JOURNAL OF CLINICAL MICROBIOLOGY, Apr. 2008, p. 15481550 Vol. 46, No.

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0095-1137/08/$08.000 doi:10.1128/JCM.01040-07
Copyright 2008, American Society for Microbiology. All Rights Reserved.

Acute Renal Failure Due to Acute Tubular Necrosis Caused by Direct

Invasion of Orientia tsutsugamushi
Dong-Min Kim,1 Dae Woong Kang,1 Jong O. Kim,1 Jong Hoon Chung,1 Hyun Lee Kim,1*
Chi Young Park,1 and Sung-Chul Lim2
Division of Infectious Diseases, Department of Internal Medicine,1 and Department of Pathology and Research Center for
Resistant Cells,2 Chosun University College of Medicine, Gwangju-si, South Korea
Received 21 May 2007/Returned for modification 5 September 2007/Accepted 31 October 2007

We describe a scrub typhus patient with acute renal failure for whom a diagnosis was made based on
serology as well as immunohistochemical (IHC) staining and an electron microscopic examination (EM) of a
renal biopsy specimen. For our case, we demonstrated by IHC staining and EM that renal failure was caused
by acute tubular necrosis due to a direct invasion of Orientia tsutsugamushi.

CASE REPORT antibody, antineutrophil cytoplasmic antibody, and cold agglu-

A healthy-looking, 33-year-old male patient received a drug
treatment for a 2-week history of cough and sputum. One day
before admission to our hospital, he complained of abdominal
pain and nausea after he played football. He was suspected of
having renal failure on examination at a local clinic and was
transferred to Chosun University Hospital in Gwang-ju, South
Korea. At the time of admission, his vital signs were a blood
pressure of 120 over 80 mm Hg, a pulse rate of 72 times/min,
a respiratory rate of 20 breaths/min, and a body temperature of
37.2C. A urinalysis showed no gross hematuria, with a urine
output of 50 ml/h. His mental status was alert. There was no
skin rash or lymphadenopathy. The patients complete blood
count showed a white blood cell count of 11,630/mm3, a he-
moglobin count of 14.5 g/dl, and a platelet count of 243,000/
mm3. An arterial blood gas analysis showed a pH of 7.404, a
partial CO2 pressure of 38.1 mm Hg, a partial O2 pressure of
79.4 mm Hg, an HCO3 concentration of 23.3 mmol/liter, and
an O2 saturation of 95.8%. His serum biochemistry results
were as follows: [Na], 135 meq/liter; [K], 4.2 meq/liter;
[Cl], 120 meq/liter; blood urea nitrogen, 39.3 mg/dl; and cre-
atinine, 5.0 mg/dl. The biochemistry results showed a total
protein level of 6.73 g/dl, albumin at 3.78 g/dl, aspartate
transaminase at 30 IU/liter, alanine aminotransferase at 18
IU/liter, creatine phosphokinase at 446 U/liter, lactate dehy-
drogenase at 565 U/liter, myoglobin at 168.4 ng/ml, fibrin deg-
radation products at 1 mg/ml (range, 0 to 5.0 mg/ml), and a
D-dimer concentration of 143.6 ng/ml (range, 0 to 255 ng/ml).
On urinalysis, hematuria (score, 3) and proteinuria (score,
4) were shown to be present. A microscopic urinalysis re-
vealed 10 to 19 red blood cells/high-power field (HPF), 2%
dysmorphic red blood cells/HPF, 1 to 4 white blood cells/HPF,
and no cast/HPF. A urinalysis using urine collected during 24 h
detected selective proteinuria (albumin, 895 mg/day). Sero-
logic tests were all negative for rheumatoid factor, antinuclear
* Corresponding author. Mailing address: Department of Internal
Medicine, Chosun University College of Medicine, 588 Seosuk-dong,
Dong-gu, Gwangju 501-717, South Korea. Phone: 82-62-220-3178. Fax:
82-62-234-9653. E-mail: hyunkim@chosun.ac.kr.
Published ahead of print on 14 November 2007.
tinin, human immunodeficiency virus, hepatitis B virus, and
hepatitis C virus antibodies, and the VDRL test was negative.
Antistreptolysin O and complement levels were all normal.
A self-employed person, our patient presented with no typical
symptoms of scrub typhus, including rash, fever, and headache.
He had a history of outdoor activity 10 days before admission. He
had previously maintained a healthy life but had a markedly
increased level of creatinine. He therefore received a renal biopsy
for further evaluation and to make a differential diagnosis from
other diseases, including rapidly progressing glomerulonephritis.
Tissue from the biopsy underwent immunohistochemical
(IHC) staining and immunofluorescent staining, in which the
primary antibody was ICR mouse hyperimmune serum immu-
nized with Orientia tsutsugamushi strain Boryong at a dilution
of 1:200. The antibody could detect other disparate strains of
O. tsutsugamushi in addition to strain Boryong in the immu-
nofluorescence assay (IFA) (data not shown). IHC staining
was performed using a streptavidin-biotin immunoperoxidase
method according to the suppliers protocol (LSAB kit; Dako,
Carpinteria, CA), as described previously (2). Using renal bi-
opsy, IHC staining, immunofluorescent staining, and electron
microscopic examination (EM), we identified the presence of
Orientia tsutsugamushi coccobacilli within the tubule. Based on
these findings, a diagnosis of scrub typhus was established for
our patient. He was immediately given doxycycline. An IFA
serological test was performed using paired sera (2). At the time
of admission, the patients IFA serologic profile showed an im-
munoglobulin M (IgM) titer of 1:10 and an IgG titer of 1:4,096.
One week after he was given doxycycline, samples from the re-
covery phase showed an IgM titer of 1:1,280 and an IgG titer of
1:4,096. A follow-up antibody test was performed to examine for
the presence of concurrent diseases. The tests were all negative
for endemic typhus, hemorrhagic fever with renal syndrome, lep-
tospirosis, and measles. He recovered without any notable com-
plications following doxycycline treatment. He was discharged
when his serum creatinine levels returned to normal.
Scrub typhus is an acute febrile disease caused by Orientia
tsutsugamushi, a gram-negative intracellular bacterium. Pa-

1548
VOL. 46, 2008 CASE REPORTS 1549

FIG. 1. Histopathologic findings for the kidneys from a patient with scrub typhus. (a) Histopathologic findings for the kidneys (hematoxylin and
eosin stain; magnification, 100). Acute tubular necrosis with chronic interstitial nephritis is illustrated. Many atrophic tubules and lumens
containing desquamated epithelial casts (asterisks) are found. (b) Immunofluorescent staining of a kidney (magnification, 100). Positive
immunofluorescent staining is indicated in the tubular structures (arrows). Scattered positive signals are also identified in the vascular structures
(asterisks). (c) Immunohistochemical staining of a kidney (magnification, 100). Positive IHC staining is indicated in the tubular structures, and
scattered positive signals are also identified in the vascular structures. (d) Ultramicroscopic findings of the renal tubular epithelial cells. Many O.
tsutsugamushi (O) cells are seen in the cytoplasm. Many small vesicles (arrows) with an O. tsutsugamushi envelope appear around the degenerated
Orientia coccobacilli (DO). Scale bar, 2.0 m.

tients with scrub typhus present with an eschar at the site of the
mite bite, a maculopapular rash, fever, myalgia, headache, and
anorexia (4). The prognosis varies between patients, ranging
from asymptomatic infection to death. Because scrub typhus
causes systemic vasculitis, it can cause meningitis, interstitial
pneumonia, acute pulmonary edema, hepatitis, and acute renal
failure in untreated cases (6, 7, 8, 9). Hematuria and protein-
uria may occur because of renal invasion in 10 to 20% of
patients with scrub typhus. Acute renal failure is not a common
entity, but it is known to be one of the serious complications
seen in patients with scrub typhus, spotted fever, or murine
typhus (3, 5, 10). Fever, headache, and rash are potential
indicators for rickettsial disease and are known to be useful
clues for the diagnosis of scrub typhus (1). However, our pa-
tient visited us with the chief complaint of a prompt deterio-
ration of renal function without the triad of symptoms of scrub
typhus, including typical skin lesions, fever, and headache. To
identify the cause of the prompt deterioration of renal func-
tion, a renal biopsy with IHC staining, immunofluorescent
staining, and EM were performed. This established a diagnosis
of scrub typhus. An early recovery was achieved following
doxycycline treatment.
In our case, a renal biopsy showed that the capillary loop and
cellularity were normal in the glomerulus. The renal tubules
underwent multifocal tubular necroses, and foci of some
mononuclear cells were identified in the infiltration of the
tubulointerstitium. Tubular epithelial cells underwent degen-
erative changes and were detached from the basement mem-
brane (Fig. 1). Epithelial casts were observed in some renal
tubules. These histopathologic findings were suggestive of
acute tubular necrosis with chronic tubulointerstitial nephritis.
Several hypotheses have been proposed to explain the mech-
anism by which O. tsutsugamushi infection causes acute renal
failure. First, it is assumed that the pathophysiology of acute
renal failure is associated with prerenal azotemia due to renal
hypoperfusion in cases of shock or volume depletion. Accord-
ing to Dumler et al., prerenal azotemia is the main pathophys-
iology of renal failure caused by the decrease of effective renal
blood flow due to increased vascular permeability in patients
with murine typhus accompanied by systemic vasculitis (1).
Hypoalbuminemia is commonly noted to occur in patients with
rickettsial disease. This has been reported to be due to the
leakage of plasma albumin into the perivascular space because
of widespread vascular damage (1). In our case, however, there
was no clear evidence of decreased blood pressure or other
signs and symptoms suggestive of volume depletion, including
diarrhea and vomiting. Furthermore, our patient had a normal
range of serum albumin levels. This led to the speculation that
acute renal failure did not occur due to prerenal azotemia in
our patient. Second, disseminated intravascular coagulation
(DIC) is considered another pathophysiological trait of renal
failure. To put this another way, renal failure is caused by
microangiopathy due to thrombosis or coagulation in multiple
organs of patients with DIC. In our case, however, there were
no notable laboratory findings suggestive of DIC or his-
topathologic findings suspected to indicate thrombosis. Third,
acute tubular necrosis might cause renal failure because of the
direct invasion of O. tsutsugamushi into a renal parenchyma.
1550 CASE REPORTS
Walker and Mattern (7) and others (10) reported that his-
topathological findings were suggestive of multiple interstitial
nephritis in patients with renal failure accompanied by murine
typhus. Our patient also had acute tubular necrosis, in which
numerous O. tsutsugamushi coccobacilli were deposited within
his renal tubules, as determined by IHC staining, immunoflu-
orescent staining, and EM. Furthermore, his renal function
promptly recovered following doxycycline treatment. These
findings support the possibility that the direct invasion of O.
tsutsugamushi into renal tubules caused acute tubular necrosis
and then resulted in acute renal failure. Neither acute glomer-
ulonephritis, nontraumatic rhabdomyolysis with myoglobin-
uria, or DIC have so far been documented to contribute to the
development of acute renal failure. Little is known about
whether the development of renal failure is associated with
DIC or acute glomerulonephritis. Further clinical studies are
therefore warranted to examine the pathophysiology of acute
renal failure in patients with scrub typhus.
In conclusion, our case highlights the following two points.
First, in order to identify the cause of the prompt deterioration
of renal function, a renal biopsy with IHC staining and EM was
performed. The adequate use of IHC staining or EM estab-
lished an early diagnosis of scrub typhus prior to serologic
follow-up. Second, for our case, we demonstrated by IHC
staining and EM for the first time that renal failure in patients
with scrub typhus is caused by acute tubular necrosis due to the
direct invasion of O. tsutsugamushi.
J. CLIN. MICROBIOL.
This study was supported by research funds from Chosun University
of 2005.
We declare no commercial interest and do not belong to any asso-
ciation that might pose a conflict of interest for this work.
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