© 2016 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd

Transplant Infectious Disease, ISSN 1398-2273

Clinical characteristics and outcomes of adenovirus

infection of the urinary tract after renal
transplantation
K. Nanmoku, N. Ishikawa, A. Kurosawa, T. Shimizu, T. Kimura, A. K. Nanmoku, N. Ishikawa,
Miki, Y. Sakuma, T. Yagisawa. Clinical characteristics and outcomes A. Kurosawa, T. Shimizu, T. Kimura,
of adenovirus infection of the urinary tract after renal transplantation. A. Miki, Y. Sakuma, T. Yagisawa
Transpl Infect Dis 2016: 18: 234–239. All rights reserved Surgical Branch, Institute of Kidney Diseases, Jichi
Medical University Hospital, Shimotsuke, Japan
Abstract: Background. Urinary tract infection caused by human
adenovirus (HAdV) after renal transplantation (RT) results in graft
loss because of concomitant nephropathy and acute rejection and
may result in death because of systemic dissemination.
Methods. We assessed the time period between RT and disease
onset, symptoms, treatment details, disease duration, renal graft
function, outcomes, and complications.
Results. HAdV infection of the urinary tract occurred in 8 of 170
renal transplant recipients. Symptoms were macrohematuria in all 8 Key words: human adenovirus; urinary tract
patients, dysuria in 7, and fever in 5. The median period from RT to infection; renal transplantation; ganciclovir; acute
disease onset was 367 (range, 7–1763) days, and the median disease tubulointerstitial nephritis
duration was 15 (range, 8–42) days. The mean serum creatinine
Correspondence to:
(sCr) level prior to onset was 1.35  0.48 mg/dL and the mean Koji Nanmoku, MD, PhD, Surgical Branch, Institute
maximum sCr level during disease was 2.34  1.95 mg/dL. These of Kidney Diseases, Jichi Medical University
values were increased by ≥25% in 5 patients. The mean sCr levels Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi,
when symptoms resolved was 1.54  0.67 mg/dL, and no 329-0498 Japan
significant difference was seen before, during, or after disease onset Tel: 81-285-58-8859
(P = 0.069). Two patients were diagnosed with HAdV viremia and 1 Fax: 81-285-44-2800
with acute tubulointerstitial nephritis revealed on biopsy. In addition E-mail: nan.nan.mock@gmail.com
to a reduction in immunosuppressant dosage, 2 patients received
gammaglobulins and 5 received ganciclovir.
Conclusion. Symptoms of all patients were alleviated, although some
Received 22 October 2015, revised 28 December
patients developed nephritis or viremia. Hence, the possibility of 2015, 2 January 2016, accepted for publication 8
exacerbation should always be considered. Adequate follow-up January 2016
observation should be conducted, and diligent and aggressive
therapeutic intervention is required to prevent the condition from DOI: 10.1111/tid.12519
worsening. Transpl Infect Dis 2016: 18: 234–239

Human adenovirus (HAdV) is an important cause of
infections in both immunocompetent and immunocom-
promised individuals (1). Because of the state of
immunosuppression, persistent HAdV infection some-
times causes serious complications in transplant recip-
ients (2). In particular, HAdV infection is one of the
most severe viral infections in renal transplant recipi-
ents (3) and can cause graft loss because of HAdV-
induced nephritis caused by infection of the urinary
tract (4, 5), resulting in acute graft rejection (6),
systemic dissemination, and death from multiple organ
failure (7). Although individual cases of severe HAdV
infection have been sporadically reported, the signifi-
cance of HAdV infection of the urinary tract after renal
transplantation (RT) is largely unknown. Therefore, we
aimed to clarify the clinical characteristics and out-
comes of HAdV infection of the urinary tract after RT.
Patients and methods
Between April 2003 and March 2013, a total of 170 RTs
(159 living donors and 11 deceased donors) were
performed at our hospital. Of these 170 consecutive

234

renal transplant recipients, urine bacteriological cul-
ture, urine cytology, and the presence of urine HAdV
DNA and BK polyomavirus (BKV) DNA were exam-
ined in those with a diagnosis of urinary tract infection
based on symptoms of macrohematuria and dysuria
(i.e., urinary frequency, urgency, and micturition pain).
A definitive diagnosis of HAdV infection of the urinary
tract was confirmed by positive results for the presence
of HAdV DNA in the urine. In addition, blood culture
and the presence of HAdV DNA in the blood were
examined in patients with fever. HAdV DNA in the
urine and blood was detected using a qualitative
polymerase chain reaction assay (8) for HAdV types
1–6, 8, 19, and 37; types 7 and 11 were also included
because of hemorrhagic cystitis. BKV DNA in the urine
was also detected using a qualitative polymerase chain
reaction assay. Furthermore, we performed cystoscopy,
computed tomography (CT), and/or magnetic reso-
nance imaging (MRI) of the abdomen and pelvis in
cases of prolonged hematuria, and renal graft biopsy in
cases of renal graft dysfunction. The renal graft biopsy
specimen was observed by light microscopy with
hematoxylin and eosin staining.
For treatment, antibiotics were administered for
suspected bacterial infection or prevention of sec-
ondary bacterial infection until the causative organism
was identified. After confirming a diagnosis of HAdV
infection of the urinary tract, immunosuppressant
dosage was reduced, while intravenous immunoglobu-
lin (IVIG, gammaglobulin at 5 g/day for each 3 days)
and ganciclovir (GCV, 5 mg/kg/day for 5–7 days)
were administered depending on the presence of
symptoms, such as fever.
The period of time between RT and disease onset,
symptoms, treatment details, disease duration, renal
graft function, outcomes, and complications were
assessed. The average patient age and serum creatinine
(sCr) levels (mean  standard deviation) were logged.
The sCr levels before, during, and after disease onset
were analyzed by repeated measures analysis of vari-
ance. A 2-tailed probability (P) value of <0.05 was
considered statistically significant.
Results
Among the 170 consecutive renal transplant recipients,
8 (6 males and 2 females) were definitively diagnosed
with HAdV infection of the urinary tract by the
presence of HAdV DNA in the urine (Table 1). All 8
patients received transplantations from ABO-compati-
ble, living-related renal donors. The mean age of the 8
patients at the time of RT was 38.8  8.2 years and the
Transplant Infectious Disease 2016: 18: 234–239
Nanmoku et al: HAdV infection after renal transplantation
mean age at the onset of HAdV infection of the urinary
tract was 40.4  7.6 years. The median period of time
between RT and onset of HAdV infection of the urinary
tract was 367 (range, 7–1763) days. Symptoms were
macrohematuria in all 8 patients, dysuria in 7, and fever
in 5. Urine bacteriological culture indicated Escherichia
coli infection in Patient 6, and blood cultures were
negative in all patients.
Urine cytology showed intranuclear inclusion bodies
in Patient 3 and 6 and both were positive for BKV DNA
in urine. Accordingly, these 2 patients were diagnosed
with a combination of HAdV and BKV viruria. Five
patients had fever, of whom 2 (Patient 3 and 7) were
diagnosed with HAdV viremia based on the presence
of HAdV DNA in the blood. The median duration of
HAdV infection of the urinary tract was 15 (range,
8–42) days. The mean sCr level prior to disease onset
was 1.35  0.48 mg/dL and the mean maximum sCr
value during the course of the disease was
2.34  1.95 mg/dL. These values increased by ≥25%
in 5 (62.5%) of the 8 patients. The mean sCr level at the
time symptoms resolved was 1.54  0.67 mg/dL. No
significant difference in Cr levels was seen before,
during, and after disease onset (P = 0.069; Fig. 1).
Cystoscopy for prolonged macrohematuria in Patient 1
revealed typical hemorrhagic cystitis presenting as
redness and bladder mucosa erosion. CT and MRI of
the abdomen and pelvis in Patient 7 showed a high
degree of inflammation from the bladder to the renal
graft (Fig. 2). Renal graft biopsy for Patients 1 and 6
showed no findings of acute rejection. However, the
cause of renal graft dysfunction in Patient 1 was acute
tubulointerstitial nephritis, as diagnosed by renal graft
biopsy (Fig. 3).
Seven patients, except for Patient 8, received intra-
venous fluids because of dehydration during hospital-
ization (Table 2). Immunosuppressant therapy
consisted of a triple regimen of calcineurin inhibitors
(CNIs), mycophenolate mofetil (MMF), and methyl-
prednisolone. CNIs included tacrolimus in 5 patients
and cyclosporine in 3. The reduction in immunosup-
pressant administration to control infection was per-
formed as follows: MMF dosage was reduced in 3
patients, and both MMF and CNI dosages were
decreased in 2. For antiviral therapy, IVIG was admin-
istered to 2 patients and GCV to 5. Three (37.5%)
patients received steroid pulse therapy for acute rejec-
tion, but each developed HAdV infection of the urinary
tract 2 days, 10 months, and 14 months after steroid
pulse therapy, respectively. Renal graft function after
HAdV infection was stable (mean sCr level of
1.68  0.62 mg/dL), although the renal graft failed in
Patient 1 because of chronic rejection 3 years after RT.
235
Nanmoku et al: HAdV infection after renal transplantation

Patient characteristics

Symptom Viral examination

Acute
Age rejection* Onset*
Pt years Gender days days Hematuria Dysuria Fever Urine HAdV DNA Blood HAdV DNA Urine BKV DNA

1 57 M 164 168 + + +
2 39 M 183 + + + +
3 33 M 13 413 + + + + + +
4 39 M 10 324 + + + +
5 45 F 1185 + + +
6 35 F 7 + + + +
7 36 M 1763 + + + + +
8 39 M 670 + + +

*Time from transplantation. All acute rejection was treated with steroid pulse therapy.
Pt, patient; M, male; HAdV, human adenovirus; BKV, BK polyomavirus; F, female.

Table 1

geneic SCT is most likely the result of the different

Discussion immunosuppressive strategies used with these proce-
dures. While immunosuppressive agents rapidly
HAdVs are classified into 7 species (A–G) and 67 types decrease after strong induction therapy in the case of
(1–67). Types 1–51 were identified by serotyping, allogeneic SCT, immunosuppressive therapy using a
whereas types 52–67 were identified by genomic multidrug combination continues for a long time during
sequencing and bioinformatic analysis (1). As the assay the maintenance phase in case of RT. Therefore, the
for HAdV detection covers only a proportion of the onset of HAdV infection might occur for a long time
currently known virus types, the occurrence of HAdV after RT. Nevertheless, administration of steroid pulse
infection of the urinary tract may have been underes- therapy for acute rejection immediately led to HAdV
timated. In addition, HAdV has been identified as the infection of the urinary tract in only 1 of 3 patients. It is
causative agent of various diseases, including acute difficult to predict the onset of HAdV infection, because
upper respiratory inflammation, pneumonia, pharynx it does not commonly occur in patients with normal
conjunctivitis, gastroenteritis, hepatitis, and myocardi- immune function.
tis (2). Moreover, in case of organ transplantation,
donor-transmitted HAdV infection may be established
in the recipient from the transplanted organ (5). In this
study, HAdV infection in Patient 6 was speculated to be
donor-transmitted because disease onset occurred after
a relatively short period (7 days) after RT because the
incubation period of HAdV is 2–14 days. Reactivation of
existing HAdV infection or primary HAdV infection was
suspected in the other 7 patients because disease onset
was >5 months after RT. In any case, the risk of HAdV
infection is increased in renal transplant recipients
because of the state of immunosuppression. The
median interval between RT and the onset of urinary
tract HAdV infection was 1 year. This interval is longer
than the interval between allogeneic stem cell trans-
plantation (SCT) and the onset of HAdV disease, which Fig. 1. Time course of renal graft function. No significant difference
is <100 days. This difference between RT and allo- between before, during, or after disease onset. Cr, creatinine.

236 Transplant Infectious Disease 2016: 18: 234–239

 Nanmoku et al: HAdV infection after renal transplantation

A B

Fig. 2. Computed tomography (A) and

magnetic resonance imaging (B) of the
abdomen and pelvis in Patient 7 showing
inflammation of the renal graft, dilated
urinary tract of the renal graft, bladder
hypertrophy, and increased concentration
of perirenal fat.

A B C

Fig. 3. Hematoxylin and eosin-stained renal graft biopsy section showing acute tubulointerstitial nephritis in Patient 1. (A) Mononuclear cell
infiltrates along the tubules (magnification 9100). (B) Interstitial edema (magnification 9100). (C) Enlarged nuclei of tubular epithelial cells
(magnification 9400).

Clinical course and treatment

sCr (mg/dL) Treatment

Pt Before Onset After Fluid Reduction in MMF Reduction in CNI IVIG GCV Treatment duration, days

1 1.57 2.92 1.64 + + + 27

2 1.07 1.38 1.07 + + + + 16
3 1.65 2.59 1.59 + + 13
4 1.62 2.13 1.65 + + 14
5 1.06 1.10 1.24 + + 12
6 0.70 0.75 0.99 + + + 24
7 2.16 6.77 3.05 + + + + 42
8 0.95 1.10 1.08 + + 8

Pt, patient; sCr, serum creatinine; MMF, mycophenolate mofetil; CNI, calcineurin inhibitor; IVIG, intravenous immunoglobulin; GCV, ganciclovir.

Table 2

Renal graft function deteriorated in 5 of the 8 patients ered to have developed HAdV nephropathy. CT and
with a definitive diagnosis of HAdV infection of the MRI findings showed ureteritis and pyelonephritis that
urinary tract. Therefore, these 5 patients were consid- spread retrograde to the urinary tract from the bladder,

Transplant Infectious Disease 2016: 18: 234–239 237

Nanmoku et al: HAdV infection after renal transplantation
because the pathological analysis of the renal graft
biopsy showed acute tubulointerstitial nephritis. How-
ever, no significant difference was seen between pre-
and post-onset of HAdV infection and renal graft
function after resolution of symptoms.
Although the association between HAdV infection
and renal graft rejection is controversial, HAdV infec-
tion may impact the clinical and histological findings of
renal graft rejection (6). HAdV infection can cause graft
rejection through a direct effect by the activation of the
innate immune system, similar to BKV infection (9).
However, HAdV infection may result in acute rejection
following a decrease in baseline immunosuppressive
therapy to allow clearance of HAdV. In contrast, an
increased dose of immunosuppressive agents employed
to treat acute rejection may activate latent HAdV
infection (10). For cases in which it is clinically difficult
to differentially diagnose acute tubulointerstitial nephri-
tis and acute rejection, real graft biopsy should be
performed.
BKV was detected by urine cytology and urine BKV
DNA in 2 patients in our cohort. In general, BKV
infection may result in persistent inhibition of renal
graft function. On the other hand, HAdV infection may
cause acute transient renal graft function. However, the
effect of superinfection with a combination HAdV and
BKV on renal graft function is unknown.
For treatment of HAdV infection of the urinary tract
after RT, reduction in immunosuppression is necessary,
similar to other viral infections (11). However, no
protocol has yet been established for immunosuppres-
sion reduction for HAdV infection of the urinary tract
after RT. Both B and T lymphocytes play an important
role in recovery from HAdV infection (10). Therefore, if
clinical improvement cannot be achieved by the reduc-
tion or discontinuation of MMF only, dosages of CNIs,
such as tacrolimus or cyclosporine, should be reduced.
Moreover, an antiviral effect can be expected following
IVIG administration, particularly in cases of hypogam-
maglobulinemia. The effectiveness of cidofovir and
IVIG for treating disseminated HAdV infection (12) and
severe necrotizing HAdV tubulointerstitial nephritis
(13) in renal transplant recipients has been reported.
However, antiviral agents should only be considered in
cases that inadequately respond to a reduction in
immunosuppression therapy and the administration of
gammaglobulin. In particular, severe cases, such as the
early onset of infection after RT because of donor-
transmitted HAdV infection and suspected systemic
dissemination due to HAdV viremia, require aggressive
antiviral therapy. As an objective index, the measure-
ment of blood HAdV load may be useful to assess the
effects of antiviral therapy (7). Among antiviral agents,
238 Transplant Infectious Disease 2016: 18: 234–239
GCV is reportedly effective against HAdV infection (14,
15) and is often used for treating cytomegalovirus
infection. The use of GCV might contribute to the
improvement in HAdV viremia and prevention of renal
graft failure in our patients. Although 2 of the 5 patients
with fever were diagnosed with HAdV viremia, no
incidence of multiple organ failure occurred because of
systemic dissemination. However, because HAdV (in
contrast to members of the herpesvirus family) lacks
viral thymidine kinase, and cellular kinases are ineffi-
cient at phosphorylating the compound, the anti-HAdV
efficacy of GCV is predictably modest (1). Ribavirin is
also reportedly effective against HAdV infection. How-
ever, the anti-HAdV activity of ribavirin is limited to
HAdV types 1, 2, 5, and 6 in vitro (16). Therefore,
ribavirin cannot be expected to be effective against
urinary tract infections caused by HAdV types 7, 11, 21,
34, 35, or 37. On the other hand, because cidofovir has
activity against all HAdV types, it is being used as the
standard treatment for HAdV infection (10). CMX001 is
a lipid conjugate of cidofovir that has been developed as
a treatment for infections by double-stranded DNA
viruses, such as HAdV. CMX001 has good oral
bioavailability, higher drug activity in the intracellular
level, and the advantage of no renal toxicity (17).
Therefore, it is highly anticipated that CMX001 may be
useful for treatment of HAdV infection of the urinary
tract after RT.
In conclusion, although urinary tract infection after
RT is a common complication, a differential diagnosis
of HAdV infection should be considered. HAdV infec-
tion was cured in all patients in this study, although
some developed nephritis or viremia. Hence, the
possibility of exacerbation should always be consid-
ered. After a definitive diagnosis of HAdV infection of
the urinary tract, adequate follow-up observation
should be conducted, and diligent and aggressive
therapeutic intervention is required before the condi-
tion worsens.
Acknowledgments:
The authors would like to thank Sachiyo Yokotsuka for
her help as a nurse coordinator, and Enago (www.
enago.jp) for the English language review.
Author contributions: K.N., N.I., and T.Y.: Concept/
design; K.N.: Data analysis/interpretation and drafting
the article. All authors reviewed and approved the final
version of this article.
Conflict of interest: The authors declare that they have
no conflict of interests.

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