromes may also occur without renal failure. In some
cases, the renal damage is reversible when the offending drug is stopped, but in other cases it is
irreversible. Frequently reversible forms include those due to 5- aminosalicylic acid, 6
mesalamine, and ifosfamide, while lithium and cyclosporine cause irreversible injury.
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Common drugs and the pathology caused:

DRUGS

ACUTE RENAL
FAILURE

NEPHROTIC
SYNDROME

CHRONIC
RENAL
FAILURE

ACE INHIBITORS

ACYCLOVIR

AMINOGLYCOSIDES

COCAINE

NSAIDS

LITHIUM

DIURETICS

CISPLATIN

NSAIDS:
Each year, up to 5% of people who take NSAIDs will develop renal toxicity, resulting in hospital
admissions and an increase in health care spending.
All NSAIDs inhibit cyclooxygenase, the enzyme that is required to convert arachidonic acid into
prostaglandins. Prostaglandins are not only involved in the inflammatory process but are present
in the kidneys. They balance the effects of vasoconstrictors (norepinephrine, angiotensin II,
vasopressin) by causing vasodilation of the afferent arteriole and, ultimately, allow adequate
renal blood supply and glomerular filtration pressure.
Unopposed vasoconstriction of the afferent arteriole in a patient taking NSAIDs causes
decreased blood flow to the kidneys, which results in decreased glomerular filtration rate and
renal ischemia.

MANAGEMENT:
NSAIDs should be avoided or used with caution in patients at high risk of renal failure. COX-2
inhibitors are included in this warning due to similar effects on renal function. Patients should
continue taking aspirin for cardio protection, because low doses do not significantly affect
prostaglandin levels in the kidneys.
Patients taking high doses of NSAIDs, individuals with underlying renal insufficiency, and the
elderly are at a greater risk of toxicity. Factors that cause decreased volume and/or blood flow to
the kidneys, such as congestive heart failure, cirrhosis, dehydration, and over diuresis, predispose
patients to ARF. When dispensing medications that can precipitate ARF, counsel patients on the
risk of using over-the-counter NSAIDs without consulting their pharmacist or physician.

ACE Inhibitors and Angiotensin II Receptor Blockers:

ACE inhibitors and angiotensin II receptor blockers are another frequent cause of ARF,
especially in patients with severe renal artery stenosis or chronic kidney disease and in those
hospitalized for congestive heart failure. Current guidelines recommend ACE inhibitors for
patients with chronic kidney disease and systolic heart failure because of their proven benefits on
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morbidity and mortality; however, low doses should be used initially, and renal function should
be monitored frequently.
Glomerular pressure is normally
high enough to maintain adequate
filtration without relying on
postglomerular resistance. In the
setting
of reduced
blood
flow,
however,
glomerular
filtration is
dependent on
resistance in the
efferent arteriole
created by
angiotensin II
mediated
vasoconstriction. ACE
inhibitors reduce the
outflow resistance from
the glomerulus, resulting
in decreased pressure and
glomerular filtration.

MANAGEMENT:
Treatment with an ACE inhibitor should be stopped if SCr increases by more than 30% and
reduced if reinitiated. A mild decrease in renal function due to ACE inhibitors is acceptable due
to the benefits that result from long-term therapy. Treatment should be started at low dosages,
especially in patients with underlying risk factors, and the dose should be titrated gradually. It is
important to avoid dehydration and excessive use of diuretics and NSAIDs.

Aminoglycoside Antibiotics:
Aminoglycosides are used to treat infections with gram-negative bacteria. They cause
nephrotoxicity in up to 10% to 20% of patients when used for a full course of therapy.
The primary mechanism of aminoglycoside-induced ARF is injury to the proximal tubule leading
to cellular necrosis. This occurs via binding of cationic charges on amino groups to tubular
epithelial cells. Tubular cell death occurs from generation of oxygen-free radicals and subsequent
alterations in cellular function.
Risk factors for aminoglycoside-induced ARF include aminoglycoside dosing (i.e., large
cumulative dose, prolonged therapy, trough concentrations >2 mg/dL), synergistic exposure to
other nephrotoxins (especially concomitant vancomycin), and underlying condition of the
patient.

AMINOGLYCOSIDE
Cationic charges on amino group
binds to tubular epithelial cells
oxygen free radicals

& subsequent alteration in cellular function.

TUBULAR CELL
DEATH

MANAGEMENT:
pharmacists monitor aminoglycoside levels during inpatient treatment. Inherent
pharmacodynamics and pharmacokinetic properties of aminoglycosides have led to more
frequent use of once-daily dosing as opposed to traditional multiple daily-dosing regimens.
Aminoglycosides display concentration-dependent killing and significant "postantibiotic" effect;
therefore, giving a higher dose less frequently is at least as effective and may decrease renal
toxicity by allowing excretion of aminoglycosides from the tubular cells prior to the next dose.

Radiocontrast Dye:
ARF is frequently caused by administration of radiographic contrast dye (RCD), which is used
for diagnostic and treatment procedures. The incidence approaches nearly 50% in patients with
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combined diabetes and pre-existing renal insufficiency. Other risk factors for RCD-induced ARF
include volume depletion, high doses of RCD, and using other drugs that cause nephrotoxicity.
Most patients experience a transient rise in SCr within two to five days after receiving RCD,
followed by recovery to baseline over the next few days. High-risk patients may experience more
severe toxicity and require dialysis. Hospital course is significantly affected due to comorbid
conditions that worsen with the onset of ARF.
Nephrotoxicity appears to result from a combination of direct tubular necrosis and renal
ischemia. Significant injury to the tubular cells and production of toxic-free radicals occur after
RCD and may be accompanied by renal vasoconstriction and ischemia.

MANAGEMENT:
Adequate hydration and discontinuation of nephrotoxic drugs is an essential part of the
prevention of RCD-induced ARF. Many small trials have shown conflicting results regarding the
use of various fluids, bicarbonate, and diuretics for prevention of RCD-induced ARF, and there
are no clear recommendations based on proven benefit.
Isotonic normal saline (1 mL/kg) may provide the most benefit and should be given at least six to
12 hours prior to RCD and continued six to 12 hours after the procedure. In addition,
administration of sodium bicarbonate one hour prior to the procedure, with continued treatment
for at least six hours after RCD, may also provide additional benefit. Diuretics should be given
only if the patient is fluid overloaded.

Cisplatin:
Cisplatin enters renal cells by passive and/or facilitated mechanisms. Exposure of tubular cells to
cisplatin activates signaling pathways that are cell death promoting (MAPK, p53, ROS, and so
on) or cytoprotective (p21). Meanwhile, cisplatin induces TNF-alpha production in tubular cells,
which triggers a robust inflammatory response, further contributing to tubular cell injury and
death. Cisplatin may also induce injury in renal vasculature, leading to ischemic tubular cell
death and decreased glomerular filtration rate (GFR). Together, these pathological events
culminate in acute renal failure.

Reference:
Clinical pharmacy and therapeutics (Roger Walker)
http://www.uspharmacist.com
http://folk.uio.no/imeea/pdf/drug%20nephrotoxicity.pdf
http://www.doctorfungus.org/thedrugs/Nephrotoxicity.php
http://www.nature.com/ki/journal/v73/n9/fig_tab/5002786f1.html