Drug-Induced Nephrotoxicity

Cynthia A. Naughton, PharmD, BCPS, North Dakota State University College of Pharmacy,
Nursing, and Allied Sciences, Fargo, North Dakota

Drugs are a common source of acute kidney injury. Compared with 30 years ago, the average patient today is older,
has more comorbidities, and is exposed to more diagnostic and therapeutic procedures with the potential to harm
kidney function. Drugs shown to cause nephrotoxicity exert their toxic effects by one or more common pathogenic
mechanisms. Drug-induced nephrotoxicity tends to be more common among certain patients and in specific clinical
situations. Therefore, successful prevention requires knowledge of pathogenic mechanisms of renal injury, patientrelated risk factors, drug-related risk factors, and preemptive measures, coupled with vigilance and early intervention.
Some patient-related risk factors for drug-induced nephrotoxicity are age older than 60 years, underlying renal insufficiency (e.g., glomerular filtration rate of less than 60 mL per minute per 1.73 m2), volume depletion, diabetes, heart
failure, and sepsis. General preventive measures include using alternative non-nephrotoxic drugs whenever possible;
correcting risk factors, if possible; assessing baseline renal function before initiation of therapy, followed by adjusting
the dosage; monitoring renal function and vital signs during therapy; and avoiding nephrotoxic drug combinations.
(Am Fam Physician. 2008;78(6):743-750. Copyright 2008 American Academy of Family Physicians.)

rugs cause approximately 20 percent of community- and hospitalacquired episodes of acute renal
failure.1-3 Among older adults,
the incidence of drug-induced nephrotoxicity
may be as high as 66 percent.4 Compared with
30 years ago, patients today are older, have a
higher incidence of diabetes and cardiovascular disease, take multiple medications, and are
exposed to more diagnostic and therapeutic
procedures with the potential to harm kidney function.5 Although renal impairment is
often reversible if the offending drug is discontinued, the condition can be costly and
may require multiple interventions, including
hospitalization.6 This article provides a summary of the most common mechanisms of
drug-induced nephrotoxicity and prevention
strategies.

Pathogenic Mechanisms
Most drugs found to cause nephrotoxicity
exert toxic effects by one or more common
pathogenic mechanisms. These include altered
intraglomerular hemodynamics, tubular cell
toxicity, inflammation, crystal nephropathy,
rhabdomyolysis, and thrombotic microangiopathy.7-9 Knowledge of offending drugs
and their particular pathogenic mechanisms
of renal injury is critical to recognizing and
preventing drug-induced renal impairment
(Table 110-31 ).


Altered IntraGlomerular Hemodynamics

In an otherwise healthy young adult, approximately 120 mL of plasma is filtered under

pressure through the glomerulus per minute,
which corresponds to the glomerular filtration
rate (GFR). The kidney maintains or autoregulates intraglomerular pressure by modulating the afferent and efferent arterial tone to
preserve GFR and urine output. For instance,
in patients with volume depletion, renal perfusion depends on circulating prostaglandins
to vasodilate the afferent arterioles, allowing
more blood flow through the glomerulus.
At the same time, intraglomerular pressure is sustained by the action of angiotensinIImediated vasoconstriction of the efferent
arteriole. Drugs with antiprostaglandin activity (e.g., nonsteroidal anti-inflammatory drugs
[NSAIDs]) or those with antiangiotensin-II
activity (e.g., angiotensin-converting enzyme
[ACE] inhibitors, angiotensin receptor blockers [ARBs]) can interfere with the kidneys
ability to autoregulate glomerular pressure and
decrease GFR.10,32 Other drugs, such as calcineurin inhibitors (e.g., cyclosporine [Neoral],
tacrolimus [Prograf]), cause dose-dependent
vasoconstriction of the afferent arterioles, leading to renal impairment in at-risk patients.11
Tubular Cell Toxicity

Renal tubular cells, in particular proximal

tubule cells, are vulnerable to the toxic effects

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
rating

References

Patients at highest risk of drug-induced nephrotoxicity are those with one or more of the following:
age older than 60 years, baseline renal insufficiency (e.g., GFR < 60 mL per minute per 1.73 m2),
volume depletion, multiple exposures to nephrotoxins, diabetes, heart failure, and sepsis.

1-3, 7, 34, 35

Assess baseline renal function using the MDRD or Cockcroft-Gault GFR estimation equation and
consider a patients renal function when prescribing a new drug.

7, 33, 41-43

Monitor renal function and vital signs after starting or increasing the dose of drugs associated
with nephrotoxicity, especially when used chronically.

7, 10, 32, 48

Drug-induced renal impairment is generally reversible, provided the nephrotoxicity is recognized

early and the offending medication is discontinued.

52

Clinical recommendation

GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, diseaseoriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
org/afpsort.xml.

of drugs because their role in concentrating

and reabsorbing glomerular filtrate exposes
them to high levels of circulating toxins.12
Drugs that cause tubular cell toxicity do so by
impairing mitochondrial function, interfering with tubular transport, increasing oxidative stress, or forming free radicals.8,13 Drugs
associated with this pathogenic mechanism
of injury include aminoglycosides, amphotericin B (Fungizone; brand not available in
the United States), antiretrovirals (adefovir [Hepsera], cidofovir [Vistide], tenofovir [Viread]), cisplatin (Platinol), contrast
dye, foscarnet (Foscavir), and zoledronate
(Zometa).12-14
Inflammation

Drugs can cause inflammatory changes in

the glomerulus, renal tubular cells, and the
surrounding interstitium, leading to fibrosis and renal scarring. Glomerulonephritis
is an inflammatory condition caused primarily by immune mechanisms and is often
associated with proteinuria in the nephrotic
range.12 Medications such as gold therapy,
hydralazine (Apresoline; brand not available in the United States), interferon-alfa
(Intron A), lithium, NSAIDs, propylthiouracil, and pamidronate (Aredia; in high doses
or prolonged courses) have been reported as
causative agents.12,13,15
Acute interstitial nephritis, which can
result from an allergic response to a suspected drug, develops in an idiosyncratic,
nondose-dependent fashion.16 Medications
that cause acute interstitial nephritis are
thought to bind to antigens in the kidney or
744 American Family Physician

Table 1. Drugs Associated with Nephrotoxicity

Pathophysiologic mechanism
of renal injury

Drug class/drug(s)
Analgesics
Acetaminophen, aspirin

Chronic interstitial nephritis

Nonsteroidal anti-inflammatory drugs

Acute interstitial nephritis, altered

intraglomerular hemodynamics,
chronic interstitial nephritis,
glomerulonephritis

Antidepressants/mood stabilizers
Amitriptyline (Elavil*), doxepin
(Zonalon), fluoxetine (Prozac)

Rhabdomyolysis

Lithium

Chronic interstitial nephritis,

glomerulonephritis, rhabdomyolysis

Antihistamines
Diphenhydramine (Benadryl),
doxylamine (Unisom)

Rhabdomyolysis

Antimicrobials
Acyclovir (Zovirax)

Acute interstitial nephritis,

crystal nephropathy

Aminoglycosides

Tubular cell toxicity

Amphotericin B (Fungizone*;
deoxycholic acid formulation more
so than the lipid formulation)

Tubular cell toxicity

Beta lactams (penicillins,

cephalosporins)

Acute interstitial nephritis, glomerulonephritis (ampicillin, penicillin)

Foscarnet (Foscavir)

Crystal nephropathy, tubular cell

toxicity

Ganciclovir (Cytovene)

Crystal nephropathy

Pentamidine (Pentam)

Tubular cell toxicity

Quinolones

Acute interstitial nephritis, crystal

nephropathy (ciprofloxacin [Cipro])

Rifampin (Rifadin)

Acute interstitial nephritis

Sulfonamides

Acute interstitial nephritis, crystal

nephropathy

Vancomycin (Vancocin)

Acute interstitial nephritis

(continued)

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Table 1. (continued)
Pathophysiologic mechanism
of renal injury

Drug class/drug(s)
Antiretrovirals
Adefovir (Hepsera), cidofovir
(Vistide), tenofovir (Viread)

Tubular cell toxicity

Indinavir (Crixivan)

Acute interstitial nephritis, crystal

nephropathy

Benzodiazepines

Rhabdomyolysis

Calcineurin inhibitors
Cyclosporine (Neoral)

Altered intraglomerular
hemodynamics, chronic
interstitial nephritis, thrombotic
microangiopathy

Tacrolimus (Prograf)

Altered intraglomerular
hemodynamics

Cardiovascular agents
Angiotensin-converting enzyme
inhibitors, angiotensin receptor
blockers

Altered intraglomerular
hemodynamics

Clopidogrel (Plavix), ticlopidine

(Ticlid)

Thrombotic microangiopathy

Statins

Rhabdomyolysis

Chemotherapeutics
Carmustine (Gliadel), semustine
(investigational)

Chronic interstitial nephritis

Cisplatin (Platinol)

Chronic interstitial nephritis, tubular

cell toxicity

Interferon-alfa (Intron A)

Glomerulonephritis

Methotrexate

Crystal nephropathy

Mitomycin-C (Mutamycin)

Thrombotic microangiopathy

Contrast dye

Tubular cell toxicity

Diuretics
Loops, thiazides

Acute interstitial nephritis

Triamterene (Dyrenium)

Crystal nephropathy

Drugs of abuse
Cocaine, heroin, ketamine (Ketalar),
methadone, methamphetamine

Rhabdomyolysis

Herbals
Chinese herbals with aristocholic acid

Chronic interstitial nephritis

Proton pump inhibitors

Lansoprazole (Prevacid),
omeprazole (Prilosec),
pantoprazole (Protonix)

Acute interstitial nephritis

Others
Allopurinol (Zyloprim)

Acute interstitial nephritis

Gold therapy

Glomerulonephritis

Haloperidol (Haldol)

Rhabdomyolysis

Pamidronate (Aredia)

Glomerulonephritis

Phenytoin (Dilantin)

Acute interstitial nephritis

Quinine (Qualaquin)

Thrombotic microangiopathy

Ranitidine (Zantac)

Acute interstitial nephritis

Zoledronate (Zometa)

Tubular cell toxicity

*Brand not available in the United States.

Information from references 10 through 31.

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act as antigens that are then deposited into

the interstitium, inducing an immune reaction.16 However, classic symptoms of a hypersensitivity reaction (i.e., fever, rash, and
eosinophilia) are not always observed.13,16
Numerous drugs have been implicated,
including allopurinol (Zyloprim); antibiotics (especially beta lactams, quinolones,
rifampin [Rifadin], sulfonamides, and vancomycin [Vancocin]); antivirals (especially
acyclovir [Zovirax] and indinavir [Crixivan]); diuretics (loops, thiazides); NSAIDs;
phenytoin (Dilantin); proton pump inhibitors (especially omeprazole [Prilosec],
pantoprazole [Protonix], and lansoprazole
[Prevacid]); and ranitidine (Zantac).13,16-19
Chronic interstitial nephritis is less likely
than acute interstitial nephritis to be drug
induced; it is also insidious in onset, and signs
of hypersensitivity are often lacking.20 Drugs
associated with this mechanism of nephrotoxicity include calcineurin inhibitors (e.g.,
cyclosporine, tacrolimus), certain chemotherapy agents, Chinese herbals containing
aristocholic acid, and lithium.11,20,21 Chronic
interstitial nephritis has been reported with
analgesics such as acetaminophen, aspirin, and NSAIDs when used chronically in
high dosages (i.e., more than 1 gram daily
for more than two years) or in patients with
preexisting kidney disease.22,23 Early recognition is important because chronic interstitial nephritis has been known to progress
to end-stage renal disease.20 Diagnosis may
be difficult because most patients do not
consider over-the-counter preparations to
be medications and tend to underreport frequency of use.
Crystal Nephropathy

Renal impairment may result from the

use of drugs that produce crystals that are
insoluble in human urine. The crystals precipitate, usually within the distal tubular
lumen, obstructing urine flow and eliciting
an interstitial reaction.13 Commonly prescribed drugs associated with production of
crystals include antibiotics (e.g., ampicillin,
ciprofloxacin [Cipro], sulfonamides); antivirals (e.g., acyclovir, foscarnet, ganciclovir
[Cytovene]); indinavir; methotrexate; and
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Drug-Induced Nephrotoxicity

Table 2. Patient-Related Risk Factors

for Drug-Induced Nephrotoxicity
Absolute or effective intravascular volume depletion

triamterene (Dyrenium).12,13,24 The likelihood of crystal

precipitation depends on the concentration of the drug
in the urine and the urinary pH.24 Patients most at risk
of crystal nephropathy are those with volume depletion
and underlying renal insufficiency.24
Chemotherapy for lymphoproliferative disease, leading to tumor lysis syndrome with uric acid and calcium
phosphate crystal deposition, has also been associated
with renal failure.25
Rhabdomyolysis

Rhabdomyolysis is a syndrome in which skeletal muscle

injury leads to lysis of the myocyte, releasing intracellular
contents including myoglobin and creatine kinase into
the plasma. Myoglobin induces renal injury secondary
to direct toxicity, tubular obstruction, and alterations in
GFR.26 Drugs may induce rhabdomyolysis directly secondary to a toxic effect on myocyte function, or indirectly by predisposing the myocyte to injury.26,27 Clinical
manifestations of rhabdomyolysis include weakness,
myalgia, and tea-colored urine.27
Statins are the most recognizable agents associated
with rhabdomyolysis, but more than 150 medications
and toxins have been implicated.26 Rhabdomyolysis with
statin monotherapy is rare, with an average reported
incidence of 0.44 per 10,000 person-years of therapy.28
Many drugs of abuse, such as cocaine, heroin, ketamine
(Ketalar), methadone, and methamphetamine, have
been reported to cause rhabdomyolysis.26,27 Drugs and
alcohol are causative factors in up to 81 percent of cases
of rhabdomyolysis, and up to 50 percent of patients subsequently develop acute renal failure.29
Thrombotic Microangiopathy

In thrombotic microangiopathy, organ damage is caused

by platelet thrombi in the microcirculation, as in thrombotic thrombocytopenic purpura.30 Mechanisms of renal
injury secondary to drug-induced thrombotic microangiopathy include an immune-mediated reaction or direct
endothelial toxicity.30 Drugs most often associated with
this pathogenic mechanism of nephrotoxicity include
antiplatelet agents (e.g., clopidogrel [Plavix], ticlopidine
[Ticlid]), cyclosporine, mitomycin-C (Mutamycin), and
quinine (Qualaquin).30,31
Preventing Drug-Induced Renal Impairment
Drug-induced nephrotoxicity tends to occur more
frequently in certain patients and in specific clinical
situations. Therefore, successful prevention requires
knowledge of patient-related risk factors, drug-related
risk factors, and preemptive measures, coupled with
746 American Family Physician

Age older than 60 years

Diabetes
Exposure to multiple nephrotoxins
Heart failure
Sepsis
Underlying renal insufficiency (glomerular filtration rate
< 60 mL per minute per 1.73 m2)
Information from references 1 through 3, 7, 34, and 35.

vigilance and early intervention.7,33 Prevention strategies

should target the prescribing and monitoring of potential nephrotoxins in at-risk patients. Whenever possible,
risk factors should be corrected before drugs associated
with nephrotoxicity are prescribed.
Patient-Related Risk Factors

Patient-related risk factors vary somewhat depending

on the offending drug. However, some risk factors are
common to all nephrotoxins and include age older than
60 years, underlying renal insufficiency (e.g., GFR of
less than 60 mL per minute per 1.73 m 2), intravascular volume depletion, exposure to multiple nephrotoxins, diabetes, heart failure, and sepsis (Table 2).1-3,7,34,35
There are conflicting reports about the influence of race
and genetic variation, as well as whether men are at
greater risk of developing acute renal failure compared
with women. 34 The risk of acute renal failure increases
with the presence of each additional risk factor. Patients
with any of these risk factors, especially those who have
more than one risk factor (e.g., a patient with diabetes and heart failure), should be closely monitored for
changes in renal function when a medication is added
or a dosage is increased.
Both absolute and effective intravascular volume
depletion are risk factors for drug-induced renal impairment. Absolute intravascular volume depletion may
occur in patients who have gastroenteritis, chronic diarrhea, aggressive diuresis, or poor oral intake.10 Effective
intravascular volume is the volume of blood perceived
by baroreceptors located in the right atrium and the kidney. Decreased effective circulating blood volume results
from sequestration of fluid into third-space compartments and is associated with sepsis, heart failure, ascites,
or pancreatitis.7,36
Drug-Related Risk Factors

Certain drugs are inherently nephrotoxic and include

aminoglycosides, amphotericin B, cisplatin, contrast dye,
and cyclosporine.7,34 For others, such as those associated
with chronic interstitial nephritis and crystal deposition,

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Table 3. Patient-Related Risk Factors and Specific Prevention Strategies for Selected Agents
Medications

Risk factors

Prevention strategies

Drugs altering intraglomerular hemodynamics

10-12,23,32

ACE inhibitors, ARBs,

NSAIDs

Underlying renal insufficiency; intravascular

volume depletion; age older than 60 years;
concomitant use of ACE inhibitors, ARBs,
NSAIDs, cyclosporine (Neoral), or tacrolimus
(Prograf)

Use analgesics with less prostaglandin activity

(acetaminophen, aspirin, sulindac [Clinoril],
nabumetone [Relafen; brand not available in the
United States])
Correct volume depletion before initiation of drug,
especially if used on a chronic basis
Monitor renal function and vital signs following
initiation or dose escalation, especially if used in
at-risk patients

Cyclosporine, tacrolimus

As above, plus: excessive dose, concomitant use

with other nephrotoxic drugs or drugs that
inhibit cyclosporine or tacrolimus metabolism

Monitor serum drug concentrations and renal function

Use lowest effective dose

Drugs associated with tubular cell toxicity7,12,13,37,38

Aminoglycosides

Underlying renal insufficiency, duration of

therapy > 10 days, trough concentrations
> 2 mcg per mL, concomitant liver disease,
hypoalbuminemia

Use extended-interval dosing

Administer during active period of day
Limit duration of therapy
Monitor serum drug levels and renal function two to
three times per week
Maintain trough levels 1 mcg per mL

Amphotericin B (Fungizone;
brand not available in the
United States)

Underlying renal insufficiency, rapid infusion,

large daily dosage, deoxycholate formulations
more so than lipid formulations, prolonged
duration of therapy

Saline hydration before and after dose administration

Consider administering as a continuous infusion over
24 hours
Use liposomal formulation
Limit duration of therapy

Contrast dye

Underlying renal insufficiency, age older than

70 years, diabetes, heart failure, volume
depletion, repeated exposures

Use low-osmolar contrast in the lowest dose possible

and avoid multiple procedures in 24 to 48 hours
0.9% saline or sodium bicarbonate (154 mEq per L)
infusion before and after procedure
Withhold NSAIDs and diuretics at least 24 hours
before and after procedure
Monitor renal function 24 to 48 hours postprocedure
Consider acetylcysteine preprocedure

Drugs associated with chronic interstitial nephropathy11,20-23

Acetaminophen, aspirin,
NSAIDs

Lithium

History of chronic pain, age older than

60 years, female sex, cumulative consumption
of analgesic > 1 gram per day for more than
two years

Avoid long-term use, particularly of more than one

analgesic

Elevated drug levels

Maintain drug levels within the therapeutic range

Use alternate agents in patients with chronic pain

Avoid volume depletion

Drugs associated with crystal nephropathy12,13,24
Acyclovir (Zovirax),
methotrexate, sulfa
antibiotics, triamterene
(Dyrenium)

Volume depletion, underlying renal

insufficiency, excessive dose, intravenous
administration

Discontinue or reduce dose

Ensure adequate hydration
Establish high urine flow
Administer orally

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; NSAID = nonsteroidal anti-inflammatory drug.
Information from references 7, 10 through 13, 20 through 24, 32, 37, and 38.

nephrotoxicity is dose dependant or related to prolonged

duration of treatment.24 Combination therapy with multiple nephrotoxins can result in synergistic nephrotoxicity, thus increasing the risk of renal injury.7 Specific
preventive measures unique to some of these drugs are
highlighted in Table 3.7,10-13,20-24,32,37,38
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Contrast-induced nephropathy is reported to be the

third most common cause of acute renal failure in hospitalized patients.2 The exact incidence, however, varies
depending on study design, type and dose of contrast
used, and presence of acute renal failure risk factors
and other comorbidities.37 The risk of contrast-induced

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American Family Physician 747

Table 4. General Measures to Prevent

Drug-Induced Nephrotoxicity
Adjust medication dosages using the Cockcroft-Gault formula
(in adults) or Schwartz formula (in children).

Preventive Measures

Assess baseline renal function using the MDRD equation, and

consider patients renal function when prescribing a new drug.

General preventive measures include using equally effective but non-nephrotoxic drugs whenever possible, corAvoid nephrotoxic combinations.
recting risk factors for nephrotoxicity, assessing baseline
Correct risk factors for nephrotoxicity before initiation of drug
renal function before initiating therapy, adjusting the
therapy.
dose
of medications for renal function, and avoiding
Ensure adequate hydration before and during therapy with
nephrotoxic drug combinations (Table 4).7,10,33 Baseline
potential nephrotoxins.
renal function can be estimated at the bedside using
Use equally effective non-nephrotoxic drugs whenever possible.
the Modification of Diet in Renal Disease (MDRD) forMDRD = Modification of Diet in Renal Disease.
mula or the Cockcroft-Gault formula in adults and the
Information from references 7, 10, and 33.
Schwartz formula for children (Table 5).41-45 The National
Kidney Foundation advocates using the MDRD formula
for the detection and staging of chronic kidney disease.44
nephropathy is highest in patients with chronic kidney GFR estimation equations are included in programs for
disease (i.e., a GFR of less than 60 mL per minute per handheld computers such as MedCalc, Archimedes,
1.73 m2), especially in the presence of diabetes.39 Other InfoRetriever, Epocrates, and Micromedex. The MDRD
risk factors include dehydration, heart failure, age is accessible online at http://nkdep.nih.gov/professionals/
older than 70 years, and concurrent use of nephrotoxic gfr_calculators/index.htm.
drugs.37 Patients with risk factors for contrast-induced
Most drugs that are eliminated renally do not require
nephropathy, especially those who have multiple risk dosage adjustment until the creatinine clearance falls
factors, require prophylactic interventions before imag- below 50 mL per minute.46 The preferred formula advoing.37 Prophylactic interventions studied have included cated by the U.S. Food and Drug Administration to guide
normal saline or sodium bicarbonate infusions and ace- drug dosing in adults is the Cockcroft-Gault formula
tylcysteine before and after imaging.38,40 However, the because it has been used in nearly all pharmacokinetic
role of acetylcysteine has yet to be defined because clini- studies to generate drug-dosing guidelines.45,47 Compared
cal trial results have been inconsistent.37
with the MDRD, the Cockcroft-Gault equation tends to
overestimate the GFR and may yield different
results depending on the patient.41 For example, the estimated GFR of a 64-year-old, 190-lb
Table 5. Formulas to Assess Renal Function
(86-kg) woman with a serum creatinine level
and Adjust Medication Dosages
of 1.3 mg per dL (110 mol per L; normal: 0.8
to 1.4 mg per dL [70 to 120 mol per L]) is
Author
Estimation formula
Purpose
59 mL per minute using the Cockcroft-Gault
MDRD41
To assess renal
eGFR = 186 serum creatinine
formula
and 44 mL per minute per 1.73 m2
function and
(mg per dL) 1.154 age (years) 0.203
according to the MDRD. In this example, both
stage chronic
(0.742 if patient is female)
kidney disease 44
formulas indicate renal insufficiency, but the
(1.210 if patient is black)
patients medications most likely would not
Cockcroft
Male: eCrCl = ([140 age (years)]
To adjust drug
require a dose adjustment.
and Gault42
ideal body weight [kg]) (serum
dosing for renal
Adequate hydration is important to maincreatinine [mg per dL] 72)
function in
45
tain
renal perfusion and avoid drug-induced
adults
Female: male eCrCl 0.85
renal impairment. Whenever possible, volSchwartz43
To adjust drug
eCrCl = (length [cm] k) serum
ume status should be assessed and corrected,
dosing for renal
creatinine (mg per dL)
if
necessary, before initiation of nephrotoxic
function in
k = 0.45 (infants one to 52 weeks of age)
agents. This is particularly true when prechildren
0.55 (children one to 13 years of age)
scribing medications such as ACE inhibitors,
0.70 (males 14 to 17 years of age)
ARBs, and NSAIDs, which induce alterations
0.55 (females 14 to 17 years of age)
in renal hemodynamics in patients who are
significantly volume depleted.10,32 Signs of
eCrCl = estimated creatinine clearance; eGFR = estimated glomerular filtration rate;
MDRD = Modification of Diet in Renal Disease.
significant intravascular volume depletion
Information from references 41 through 45.
include orthostatic hypotension, blood pressure of less than 90/60 mm Hg, and decreased
748 American Family Physician

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Drug-Induced Nephrotoxicity

skin turgor accompanied by a loss of more than 5 percent

of baseline body weight.1-4 Currently, there is no consensus on the optimal solution, volume, or timing of fluids
to restore renal perfusion.7
A systems approach involving computerized physician
order entry and clinical decision support may reduce
the danger of exposing at-risk patients to nephrotoxins,
but such systems are greatly underused in the ambulatory setting.48 Forming collaborations between those
who prescribe drugs and clinical pharmacists is a good
option and should be pursued and developed, although
funding such efforts may be a challenge.48 Two reports
from the Institute of Medicine recognized that pharmacists are an essential resource in safe medication use
and that pharmacist-physician-patient collaboration
is important.49,50 The clinical and economic impact of
clinical pharmacists in other settings has been extensively reviewed and summarized in the literature.51
Vigilance

In one large cohort study of Medicare enrollees in the

ambulatory setting, inadequate laboratory monitoring played a role in 36 percent of all preventable adverse
drug events.48 In addition, when assessing baseline renal
function, physicians should consider monitoring serum
creatinine levels after starting or increasing the dosage
of drugs associated with nephrotoxicity, especially those
used chronically in patients with multiple risk factors for
renal impairment. A systems approach toward adopting an electronic medical record may provide a practical
method for automated monitoring of all patients in general, and patients at risk of nephrotoxicity in particular.

there are no standard guidelines used to interpret

changes in serum creatinine, a 50 percent rise from
baseline, an increase of 0.5 mg per dL (40 mol per L) or
more when baseline serum creatinine is less than 2 mg
per dL (180 mol per L), or an increase of 1 mg per dL
(90 mol per L) or more if baseline creatinine is greater
than 2 mg per dL have been used as biochemical criteria
of acute renal failure.1,2,32
At the first sign of renal dysfunction, the patients
medication list should be reviewed to identify offending agents. If multiple medications are present and the
patient is clinically stable, physicians should start by discontinuing the drug most recently added to the patients
medication regimen. Attention should then be directed
at avoiding further renal insults by supporting blood
pressure, maintaining adequate hydration, and temporarily discontinuing all other possible nephrotoxins.53
This is one in a series of Clinical Pharmacology articles coordinated
by Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Mass.

The Author
Cynthia A. Naughton, PharmD, BCPS, is the associate dean of academic affairs and assessment in the College of Pharmacy, Nursing, and
Allied Sciences at North Dakota State University, Fargo. At the time this
article was written, Dr. Naughton served as a clinical pharmacy specialist
at the Family HealthCare Center in Fargo. Dr. Naughton received her doctor of pharmacy degree from North Dakota State University, Fargo.
Address correspondence to Cynthia A. Naughton, PharmD, BCPS, North
Dakota State University, College of Pharmacy, Nursing, and Allied Sciences, Sudro 123D, Fargo, ND 58105 (e-mail: Cynthia.Naughton@ndsu.
edu). Reprints are not available from the author.
Author disclosure: Nothing to disclose.

Recognition and Early Intervention

Most episodes of drug-induced renal impairment are

reversible. Renal function generally returns to baseline
provided the impairment is recognized early and the
offending medication is discontinued.52 Failure to act on
available information relating to clinical findings or laboratory results was the most common monitoring error,
occurring in 37 percent of preventable adverse drug
events, including those affecting the kidney, in older
ambulatory patients.48
A decrease in renal function as evidenced by a rise in
serum creatinine levels following the initiation of a drug
signals the possibility of drug-induced renal injury. An
exception to this is an increase in serum creatinine following the initiation of cimetidine (Tagamet) or trimethoprim (Proloprim), because they compete with
creatinine for tubular secretion and are not associated
with kidney damage or urine abnormalities.52 Although
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