Drug-Induced Renal Failure: Update on New
Medications and Unique Mechanisms of
Nephrotoxicity
MARK A. PERAZELLA, MD
ABSTRACT: Medications cause renal failure through a
variety of mechanisms. Hemodynamic renal failure may
result from drugs that reduce renal prostaglandins and
hence renal blood flow and glomerular filtration rate. A
relatively new group of drugs with this potential is the
cyclooxygenase-2 selective inhibitors. Direct renal tu-
bular toxicity has also been described with a number of
new medications with unique effects on the epithelial
cells of the kidney. These include the antiviral agents
cidofovir, adefovir, and tenofovir as well as the bisphos-
phonate pamidronate. Additionally, crystal deposition in
the kidney may promote the development of renal fail-
T herapeutic agents have long been associated
with the development of iatrogenic renal fail-
ure. The mechanisms of drug toxicity can vary a
great deal based on the pharmacologic action, me-
tabolism, and ultimate pathway of excretion of the
agent administered. Altered renal hemodynamics,
resulting in prerenal azotemia, is a common form of
nephrotoxicity. It is often rapidly reversible upon
discontinuation of the culprit medication. Intrarenal
injury, especially in the renal tubular cells, may
result from treatment with certain types of drugs.
Nephrotoxic effects may develop in glomerular and
tubular epithelial cells as a result of mechanisms
that disrupt normal cellular functions (mitochon-
dria, membrane integrity, etc), induce renal injury
through intratubular obstruction (crystal deposi-
tion), and promote cellular swelling and tubular
luminal occlusion (osmotic effects).
This review will focus on a few new and/or unique
causes of drug-induced renal failure. It is not meant
to exhaustively review all potential agents but
rather to highlight some of the medications that
From Section of Nephrology, Department of Medicine, Yale
University School of Medicine, New Haven, Connecticut.
Submitted November 1, 2002; accepted January 10, 2003.
Correspondence: Mark A. Perazella, M.D., FACP, Section of
Nephrology, Department of Medicine, Yale University School of
Medicine, LMP 2071, 333 Cedar Street, New Haven, CT 06520-
8029 (E-mail: mark.perazella@yale.edu).
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ure. Several different drugs have been described to
induce crystal nephropathy, including the antiparasitic
drug sulfadiazine, the antiviral agent acyclovir, and the
protease inhibitor indinavir. Finally, an unusual form of
renal failure characterized by swollen, vacuolated prox-
imal tubular cells can develop from hyperosmolar sub-
stances. Agents recently described to induce an “osmot-
ic nephrosis” include intravenous immunoglobulin and
the plasma expander hydroxyethyl starch. KEY INDEX-
ING TERMS: Nephrotoxicity; Renal failure; Drugs; Med-
ications; Crystal nephropathy; Osmotic nephrosis. [Am
J Med Sci 2003;325(6):349–362.]
have been described to injure the kidney via various
mechanisms of action.
Hemodynamic Renal Failure
COX-2 Selective Inhibitors.
A new class of selective nonsteroidal anti-inflam-
matory drugs (NSAIDs) was designed based on the
discovery of 2 cyclooxygenase (COX) isoforms
(COX-1 and COX-2).1,2 The COX-2 selective inhibi-
tors are speculated to reduce end organ injury by
sparing homeostatic or “constitutive” COX-1 enzyme
function.1– 4 In contrast, therapeutic effects result
from the inhibition of the “inducible” COX-2 enzyme
that primarily mediates inflammatory processes.1,2
Thus, COX-2 selective inhibitors target the produc-
tion of pro-inflammatory prostaglandins by COX-2
without interrupting normal cell function mediated
by COX-1.1,2 This paradigm suggests that these
drugs can effectively reduce pain, fever and inflam-
mation without disturbing homeostatic COX-1 en-
zyme function. In 1999, the COX-2 selective inhibi-
tors celecoxib and rofecoxib were introduced into
clinical practice to provide analgesia and anti-in-
flammatory effects while also sparing end organ
toxicity.3,4 In fact, treatment with these new drugs
has resulted in therapeutic efficacy as well as a
significant reduction in gastrointenstinal toxicity.3,4
Prostaglandins (PG) are the major products of
COX enzyme metabolism.5–7 The synthesis of pros-
349
Drug-Induced Nephrotoxicity
Table 1. Characteristics of COX-1 and COX-2 Enzymes
COX-1 Enzyme COX-2 Enzyme
Chromosome 9 Chromosome 1
22-kilobase gene 8-kilobase gene
Gene unresponsive to triggers Gene responds to triggers
Constitutive Inducible (by cytokines, etc)
Tissue expression Tissue expression
GI tract Macrophages
Kidney Synoviocytes
Brain Cartilage
Vasculature Kidney
Platelets Brain
Unchanged by Glucocorticoids Blocked by Glucocorticoids
GI, gastrointestinal.
taglandins from arachidonic acid is catalyzed by 2
different isomers of COX, COX-1 or COX-2 (Table 1).
These isozymes are approximately 65% identical in
their amino acid sequences and nearly identical at
their catalytic site.2,7 Conservation of their struc-
tures at the catalytic site allows these isoforms to
carry out similar enzymatic functions and produce
similar prostaglandins. COX-1 is a 22-kilobase gene
located on human chromosome 9, whereas the 8-ki-
lobase COX-2 gene resides on chromosome 1.2,7 The
COX isoforms can also be distinguished by their
respective patterns of gene transcription. The
COX-2 DNA sequence identifies it as an “inducible”
gene that has a number of sites that link its tran-
scription to the presence of appropriate protein trig-
gers, such as cytokines, growth factors, or hor-
mones.2,7 In contrast, the gene sequence of COX-1
lacks the sites that are required to facilitate rapid
protein transcription in response to stimuli, consis-
tent with a gene that expresses its constitutive prod-
uct protein without any prerequisite signal. The
differences in gene regulation between the COX iso-
mers provide a molecular basis for their purported
roles as “constitutive” (COX-1) and “inducible”
(COX-2) enzymes. However, the COX-2 isoform is
also constitutively expressed and up-regulated in
the kidney and may reflect important homeostatic
functions of this isoform.2,8 –11 Thus, the concern was
raised that inhibition of COX-2 may compromise
kidney function in a manner similar to that of tra-
ditional NSAIDs.
The major role of COX-derived prostaglandins is
in the preservation of renal function when patho-
logic states supervene and compromise physiologic
processes in the kidney. Intravascular volume deple-
tion, as seen with vomiting, diarrhea, and diuretic
therapy, stimulates PG synthesis to optimize renal
blood flow.5,6,12,13 Also, effective decreases in renal
blood flow (RBF) as seen with congestive heart fail-
ure (CHF), cirrhosis and nephrotic syndrome en-
hance compensatory PG production.5,6,12,13 PGI2 and
PGE2 antagonize the local effects of circulating va-
soconstrictors [angiotensin II (AII), endothelin, va-
350
Table 2. Clinical Syndromes Associated with Traditional
NSAIDs
Acute
Acute vasomotor renal failure
Hypertension, edema, CHF
Hyponatremia
Hyperkalemia/metabolic acidosis
Acute tubulointerstitial nephritis
Acute papillary necrosis
Chronic
Nephrotic syndrome (minimal change, membranous)
Chronic papillary necrosis
Analgesic nephropathy
Renal cancer
CHF, congestive heart failure.
sopressin, catecholamines] that would normally
maintain systemic blood pressure at the expense of
the renal circulation.5,6,12,13 Prostaglandin produc-
tion is also increased in chronic kidney disease
(CKD).14,15 Up-regulation of PG synthesis in CKD is
induced by intrarenal mechanisms activated to pro-
mote perfusion of remnant nephrons.14,15 Impair-
ment of PG production in this setting is associated
with short-term reductions in RBF and glomerular
filtration rate (GFR). Renal PGs also importantly
modulate salt and water homeostasis. In response to
volume overload and salt loading, PG inhibition of
tubular NaCl reabsorption increases salt excre-
tion.5,6,12,13 Antagonism of vasopressin effect on wa-
ter channels by these autocoids also facilitates ex-
cretion of a water load.5,6,12,13 Regulation of
medullary blood flow by PGE2 also contributes to the
kidney’s ability to modify renal solute excre-
tion.5,6,12,13 Taken together, these modulating effects
regulate intravascular volume status and plasma
osmolality.
In the same way that inhibition of COX enzyme by
NSAIDs produces therapeutic drug effects, disrup-
tion of COX function also precipitates renal dysfunc-
tion, leading to the well-described clinical syn-
dromes of NSAID-associated nephrotoxicity (Table
2). ARF and disturbances in fluid and electrolyte
balance induced by this class of drugs are the major
acute effects of NSAIDs on the kidneys.
Despite the initial data that implied inducible
COX-2 formation was limited mainly to inflamma-
tory tissues, several animal models localize the
COX-2 isoform to the healthy kidney. In fact, COX-2
mRNA and protein expression in the mammalian
kidney are among the highest observed in any tis-
sues.16,17 COX-2 protein has been isolated from rat
medullary thick ascending limb cells and has been
induced by AII in cultured rat vascular smooth mus-
cle cells.11,18,19 COX-2 has also been localized to the
macula densa of the juxtaglomerular apparatus, the
adjacent thick cortical ascending limb cells, and to
the medullary interstitial cells at the tip of the
papilla and outer medulla in rats.10,11,20 –22 Renal
June 2003 Volume 325 Number 6

Table 3. Up-regulated Renal Expression of COX-2 Enzyme
Stimulus Renal Localization
Salt restriction Renal cortex
Macula densa
Thick ascending limb of Henle
ACE inhibitor/ARB Renal cortex
Macula densa
Salt loading Renal medulla
Medullary interstitial cells
Water deprivation Medullary interstitial cells
Experimental heart failure Renal medulla
ARB, angiotensin II receptor blocker.
expression of COX-2 is increased by a variety of
physiologic maneuvers (Table 3). Chronic salt re-
striction also enhanced COX-2 expression in the
renal cortex and increased the number of COX-2
producing cells in both the macula densa and the
adjacent thick ascending limb.10,20 Increases in rat
cortical (macula densa) COX-2 expression were also
observed after administration of either angiotensin-
converting enzyme (ACE) inhibitors or angiotensin
receptor type 1 antagonists.23 In salt-restricted rats,
renin production by macula densa cells was stimu-
lated by COX-2– derived PGs; notably, renin release
was inhibited by a COX-2–specific inhibitor.24 Salt
loading induced COX-2 expression in the medulla of
rats, suggesting a role of this isoform in facilitating
natriuresis.20 During water deprivation, COX-2 ex-
pression was stimulated to promote medullary in-
terstitial cell survival during the hypertonic stress
of dehydration.25,26 Finally, up-regulated expression
of medullary COX-2, but not COX-1, occurred in an
experimental heart failure model in rats, suggesting
that this isoform produces PGs that maintain med-
ullary blood flow and natriuresis in the face of de-
creased renal perfusion from CHF.27
The important role of the renal COX-2 isoform and
selective COX-2 inhibition in regulating RBF and
GFR, salt and water excretion, and renin secretion
are noted in the following animal studies. Selective
COX-2 inhibition in sodium-restricted dogs pre-
treated with norepinephrine induced a significant
decrease in RBF and GFR compared with dogs that
did not receive nimesulide.28 COX-2 inhibition with
rofecoxib in rats treated with either furosemide or
hydrochlorothiazide attenuated the diuresis and na-
triuresis associated with these drugs compared with
rats administered vehicle.29 Celecoxib was also
shown to raise systemic blood pressure and induce
fluid retention in normotensive rats and exacerbate
hypertension in rats rendered hypertensive by long-
term nitric oxide inhibition.30 Thus, COX-2 stimu-
lated PGs play a key role in preserving normal
cardiorenal physiology in animals.
COX-2 expression has also been demonstrated in
renal tissue obtained from adult human nephrec-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
tomy specimens, providing critical insight into the
potential role of this isoform in human renal physi-
ology.8 COX-2 enzyme was found in glomerular
podocytes and endothelial cells of arteries and veins
of these specimens. Using immunolocalization,
COX-2 expression was also demonstrated in the
macula densa in human kidney tissue from autopsy
specimens procured from 10 elderly patients.31
COX-2 immunoreactivity was also noted in afferent
arterioles and medullary interstitial cells, with lim-
ited staining observed in the thick loops of Henle.
Kidney tissue from patients with Bartter-like syn-
drome and CHF expressed COX-2 protein in the
macula densa.32 In contrast, control kidneys from
subjects without underlying renal or cardiovascular
disease did not have COX-2 protein in the macula
densa, but it was detected in medullary interstitial
cells.
Evaluation of COX-2 selective inhibitors on renal
function in human subjects has clarified the role of
the COX-2 isoform in the human kidney and pro-
vided insight into the effects of these drugs on GFR.
Selective COX-2 and nonselective COX inhibition
was examined in 40 healthy male volunteers (GFR
⬎ 100 mL/min) who were salt-restricted to induce
prostaglandin dependence.33 The subjects were ran-
domized to receive 200 mg of celecoxib twice per day,
400 mg of celecoxib twice per day, 500 mg of
naproxen twice per day, or placebo for 7 days. Tran-
sient but clinically significant decreases in RBF (⬇
⫺100 mL/min) and GFR (⬇ ⫺20 mL/min) were
noted after 1 day of therapy only in the 400-mg
celecoxib group. Renal blood flow and GFR were
decreased for both celecoxib and naproxen on day 7.
A second study evaluating the effect of selective
COX-2 drugs on GFR was undertaken in a slightly
higher risk group. The renal effects of multiple doses
of rofecoxib and indomethacin were studied in a
group of salt-restricted elderly subjects.34 Sixty pa-
tients whose creatinine clearances ranged between
30 and 80 mL/min were randomized into 1 of 4
groups that received 12.5 mg of rofecoxib per day, 25
mg of rofecoxib per day, 50 mg of indomethacin three
times per day, or placebo for 6 days. The 12.5- and
25-mg rofecoxib doses significantly decreased glo-
merular filtration rate by 10.2 and 9.6 mL/min,
respectively, whereas indomethacin similarly de-
creased GFR by 7.8 mL/min. These data suggest
that salt-depleted subjects and patients with mild to
moderate CKD are at risk to develop a reduced GFR
when treated with a COX-2 selective inhibitor, rem-
iniscent of traditional NSAID renal toxicity.
Clinically significant cases of nephrotoxicity from
COX-2 selective inhibitors have been published in
the medical literature.35– 42 Celecoxib and rofecoxib
were documented to cause acute renal failure (ARF)
and hyperkalemia in 3 patients.35 It is notable that
all of these patients had multiple risk factors for
NSAID-induced nephrotoxicity, including underly-
351
Drug-Induced Nephrotoxicity
ing chronic renal failure and true or “effective” vol-
ume depletion. The acute deterioration in renal
function returned to baseline after discontinuation
of COX-2 inhibitor and treatment of the associated
intravascular volume disturbance. One patient re-
quired hemodialysis for severe hyperkalemia. Since
this series of cases, several other reports of renal
failure and/or electrolyte disorders have been de-
scribed with the selective COX-2 inhibitors.36 – 42
Taken together, these cases suggest that ARF, hy-
perkalemia, and sodium retention can occur with
selective COX-2 inhibitor therapy in high-risk pa-
tients with prostaglandin-dependent disease states.
As evidenced by the expression of the COX-2 en-
zyme in animal and human kidneys as well as the
current clinical data in humans, it seems that the
COX-2 isoform is necessary to preserve kidney func-
tion in patients with prostaglandin-dependent
states. The COX-2 inhibitors do not seem to have
renal-sparing effects and should be considered
equivalently nephrotoxic as the traditional NSAIDs.
These drugs should be used cautiously in patients
with underlying risk for NSAID nephrotoxicity.
ACE Inhibitors/Angiotensin II Receptor Blockers.
Hemodynamic renal failure may also be a conse-
quence of therapy with medications that modulate
the renin-angiotensin system. Like NSAIDs, these
drugs precipitate a syndrome identical to prerenal
azotemia from other causes. As a large body of lit-
erature exists on this effect, this review will be
limited to a brief description of mechanism and risk
factors for the development of ARF from these
drugs.43,44
Activation of the angiotensin type 1 receptor on
the efferent arteriole by AII raises intraglomerular
capillary pressure and augments GFR, particularly
in situations in which where renal blood flow is
compromised.43 Also, AII constricts vessels in the
systemic circulation, raising arterial blood pressure
and promoting renal perfusion.43 In the absence of
disease states that alter renal perfusion, blockade of
AII formation or binding to angiotensin type 1 re-
ceptors has little effect on renal function. Superim-
position of clinical situations that impair renal per-
fusion, such a critical renal artery stenosis, true
volume contraction (vomiting, diarrhea, diuretics),
effective volume depletion (cirrhosis, decompen-
sated heart failure, nephrosis), and severe nephro-
sclerosis increase risk of hemodynamic renal failure
from ACE inhibitors and AII receptor blockers.44
The simultaneous reduction in systemic blood pres-
sure and fall in transglomerular capillary pressure
(due to loss of efferent arteriolar vasoconstriction)
precipitates a decline in GFR and renal failure. It
seems that this effect is similar for both ACE inhib-
itors and AII receptor blockers, which is not unex-
pected, because they both ultimately blunt efferent
352
arteriolar tone through reduction in AII synthesis or
effect.
Tubular Epithelial Cell Toxicity
As with hemodynamic renal failure, direct injury
to the renal tubular epithelia occurs frequently after
therapy with certain medications. This form of renal
failure is typically described as toxic acute tubular
necrosis. A relatively new class of drugs employed to
treat various viral infections has been noted to have
significant nephrotoxicity. The acyclic nucleoside
phosphonates cidofovir and adefovir are antivirals
that possess significant nephrotoxicity. A structur-
ally similar agent, tenofovir disoproxil fumurate
(DF) has also been noted to cause ARF and tubular
dysfunction. In addition, pamidronate, a drug that
has been employed widely to reduce hypercalcemia
and modulate metastatic bone disease has also been
associated with renal epithelial cell toxicity and re-
nal failure. The renal effects of these drugs will be
reviewed.
Cidofovir, Adefovir, and Tenofovir DF. Cido-
fovir and adefovir cause direct proximal tubular
injury.45–51 A spectrum of injury ranging from iso-
lated proximal tubular defects (Fanconi-like syn-
drome) to severe acute tubular necrosis requiring
renal replacement therapy has been described with
both drugs.45–51 The structural similarity between
these drugs and naturally occurring nucleotides is
thought to underlie their nephrotoxic effects. Cido-
fovir is a nucleotide analog of cytosine that forms
cidofovir-phosphocholine, an analog of cytidine
5-diphosphocholine, within cells.45– 49 It is specu-
lated that cidofovir-phosphocholine interferes with
the normal synthesis and/or degradation of mem-
brane phospholipids, resulting in proximal tubular
injury and, in extreme cases, cell necrosis. Adefovir
is a nucleotide analog of adenine that undergoes
mono and di-phosphorylation within cells.50,51 After
phosphorylation, the analog interferes with a vari-
ety of ATP-related processes. Disruption of ATP
synthesis, impairment of various ATP-dependent
processes, and/or disturbed transport of adenine nu-
cleotides in the Golgi apparatus and mitochondria
underlie this drug’s toxicity.50,51
It is apparent that the cytotoxicity of these drugs
for proximal tubular epithelia is related to their
mode of excretion. Proximal tubular cells express an
organic anion transporter (human renal organic an-
ion transporter-1) that efficiently transports various
acyclic nucleotide analogs, including cidofovir and
adefovir.52,53 This transporter resides on the baso-
lateral membrane of proximal tubular cells and me-
diates active uptake of these drugs into the cells
from the peritubular circulation. Once these agents
accumulate in tubular cells, they interfere with var-
ious cell processes and are then secreted into the
tubular lumen via apical membrane carriers or
June 2003 Volume 325 Number 6

channels.54,55 It is this pathway of drug elimination
by the kidney that fosters proximal tubular injury.
Based on these data, renal injury can be avoided or
reduced by employing the following guidelines.
Proper drug dosing for the prevailing level of renal
function, avoidance in patients with significant re-
nal impairment, and intravascular volume expan-
sion with intravenous fluids before drug initiation
will reduce ARF. In addition, administration of pro-
benecid, which competes with these agents for the
organic anion transporter and reduces proximal tu-
bular uptake of these analogs, decreases
nephrotoxicity.52
Tenofovir DF is a novel nucleotide analog that
also belongs to the class of acyclic nucleoside phos-
ponates.56,57 This new antiviral agent is a reverse
transcriptase inhibitor recently approved to treat
HIV infection.56,57 A few studies have documented
efficacy and safety with once daily dosing of this
drug.56,57 However, a persistent concern for tenofo-
vir DF is the potential for adverse renal effects. This
agent, like cidofovir and adefovir, has structural
similarities to naturally occurring nucleotides. Be-
cause of these similarities, it is possible that tenofo-
vir DF can also interrupt cellular functions through
the same mechanisms described for cidofovir and
adefovir. In addition, because tenofovir DF is an
organic anion (like cidofovir and adefovir), active
uptake by the organic anion transporter in proximal
tubular cells is also likely. In fact, pharmacokinetic
studies on tenofovir DF reveal that renal clearance
of the drug exceeds creatinine clearance, indicating
active tubular secretion of the drug.56,57 Until re-
cently, studies suggested that tenofovir DF is not
associated with severe nephrotoxicity.54,55 Only 1
patient of 18 who were receiving either 300 or 600
mg per day developed an increase in serum creati-
nine after 35 days of therapy.57 None of the patients
receiving lower doses (75 and 150 mg per day) man-
ifested a rise in serum creatinine. In yet another
study, evaluating tenofovir DF, 189 patients were
randomized to placebo, 75, 150, or 300 mg per day.56
The median serum creatinine values for the 4 orig-
inal dose groups remained constant (0.8 to 0.9 mg/
dL) through 48 weeks on treatment. Two patients
developed a 0.5 mg/dL or greater rise in serum
creatinine. These initial data suggested that tenofo-
vir DF is minimally nephrotoxic. However, 2 cases of
ARF and tubular injury have recently been
reported.58,59
The first patient described by Coca and Pera-
zella58 had underlying CKD (baseline serum creati-
nine of 1.8 –2.0 mg/dL) and developed ARF after 6
weeks of therapy with tenofovir 300 mg per day.
Renal biopsy demonstrated blebbing and necrosis
limited to proximal tubular cells (Figure 1). Renal
function returned to baseline after discontinuation
of tenofovir DF. A second case of tenofovir DF-asso-
ciated ARF (serum creatinine of 2.2 mg/dL) and
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
Figure 1. Light microscopy reveals blebbing and necrosis (ar-
rows) of proximal tubular cells caused by treatment of HIV
infection with tenofovir DF.
Fanconi syndrome has been reported in abstract
form.59 This patient developed renal disease after 4
months of therapy with tenofovir DF (300 mg/day).
Renal biopsy demonstrated extensive necrosis and
vacuolization of proximal tubular cells. Rapid im-
provement in renal function and tubular defects
occurred after discontinuation of tenofovir. These 2
cases suggest that administration of tenofovir DF
can cause renal failure and proximal tubular injury
in patients receiving the recommended dose of 300
mg per day. Patients with CKD are probably at more
risk and administration of tenofovir to these pa-
tients should be avoided or undertaken with caution
and close monitoring.
Pamidronate. Pamidronate is employed fre-
quently to treat malignancy-associated hypercalce-
mia and osteolytic lesions.60 – 62 Recently, this widely
used bisphosphonate has been noted to cause neph-
rotoxicity in patients with multiple myeloma, meta-
static breast cancer, and Langerhan histiocytosis.
Dose-dependent nephrotoxicity has been previ-
ously described in rats infused with relatively high
doses (5–50 mg/kg) of pamidronate.63 High-dose
therapy in rats was associated with an increase in
malate dehydrogenase, a sensitive marker of neph-
rotoxicity.63 Also, an elevation in serum urea con-
centration was noted in these rats.63 Six patients
with multiple myeloma, 1 patient with metastatic
breast cancer, and 1 patient with Langerhan histi-
ocytosis developed renal failure with relatively high
doses and/or prolonged courses of pamidronate.64,65
Doses ranging from 90 to 360 mg of pamidronate
monthly were administered to 5 patients, whereas 1
patient received 90 mg for 15 months, 1 received 90
mg for 11 months, and 1 received 60 mg for 48
months. It is important to note that these patients
also received multiple potentially nephrotoxic che-
353
Drug-Induced Nephrotoxicity

Table 4. Drugs Associated with Crystal Nephropathy

Drug Type Prevention of ARF Treatment of Established ARF

Acyclovir Avoid rapid intravenous bolus Discontinue or reduce dose

Adjust dose for renal function Volume resuscitate to euvolemia
Establish euvolemia before therapy Establish high urine flow
Establish high urine flow Hemodialysis

Sulfonamides Adjust dose for renal function Discontinue or reduce dose

Establish euvolemia before therapy
Establish high urine flow
Alkalinize the urine (pH ⬎ 7.15)
Volume resuscitate to euvolemia
Establish high urine flow
Alkalinize the urine (if possible)
Alleviate urinary obstruction
Hemodialysis

Methotrexate Adjust dose for renal function Discontinue or reduce dose

Establish euvolemia before therapy Volume resuscitate to euvolemia
Establish high urine flow Establish high urine flow
Alkalinize the urine (pH ⬎ 7.0) Alkalinize the urine (if possible)
High-flux hemodialysis
Leucovorin rescue

Indinavir Establish euvolemia before therapy Discontinue or reduce dose

Establish high urine flow Volume resuscitate to euvolemia
? Acidify the urine Establish high urine flow
Alleviate urinary obstruction

motherapeutic agents. ARF and nephrotic protein-
uria developed in all patients; 5 of 8 required dialy-
sis therapy. Renal biopsies in these patients were
pertinent for glomerular and tubular injury, al-
though the glomerular disease was most prominent.
On light microscopy, the glomeruli exhibited collaps-
ing focal and segmental glomerulosclerosis in 7 pa-
tients and minimal change in 1 patient.64,65 Exten-
sive foot process effacement of the glomerular
podocytes (visceral epithelial cells) without dense
deposits on electron microscopy was present in all
cases. On light microscopy, tubular changes were
diffuse and severe, with tubular atrophy, luminal
ectasia, loss of brush border, cytoplasmic vacuoliza-
tion, focal microcyst formation, and mild-to-severe
interstitial fibrosis. Electron microscopy demon-
strated extensive degenerative changes of the tu-
bules including epithelial simplification, loss of api-
cal brush border, and dilation of endoplasmic
reticulum. Immunofluorescence staining revealed
minimal staining for C3 and IgM in 2 biopsies, with
no evidence of light chain deposition.
The literature has relatively little documentation
of the nephrotoxicity of pamidronate and in general
this drug is considered to be safe.66 – 68 The above
reports support the notion that this drug can induce
injury in glomerular and tubular epithelial cells.
The mechanism of renal epithelial cell toxicity in-
duced by pamidronate is speculated to involve inhi-
bition of ATP-dependent metabolic pathways
through incorporation of the drug into ATP ana-
logs.64 This effect would impair cell energetics and
cause apoptosis and cell death. Pamidronate can
increase production of various cytokines and inter-
feron-␥, driving local nephrotoxic effects in epithe-
lial cells.64 Bisphosphonates may also promote renal
injury, particularly in glomerular epithelial cells,
through disruption of the cytoskeleton of these
cells.64 This effect is of particular interest given that
disturbances in cell cycle control elements of these
cells can precipitate dedifferentiation of podocytes,
leading to injury and proteinuria as observed in
HIV-associated nephropathy.69 Patients receiving
either high doses or prolonged courses seem to be at
highest risk. Therefore, pamidronate therapy in
these patients should be regularly monitored for
changes in renal function and/or increases in uri-
nary protein excretion. Any change in these param-
eters should prompt discontinuation of pamidronate
and further evaluation.
Crystal Nephropathy
Deposition of crystals in the kidneys can cause
renal failure.67 The renal injury occurs from crystals
that, because of their relative insolubility in human
urine, tend to precipitate in distal tubular lu-
mens.70 –73 A number of routinely prescribed medi-
cations (Table 4) cause crystal-induced renal dis-
ease, termed crystal nephropathy.70 –73 Importantly,
characteristics common to patients who receive
these medications seem to predispose to the devel-
opment of intratubular crystal deposition and tubu-
lar obstruction.74
Among the factors that increase the likelihood of
renal crystal deposition, severe volume contraction,
from either “true” or “effective” causes, is the single
most important.70,74 Patients who suffer from

354 June 2003 Volume 325 Number 6


chronic diarrhea, anorexia with nausea/vomiting,
febrile illnesses, adrenal insufficiency, and renal
salt wasting commonly develop “true” intravascular
volume depletion.70,74 “Effective” decreases in intra-
vascular volume will result from fluid sequestration
in third-space compartments as seen with pancre-
atitis, ascites, heart failure, and pleural effu-
sions.70,74 These volume-related factors promote
sluggish urine flow rates increasing the risk of crys-
tal deposition within the tubules. Underlying renal
impairment is another important risk factor for the
development of crystal-induced ARF in these pa-
tients. Increased risk probably results from the ex-
posure of a fewer number of functioning nephrons to
the crystal-forming agent. Excessive drug dosing for
the underlying glomerular filtration rate will also
contribute to the development of ARF. Finally, met-
abolic perturbations, including several forms of met-
abolic acidoses or alkaloses, may also exacerbate
intrarenal crystal deposition by causing either high
or low urinary pH.70,74 The importance of urine pH
in this setting is dependent on the solubility char-
acteristics of the culprit drug or endogenous crystal.
As an example, medications that are weak acids
(sulfadiazine) will precipitate in an acid urine,
whereas a drug such as indinavir will precipitate in
an alkaline urine.
Sulfadiazine. High-dose oral sulfadiazine is re-
quired to adequately treat infection with toxoplas-
mosis. Therapy with sulfadiazine was 1 of the first
therapeutic agents noted to cause crystal nephrop-
athy.75– 81 Sulfadiazine is excreted in the urine (66
%) as both parent compound and its metabolite
acetylsulfadiazine.75 Because this drug is a weak
acid, it is relatively insoluble in an acid urine and
will tend to precipitate in tubular lumens when the
urine pH falls below 5.5.75 Precipitation in the kid-
neys causes obstruction of the tubular lumens in the
distal nephron from crystals admixed with cellular
debris and proteinaceous material.75– 81 The admin-
istration of 4 to 6 g/day of sulfadiazine significantly
increases the likelihood of sulfa-crystal precipitation
in the distal nephron.75– 81 Oliguric ARF, which de-
velops within approximately 1 week of therapy, her-
alds the development of sulfa-crystal tubular and/or
calyceal deposition.75– 81 Patients are typically
asymptomatic but may complain of back, flank, or
abdominal discomfort.75 Anywhere from less than
1% to as many as 29% of patients treated with
sulfadiazine have been noted to develop ARF.75– 81
Examination of the urine sediment in these patients
typically reveals red blood cells mixed with a variety
of sulfadiazine crystals.75 Needle-like crystals, ro-
settes, and crystals resembling “shocks of wheat”
are often noted. Crystalluria has been documented
to occur in up to 49% of patients infected with
HIV.75– 81 Sludge, calculous material, and small ra-
diolucent uroliths may also lodge in the renal paren-
chyma and/or calyces and appear as bilateral lay-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
ered clusters of echogenic material on renal
ultrasonography in the setting of sulfadiazine
therapy.78
Prevention of nephrotoxicity is possible if prompt
correction of hypovolemia with an isotonic intrave-
nous solution and induction of a generous diuresis
(100 to 150 mL/hour) is undertaken.75– 81 A loop
diuretic will promote high urine flow rates, with the
goal of matching fluid intake with urine output to
achieve euvolemia. Maintaining a urine pH above
7.15 with sodium bicarbonate increases the solubil-
ity of sulfadiazine by more than 20-fold and will
decrease crystal precipitation. Proper dosing of
these drugs in relation to calculated GFR is also
important in the prevention of nephrotoxicity.75
Daily monitoring of the urine for crystal formation
will allow prompt adjustment of sulfadiazine dosing
and more aggressive manipulation of both urinary
pH and flow rates. In patients who have developed
ARF from sulfadiazine, treatment entails fluid re-
suscitation to achieve a vigorous diuresis in an at-
tempt to clear crystals obstructing tubular lu-
mens.75– 81 Alkali therapy is reasonable if a good
urine flow rate is established. Discontinuation of the
medication is usually required, at least initially, in
this setting. Occasionally, continued treatment with
sulfadiazine is tolerated with induction of high urine
flow rates and urinary alkalinization. Ureteral cath-
eterization or nephrostomy tube placement, followed
by lavage with 5% bicarbonate solution, may dis-
solve stones in patients with total obstruction at the
level of the renal pelvis or calyces.76,81 Dialysis,
which efficiently removes sulfadiazine may be nec-
essary in some cases.75
Acyclovir. Intravenous acyclovir therapy is often
required when infections with varicella zoster and
herpes simplex develop in immunocompromised pa-
tients. Urinary excretion of acyclovir occurs through
both glomerular filtration and tubular secre-
tion.82– 84 The drug reaches high concentrations in
the tubular lumen after the rapid clearance of acy-
clovir from the plasma. Renal excretion of un-
changed drug accounts for approximately 62 to 91%
of acyclovir elimination.82– 84 Acyclovir is relatively
insoluble in the urine, with a maximum solubility of
2.5 mg/mL at physiologic pH.82– 84 Rapid intrave-
nous bolus administration of acyclovir (500 mg/m2)
contributes to intratubular precipitation of crys-
tals.82,84,85 This combination of characteristics un-
derlies the tendency for intravenous infusion of acy-
clovir to cause intratubular precipitation of crystals
in the kidney. In contrast, low-dose intravenous and
oral acyclovir therapy are generally well tolerated;
however, they can also cause ARF in the setting of
severe volume depletion and excessive oral drug
dosage.21,22,86,87 Animal experiments have demon-
strated acyclovir crystal deposition in collecting tu-
bules within 30 minutes of a single 50-mg intraperi-
toneal injection in mice.88 Deposition of crystals in
355
Drug-Induced Nephrotoxicity
tubular lumenal results in intrarenal nephron ob-
struction, whereas severe intraparenchymal precip-
itation of crystals can impinge on the renal venous
network and lead to impaired renal blood flow.83
These 2 events promote ARF.
Asymptomatic renal insufficiency is most com-
mon, but nausea/vomiting and flank or abdominal
pain will occasionally accompany renal failure.72– 84
Crystal nephropathy often develops within 24 to 48
hours of acyclovir administration. Three large series
observed a 12 to 48% incidence of acyclovir-associ-
ated renal failure.82– 84 Urinalysis usually reveals
both hematuria and pyuria, whereas birefringent
needle-shaped acyclovir crystals can also be seen in
the urine sediment with polarizing microscopy.82– 84
Although some patients require temporary dialysis,
most recover renal function with discontinuation of
acyclovir and volume resuscitation.89
Prevention of acyclovir deposition in the kidneys
can be accomplished by avoiding rapid bolus infu-
sion of acyclovir and infusing the drug slowly.82– 87
Volume repletion and induction of high urinary flow
rates (100 to 150 mL/hour) before drug administra-
tion will also prevent crystal precipitation and sub-
sequent tubular obstruction [Table 1].82– 87 Therapy
with a loop diuretic may facilitate high urinary flow
rates, but caution to avoid volume depletion must be
employed. Importantly, a reduction in acyclovir dose
is critical in patients with underlying renal insuffi-
ciency. To this end, calculation of the proper acyclo-
vir dose for prevailing GFR will significantly reduce
acute renal impairment. Treatment of established
renal failure includes induction of a diuresis with a
loop diuretic to wash out obstructing crystals. Atten-
tive supportive care, including adjustment of medi-
cation dosages, a restricted diet, and both metabolic
and volume management, is required.82– 87 Hemodi-
alysis, which removes significant amounts of acyclo-
vir, may be indicated when renal failure is severe.89
Indinavir. Indinavir is a protease inhibitor that
is employed to treat HIV infection.90 This drug has
recently been noted to cause crystal nephropathy,
isolated crystalluria, and nephrolithiasis.28 –34,91–97
Approximately 20% of the administered drug is
cleared by the kidneys, of which 11% is parent com-
pound and the rest a variety of metabolites.94 Indi-
navir is very soluble at a urine pH of 3.5 (100
mg/mL) but relatively insoluble at higher levels of
urinary pH (0.035 mg/mL at pH 6.0; 0.02 mg/mL at
pH 7.0).92,93 Not unexpectedly, precipitation of indi-
navir crystals occurs in tubular lumenae (Figure 2)
from the very low solubility of this drug in human
urine at a pH range of 5.5 to 7.0. Consequently,
intrarenal tubular obstruction can cause acute or
chronic renal failure.91–97 In addition, interstitial
fibrosis and obstructing indinavir calculi can also
promote impaired renal function.91,96
Classic renal colic, dysuria, back/flank pain, or
gross hematuria have been described in HIV-in-
356
Figure 2. Light microscopy reveals deposition of indinavir crys-
tals (arrows) admixed with protein in the tubular lumen of a
patient treated with indinavir. The star highlights intersitial
fibrosis. [Reproduced from Reilly RF, Tray K, Perazella MA.
Indinavir nephropathy revisited: a pattern of insidious renal
failure with identifiable risk factors. Am J Kidney Dis 2001;38:
E23–E28. Copyright © 2001 WB Saunders. Used with
permission.]
fected patients treated with indinavir.94 In 1 series,
urologic symptoms developed in 8% of patients
treated with indinavir.94 In asymptomatic patients,
only abnormal serum (blood urea nitrogen, creati-
nine) or urine (red and white blood cells, crystals)
tests provide evidence of renal injury from indinavir
crystals.94 Crystals of varying shapes including
platelike rectangles, fan-shaped crystals, and star-
burst forms are visualized upon examination of the
urine using a lambda plate and/or polarizing light
microscopy.94 Indinavir stones may be passed spon-
taneously or removed by urologic procedures to con-
trol pain or relieve urinary obstruction.94,96 Chemi-
cal analysis of stones reveals a composition
consisting of a mixture of indinavir and indinavir
metabolites.93,94,96 Most cases of renal failure with
indinavir therapy have been mild and reversible;
however, more severe renal failure from obstructing
indinavir calculi and chronic kidney disease have
also been reported.91–98
Indinavir therapy should be accompanied by the
daily intake of at least 2 to 3 liters of fluid by
patients to maintain high urinary flow rates and
prevent crystal deposition in the kidneys.91–97 Be-
cause indinavir is metabolized primarily in the liver
through the P450III A pathway, the dose of drug
should be reduced in patients with severe hepatic
impairment. Acidification of the urine to a pH of 3.5
to 4.5 will improve indinavir solubility, but is ex-
tremely difficult to achieve and is potentially harm-
ful. Therefore, this form of therapy is not recom-
mended. Discontinuation of indinavir generally
reverses nephrotoxicity; however, CKD from inter-
June 2003 Volume 325 Number 6

stitial fibrosis has been noted with late recognition
of drug nephrotoxicity.98 Volume expansion allows
therapy with indinavir to continue safely in approx-
imately 75% of patients.94
The deposition of crystalline material in the kid-
neys of immunocompromised patients and those in-
fected with HIV is an important renal complication
of drug therapy. Often, patients requiring treatment
with culprit drugs are at highest risk to develop
crystal nephrotoxicity from pre-existing intravascu-
lar volume depletion, metabolic disturbances, con-
comitant nephrotoxic drug therapy, and underlying
renal insufficiency. Recognition of at-risk physiology
in such patients can often prevent or reduce the
development of crystal-induced acute renal insuffi-
ciency. Supportive care, adjustment of medication
dose, and initiation of dialysis may be required in
some patients. Fortunately, renal insufficiency is
typically reversible over time.
Osmotic Nephrosis
It has been debated whether hyperosmolar agents
can induce renal tubular injury. Induction of cell
swelling and vacuolization (causing disruption of
cellular integrity) as well as tubular luminal occlu-
sion from swollen tubular cells are the mechanisms
thought to underlie the development of renal failure
with these agents. In the early 1940s, the demon-
stration of severe swelling of proximal epithelial
cells was reported in patients who died of renal
failure after administration of intravenous su-
crose.99 This entity was given the name sucrose
nephropathy.99 Studies in experimental animals
performed at that time revealed that proximal tubu-
lar cell swelling could be reproducibly induced by
intravenous infusion of sucrose.100,101 Furthermore,
alterations in renal function in these animals
seemed to depend on the severity of cell swelling and
tubular obstruction.100,101 After these animal stud-
ies, this lesion was also observed with parenteral
infusion of other filtered macromolecules such as
mannitol, dextran, and radiocontrast.102,103 It was
speculated that the mechanism underlying this le-
sion involved the uptake of nonmetabolizable mole-
cules by pinocytosis into proximal cells, followed by
the accumulation of cellular water due to the oncotic
gradient generated across the cell membrane.102,103
More recently, both intravenous immune globulin
(IVIG) and hydroxyethyl starch have been demon-
strated to cause an “osmotic nephrosis.”
IVIG. IVIG was initially introduced as a prophy-
lactic therapy for infection in patients with deficien-
cies of immunoglobulins and a variety of immune-
mediated disorders.104 IVIG-associated ARF was
first reported in 1987.105 Since the initial report,
more than 50 cases of IVIG-related acute renal in-
sufficiency have been documented in the literature.
The temporal association of ARF with IVIG infusion
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
as well as the exclusion of other causes of ARF
supported the possibility of IVIG as the cause of
renal insufficiency.
It was observed that acute renal insufficiency af-
ter this therapy developed in older patients and
those with preexisting renal disease.105–124 Greater
than 60% of patients who developed renal failure
were either older than 65 years of age or had renal
insufficiency (mean baseline serum creatinine was
1.7 mg/dL). Unrecognized renal impairment in the
elderly may have provided a predisposition to neph-
rotoxicity in this group. The daily dose of IVIG did
not seem to play a major role in the development of
ARF; however, a small number of patients benefited
from either a lower dose or a longer dosing interval
upon reintroduction of IVIG therapy after recovery
from renal failure.111,120,121
The clinical course of the cases of IVIG-associated
renal insufficiency seemed to follow a consistent pat-
tern. ARF developed after approximately 3 days of
therapy, with a range of 1 to 10 days in the patients.
Oliguric renal failure occurred more commonly than
nonoliguric renal failure.105,107–109,111–113,116,121,123 The
duration of renal insufficiency was approximately 2
weeks (range 3– 42 days), and renal replacement
therapy was required in one third of the pat-
ients.108 –111,113,119 –124 In 84% of cases, ARF was revers-
ible, and renal function returned to baseline upon
discontinuation of IVIG therapy. Of those patients
who did not recover renal function to baseline, 5 died,
2 had stable chronic renal failure, and 1 required
maintenance hemodialysis.
Several immunoglobulin preparations were used
in the cases in which renal failure developed.105–124
However, the Sandoglobulin (Sandoz, East Hanover,
NJ) brand of IVIG was employed in more than 80%
of the cases. Notably, the stabilizing agent used in
Sandoglobulin is sucrose. In contrast, most other
immunoglobulin products employed maltose and
other carbohydrates as the stabilizing agent. This
raised the suspicion that the stabilizing agent, su-
crose, might play an important role in the develop-
ment of acute renal insufficiency. However, the pre-
dominance of cases of Sandoglobulin-associated
renal failure may be explained in part by the rela-
tively frequent use of this brand of IVIG.
Renal biopsy was performed in 10 of the cases,
whereas a clinical diagnosis of IVIG-associated ARF
was made in the remaining patients. Eight of 10
biopsy specimens revealed a common pattern of
unique histopathologic lesions.107,112,113,121,125 The
renal lesions were characterized by marked cellular
swelling, cytoplasmic vacuolization, and degenera-
tion of proximal tubular epithelium. In addition,
some tubular lumina were narrowed or completely
occluded by the swollen cells. The glomeruli were
usually spared, although 1 biopsy specimen demon-
strated mesangial proliferation.113 Except in 1 pa-
tient who had an underlying IgA nephropathy,123
357
Drug-Induced Nephrotoxicity
immune deposits were consistently absent by both
electron microscopy and immunofluorescent studies.
Based on the available renal histopathological
studies, it seems likely that renal injury in the
majority of patients treated with IVIG is caused by
the uptake of sucrose into proximal tubular epithe-
lial cells.107,112,113,121 Cellular uptake of this filtered
macromolecule results in swelling of proximal tubu-
lar cells, which can lead to narrowing and occlusion
of the tubular lumina. The evolution of structural
changes that follow an intravenous infusion of su-
crose has been described in experimental ani-
mals.100,126 Swelling and vacuolization of tubular
cells develop as early as 1 hour after sucrose infu-
sion in dogs and reach maximum severity at approx-
imately 48 to 72 hours.100 By day 7 after infusion,
resolution of these lesions commences and ap-
proaches completion by approximately 2 weeks. Su-
crose has been shown to enter proximal tubular cells
via pinocytosis, whereupon sucrose-containing pino-
cytotic vesicles coalesce to form vacuoles that subse-
quently fuse to cytoplasmic lysosomes and form
phagolysosomes.126 Because renal cells do not pos-
sess the enzymes necessary to digest sucrose, they
are unable to metabolize this carbohydrate. As a
result, sucrose accumulates in the cell cytoplasm
and leads to the progressive accumulation of cellular
water and massive cell swelling.127
The mechanism that underlies IVIG-associated
ARF seems similar to the animal model of sucrose
nephropathy.112,113,121,122 The role of sucrose in the
development of renal insufficiency after IVIG infu-
sion is supported by several pieces of data. The
majority of reported cases of IVIG-related ARF
(83%) occur in association with Sandoglobulin ther-
apy, which contains sucrose. Other IVIG prepara-
tions contain maltose and other carbohydrates and
have rarely been associated with ARF. This occur-
rence probably relates to the fact that maltose is
digested and metabolized by kidney cells, whereas
sucrose is not.122 Furthermore, patients who have
been treated with maltose-containing IVIG without
complication have subsequently developed ARF
when treated with sucrose-containing IVIG.107,113
The clinical time course of renal failure associated
with immunoglobulin therapy corresponds closely to
the rate of clearance of sucrose molecules from prox-
imal tubular cells in animal studies.100,126 Finally,
lesions identical to those described with sucrose
nephropathy were found in 8 of 10 renal biopsy
specimens of patients treated with IVIG.
Because sucrose seems to be the main culprit
associated with the development of osmotic nephro-
sis with IVIG, a reduction in nephrotoxicity may be
achieved by avoiding IVIG which uses sucrose as a
stabilizer.122 Also, IVIG preparations containing su-
crose should be used cautiously in patients with
pre-existing renal insufficiency and older age. Lim-
358
iting the dose of IVIG administered or lengthening
the dosing interval may also benefit these patients.
Hydroxyethyl Starch. Hydroxyethylstarch
(HES) is an amylopectin substituted with hydroxy-
ethyl groups that is used to expand plasma volume
and improve hemodynamics in hypotensive pa-
tients. It accomplishes this action through increas-
ing plasma refilling from the interstitial and intra-
cellular space through its oncotic effects. An
association of nephrotoxicity with HES was noted
when renal transplant recipients who received kid-
neys from brain dead donors administered HES de-
veloped ARF.128,129 Interestingly, the classic “osmot-
ic nephrosis” lesions described for sucrose, dextran,
mannitol, and IVIG were present in the biopsy spec-
imens obtained from these patients. Because of
these initial descriptions, however, controversy sur-
rounding this association has existed based on re-
ports refuting any connection of HES with renal
failure.130,131 Recently, several reports and studies
provide data to support the contention that HES
therapy is associated with the development of renal
dysfunction.
Three cases of ARF ascribable only to therapy
with HES have been described in the postoperative
setting.132,133 Transient ARF developed after caesar-
ian section in 2 healthy female patients who re-
ceived intravenous HES to expand intravascular
volume postoperatively.133 Another surgical patient
who was administered HES (500 mL) for transient
intraoperative hypotension developed oliguric renal
failure in the postoperative period.132 Work up for
possible causes was negative; on day 4, the patient
underwent renal biopsy that demonstrated osmotic
nephrosis-like lesions in the proximal tubules (Fig-
ure 3). A multicenter study evaluated the effects of
HES (6%) and gelatin (3% fluid-modified) on renal
function in patients with severe sepsis.134 ARF, oli-
guria, and peak serum creatinine concentrations
were significantly higher in the HES group than in
the gelatin group. Multivariate analysis revealed
that HES administration was a risk factor for ARF.
Similarly, a well-matched case control study docu-
mented an increased risk for delayed graft function
in renal transplant recipients who received HES as
a volume expander.135
As with IVIG, where sucrose is the osmotic agent
associated with ARF and osmotic nephrosis, HES
also seems to cause renal dysfunction through the
development of proximal tubular swelling and vac-
uolization (osmotic nephrosis). Like sucrose, HES in
taken up by proximal tubular cells, where it is not
able to undergo degradation by the cell. Intracellu-
lar HES then generates an oncotic gradient across
the cell membrane that causes intracellular accu-
mulation of water and cellular swelling. Studies
where this plasma expander did not induce nephro-
toxicity employed HES preparations with low molec-
ular weights and lower degrees of substitution
June 2003 Volume 325 Number 6

Figure 3. Light microscopy of renal tissue obtained from patient
treated with hetastarch for intravascular volume resuscitation.
The straight arrows demonstrate swollen proximal tubular cells;
the curved arrow demonstrates occlusion of the tubular lumen
from swollen cells. [Reproduced from LaBarthe AD, Jacobs F,
Blot F. Acute renal failure secondary to hydroxyethylstarch ad-
ministration in a surgical patient. Am J Med 2001;111:417– 8
Copyright © 2001 Elsevier Science. Used with permission.]
(number of hydroxyethylations at carbon positions
C2, C3, or C6). A few practical points to reduce the
occurrence of osmotic nephrosis with HES therapy
are worth noting. It seems reasonable to avoid ther-
apy with HES in patients with pre-existing renal
disease, to employ low-molecular-weight HES with
low degrees of substitution (HES 200/0.5) and to
administer doses below the recommended upper
limit (33 mL/kg/day).
Conclusion
Renal injury and clinical renal failure can occur
through a variety of mechanisms after administra-
tion of different therapeutic agents. Drug toxicity
can develop from hemodynamic effects, direct tubu-
lar injury from epithelial cell toxins, intratubular
obstruction from insoluble crystals, and cellular
swelling from osmotic agents. These adverse drug
effects need to be kept in mind when evaluating the
patient who develops renal failure after therapy
with certain types of medications.
References
1. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygen-
ase-2 selectivity of widely used nonsteroidal anti-inflamma-
tory drugs. Am J Med 1998;104:413–21.
2. Crofford LJ. COX-1 and COX-2 Tissue expression: Impli-
cations and predictions. J. Rheumatol 1997;24(Suppl 49):
15–9.
3. Siverstein FE, Faich G, Goldstein JL, et al. Gastroin-
testinal toxicity with celecoxib vs. nonsteroidal anti-inflam-
matory drug for osteoarthritis and rheumatoid arthritis.
JAMA 2000;284:1247–55.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
4. Bombardier C, Laine L, Reicin A, et al. Comparison of
upper gastrointestinal toxicity of rofecoxib and naproxen in
patients with rheumatoid arthritis. N Engl J Med 2000;343:
1520 – 8.
5. Clive DM, Stoff JS. Renal syndromes associated with non-
steroidal antiinflammatory drugs. N Engl J Med 1984;310:
563–72.
6. Schlondorf D. Renal complications of nonsteroidal anti-
inflammatory drugs. Kidney Int 1993;44:643–53.
7. Smith WL, DeWitt DL. Biochemistry and prostaglandin
endoperoxide H synthase-1 and synthase-2 and their differ-
ential susceptibility to nonsteroidal anti-inflammatory
drugs. Semin Nephrol 1995;15:179 –94.
8. Komhoff M, Grone H-J, Klein T, et al. Localization of
cyclooxygenase-1 and -2 in adult and fetal human kidney:
implication for renal function. Am. J. Physiol. 1997;272:
F460 –F468.
9. Hao CM, Komhoff M, Guan Y, et al. Selective targeting of
cyclooxygenase-2 reveals its role in renal medullary inter-
stitial survival. Am J Physiol 1999;277:F352–F359.
10. Harris RC, McKanna JA, Akai Y, et al. Cyclooxygenase-2
is associated with the macula densa of rat kidney and
increases with salt restriction. J Clin Invest 1994;94:2504 –
10.
11. Fitzpatrick FA, Soberman R. Regulated formation of
eicosanoids. J Clin Invest 2001;107:1347–51.
12. Smith WL, Lagenbach R. Why there are two cyclooxygen-
ase isozymes. J Clin Invest 2001;107:1491–5.
13. Palmer BF, Henrich WL. Clinical acute renal failure with
nonsteroidal anti-inflammatory drugs. Semin Nephrol 1995;
15:214 –27.
14. Niwa T, Maeda K, Shibata M. Urinary prostaglandins
and thromboxane in patients with chronic glomerulonephri-
tis. Nephron 1987;46:281–7.
15. Smith WL. Prostanoid biosynthesis and mechanisms of
action. Am J Physiol 1982;263:F181–F187.
16. Breyer MD, Harris RC. Cyclooxygenase 2 and the kidney.
Curr Opin Nephrol Hypertension 2001;10:89 –98.
17. Whelton A, Hamilton CW. Nonsteroidal anti-inflamma-
tory drugs: effects on kidney function. J Clin Pharmacol
1991;31:588 –98.
18. Guan Y, Chang M, Cho W, et al. Cloning, expression, and
regulation of rabbit cyclooxygenase-2 in renal medullary
interstitial cells. Am J Physiol 1997;273:F18 –F26.
19. Ohnaka K, Numaguchi K, Yamaka W, et al. Induction of
cyclooxygenase-2 by angiotensin II in cultured rat vascular
smooth muscle cells. Hypertension 1999;35:68 –75.
20. Yang T, Singh I, Pham H, et al. Regulation of cyclooxy-
genase expression in the kidney by dietary salt intake. Am J
Physiol 1998;274:F481–F489.
21. Kester M, Coroneous E, Thomas P, et al. Endothelin
stimulates prostaglandin endoperoxide synthase-2 mRNA
expression and protein synthesis through tyrosine kinase
signaling pathway in rat cells. J Biol Chem
1994;269:22574 –22580.
22. Ferreri NR, An SJ, McGiff JC. Cyclooxygenase-2 expres-
sion and function in the medullary thick ascending limb.
Am J Physiol 1999;277:F360 –F368.
23. Harris RC, Breyer MD. Physiological regulation of cyclo-
oxygenase-2 in the kidney. Am J Physiol Renal Physiol
2001;281:F1–F11.
24. Traynor TR, Smart A, Briggs JP, et al. Inhibition of
macula densa-stimulated renin secretion by pharmacologi-
cal blockade of cyclooxygenase-2. Am J Physiol 1999;277:
F706 –F710.
359
Drug-Induced Nephrotoxicity
25. Yang T, Schnermann JB, Briggs JP. Regulation of cyclo-
oxygenase-2 expression in renal medulla by tonicity in vivo
and in vitro. Am J Physiol 1999;277:F1–F9.
26. Hao CM, Yull F, Blackwell T, et al. Dehydration activates
an NF-␬B-driven, COX2-dependent survival mechanism in
renal medullary interstitial cells. J Clin Invest 2000;106:
973– 82.
27. Abassi Z, Brodsky S, Gealekman O, et al. Intrarenal
expression and distribution of cyclooxygenase isoforms in
rats with experimental heart failure. Am J Physiol Renal
Physiol 2001;280:F43–F53.
28. Llinas MT, Lopez R, Rodriguez F, et al. Role of COX-2-
derived metabolites in regulation of the renal hemodynamic
response to norepinephrine. Am J Physiol Renal Physiol
2001;281:F975–F982.
29. Kammerl MC, Nusing RM, RichthammerW, et al. Inhi-
bition of COX-2 counteracts the effects of diuretics in rats.
Kidney Int 2001;60:1684 –91.
30. Muscara MN, Vergnolle N, Lovren F, et al. Selective
cyclo-oxygenase-2 inhibition with celecoxib elevates blood
pressure and promotes leukocyte adherence. Br J Pharma-
col 2000;129:1423–30.
31. Nantel F, Meadows E, Denis D, et al. Immunolocaliza-
tion of cyclooxygenase-2 in the macula densa of human
elderly. FEBS Lett 1999;457:475–7.
32. Komhoff M, Jeck NDM, Seyberth HW, et al. Cyclooxy-
genase-2 expression is associated with the renal macula
densa of patients with Bartter-like syndrome. Kidney Int
2000;58:2410 –24.
33. Rossat J, Maillard M, Nussberger J, et al. Renal effects
of selective cyclooxygenase-2 inhibition in normotensive
salt-depleted subjects. Clin Pharmacol Ther 1999;66:76 – 84.
34. Swan SK, Lasster KC, Ryan CF, et. al. Effect of cycloox-
ygenase inhibition on renal function in elderly persons re-
ceiving a low-salt diet. A randomized, controlled trial Ann
Intern Med 2000;133:1–9.
35. Perazella MA, Eras J. Are selective COX-2 inhibitors
nephrotoxic? Am J Kidney Dis 2000;35:937– 40.
36. Braden GL, O’Shea M, Mulhern J, et al. COX-2 inhibitor
acute renal failure: Association with hyperkalemia & type
IV renal tubular acidosis [abstract]. J Am Soc Nephrol
2000;11:126A.
37. Stafford C, Bestoso JT. Celecoxib-induced acute renal
failure [abstract]. J Am Soc Nephrol 2000;11:134A.
38. Perazella MA, Tray K. Selective COX-2 inhibitors: A pat-
tern of nephrotoxicity similar to traditional nonsteroidal
anti-inflammatory drugs. Am J Med 2001;111:64 – 67.
39. Graham MG. Acute renal failure related to high-dose cele-
coxib. Ann Intern Med 2001;135:69 –70.
40. Pfister AK, Crisalli RJ, Carter WH. Cyclooxygenase-2
inhibition and renal function [letter]. Ann Intern Med 2001;
134:1077.
41. Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial
nephritis associated with the selective COX-2 enzyme inhib-
itor, rofecoxib. Lancet 2001;357:1946 –7.
42. Gadalean F, Barreto G, Epstein M. Acute renal failure
induced by COX-2 specific inhibitors [abstract]. J Am Soc
Nephrol 2001;12:779A.
43. Navar LG, Harrison-Bernard LM, Imig JD, et al. Intra-
renal angiotensin II generation and renal effects of AT1
receptor blockade. J Am Soc Nephrol 1999;10:S266 –S272.
44. Packer M, Lee WH, Medina N, et al. Functional renal
insufficiency during long-term therapy with captopril and
enalapril in severe congestive heart failure. Ann Intern Med
1987;106:346 –55.
360
45. Lalezari JP. Cidofovir: a new therapy for cytomegalovirus
retinitis. J Acquir Immune Defic Syndr Hum Retrovirol
1997;14:S22–S26.
46. Lalezari JP, Kuppermann BD. Clinical experience with
cidofovir in the treatment of cytomegalovirus retinitis. J
Acquir Immune Defic Syndr Hum Retrovirol 1997;14:S27–
S31.
47. Anonymous. Parenteral cidofovir for cytomegalovirus ret-
initis in patients with AIDS: the HPMPC peripheral cyto-
megalovirus retinitis trial. A randomized, controlled trial.
Studies of Ocular complications of AIDS Research Group in
Collaboration with the AIDS Clinical Trials Group. Ann
Intern Med 1997;126:264 –74.
48. Lalezari JP, Holland GN, Kramer F, et al. Randomized,
controlled study of the safety and efficacy of intravenous
cidofovir for the treatment of relapsing cytomegalovirus
retinitis in patients with AIDS. J Acquir Immune Defic
Syndr Hum Retrovirol 1998;17:339 – 44.
49. Meier P, Dautheville-Guibal S, Ronco PM, et al. Cido-
fovir-induced end-stage renal failure. Nephrol Dial Trans-
plant 2002;17:148 –9.
50. Cundy KC, Barditch-Crovo P, Walker RE, et al. Clinical
pharmacokinetics of adefovir in human immunodeficiency
virus type 1-infected patients. Antimicrob Agents Che-
mother 1995;39:2401–5.
51. Fisher E, Brosgart C, Cohn D, et al. Safety of adefovir
dipivoxil (ADV) and incidence of proximal tubular disorders
(PRTD) in a placebo-controlled trial in patients with ad-
vanced HIV disease. Proceedings of the 6th Conference on
Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb
4; Chicago, Illinois. Alexandria (VA): Foundation for Retro-
virology and Human Health; 1999. [Abstract 678]
52. Ho ES, Lin DC, Mendel DB, et al. Cytotoxicity of antiviral
nucleotides adefovir and cidofovir is induced by the expres-
sion of human renal organic anion transporter 1. J Am Soc
Nephrol 2000;11:383–93.
53. Cihlar T, Lin DC, Pritchard JB, et al. The antiviral
nucleotide analogs cidofovir and adefovir are novel sub-
strates for human and rat renal organic anion transporter 1.
Mol Pharmacol 1999;56:570 – 80.
54. Roch-Ramel F. Renal transport of organic anions. Curr
Opin Nephrol Hypertens 1998;7:517–24.
55. Sweet D, Wolff N, Pritchard J. Expression cloning and
characterization of ROAT1. J Biol Chem 1997;272:30088 –
30095.
56. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in
antiretroviral-experienced patients: results from a 48-week,
randomized, double-blind study. AIDS 2002;16:1257– 63.
57. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase I/II
trial of the pharmacokinetics, safety, and antiretroviral ac-
tivity of tenofovir disoproxil fumarate in human immunode-
ficiency virus-infected adults. Antimicrob Agents Che-
mother 2001;45:2733–9.
58. Coca S, Perazella MA. Acute Renal failure associated with
tenofovir: evidence of drug-induced nephrotoxicity Am J
Med Sci 2002;324:342– 4.
59. Verhelst D, Monge M, Meynard JL, et al. Fanconi syn-
drome and renal failure induced by tenofovir: a first case
report. Am J Kidney Dis 2002;40:1331–3.
60. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of
pamidronate in reducing skeletal events in patients with
advanced multiple myeloma. N Engl J Med 1996;334:488 –
93.
61. Hortbagyi GN, Theriault RL, Lipton A, et al. Long-term
prevention of skeletal complications of metastatic breast
cancer with pamidronate. J Clin Oncol 1998;16:2038 – 44.
June 2003 Volume 325 Number 6

62. Physician’s desk reference. 54th ed. Montvale (NJ): Medical
Economics Company; 2000. Pamidronate; p. 1998 –2002.
63. Green JR, Seltenmeyer Y, Jaeggi KA, et al. Renal tol-
erability profile of novel, potent bisphosphonates in two
short-term rat models. Pharmacol Toxicol 1997;80:225–30.
64. Markowitz GS, Appel GB, Fine PL, et al. Collapsing
focal segmental glomerulosclerosis following treatment with
high-dose pamidronate. J Am Soc Nephrol 2001;12:1164 –
72.
65. Lockridge L, Papac RJ, Perazella MA. Pamidronate-
associated nephrotoxicity in a patient with Langerhan’s
histiocytosis. Am J Kidney Dis 2002;40:E2.
66. Rey J, Daumen-Legre V, Pham T, et al. Uveitis, an
under-recognized adverse effect of pamidronate. Joint,
Bone, Spine 2000;67:337– 40.
67. Machado CE, Flombaum CD. Safety of pamidronate in
patients with renal failure and hypercalcemia. Clin Nephrol
1996;45:175–9.
68. Ali SM, Esteva FJ, Hortobagyi G, et al. Safety and
efficacy of bisphosphonates beyond 24 months in cancer
patients. J Clin Oncol 2001;19:3434 –7.
69. Shankland SJ, Eitner F, Hudkins KL, et al. Differential
expression of cyclin-dependent kinase inhibitors in human
glomerular disease. Role in podocyte proliferation and mat-
uration. Kidney Int 2000;58:674 – 83.
70. Berns JS, Cohen RM, Stumacher RJ, et al. Renal as-
pects of therapy for human immunodeficiency virus and
associated oppurtunistic infections. J Am Soc Nephrol 1991;
1:1061– 80.
71. Fogazzi GB. Crystalluria: a neglected aspect of urinary
sediment analysis. Nephrol Dial Transplant 1996;11:379 –
87.
72. Conger JD. Acute uric acid nephropathy. Med Clin North
Am 1990;74:384 –92.
73. Ogea Garcia JL, Villanueva Marcos JL, Jurado R.
Burkitt’s lymphoma and AIDS. Their presentation as tu-
moral hepatomegaly and acute kidney failure due to tubular
deposit of urates. Ann Intern Med 1993;118:37–39.
74. Perazella MA, Brown E. Electrolyte and acid-base disor-
ders associated with AIDS: An etiologic review. J Gen Intern
Med 1994;9:232– 6.
75. Simon DI, Brosius FC, Rothstein DM. Sulfadiazine-in-
duced crystalluria revisted. The treatment of Toxoplasma
encephalitis in patients with acquired immune defiency
syndrome Arch Intern Med 1990;150:2379 – 84.
76. Carbone LG, Bendixen B, Appel GB. Sulfadiazine-asso-
ciated obstructive nephropathy occurring in a patient with
acquired immune deficiency syndrome. Am J Kidney Dis
1988;12:72–75.
77. Hein R, Brunkhorst R, Thon WF. Symptomatic sulfadi-
azine crystalluria in AIDS patients: A report of two cases.
Clin Nephrol 1993;39:254 – 6.
78. Sasson JP, Dratch PL, Shortsleeve MJ. Renal ultra-
sound findings in sulfadiazine- induced crystalluria. Radiol-
ogy 1992;185:739 – 40.
79. Molina JM, Belenfant X, Doco-Lecompte T. Sulfadia-
zine-induced crystalluria in AIDS patients with toxoplasma
encephalitis. AIDS 1991;5:587–9.
80. de Sequera P, Albalate M, Hernandez J, et al. Acute
renal failure due to sulfadiazine crystalluria in AIDS pa-
tients. Postgrad Med J 1996;72:557– 8.
81. Diaz F, Collazos J, Mayo J, et al. Sulfadiazine-induced
multiple urolithiasis and acute renal failure in a patient
with AIDS and Toxoplasma encephalitis. Ann Pharmacol
1996;30:41– 42.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Perazella et al
82. Sawyer MH, Webb DE, Balow JE, et al. Acyclovir-in-
duced renal failure. Clinical course and histology. Am J Med
1988;84:1067–71.
83. Brigden D, Rosling AE, Woods NC. Renal function after
acyclovir intravenous injection. Am J Med 1982;73(Suppl
1A):182–5.
84. Keeney RF, Kirk LE, Brigden D. Acyclovir tolerance in
humans. Am J Med 1982;73(Suppl 1A):176 – 81.
85. Bean B, Aeppli D. Adverse effects of high-dose intravenous
acyclovir in ambulatory patients with acute herpes zoster.
J Infect Dis 1985;151:362–5.
86. Giustina A, Romanelli G, Cimino A, et al. Low dose
acyclovir and acute renal failure [letter]. Ann Intern Med
1988;108:312.
87. Eck P, Silver SM, Clark EC. Acute renal failure and coma
after a high dose of oral acyclovir [letter]. N Engl J Med
1991;325:1178.
88. Dos Santos M, Dos Santos OF, Boim MA, et al. Nephro-
toxicity of acyclovir and ganciclovir in rats: Evaluation of
glomerular hemodynamics. J Am Soc Nephrol 1997;8:361–7.
89. Krieble BF, Rudy DW, Glick MR, et al. Acyclovir neuro-
toxicity and nephrotoxicity-the role for hemodialysis. Am J
Med Sci 1993;305:36 –39.
90. Gulick R, Mellors J, Havlir D, et al. Treatment with
indinavir, zidovudine, and lamivudine in adults with Hu-
man Immunodeficiency Virus infection and prior antiretro-
viral therapy. N Engl J Med 1997;337:734 –9.
91. Tashima KT, Horowitz JD, Rosen S. Indinavir nephrop-
athy (letter). N Engl J 8 Med 1997;336:138 –9.
92. Perazella MA, Kashgarian M, Cooney E. Indinavir ne-
phropathy in an HIV-infected patient with renal insuffi-
ciency and pyuria. Clin Nephrol 1998;50:194 – 6.
93. Daudon M, Estepa L, Viard JP, et al. Urinary stones in
HIV-1 positive patients treated with indinavir. Lancet 1997;
349:1294 –305.
94. Kopp JB, Miller KD, Mican JA, et al. Crystalluria and
urinary tract abnormalities associated with indinavir. Ann
Intern Med 1997;127:119 –25.
95. Bach MC, Godofsky EW. Indinavir nephrolithiasis in
warm climates [letter]. J Acquir Immune Defic Syndr Hum
Retrovirol 1997;14:296 –7.
96. Berns JS, Cohen RM, Silverman M, et al. Acute renal
failure due to indinavir crystalluria and nephrolithiasis:
report of two cases. Am J Kidney Dis 1997;30:558 – 60.
97. Grunke M, Valerius T, Manger B, et al. Renal dysfunc-
tion in a Human Immunodeficiency Virus-infected patient
who was treated with indinavir. Clin Infect Dis 1997;25:
1270 –1.
98. Reilly RF, Tray K, Perazella MA. Indinavir nephropathy
revisited: pattern of insidious renal failure with identifiable
risk factors. Am J Kidney Dis 2001;38:E23–E28.
99. Anderson W, Bethea W. Renal lesions following adminis-
tration of hypertonic solutions of sucrose. JAMA 1940;114:
1983–7.
100. Lindberg H, Wald M. Renal changes following the admin-
istration of hypertonic solutions. Arch Int Med 1939;63:907–
18.
101. Rigdon RH, Cardwell ES. Renal lesions following the
intravenous injection of hypertonic solution of sucrose: a
clinical and experimental study. Arch Int Med 1942;69:670 –
90.
102. DiScala V, Mautner W, Cohen J, et al. Tubular alter-
ations produced by osmotic diuresis with mannitol. Ann Int
Med 1965;63:767–75.
103. Morgan T, Little J, Evans W. Acute renal failure associ-
ated with low-molecular weight dextran infusion. Brit Med
J 1966;2:737–9.
361
Drug-Induced Nephrotoxicity
104. Anonymous. ASHP therapeutic guidelines for intravenous
immune globulin. ASHP Commission on Therapeutics. Clin
Pharm 1992;11:117–36.
105. Barton J, Herrera G, Galla J, et al. Acute cryoglobuline-
mic renal failure after intravenous infusion of gamma glob-
ulin. Am J Med 1987;82:624 –9.
106. Schifferli J, Leske M, Favre H, et al. High dose intrave-
nous IgG treatment and renal function. Lancet 991;337:
457– 8.
107. Rault R, Piraino B, Johnston J, et al. Pulmonary and
renal toxicity of intravenous immunoglobulin. Clin Nephrol
1991;36:83– 86.
108. Ellie E, Combe C, Ferrer X. High-dose intravenous im-
mune globulin and acute renal failure. N Engl J Med 1992;
327:1032–3.
109. Stewart R, Winney R, Cash J. Renal toxicity of intrave-
nous immunoglobulin [letter]. Vox Sang 1993;65:244.
110. Ruggeri M, Castaman G, de Narde G, et al. Acute renal
failure after high-dose intravenous immune globulin in a
patient with Idiopathic Thrombocytopenic Purpura. Haema-
tologica 1993;78:338 –9.
111. Pasatiempo A, Kroser J, Ruducek M, et al. Acute renal
failure after intravenous immunoglobulin therapy. J Rheu-
matol 1994;21:347–9.
112. Ahsan N, Palmer B, Wheeler D, et al. Intravenous im-
munoglobulin-induced osmotic nephrosis. Arch Intern Med
1994;154:1985–7.
113. Cantu T, Hoehn-Saric E, Burgess K, et al. Acute renal
failure associated with immunoglobulin therapy. Am J Kid
Dis 1995;25:228 –34.
114. Poullin P, Moulen B, Ollier J, et al. Hyperoncotic renal
failure after intravenous immunoglobulin therapy. Presse
Med 1995;24:441– 4.
115. Arunabh S, Kuman G, Avila V. Acute renal failure in-
duced by intravenous immune globulin. Am Fam Physician
1996;53:862–3.
116. Corvetta A, Della Bitta R, Gabriella A, et al. Use of high
dose intravenous immunoglobulin in systemic lupus ery-
thematosus: report of three cases. Clin Exp Rheum 1989;7:
295–9.
117. Rostoker G, Philippon C, Belghitti D, et al. Intravenous
IgG for glomerulonephritis and renal function. Lancet 1991;
338:544 –55.
118. Kobosko J, Nicol P. Renal toxicity of intravenous immu-
noglobulin. Clin Nephrol 1992;37:216 –7.
119. Phillips AO. Renal failure and intravenous immunoglobu-
lin [letter]. Clin Nephrol 1992;37:217.
120. Donatini B. Transient renal dysfunction in diabetic pa-
tients after IVIG therapy [letter]. J Int Med 1992;232:376.
121. Tan E, Hajinazarian M, Bay W, et al. Acute renal failure
resulting from intravenous immmunoglobulin therapy. Arch
Neurol 1993;50:137–9.
362
122. Winward DB, Brophy MT. Acute renal failure after ad-
ministration of intravenous immunoglobulin: review of the
literature and case report. Pharmacotherapy 1995;15:765–
72.
123. Hansen-Schmidt S, Silomon J, Keller F. Osmotic ne-
phrosis due to high dose immunoglobulin therapy contain-
ing sucrose (but not with glycine) in a patient with immu-
noglobulin A nephritis. Am J Kidney Dis 1996;28:451–3.
124. Friedman KD, Saddler MC, Tarnover AC, et al. Tran-
sient renal failure in a patient with idiopathic thrombocy-
topenic purpura after treatment with concomitant protein-A
immunosorption and intravenous immune globulin. Blood
1992;80(Suppl 1):483a.
125. Tsinalis D, Dickenmann M, Brunner F, et al. Acute
renal failure in a renal allograft recipient treated with
intravenous immunoglobulin. Am J Kidney Dis 2002;40:
667–70.
126. Schwartz SL, Johnson CB. Pinocytosis as cause of su-
crose nephrosis. Nephron 1971;8:246 –54.
127. Cayco AV, Perazella MA, Hayslett JP. Renal insuffi-
ciency following intravenous immune globulin therapy: a
report of two cases and analysis of the literature. J Am Soc
Nephrol 1997;8:1788 –94.
128. Legendre C, Thervet E, Page B, et al. Hydroxyethyl-
starch and osmotic-nephrosis-like lesions in kidney trans-
plantation. Lancet 1993;342:248 –9.
129. Cittanova ML, Lebanc I, Legendre C, et al. Effect of
hydroxyethylstarch in brain-dead kidney donors on renal
function in kidney-transplant recipients. Lancet 1996;348:
1620 –2.
130. Deman A, Peeters P, Sennesael J. Hydroxyethyl starch
does not impair immediate renal function in kidney trans-
plant recipients: a retrospective, multicentre analysis.
Nephrol Dial Transplant 1999;14:1517–20.
131. Bernard C, Alain M, Simone C, et al. Hydroxyethyl-
starch and osmotic nephrosis-like lesions in kidney trans-
plants. Lancet 1996;348:1595.
132. LaBarthe AD, Jacobs F, Blot F. Acute renal failure sec-
ondary to hydroxyethylstarch administration in a surgical
patient. Am J Med 2001;111:417– 8.
133. Dickenmann MJ, Filipovic M, Schneider MC, et al.
Hydroxyethylstarch-associated transient acute renal failure
after epidural anaesthesia for labour analgesia and caesar-
ean section. Nephrol Dial Transplant 1998;13:2706.
134. Schortgen F, Lacherade JC, Brunner F, et al. Effects of
hydroxyethylstarch and gelatin on renal function in severe
sepsis: a multicentre randomised study. Lancet 2001;357:
911– 6.
135. Edwards CA, Knoll GA. Hydroxyethylstarch (HES) and
the risk of delayed graft function (DGF) following renal
transplantation. J Am Soc Nephrol 2002;13:375–376A.
June 2003 Volume 325 Number 6