Granulomatous interstitial nephritis associated with atypical drug-induced hypersensitivity syndrome induced by carbamazepine.

Abstract

We report the case of a 70-year-old female patient with granulomatous interstitial nephritis (GIN) induced by carbamazepine (CBZ). The patient had a 22-year history of bipolar disorder. Approximately 50 days before admission to our hospital, she was switched from valproic acid to 200 mg/day CBZ for mood swings. Forty days later, she presented with mild transient platelet depletion and liver dysfunction along with a C-reactive protein (CRP) level of 2.65 mg/dL. At that time, she discontinued CBZ without consulting the doctor. She subsequently developed high fever and a pruritic maculopapular rash. Laboratory tests revealed an elevated CRP level (11.98 mg/dL) and serum creatinine (sCr) of 1.6 mg/dL. Hence, she was admitted to our hospital, where she showed eosinophilia and immunoglobulin suppression. She was diagnosed with atypical drug-induced hypersensitivity syndrome (DIHS). All drugs prescribed by the previous doctor were discontinued. A lymphocyte transformation test showed CBZ positivity; a renal biopsy revealed many granulomatous lesions connected to arterioles, without angionecrotic findings. The patient had no history of allergic disorders or tuberculosis. Because of psychological instability, we treated her conservatively without steroid administration. She had a good recovery except for mild residual renal insufficiency (sCr, 1.0 mg/dL). Although granuloma formation has been observed in kidney biopsy specimens of rare cases with DIHS, no previous studies have reported on the relationship between arterioles and granuloma formation.

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CASE REPORT
Granulomatous interstitial nephritis associated with atypical
drug-induced hypersensitivity syndrome induced
by carbamazepine
Eriko Eguchi•Keiji Shimazu•Kensuke Nishiguchi•
Soushi Yorifuji•Atsuo Tanaka•Takashi Kuwahara
Received: 23 April 2011/Accepted: 22 August 2011/Published online: 23 September 2011
? The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
patient with granulomatous interstitial nephritis (GIN)
induced by carbamazepine (CBZ). The patient had a
22-year history of bipolar disorder. Approximately 50 days
before admission to our hospital, she was switched from
valproic acid to 200 mg/day CBZ for mood swings. Forty
days later, she presented with mild transient platelet
depletion and liver dysfunction along with a C-reactive
protein (CRP) level of 2.65 mg/dL. At that time, she dis-
continued CBZ without consulting the doctor. She subse-
quently developed high fever and a pruritic maculopapular
rash. Laboratory tests revealed an elevated CRP level
(11.98 mg/dL) and serum creatinine (sCr) of 1.6 mg/dL.
Hence, she was admitted to our hospital, where she showed
eosinophilia and immunoglobulin suppression. She was
diagnosed with atypical drug-induced hypersensitivity
syndrome (DIHS). All drugs prescribed by the previous
doctor were discontinued. A lymphocyte transformation
test showed CBZ positivity; a renal biopsy revealed many
granulomatous lesions connected to arterioles, without
angionecrotic findings. The patient had no history of
allergic disorders or tuberculosis. Because of psychological
instability, we treated her conservatively without steroid
administration. She had a good recovery except for mild
residual renal insufficiency (sCr, 1.0 mg/dL). Although
granuloma formation has been observed in kidney biopsy
specimens of rare cases with DIHS, no previous studies
We report the case of a 70-year-old female
have reported on the relationship between arterioles and
granuloma formation.
Keywords
Drug-related rash with eosinophilia and systemic
symptoms ? Granulomatous interstitial nephritis ?
Granuloma ? Carbamazepine
Drug-induced hypersensitivity syndrome ?
Introduction
Drug-related rash with eosinophilia and systemic symp-
toms (DRESS) or drug-induced hypersensitivity syndrome
(DIHS) is a life-threatening multiorgan systemic reaction
characterized by rash, fever, lymphadenopathy, hepatitis,
and leukocytosis with eosinophilia [1]. These conditions
are caused by a limited number of drugs, including car-
bamazepine, phenytoin, phenobarbital, zonisamide, allo-
purinol, dapsone, salazosulfapyridine, and mexiletine [2].
Renal dysfunction associated with DIHS/DRESS has
been reported to occur in 10% of cases and is attributable to
acute interstitial nephritis (AIN) [2, 3]. In rare cases with
DIHS, granuloma formation has also been described, i.e.,
granulomatous interstitial nephritis (GIN) [4–6].
Here we describe the case of a patient with bipolar
disorder and biopsy-proven GIN that developed during the
course of carbamazepine-induced DIHS/DRESS.
Case report
A 70-year-old woman was admitted to our hospital because
of high fever and acute kidney injury. She had been visiting
a psychiatric clinic for bipolar disorder since the age of
48 years and another medical clinic for mild hypertension
E. Eguchi (&) ? K. Shimazu ? K. Nishiguchi ? S. Yorifuji ?
A. Tanaka ? T. Kuwahara
Department of Nephrology, Saiseikai Nakatsu Hospital,
2-10-39 Shibata, Kitaku, Osaka, Osaka 530-0012,
Japan
e-mail: 13008@nakatsu.saiseikai.or.jp
123
Clin Exp Nephrol (2012) 16:168–172
DOI 10.1007/s10157-011-0531-0

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since the age of 63 years. She had no history of allergic
disorders or tuberculosis.
Approximately 50 days before admission, she was
switched from valproic acid to 200 mg/day carbamazepine
(CBZ) for mood swings. Approximately 40 days after ini-
tiation of CBZ, she presented with purpura on the legs. She
visited her regular physician. Laboratory analyses revealed
platelets of 10.6 9 104/lL, aspartate aminotransferase
(AST) of 62 IU/L, alanine aminotransferase (ALT) of
107 IU/L, C-reactive protein (CRP) of 2.65 mg/dL, and
serum creatinine (sCr) of 0.76 mg/dL. Tranexamic acid
(750 mg/day) and levofloxacin (LVFX, 300 mg/day) were
prescribed. At that time, she discontinued CBZ without
consulting her doctor. Three days later, she developed fever
of[38?C, although the purpura had disappeared. She vis-
ited our hospital, where laboratory results showed an
increased platelet count (12.8 9 104/lL), slightly deterio-
rating liver dysfunction (AST, 70 IU/L; ALT, 123 IU/L),
and an elevated CRP level (4.7 mg/dL). We suspected some
viral infection as the cause of her symptoms and bed rest
was prescribed. Four days after the onset of fever, a pruritic
maculopapular rash appeared on the trunk and extremities.
Because of the prolonged high fever and an elevated CRP
level (7.13 mg/dL), she was referred to our hospital again.
Laboratory tests revealed deteriorating renal function (sCr,
1.6 mg/dL) without urinalysis abnormalities and a further
elevated CRP level (11.98 mg/dL), although liver function
improved (AST, 14 IU/L; ALT, 41 IU/L). She was hospi-
talized the next day.
On admission, her blood pressure was 130/70 mmHg,
pulse rate was 68 beats/min, and body temperature was
38.2?C. A diffuse skin rash was present on the trunk and
limbs. The chest, heart, and abdominal findings were
unremarkable. No superficial
swelling of the joints were observed.
Laboratory data on admission revealed eosinophilia and
immunoglobulin (Ig) suppression with no evidence of
paraproteinemia (Table 1). Complement levels were nor-
mal. Renal ultrasonography revealed symmetrical and
unobstructed kidneys with normal cortical echotexture.
Computed tomography findings of chest and abdominal
were unremarkable. No ophthalmological complications
were observed.
As systemic drug allergy was suspected, all drugs pre-
scribed by the previous doctor were discontinued. The
lymphocyte transformation test showed CBZ positivity and
LVFX negativity;CBZ was therefore considered to be the
causative drug. Reactivation of human herpes virus
(HHV)-6 and HHV-7 was not detected. The patient was
diagnosed with DRESS and atypical DIHS because she
fulfilled all three criteria for DRESS diagnosis and five
of the seven criteria for DIHS diagnosis, which were as
follows: maculopapular rash developing approximately
lymphadenopathiesor
6 weeks after initiation of CBZ, prolonged clinical symp-
toms 2 weeks after discontinuation of CBZ, fever[38?C,
renal dysfunction, and eosinophilia [2, 11].
Followinghospitalization,
insomnia and nocturnal delirium. Psychiatric consultation
disclosed a hypomanic state. Because her physical symp-
toms had not worsened, we decided to treat her conserva-
tively without steroids.
The general condition of the patient improved with
conservative therapy (Fig. 1). Approximately 10 days after
admission, her temperature returned to normal and the skin
rash disappeared. Approximately 10 days later, eosino-
philia improved and CRP levels normalized.
A renal biopsy was performed 11 days after admission
(Figs. 2, 3). Eight glomeruli were evident; one was scle-
rosed and the remaining were almost normal. The inter-
stitium showed patchy infiltration of inflammatory cells
and non-caseating granulomas with multinucleated giant
cells connected to some arterioles. The findings of an
immunofluorescent study were non-specific. The patient
was diagnosed with acute GIN.
One month after admission, the sCr level decreased to
1.0 mg/dL and Ig levels returned to normal.
Although olanzapine and lorazepam were administered
to control the hypomanic state, they were poorly tolerated
because of episodes of akathisia. Eventually, administra-
tion of Yokukansan, which is a traditional Chinese herb,
resulted in a reasonably stabilized mood without side
effects.
The patient was discharged and remained in a stable
condition throughout follow-up.
sheoften experienced
Discussion
GIN is a relatively rare histological diagnosis, comprising
only a small proportion of all renal biopsies [7–10].
Common causes of GIN are drugs, sarcoidosis, infections,
and Wegener’s granulomatosis; drugs account for 25–45%
of GIN cases [7–10]. Medications associated with GIN
include anticonvulsants, antibiotics, non-steroidal anti-
inflammatory drugs, allopurinol, and diuretics [7–10].
Although the pathological mechanism underlying GIN is
not completely understood, a T-cell-mediated reaction is
likely responsible because of the predominance of mono-
nuclear cells (mainly T cells) in the interstitial infiltrates,
the presence of granulomas, and the absence of Ig depo-
sition in the tubules or interstitium [7].
DRESS is a life-threatening multiorgan systemic reac-
tion accompanied by the stepwise development of fever,
skin rash, leukocytosis with eosinophilia, and liver or renal
dysfunction [11]. DIHS is an almost identical disease
concept, although an association with HHV-6 reactivation
Clin Exp Nephrol (2012) 16:168–172169
123

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and a prolonged course are emphasized in DIHS [1]. The
criteria for DIHS diagnosis include a maculopapular rash
developing [3 weeks after initiation of therapy with a
limited number of drugs, prolonged clinical symptoms
2 weeks after discontinuation of the causative drug, fever
[38?C, liver abnormalities (ALT, [100 IU/L), leukocyte
Table 1 Laboratory data on
admission
HPF high-power field
UrinalysisChemistry
Specific gravity1.011Total protein6.0 g/dL
pH5.5 Albumin3.8 g/dL
Protein NegativeBlood urea nitorgen 21.3 mg/dL
Occult blood
N-Acetyl-b-d-glucosaminidase
b2-Microglobulin
Bence-Jones protein
NegativeCr1.7 mg/dL
4.2 U/L
4010 lg/L
Negative
Sodium139 mEq/L
Potassium 3.9 mEq/L
Calcium 8.7 mg/dL
Urine sediment
AST14 IU/L
Red blood cells
\1/HPF
\1/HPF
Negative
ALT41 IU/L
White blood cells
Cast
Serology
CRP11.08 mg/dL
Hematology
IgG 780 mg/dL
White blood cells8400/lL
5%
IgA32 mg/dL
Stab cells IgM37 mg/dL
Segmented cells 51%C3127 mg/dL
Eosinophils18%C4 33 mg/dL
Monocytes 7%CH50 56 U/mL
\409
Negative
Lymphocytes 19%
318 9 104/lL
10.1 g/dL
FANA
Red blood cells
MPO-ANCA
HemoglobinPR3-ANCANegative
Hematocrit29.7%
27.9 9 104/lL
Platelets
Fig. 1 Clinical course and
changes in serum creatinine
(sCr) and C-reactive protein
(CRP)
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123

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abnormalities including leukocytosis ([11000/lL), atypi-
cal lymphocytosis ([5%) or eosinophilia ([1500/lL),
lymphadenopathy, and HHV-6 reactivation [2]. Diagnosis
of definite or typical DIHS requires the presence of all
seven criteria. Probable or atypical DIHS is diagnosed in
patients fulfilling the first five criteria in whom HHV-6
reactivation cannot be detected. Renal dysfunction can
serve as a substitute for liver abnormalities. Recent studies
have demonstrated that other herpes viruses, such as
cytomegalovirus, Epstein–Barr virus, and HHV-7, can be
sequentially reactivated during the course of this syndrome
[12].
The clinical features of DIHS/DRESS, distinguished
from other types of drug reactions, include paradoxical
deterioration after withdrawal of the causative drugs and
frequent flare-ups as observed in immune reconstitution
syndrome (IRS) [1, 13]. A limited number of drugs such as
anticonvulsants have been reported to cause DIHS/DRESS
[1]. Typically, a decrease in serum Ig levels, including IgG,
IgA, and IgM, is observed at the onset of DIHS/DRESS
[1]. An increase in Ig levels is observed several weeks after
withdrawal of the causative drugs, and the levels finally
return to normal. This transient hypogammaglobulinemia is
likelyattributabletoapharmacologically
immunomodulatory effect on the immune system by the
causative drugs [1, 14–16].
Superficial perivascular lymphocytic infiltration, pre-
dominantly consisting of T cells, and tissue eosinophilia
are common pathological findings of skin biopsy [1, 17].
Although only a small number of reports are available on
histological analyses of the other involved organs, renal
failure in some cases with DIHS/DRESS has been attrib-
uted to AIN [2]. In rare cases with DIHS, granuloma for-
mation has also been observed and reported as GIN or
granulomatous necrotizing angiitis [4–6]. Our patient
showed granulomatous lesions connected to arterioles,
without findings of apparent angionecrosis. There have
been no previous reports of GIN similar to the present case,
and the significance of this finding is unclear.
Granulomas can be found in other organs, such as the
skin, liver, and colon, in association with DIHS/DRESS
[4–6, 18]. Furthermore, granuloma formation is a histo-
logical hallmark of IRS [13]. Some researchers propose
that DIHS/DRESS is a manifestation of the newly observed
IRS [13]. Further investigations into the pathogenesis of
these syndromes are expected.
Systemic corticosteroid therapy is recommended for
treating patients with DIHS/DRESS who do not show
improvement even after withdrawal of the causative drug
[1]. The usual dosage is 40–60 mg/day prednisolone,
which should be carefully tapered to prevent flare-ups.
Mild cases that recover with only supportive care do not
require corticosteroids [1, 4]. The use of systemic corti-
costeroids may increase the risk of infectious complica-
tions including virus reactivation. Other treatment options
include intravenous IgG [1, 14]. Even after resolution of
clinical manifestations, a number of drugs should be
avoided because unexplained cross-reactivities to multiple
drugs with structures totally different from the original
causative drugs have been reported [1].
Fortunately, our case recovered with conservative ther-
apy. We believed that we might have difficulty in achiev-
ing a good psychiatric control if systemic corticosteroids
mediated
Fig. 2 Granulomatous interstitial nephritis. The granuloma is con-
nected to the wall of the arteriole and surrounded by diffuse
interstitial infiltration of lymphocytes. Periodic acid–Schiff stain,
9400
Fig. 3 Numerous epithelioid cells comprising the granuloma appear
to be involved in the middle or outer layer of the arteriole wall. The
glomerulus (right lower side) is essentially normal. Periodic acid–
silvermethenamine stain, 9200
Clin Exp Nephrol (2012) 16:168–172171
123

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were required. Only a limited number of options were
available for psychiatric management of the patient
because of intolerance to various psychotropic drugs and a
possible cross-reactivity to multiple drugs after developing
DIHS/DRESS.
HHV-6 and HHV-7 reactivation was not detected in our
case. These viruses have been demonstrated to be involved
in the flare-up and severity of this syndrome; therefore, the
absence of a detectable HHV-6 and HHV-7 reactivation
may have accounted for the milder form of disease in our
case [19, 20].
In summary, we report a case of GIN associated with
CBZ-induced DIHS/DRESS. Supportive care after drug
discontinuation resulted in a good recovery. Early recog-
nition of this syndrome is the most important step in
treatment because a number of drugs such as anticonvul-
sants and antibiotics may worsen the clinical symptoms
due to unexplained cross-reactivities.
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