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DISEASE OF THE MONTH
Acute
Interstitial
DONNA
M. MICHEL
Department
Acute
renal
associated
exhibit
this
with
article,
we
presentation,
(AIM)
most
within
In the final
summarize
portion
decrements
the
the
and approach
pertinent
in renal
San
Diego,
and
etiology,
and
for AIN.
experimental
treatment
of
Ricketisia.
tious
agents
AIM
In
clinical
treatment
we discuss
and
and
function
as well.
epidemiology,
to diagnosis
pathogenesis
cause of acute
glomenubonc-
tububointerstitium
of the article,
to the
J. KELLY
of California,
is an important
forms
of acute
significant
inflammation
CAROLYN
University
ne-
occur
Epidemiology
and/or
renal
proteinunia,
interstitial
evaluation
(2).
of acute
accounted
for
biopsy
for
approximately
ncphnitis
evaluation
1%
were
In examining
renal
15%
failure,
of lesions
however,
The
diated
of AIN
drug
hypersensitivity
diseases,
Drug
of AIM
can
to
have
biopsicd
interstitial
for
gboruerular
reactions
in the antibiotic
era.
in clinical
cases
drugs
implicated
its
for drug-induced
propensity
clinical
to
cause
practice.
These
cases
ncphnitis
from
in drug-induced
sulfonamides,
and
(NSAIDs).
that
have
Table
been
it
is
groups
AIM include
nonstenoidal
1 provides
associated
common
drugs
in
areas
miscellaneous
of
the
causative
this
with
widely.
The
(4-6).
rarely
used
most
been
As a result
of
anymore
in
impli-
listing
world
agents
organisms
with
of drugs
ready
such
access
to
bacteria,
as
antibiotics
viruses,
Toxoplasma,
it is important
of interstitial
Clinical
Presentation
(7).
and
other
Leishmania,
The
unifying
of renal
seen
of
on
renal
described
typically
lesion.
in the
contribute
Because
more
closely
of glomerular
include
biop-
gboruenubonephnitis
renal
to
func-
with
interstitial
pathology,
we
“gbomerulonephnitis”
San Diego
Drive. San
and
dysfunction.
Many
Diagnosis
of AIN
in AIM
is that
of an abrupt
physicians
who
have
training
in ncphrobogy
believe
that AIN only
after initiation
of therapy
with an offending
invariably
associated
nophilunia,
and
drug
with
that
fever,
prior
as a potential
rash,
tolerance
cause
and
occurs
drug,
2 to 3 wk
that it is
cosinophilia/cosi-
of a medication
of AIN.
onset
not received
eliminates
All of these
assumptions
arc false. AIM is a heterogeneous
disorder
not only in etiology,
but also in presentation,
laboratory
findings,
and outcomes.
The diagnosis
is most commonly
considered
in hospitalized
patients
who
experience
a progressive
The etiology
of acute renal failure
unclear,
especially
if they
arc
naruic
1046-6673/0903-0506$03.00/0
Journal of the American
Society of Nephrology
Copyright
© 1998 by the American
Society of Nephrology
in conjuncinterstitium.
ncphnitis.
presentation
medications,
Correspondence
to Dr. Carolyn I. Kelly. University
of California,
and Veterans Affairs Medical Center I I 1-H. 3350 La Jolla Village
Diego. CA 92161.
biopsies
in etiology.
not
gboruenular
to formally
as a cause
that
AIN.
include
of the
inter-
renal
is usually
it does
synfinding
idiopathic
cases,
antibodies
of the
forms
finding
report,
essen-
which
prototype
commonly
detailed
various
be found
or as a defin-
so-called
of such
is frequently
pathologic
biopsy
classification
believe
cause
have
with
may
as an isolated
autoirumune
tionab
deterioration
correlates
pathology
than with the extent
penicillins,
cephabosponins,
anti-inflammatory
agents
a more
with
cate-
immune-rue-
the frequency
is methicillin
AIN,
general
Numerous
infections
have been reported
to cause AIN, but
infection-associated
AIM has become
increasingly
uncommon
Reported
Although
the
illness,
ncphnitis
patients
isolated
ncphnitis-uvcitis”
presents
number
are presumably
Tububointerstitiab
idiopathic.
many
varies
Medication
cated
and
of AIM,
AIM
five
arc the most
Although
implicated
arc
into
infection,
disease,
hypersensitivity
individual
agent
In a small
or
an
syndrome,
cirrhosis,
exhibit
anti-tubular
basement
membrane
tion with
mononuclear
cell infiltration
(3).
reactions,
biliary
AIM
of a defined
as
AIM
Sjogren’s
of heruatunia
sies
be classified
cases,
absence
of infec-
kidney-limited
occur
lesions.
primary
nephnitis.
list
crythematosus,
although
most
in systemic
lupus crytheruatosis
gbomerular
In some
pathologist’s
causes
either
of the “tububointerstitial
(7).
stitial
detailed
It can
in the
of AIN
gonies:
with
1 % of total
personnel
in
found
patients
a more
of sarcoidosis,
cryogbobulinemia,
(8).
Etiology
Center,
AIN.
processes.
accompanying
ing component
reported
to occur in approximately
( 1 ). In a series of male military
with
in association
as a manifestation
drorue
undergoing
Medical
2 provides
autoimmunc
occurs
work
interstitial
Table
renal
lesion
in systemic
lupus
commonly
interstitial
nephritis
tial
Finland
Affairs
associated
can
systemic
phritis.
AIM has been
biopsy
material
Veterans
California.
interstitial
nephritis
failure.
In addition,
phritis
and
of Medicine,
Diego.
San
Nephritis
undergoing
instability.
In such
diuresis,
and/or
settings,
placed
low
renal
if there
is no concomitant
ophilia,
suggest
excluding
on
or cosinophiluria.
AIM
when
the diagnosis.
the
their
In some
hemody-
interstitial
nephnitis
diagnosis
fever,
these
skin
of acute
rash,
accompanying
absence
series,
creatininc.
exhibiting
differential
Although
present,
in serum
patients
is frequently
receiving
multiple
complex
is frequently
failure
rise
in such
infected,
is
the triad
not
cosinsigns
helpful
of rash,
in
fever,
Acute
Table
I.
Drugs
Beta-bactaru
associated
with
Table
AIN
antibiotics
2.
Infections
with
Nephritis
507
lactam-associated
AIM
AIN
Bacteria
ructhiciblin
Streptococci
ampicillin
Staphylococci
penicillin
dipthcnia
oxacillin
Brucella
nafcillin
ccphabosponins
begionella
Other
associated
Interstitial
Campvlobacter
antibiotics/anti-infectives
Viruses
sulfonamides
cytoruegalovirus
rifampin
polymyxin
Epstein-Barr
virus
Hantaan virus
cthambutol
HIV
tetracycline
rubeola
vancomycin
Other
erythromycin
Toxoplasma
ciprofloxacin
Mvcoplasma
acycbovir
Rickettsia
indinavir
Leishmania
alpha-interferon
syphilis
NSAIDs
leptospirosis
fenoprofen
indomethacin
naproxen
ibuprofen
tial nephnitis
(10,1 1).
tolmetin
and,
In the original
diflunisal
of renal
piroxicam
therapy.
ketoprofen
time course,
dicbofenac
kinetics.
Diuretics
after
onset
a medication
chborthalidone
plc,
many
tniamtcrene
use
have
has
been
with
a drug
previously
people
also
who
develop
the
described
AIM
has
with
months
NSAID
to years.
AIM
frequently
in response
discontinuously
(e.g.
to
rupted
therapy
In addition
albopuninob
ciated
AIM
aspirin
tions.
For
carbaruazepine
80%
phenindione
association
cbofibrate
rash,
phenylpropanolamine
aldomet
AIM ( I 2). In addition
to the atypical
time course
noted above,
patients
with MSAID-induccd
AIM arc usually
older, although
phenobarbitab
this
azathiopnine
ation
diazeparn
NSAID-induccd
captopril
cian
to take
tients
with
inflammatory
interstitial
nephritis;
NSAIDs.
nonsteroidal
anti-
agents.
and
These
eosinophilia
symptoms
can
was
seen
in
less
common
than
30%
of
in drug-associated
patients
(9).
intersti-
scnibed
also
example,
with
display
varied
presents
renal
with
are
reflect
the
of
acute
renal
failure
AIM
is strong
a careful
a variety
not
medication
medications.
report
of
but
Although
of NSAIDs,
and
MSAIDs
usage
should
The
prompt
over
when
limit
most
patients
relapses
have
associwith
the
NSAID
rather
in
(fever,
syndrome
presentations.
NSAID
history,
usage.
ncphrotic
regarding
clinical
signs
to
MSAID-associated
of NSAID
and
history
consistent
of
discontinuation
prevalence
with
(up
proteinunia
Extrarenal
uncommon
inter-
presenta-
frequently
ncphrotic-range
insufficiency.
may
will
AIM
.
drug-asso-
clinicopathobogic
MSAID-associated
cosinophilia)
availability
arc most
with rifampin
for tuberculosis).
to exhibiting
heterogeneous
kinetics,
of the time)
patients
their
taken
to
For exam-
in association
more
been
in response
cimetidinc
sulfinpyrazone
acute
arc
individual
de novo
for
of
some
AIN,
they
types
2 to 3 days)
diphenylhydantoin
a
when
“classic”
other
by the individual.
medications
to occur
to this
(within
an
occur
onset
1 0 to 20 d of drug
exhibit
rapidly
tolerated
taking
drugs
can
to which
It can
AIM,
after
in addition
AIM
it can occur
sensitized.
been
that
of
For example,
furoscmidc
occurred
recognized
the
rechallenge
beta
on methicillin-associated
typically
It is now
previously
drugs
reports
dysfunction
thiazides
Other
in particular,
usage
Given
the
physiin pa-
the
wide
counter,
many
questioned
about
their
will
been
report
to pre-
recover
after
reported
after
508
Journal
reinitiation
the American
of
of therapy
or different
class
AIM can
with
Society
different
MSAIDs
of compounds
also
occur
one
of Nephrology
in patients
with
patients,
rapid than expected
decline
in renal function.
patients
are on many
medications,
they may
for this
chronic
renal
lated
to drug
renal
dysfunction
suggestive
cytcs.
and
and
of AIM.
Many
that
decade
this
their
have
gressed,
in one
Neither
case,
was
has
Another
over
(13),
caused
country,
6 wk
(and
itantly,
It
rare)
have
The
syndrome.
renal
from
forms
appeared
uveitis
insufficiency.
to drug
disease,
Current
Diagnosis
ncphritis,
by
culture
the
stain,
the
diagnosis
found
positive
predictive
in which
urine
conditions
eluded
prostatitis,
in
bladder
carcinoma,
gran-
is typically
and modwell
but most
in
tent with AIN,
there
arc
no single
laboratory
commonly
which
interstitial
nunia
FcNa
associated
our
AIN,
temporary
practice
to
patients
the
sponses.
pathology
utility
Patients
creased
test can diagnose
consisAIM,
and
one
AIM
gbomerular
of
display
of
with
of patients
patients
useful
positive
skin
prohibit
ultrasonic
with
Some
have
in the
AIM
of six patients
comparable
distinguish
diagnosis
acute
tubular
had
with
intensely
acute
wide-
imaging
of
failure.
with
In
in-
to or higher
AIM
proposed
positive
from
that
of AIM,
necrosis
tubular
limited
(10).
are no distinguishing
that
tests
re-
and
currently
undergo
it from
(6),
in con-
hypersensitivity
standardization
frequently
failure.
a
methiciblin-
on presentation.
demonstrate
AIM
There
Isosthe-
rarely
of AIN
for testing
echogenicity
in cases
(12).
as part of an evaluation
of acute renal
size is typically
normal-to-enlarged
renal
patients
in AIM,
with
in up to 50%
test
(15).
Some
except
reports
consistent
available
imaging
be
with
diagnostic
cortical
ultrasonic
h (15),
AIM
20%
will
lack
in-
as a diagnostic
test characteristics.
vary considerably
of this
with
of the liver
guishing
findings
agent,
of drugs
their kidneys
AIM,
kidney
cases
AIN
Unfortunately,
numbers
seen
(17).
found
disease.
eosinophibs
associated
than
speci-
30%
gloruerubonephritis,
1 g/24
are obigunic
with
offending
were
in early
less
a condiseases,
of 40%,
cosinophils
Patients
was
is that
with
renal
of only
may
arc
sensitive
finding
of cosidiagnostic
for
atheroembolic
Although
oliguria
impression
mononuclear
gborucrular
laboratory
(15).
or Hansel’s
more
other
of NSAID-induced
in AIM.
Eosinophils
value
urine
lesions
setting
is common
spread
correlates
by many
renal
it is less than
as in the
(see below).
In
focal
glomerulan
cell
and
be
I 5).
in patients
progressive
abandoned
can
stain
a sensitivity
because
of the aforementioned
The magnitude
of protcinuria
low
Steroids
are effective
and ocular
disease,
to have
rapidly
have
(
times
with
was
of the
concom-
its presence
and
in AIM,
by bacterial
in an interstitial
been proposed
that the
specific
and possibly
ficity
cells
cosinophibunia
five
to those
beu-
blood
reported
Wright’s
approximately
are not as
ncphritis.
be sterile
of AIN
by either
of AIM
of 72%,
been
and
cosinophilunia
test
in such
being
renal
of dis-
red
leukocytes
diagnosis
in comparing
(16),
acute
of A/N
clinical
and
latter
acute
displays
free
have
urinary
be detected
(16). Although
it has
nophilunia
is relatively
firmed
Pubertal
be massive.
This
function
exhibited
of
can
to
typically
should
Eosinophilia
in the presumptive
urine
precede,
to treatment
type
process.
AIM
syndrome)
interstitial
AIM
urine
the
with
Patients
occasionally
The
sepsis.
at which
of dysfunction
cell casts
rare.
or
rate
related
with
if one is to implicate
in the
injury,
the
red blood
inflammatory
associ-
may
contrast),
categories.)
and
less
to ncphrotoxins
in the
characteristic
casts,
extremely
Some
patients,
approaches
arc
nephrobogists
marrow
intravenous
in patients
display
creatininc.
is, in our experience,
abnormalities
bcukocyte
may
Although
urinalysis
AIM
and
secondary
variation
abnormalities
unequivocally
with
nitrogen
failure
in all of these
Although
they
The diagnosis
is often
as malaise,
weight
boss,
Bone
urea
or
for
patients
rises
renal
electrolyte
but
standard”
blood
is a wide
rises
display
AIN
of unother
ne-
occur
acute
there
failure
renal
in
aminoglycosides
creatininc
Other
described
Its pathogenesis
of the interstitium
can
the rapid decline
in renal
Laboratory
First
hypersensitivity
such as the
infiltration
well with
dictated
as
“gold
Typically,
the creatinine
with
(Obviously,
(14).
in HIV-infected
arc usually
present.
is that
in the literature.
may
seen
patients.
iru-
as well.)
by acute
interstitial
sclerosis
such
with
“immunoin the HIV-
acute
gbomenubonephnitis
with acute gbomenubonephnitis
AIM due
of renal
disease.
that
lymph
node granulomas
to the initial
report,
occur
accompanying
in any patient
crate-to-severe
(such
helpful
“pro-
two HIVthat pro-
of AIM
nephnitis.
AIN
present
differ
some
subgroup
criterion.
nephnitis
can
of
for
was
nephnitis
the interstitial
relapses
first
rate
renal
is possible
is not a major diagnostic
for both the interstitial
although
at which
than
(15).
the
the high
and better-maintained
of renal disease
seen
cosinophilic
fever.
or follow
rate
rapid
The
infrequently
explanation
to end-stage
is characterized
cases
and
The
beukocy-
immunity
are most commonly
affected.
by systemic
symptoms
such
myalgias,
uloma
therapy
despite
to interstitial
syndrome
of similar
increases
the
diagnosis.
crete tubular
segments
(such as Fanconi’s
prominent
in AIM as they are in chronic
leuko-
change,
and interstitial
nephnitis
may
(It is important
to point
out that
linked
by a diffuse
females
preceded
progressive
failure,
interstitial
within
remains
the
can
findings
have
recently
seen
interstitial
nephnitis
ated with bone marrow
and
known
cause
(14). Subsequent
ports
ne-
accelerated
how
A possible
nephnitis-uveitis
this
on
patients
proteinunic.
interesting
tububointerstitial
1975
membranes,
cell-mediated
therapy
the types
been
with
urinary
basement
exposure.
population
will
more
prominent.
Indinavir
no
of chronic
context,
we
with marked
patient
infected
become
in this
drug
proved
antiretrovirab
competence”
that
with
were
commented
depressed
In this
patients
a
Because
be at in-
patients
setting
in HIV-infected
and
is that
exhibits
biopsy
establishing
kocytcs,
of the epidemic
tective.”
infected
In
or laboratory
there
tubular
diagnosed
hospitalization
renal
failure.
(presumably
presented
physical
in the
seen
AIM
who
In particular,
nephrologists
was
have
superimposed
no other
fibrosis
and thickened
tuna is less likely.
if a patient
We
hypersensitivity)
It is possible
AIM
AIM
complication.
failure
the same
renal
more
these
risk
suspect
chronic
such
creased
should
in either
(12).
than
on
other
of
forms
gallium
scanning
particularly
(
in distin-
1 5). In one
gallium
necrosis
that
characteristics
series,
scans,
had
nine
but
not
a positive
Acute
scan
I 1 ). The
(
by
its
tial nephritis,
scans
its lack
were
minimal
ity
utility
of gallium
scanning
in cases
of subacute
unpredictability
also
change
of
false
severe
in
disease,
results
disease
(since
to transferrmn
and
with
patients
series,
with
gallium
(15).
Renal
Biopsy
The
dominated
by interstitial
positive
foci
and
the possibil-
iron
overload
resembles
fernitin)
croscopy.
intersti-
In current
ferric
or
iron
and
Treatment
undergo
a percutaneous
biopsy
in patients
whom
probable
eliminated.
tion,
and
how
in whom
for therapy.
are
either
instability,
must
ogy
renal
with
is the
infiltrate
infection,
can
is a mixed
and,
cell
one,
comprised
occasionally,
cells
and ruonocyte/macrophages.
predominate
in the infiltrate
blood.
In
some
mononuclear
can
need
ology.
AIM
cases
cell
Granubomas
not
Most of the
in a CD4/CD8
of
infiltrate
implicate
with
is typically
exhibit
assume
an
positive
II major
histocompatibility
teins,
intercellular
adhesion
cular
cell
kines
adhesion
released
heightened
cells.
By electron
of the
tubular
thickened
In
from
infiltrating
microscopy,
basement
and
microscopy
is
that
and
of
there
fusion
lesion,
of
the
efficacious
it seems
in renal
variations
and
suspected
drug
function.
It
is
not
test,
and
case
of drug-induced
if one
of
dialytic
therapy
with
an
would
with
could
be much
reliably
AIM,
renal
determine
insufficiency
may
may
be required
result
areas
logic
therapy
in
T
therapy
of continuity
as other
autoirumunc
biopsy
of
,
electron
palight
mi-
be
drugs.
of AIM
present.
In
delayed,
there
Such
disease
many
nephnobogists
patients
patients
may
The
and
have
by
First,
before
purpose
a rapidly
associated
the
below).
the
diagnosis
degree
from
sys-
It is rarely
AIN.
pharmacologic
for
biopsy
degree
biopsy,
with
phanmaco-
that
initiation
the
be a substantial
benefit
either
we believe
of the
to assess
rarely
favor
particularly
on renal
(see
AIM.
in whom
pharruaco-
gbomerubonephritis,
appropriate
performed
not produce
consider
who
and
measure.
involvement
and
the
significant,
must
nephnitis
in the
patients,
does
manifested
of interstitial
in drug-associated
suppressive
sis.
as
or diffuse
if it
agent,
as a supportive
in patients
nephritis,
is usually
quite
in the setting
of infection-associated
are several
important
guidelines
should
diagnosis
exhibsimple
noninvasive
which
be
In addition,
creatinine
In forms
appropriate
There
to cyto-
AIM.
therapy
interstitial
teruic
docu-
and
In some
pharmacologic
or both.
be
these
specific
is responsible.
early
serum
to
a
and explained
to
cases in which
straightforward
and
basement
rising
to the
that
drug
more
a sensitive
for
by activated
familiar
because
therapy
severe
scenarios
emphasize
offending
logic
fre-
or
withdraw
two
needs
function
in primary
or 1gM
less
toxic,
taken.
diagnosed
degree
arc
of the
more
these
to
in renal
of AIM
be
drugs
to first
making
one
may
several)
with
decision
function,
expressing
(or
reaction
rechablenged
deterioration
were
the
substi-
If multiple
for
important
in renal
in AIM,
suspect
Between
hypersensitivity
were
a rapid
easily
associated
with AIM and determine,
there is evidence
of stabilization
or
improvement
IgG
be
reasonable
in clinical
nephrobogist.
one
be substituted
agents,
In patients
cli-
cells
by
only
practicing
could
membrane.
processes
suspect,
can
in
being
approach.
discontinuation
the gbomerular-associated
i.e.
normal
gloruerubar
foot
potentially
If all
drug
epithebial
be a loss
as well
basement
AIM,
nil
can
are
suspects
can
is a reasonable
those
should
agent
drug
medication.
that
it
offending
approach
individual
suspected
another
for,
Treatment
the
as the
cells
with
clinical
each
is
value
are
potentially
in whom
tubular
and
substituted
steps
T cells
to that
secondary
epithelial
membrane
multilayered
NSAID-associated
thobogy
cells
of tubular
for
ited
,
is likely
of
any
situations
multiple
a reasonable
whether
tuted
patients
complex
(MHC)
glycopromolecule1 and, occasionally,
vasThis
and
easily
reactions
for either
Tubular
phenotype
molecule.
recognition
inter-
granulomas.
kidney
the
staining
pattern.
“activated”
CD4
similar
by
Occasionally,
on granular
the
inflamma-
nephritis,
of the
cases,
AIM
although
to its baseline
clinical
taking
likelihood
followed,
to return
difficult
is
be discontinued,
promptly,
ruented
well in the patient’s
medical
record
the patient.
We have seen several
unfortunate
pathol-
or tuberculosis
staining
culprit,
are
function
more
such
the
are many
hypersensitivity
sarcoidosis
negative.
may
in a linear
quently
circum-
cosinophibs
interstitial
drug
In
The
patient
should
If diagnosed
guidelines
renal
improvement
renal
associated
with
T lymphocytes
is accompanied
be seen
Immunofluorescence
membrane
class
primary
drugs.
for
Such
and
time,
ratio
the
less
of T lymphocytes,
plasma
if these
the agent most commonly
after several
days, whether
The
B). In the interstitial
nephnitis
disease,
the infiltrate
is typically
gbomerular
is
although
is supportive
therapy.
diagnosis
of AIM has
drugs
treated.
hemodynaruic
within
or patchy.
below).
offending
infections
weeks
which
is critical
microscopic
infiltrate
be diffuse
(see
likely
basis.
of the bight
take
agents
is contemplated
1 , A and
(Figure
and
biopsy
percutaneous
on an individual
inflammatory
nephnitis
atrophy,
remain.
treatment
in AIM
(or biopsy-proven)
potentially
reversible
may
is unclear
drug
AIM
for
we
diagnosis
Renal
insufficiency.
aspect
lesions
monocytes,
in
the
diagnosis
in whom
ongoing
advanced
These
made,
consider
contemplated,
offending
candidates
of
prominent
in AIM
tory
good
be easily
of AIN
most
stitium.
the
in
discontinua-
persists.
in whom
patients
not
be dealt
Pathology
The
inflammation
because
or
is
renal
and
can
drug
to establish
the potentially
Frequently,
as a diagnosis
stances
much
AIM do not
likely,
use,
after
biopsy
in patients
in those
as drug
therapy
a renal
with
seems
to improve
interstitial
and tubular
can
509
of AIN
or underlying
Diagnosis
We do not advocate
diagnosis
immunosuppressive
indicated
biopsy,
biopsy.
such
fail
recommend
is also
in the
of patients
the
precipitants,
determine
and
renal
in whom
If patients
strongly
and
the majority
cells
The mainstay
of
After a presumptive
usually
practice,
in “chronic”
fibrosis
of inflammatory
been
Role
of Percutaneous
of A/N
pathology
Nephritis
gboruenulonephritis,
pycboncphnitis),
in
however,
or chronic
(in Linton’s
patients
and
positive
liver
binds
of specificity
noted
is limited,
Interstitial
of
a renal
irumuno-
is to confirm
of interstitial
of
AIM
of interstitial
treatment
with
the
fibrosis
has
been
fibro-
irumuno-
5 10
Journal
of the American
Society
of Nephrology
1. Fatal
Figure
acute interstitial
nephritis
in a patient with scarlet fever.
Glomeruli
are normal.
Magnification.
X246.
(B) The cells
infiltrate.
eosinophils.
are rare.
in Cabot RC, Halbory
Focal tubular
invasion
by mononuclear
TB: Case records
of the Massachusetts
cells is present
(arrows).
Magnification,
General
Hospital.
N Engl J Med 200:
from Colvin RB, Fang LST: Interstitial
nephnitis.
In: Renal Pathology
BM. 1st Ed., Vol. I, Philadelphia.
Lippincott.
1989, pp 728-776).
suppressive
drugs
and
are
potentially
at more
risk
for
wit/i
side
effects.
Second,
although
used
immunosuppressive
remember
trials
dcncc
small,
that
there
corticosteroids
drugs
have
been
for
are the most commonly
AIM,
it is important
no
prospective,
uncontrolled,
nonrandomized
of 14 patients
with
studies
(3).
methicillin-induced
to
randomized
performed
to assess
the efficacy
of this treatment.
for efficacy
has come from anecdotal
case reports
tive analysis
Eviand
In a retrospecAIM,
average
serum creatininc
at follow-up.
peak serum crcatininc
to new baseline
and a shorter
(9.3 versus
Clinical
eight
time
54
d)
and
X615.
142-145.
Functional
fall in serum
creatininc
returned
Of the
slowly,
insufficiency.
There
edited
by Tisher
examined
with
onset
within
to near
to 90 mI/mm.
renal
function
(Original
slides from case reported
1929) (Reprinted
with permission
Correlations,
(6). Pusey
et al. retrospectively
biopsy-proven
AIN treated
nisolonc.
All responded
with
function
of 14 patients
received
prednisonc
therapy,
with an average
daily
dose
of 60 rug for a total
mean
duration
of 9.6 d.
Prcdnisonc
therapy
was associated
with a higher
percentage
of
patients
returning
to their previous
serum
creatinine
level,
a
lower
from
(A) The interstitium
is edematous
and contains a dense mononuclear
are chiefly
lymphocytes
and plasma cells. Granulocytes.
including
seven
high-dose
of diuresis
with
Brenner
patients
with
IV mcthylprcdor a spontaneous
72 h. In all treated
normal,
CC.
patients,
creatinine
clearances
renal
60
two patients
not treated,
one recovered
and one progressed
to chronic
renal
were
no
detectable
adverse
effects
from
the short courses
of steroids
used in either
study ( 18). There
have been no trials that establish
the optimum
dosing
or duration
of corticosteroid
therapy.
Because
detected
10 to 14 d after onset
and a duration
of azotemia
greater
be
likelihood
dow
of recovery
of opportunity,
of renal
if one
interstitial
fibrosis
can
of interstitial
inflammation
than 1 to 2 wk decreases
the
function,
is going
the appropriate
to treat
with
steroids,
winis
Acute
probably
narrow,
(19). Prednisone
daily
has
tamed
been
by that
should
have
and
treatment
of approximately
response
the drugs
Some
7 to 14 d after onset
dose of approximately
recommended,
for a period
significant
and
i.e., within
in an oral
time,
recommended
is based
nience,
are
many
failure
of
nisone
as first-line
Usage
of both
AIN
on
but
efficacy
with
time.
this
has
cyclophosphamide
is supported
by investigations
basement
renal biopsy.
membrane
plasmaphcrcsis
anti-glomerubar
basement
using
exchanges
day
3- to 4-L
for another
reports
We
tion
atcd
week
are not aware
regimens
interstitial
continued
adjunct
in those
daily
of reports
in patients
ncphritis
therapy
reported
disease.
of drug
that
drug.
It may
well
come
The
(22).
Kida
along
antiin the
biopsy-proven
logic
changes,
Most
AIM
of the available
patients
with
drug-associated
in serum
long-term
information
missed
several
end
weeks,
is derived
come
a lesion
hallmarks
characterized
of chronic
or even
lesion
by fibrosis
interstitial
from
ncphnitis,
the
serum
if the diagnosis
is mistakenly
lenged
with a drug and develops
a hypersensitivity
rapid in onset and severe
in intensity,
the patient
with significant
renal
dysfunction
placement
therapy.
The inflammatory
it is
of AIM.
discontinued,
to baseline
of the spectrum,
on if a patient
and
is
rechal-
may
response
be left
require
renal
of AIM can
tubular
rebe-
atrophy,
if the inciting
factors
persist.
Arc
there
clinician
and
Bohle
cases
specimens,
or
all
to
morphologic
prognosis
compared
of AIM,
provide
nosis
clinical
to predict
clinical
of which
determine
factors
for
patients
and
morphologic
had
whether
been
with
confirmed
histologic
conclusive
information
regarding
of AIM ( 1 ). Serum
creatinine
values
by
expression
were
I to 6%
an
adverse
acute
renal
of vimentin
not
found
prognostic
(as an
to predict
factor
out-
is the severity
and
prognosis
by analyzing
clinical
of 14 patients
laboratory
features
course
(23).
They
both
noted
data,
early
and
histo-
bate
in the
two
phases
to
the
recovery
following
year.
In their
series,
half of the patients
ultimately
displayed
a higher
baseline
serum
creatininc.
GFR correlated
with the degree
of early improvement,
gesting
that
prognosis.
the
latter
Age
GFR,
whereas
initial
renal
may
at onset
be a reliable
of AIM
other
indices
such
and
gender
to outcome.
Severity
closely
with
predictor
correlated
symptoms,
as extrarenab
had
no
studied
Final
sug-
of long-term
inversely
with
final
manifestations,
significant
of the interstitial
final
relation-
lesion
was
noted
to
GFR.
Pathogenesis
of AIN
Insights
from Animal
AIM.
In general,
if
(within
1 wk of the rise
and the drug is promptly
is favorable
for a return
At the other
for
etiologies,
for all causes
on outcomes
accompanied
of
dcsensitizadrug-associbenefit
from
be feasible.
diverse
prognosis
probable
drug-associated
AIM is detected
early
creatinine),
outcome
creatinine.
with
a general
presence
with
the long-term
AIM
of what
that
enable
AIM?
findings
by
in 30
pathologic
findings
the course
were used
the
Laberkc
could
and progas clinical
and Prospects
Models
we know
been
is associated
to establish
The
correlated
those
(22).
examined
with
ship
of AIN
Because
difficult
tubular
important
fibrosis
et al.
Prognosis
had a poorer
prognosis
for complete
The phenotype
of infiltrating
cells,
damage)
most
and
infiltration.
latter.
AIM
and
of tubular
Most
Prognosis
with
of tubulitis,
infiltration
diffuse
also
failure
of >3 wk duration
recovery
of renal function.
correlate
who have experienced
and who could otherwise
with
Patients
diffuse
from AIM: an initial phase of rapid improvement
in GFR (the
first 6 to 8 wk) followed
by slow improvement
in GFR over the
of
(3).
of the use
the
Their
histobogi-
models
Anecdotal
1 9).
for
of disease.
disease
The use of
to its use in
(
with
infiltrate
assessment
prognosis
5 11
A to treat
Plasruapheresis
then every other
5 d and
mixed
better
Nephritis
to differentiate
incompletely
in the
of interstitial
on.
therapy
in whom
recommended
been
irumu-
arc demonstrable
for
been
the
the potent
occurrence.
be analogous
membrane
have
Given
cycbosporin
antibodies
has
on its success
any
in experimental
This is an uncommon
in this setting
would
is significantly
degree
expe-
after
of
not been
and
interstitial
nephritis
(20,21).
Plasruaphcrcsis
may be considered
with prednisonc
or cycbophosphamide
tubular
In our
agents
the
in
nec-
cases
and/or
and
it is important
AIN
patchy
prognosis.
cycbophos-
cell-mediated
immune
reefficacious
agent
than pred-
a more
therapy,
not
is no improvement
therapy
(3). This
cytotoxic
diminishes
cycbophospharuide
it may well be
be
with
experience.
to use
because
therapy
of
will
course
that
between
with
neutrophils
therapy
anecdotal
corticosteroids,
nosuppressive
effects
sponses,
on
no
evaluating
indicate
cally
has been
probably
for
findings
(3).
adjunct
hesitant
criteria
be main-
If there
there
phamide
at 1 to 2 mg/kg
per d if there
serum
creatininc
after a trial of steroid
ommendation
should
4 wk.
be discontinued
of azotcruia
1 mg/kg
Interstitial
culled
from
(24,25).
Although
induced
interstitial
about
the
T cell-mediated
nephritis
membrane
with antibody
deposition
and mononuclear
cell
with
tial
basement
immunization)
systemic
[29],
purpose
disease
interstitial
new
classify
ferent
of
the
different
models
antigen-nonspecific.
Antigen-driven
interstitial
mice);
and
intersti-
discase/protcinuria
with
amino[30]).
The
of distinct
model
systems
is useful
for
disease
that is diverse
in both etiology
phenotype.
and
interstitial
of therapy
(26);
[28],
treatment
gbomenuloncphnitis
of developing
systems
types
has
induced
with antigen
ncphnitis
associated
gbomcrular
tems
is to discover
better
ways
Identifying
the relevant
mediators
model
nephritis
(MRL-fas’’
with
protcinunia
crcsccntic
availability
of a variety
the study of a human
and in irumunopathologic
The
of AIM
along the tubular
basement
infiltration
of the interstitium
membrane
(27);
associated
(protein-overload
nuclcosides
pathogcncsis
interstitial
autoirumunity
ncphnitis
Therapy
experimental
work in animal
model
systems
there
is no good
model
system
for drugncphnitis,
there arc model systems
of spon-
taneous,
(anti-tubular
in adjuvant
for
in such
types
of interstitial
of
model
sys-
treating
of renal
human
injury
disease.
in rodent
ncphnitis
has
facilitated
testing
model
systems.
It is useful
immunopathology
nephnitis
irumunopathobogy
characterizing
of
as either
is the
seen
antigen-driven
end
product
to
in dif-
or
of an
5 12
Journal
of
the American
Society
of
Nephrology
Antigen
Inactivation
Activation
Antigen specific
activation
Nonspecific
immune
cell
activation
:1II
Cytokines
gamma
Class II
IFN, TNF alpha
VCAM
ICAM-1
MHC
Figure
2. Diagram
depicts
antigen
this
antigen
(depicted
of mechanisms
uptake
are presented
as a triangle).
and
underlying
processing
by cell-surface
For the Th cells
immune
by professional
major
injury
in acute
histocorupatibility
to be activated,
interstitial
antigen-presenting
they
cells,
complex
must
receive
nephritis.
such
(MHC)
a second
The
portion
as a dendritic
cell
proteins
costimulatory
of the figure
to the antigen
signal
above
the dashed
or ruacrophage.
Peptide
receptor
on the T helper
(depicted
as the circle-ellipse
line
fragments
(Th)
of
cell
couple).
Acute
immune
response
mark
of such
cells
that
bear
These
organ
A general
receptors
mechanisms.
for
responses
activation.
The
human
interstitial
related
AIM,
haptens,
may
that
bind
to serum
been
be
abbe
(3 1). Once
tionally
to
helper
of B cells
of specific
induce
as those
bind
ncphnitis
represents
responses
arc
ultimately
and
and
by
the
Freund’s
and
evidence
This
immunization
cells.
IgG
Within
is detectable
both
deposited
antibody
At these early time
infiltrate
studies
In the absence
line
within
along
points,
of neutrophils
performed
of this second
depicts
time
of
signal,
effector
from
a
the
and
circulation
interstitiuru.
demonstrate
a
Func-
a depressed
the Th cell is inactivated,
mechanisms
of
injury
that
such
oxide
(as depicted
along
the tubular
basement
membrane)
strong
antibody
epithelial
recruit
so-called
nonspe“antibody-
Activated
macro-
a
number
of
these,
the rcmembrane
are
renal
macrophages
cells.
The
oxide,
robe
the
can
nitro-
unresolved.
evidence
participant
result
of reactive
is currently
injury,
is a critical
rather
thase inhibition
Renal injury
In
is convincing
in epithebial
than
This may be
in the setting
an effect
cell
injury.
basement
cells
cells,
can
or deposit
and
present
under
tubular
Th
epithelial
I MHC
cells
T cells
on the left side of the figure.
cell
activation.
as antigen-antibody
These
include
circumstances
to T cells,
CD4
II MHC
manner.
These
The portion
and
Antigen-specific
which can react
can
in
(CD4)T
induce
or
cells
of the figure
antigen-specific
Th cells
tubular
resulting
and CD8
T cells
These cells recognize
a class
killer
(NK) cells.
and make antibody,
complexes.
model,
the target
antigen
is synthesized
by
some
in either
syn-
T cells.
antigen
(CD8)-rcstricted
oxide
disease
recognize
glycoprotcin
this
nitric
by antigen-specific
membrane
the activation
of the latter (33). Both
arc present
within
the tububointerstitium.
class
from
epithelial
cpithclial
attributable
to an augof nitric oxide synthase
of inducible
within
the kidney.
can also be initiated
mechanisms.
The nonspecific
mechanisms
include
activation
of macrophages
and natural
include
activation
of both B and T cells. B cells are induced
to differentiate
into plasma
cells
antigen
is no
tubular
can
via
activated
as nitric
of ischemic
nitric
from
to epithebial
functional
levels
(32).
mented
immune
response
as depicted
result
species,
tubular
as
There
membrane
pathways.
that infiltrate
the interstitium
within
the interstitiuru.
This
B cells
antigen-
site,
publi-
to the
the loss of an intact basement
membrane
of the tubular
segment.
The release
of
species
In the anti-tubular
in the
T and
to the
for
injury
of antigen-spe-
to renal
cytotoxicity”
injury
inhibition,
complete
results
submitted
of antibody
cells
F. Gabbai.
In anti-tubular
basement
membrane
disease,
treatment
of immunized
animals
with selective
inhibitors
of the cytokincinducible
nitric
oxide
synthase
(such
as L-MIL)
results
in
marked
augmentation
of disease,
at both the histologic
and
of
with
gen
that
disease
in
oxygen
models
and
We
immunization,
the
effector
cellular
in oxidant
interstitial
of rodents
in injury
deposition
the
hyper-
tububointer-
a combination
basement
results
Kelly,
phages
within
the interstitiuru
can
release
potentially
harmful
secretory
products.
Among
lease of enzymes
that can degrade
basement
antag-
data
from
mechanisms.
reactive
a variety
rat,
At
and
with
irreversible
effector
the
cytotoxic
dependent
the tubular
basement
memthere additionally
may be a
within
at this
alone
C.
anti-tubular
such
with
of antigen-specific
7 to 10 d after
the
However,
cific
cytotox-
membrane
process
that
T cells,
mechanisms
strains
nonspecific
deposition
they
of
emulsified
and
nephnons
in autoimmune
points,
cells.
fall in GFR
to compensate
Norway
time
results
likely crucial,
because
will hamper
regeneration
with
information
preparation
differentiation
the host.
dashed
cific
Brown
killer
The
functioning
the
replaced
of T cells,
natural
depressed.
of
(in
been
comprised
and
changes
later
tububointerstitium
in the
production
basement
susceptible
antigen
adjuvant.
activation
this
these
have
S. Thomson,
in the
At
immunization
infiltrate,
nephrons
hemodynamic
ncphnitis
and
a loss
addi-
by
summarize
stitial
of
cells
and
disease
Anti-tubular
immunizing
tubular
tional
cation).
like
model
system
of AIM
of interstitial
ncphnitis.
to briefly
supplement
systems.
is induced
effector
regulated
studied
model
system
then
model
diffuse
of
the removal
of antigen
from the system,
death of immune
cell populations,
idio-
is the most widely
an antigen-driven
disease
linearly
branc.
Hammond,
Gboruerular
both
cell
is significantly
(T.
filtration
MHC-
resulting
T helper
hypersensitivity
interactions,
use this model
specific
to
GFR
remaining
such
are activated,
cells,
onistic,
inhibitory
cytokincs.
Anti-tubular
basement
membrane
within
directly
T cells
of other
delayed-type
anti-idiotypic
renal
drugs,
point,
after
Nephritis
the interstitium
macrophages,
of the
molecules
some
Activated
the differentiation
mediating
These
other
by MHC
to plasma
antibody.
mechanisms,
including
the programmed
cell
will
behave
proteins
cells,
result
be
in
2 to 3 wk
mononuclear
plasma
failure
In drug-
drugs
or cellular
presented
a largely
is the
forms
defined.
Alternatively,
with
By
within
2.
(24,25).
in most
the relevant
and
may
differentiation
typic
elsewhere
GFR.
the neutrophils
an-
that have direct
effects
on target cells and
activate
nonspecific
effecton
cells, such as natural
and macrophages.
Activated
T helper
cells induce
production
icity.
not
nephron
rat),
B cells,
cytokines
additionally
killer cells
the
have
peptides.
complexes
produce
B
in parcn-
in Figure
antigens
likely
sulfaruethoxazole,
pcptidc
detail
target
are processed
as hapten-modified
T and
,
tissue-injurious
in more
single
this time
is summarized
relevant
it seems
i.e.
result
or one cross reactive
with it, must
to T cells in a manner
that results
nephritis
which
subsequently
as
understanding
is outlined
First, the target antigen,
expressed
and presented
T cell
several
can
hall-
of immune
for antigen,
through
immune
The
expansion
cells
framework
information
antigen(s).
cbonal
antigen-specific
injury
tigen-dniven
This
to a specific
is the
cell-surface
lymphocytes.
chymal
mounted
a response
Interstitial
can
below
the
-nonspecific
mechanisms
with a kidney
effector
T cells,
which may be cytotoxic
to tubular epithelial
cells (T(.TL) leading to necrosis or apoptosis
or inflammatory
(Tt)TH)
leading
to mononuclear
cell
infiltration
and occasionally
granulorua
formation.
Finally. the cytokines
produced
by infiltrating
T cells may induce the expression
of a number
ofccll
surface
molecule-l
molecules
IICAM-l]),
on organ
which
parenchymal
amplify
the
cells
immune
(such
response.
as class
II MHC,
vascular
cell adhesion
molecule
[VCAM],
or intercellular
adhesion
514
Journal
Table
of the American
3. Experimental
Society
therapies
of Nephrology
in interstitial
3.
ncphritis
Neilson
EG:
Antigen-Nonspecific
Protein-calorie
Ref.
restriction
Cycbophosphamide
Cycbosponin
A
PGE1
Antigen-Specific
Ref.
40
Anti-idiotypic
immunity
20
Antigen-specific
42
43
21
regulatory
T cells
Antigen
feeding
44
41
Antigen
45
in incomplete
Freund’s
4.
delayed-type
antigen,
hypersensitivity
Baldwin
D, Levin
due
and they
can
be cytotoxic
to the
to tubular
toxic
cells
proteins
express
granzymcs
of cytotoxicity
In forms
7.
cells
or even
proteinuria
The
nonspecific
ncphnitis
infiltrate
is an
area
of active
of tissue
injury
cell-dominated
tions
Attention
infiltrates.
has
effector
14.
been
15.
16.
the mcdi-
likely
quite
different
than with T
This may have important
implica-
basement
cific
antigen-nonspecific
and
enumerated
systems
in Table
to block
forms
3. In general,
the induction
of
treatment.
it is much
of immune
to turn off ongoing immune responses.
These
easier
clinical
target
trials
arc relatively
nephritis.
renal
between
clinical
263-273,
failure
Semi,z
of drug-induced
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