Open Journal of Nephrology, 2012, 2, 1-4
http://dx.doi.org/10.4236/ojneph.2012.21001 Published Online March 2012 (http://www.SciRP.org/journal/ojneph)
A Case of Cytomegalovirus-Induced Arthritis after
Lymphocyte-Depleting Therapy for Kidney
Allograft Rejection
Richard Fuquay1*, James Eric Cooper2
1Health Science Center Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, USA
2Health Science Center Division of Renal Diseases and Hypertension, Transplant Center, University of Colorado Denver, Aurora,
USA
Received January 14, 2012; revised February 13, 2012; accepted February 23, 2012
ABSTRACT
Cytomegalovirus viremia and tissue-invasive disease are common after kidney transplantation. Chemoprophylaxis has
made substantial improvement in this clinical problem. Here we report a 29-year-old woman who had kidney allograft
rejection and received lymphocyte-depleting therapy. She presented with a new oligo-arthritis that led to 2 successive
arthrocenteses. The etiology of the inflammation could not be determined initially. On the second arthrocentesis, a
synovial fluid cytomegalovirus polymerase chain reaction test was positive. The patient responded to treatment with
valganciclovir, had negative follow-up serum cytomegalovirus polymerase chain reaction tests, and experienced resolu-
tion of her joint inflammation. We review briefly the data for cytomegalovirus chemoprophylaxis, preemptive screening,
and treatment recommendations.
Keywords: Cytomegalovirus (Mesh); Arthritis (Mesh); Kidney Transplantation (Mesh); Immunosuppression (Mesh);
Chemoprevention (Mesh); Valganciclovir (Mesh)
1. Case Report and Methods
A 29-year-old woman with a history of ESRD due to
vesico-ureteral reflux underwent living non-related do-
nor kidney transplantation in January 2009. She was
seropositive for cytomegalovirus (CMV) IgG antibod-
ies and received a kidney from a CMV seropositive do-
nor. She received 3 days of lymphocyte-depleting induc-
tion with thymoglobulin and was placed on maintenance
immunosuppression consisting of tacrolimus, myfortic,
and prednisone, as well as valganciclovir 450 mg per day
for chemoprophylaxis against CMV disease. Serum
creatinine (SCr) fell to a nadir of 1.0 mg/dL (normal, 0.4
to 1.2 mg/dL) following transplant. The patient pre-
sented with a SCr of 4.15 mg/dL at 4 months and 2
weeks after her transplant surgery. (The patient later admit-
ted to medication nonadherence.) Valganciclovir was
stopped due to deteriorating graft function.
On day 1 of her course, the patient was admitted for
renal allograft biopsy which revealed Banff IIa rejec-
tion with severe interstitial inflammation, focal endo-
thelialitis, and negative staining for C4d. She began a
course of lymphocyte-depleting therapy with thymo-
globulin 1.5 mg/kg per day, which was changed to
muromonab-CD3 (OKT3) 5 mg per day after 3 days
due to development of a rash. She received 9 total
doses of lymphocyte-depleting therapy for acute rejec-
tion, resulting in a new baseline SCr of 2.8 mg/dL.
On day 8 of her course, she experienced abrupt on-
set of bilateral knee and hip pain, severely limiting her
ability to walk. She was afebrile, but had warmth and
effusion most pronounced over the right knee. There was
no rash. The plasma white blood cell (WBC) count was
25,800 cells/µL (normal, 4.0 to 11.1 cells/µL). Arthro-
centesis of the right knee was performed; gram stain re-
vealed no organisms, but heavy neutrophils. The synovial
fluid WBC count was 48,400 cells/µL (normal, <200
cells/µL). The fluid was turbid, and there were no
crystals.
Cultures of synovial fluid and blood did not grow any
organisms. The patient was treated empirically with in-
travenous ertapenem 500 mg per day and vancomycin
750 mg per day, for a total course of 14 days. Her knee
pain slowly improved, and she was able to resume am-
bulation. She was discharged on day 11 of her course.
On day 17 of her course, the patient was readmitted
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R. FUQUAY ET AL.
2
with a SCr of 3.9 mg/dL. Repeat allograft biopsy showed
Banff Ib rejection with mild interstitial fibrosis and tubu-
lar atrophy, resulting in 6 more doses of OKT3. SCr fell
to a new baseline of 2.9 - 3.3 mg/dL.
On day 28 of her course, the patient was readmitted for
knee pain. A repeat arthrocentesis of the right knee was
performed, and the rheumatology consult service saw the
patient. The leading diagnoses under consideration were
serum sickness reaction, palindromic rheumatoid arthritis,
and seronegative spondyloarthropathy. A CMV poly-
merase chain reaction (PCR) was ordered on the synovial
fluid. The synovial fluid CMV PCR was positive at 1660
copies/mL (nl, <100 copies/mL). On day 30, the serum
CMV and Epstein-Barr virus (EBV) PCR tests were
positive at 113,500 and 71,950 copies/mL, respectively
(CMV and EBV PCR normal, <100 copies/mL). HSV
PCR was negative. Other negative serologies included
HIV, hepatitis B, hepatitis C, and parvovirus IgM.
After the second arthrocentesis, the patient was started
on renally-adjusted valganciclovir at 450 mg every other
day. She experienced rapid improvement in her joint pain
and swelling. The patient completed a three-month
course of valganciclovir (adjusted for changes in renal
function). She continues to have intermittent pain in the
right knee, but there is no warmth or swelling. Subse-
quent serum PCR screens for CMV showed a nearly
10-fold reduction at 12 days after initiation of valganci-
clovir, and undetectable levels 48 and 52 days after ini-
tiation of treatment. EBV PCR was repeated 6 weeks
after start of valganciclovir and found to be negative.
2. Discussion
We present here a case of CMV-induced acute oligo-
arthritis after lymphocyte-depleting immunosuppression
for acute renal allograft rejection. CMV infection is a
major cause of morbidity and mortality in the renal
transplant population, and CMV pneumonitis was a ma-
jor cause of death in renal transplant recipients before the
availability of chemoprophylaxis [1]. In addition, CMV
infection and disease have been found to be associated
with acute rejection as well as overall mortality in kidney
transplant recipients [2].
Arthritis is a rare manifestation of CMV disease,
which to our knowledge has only been described in two
renal transplant recipients [3,4] and one bone marrow
transplant recipient [5]. Of the two renal transplant pa-
tients with CMV arthritis, the earlier patient died without
any direct treatment of the CMV disease in 1978. The
later patient received first intravenous, and then oral,
ganciclovir with resolution of the infection in 1999. Both
had synovial fluid aspirations with neutrophilic pre-
dominance. The differential diagnosis of acute arthritis in
immunocompromised hosts includes, but is not limited to,
infectious diseases, metabolic disorders such as gout,
connective tissue diseases, and drug reactions including
serum sickness. Additionally, idiopathic transudative
effusions have been described in a case series of 37 kid-
ney transplant recipients at Indiana University that had
11 cases of arthritis with effusion. Sampling revealed that
all effusions were transudative, free of crystals, and had
an average WBC count of 28 cells/uL [6]. The differen-
tial diagnosis of post-transplant arthralgia is presented in
Table 1.
To our knowledge, this case is the first to describe
successful treatment of CMV-induced arthritis with val-
ganciclovir, the orally available prodrug of ganciclovir.
Valganciclovir has an oral bioavailability of 70%, com-
pared to 7% for ganciclovir [10]. A study by Asberg, et
al compared the efficacy of oral valganciclovir to intra-
venous ganciclovir in 321 solid organ transplant recipi-
ents with tissue-invasive CMV disease [11]. Patients
were randomized to receive 21 days of either 900 mg
oral valganciclovir twice daily or 5 mg/kg intravenous
ganciclovir twice daily, followed by 49 days of valganci-
Table 1. Differential diagnosis of arthritis in a renal transplant patient.
Etiology of post-transplant arthral g i a : Synovial fluid characteristics [7,8] Clinical notes
Septic (bacterial, and rarely viral, fungal, or
spirochetal)
10,000 to 100,000 wbc/µL; >90%
neutrophils; opaque to purulent
Culture sensitivities vary with bacterial
organism; other infections require PCR or
special culture techniques
Serum sickness 2000 to 75,000 wbc/µL; >50%
neutrophils; yellow to opaque
Fever and rash accompany polyarthralgias 1 - 2
weeks after exposure; caused by immune
complex deposition and complement activation
Metabolic/crystalline (gout and pseudogout) >3000 wbc/µL; <50% neutrophils; yellow to
opaque
Cyclosporine impairs tubular excretion of uric
acid; in one study it caused gout in 24% of renal
transplant patients [9]
Autoimmune (RA, lupus) 2,000 to 75,000 wbc/µL; > 50% neutrophils;
yellow to opaque
Diagnosis based on American College of
Rheumatology
Non-inflammatory <2000 wbc/µL; <75% neutrophils; yellow
+/− bloody Consider trauma, OA

R. FUQUAY ET AL. 3
clovir therapy. At one year of follow up, rates of CMV
recurrence were similar between groups (14.8% and
15.5% for valganciclovir and ganciclovir groups, respe-
ctively, p = 0.89), as was patient survival and renal func-
tion.
This case highlights the importance of CMV chemo-
prophylaxis in heavily immunosuppressed patients. In this
case, induction therapy was followed by chemoprophy-
laxis, but not subsequent courses of lymphocyte-deple-
ting therapy for acute rejection, which led to a complica-
tion. Induction therapy or treatment of rejection with
lymphocyte-depleting therapy raises the risk of CMV
infection and disease. In one study, adding OKT3 treat-
ment as induction therapy raised the incidence of CMV
disease from 21% to 59% [23]. USRDS data have shown
that recipients of CMV seropositive kidneys who do not
receive prophylaxis have increased rates of CMV disease,
allograft loss, and healthcare costs [12]. A recent Coch-
rane review found that prophylaxis for high risk patients
reduces CMV infection, disease, and mortality in solid-
organ transplant recipients by 39%, 58% and 37%, re-
spectively [13].
In this patient, CMV prophylaxis was withheld in the
days following lymphocyte-depleting therapy due to con-
cerns for side effects related to the patient’s fluctuating
renal function. Valganciclovir is known to cause anemia
and leucopenia, but in severe cases involving improper
dosing, fatalities have been reported [14]. In -vitro studies
have shown that ganciclovir inhibits T-lymphocyte acti-
vation and proliferation at therapeutic concentrations
[15].
The patient may have benefited from a preemptive
screening strategy, which has been recommended as an
alternative to universal prophylaxis in kidney transplant
recipients at risk for CMV infection [16,17]. While pro-
phylaxis has been associated with superior graft and pa-
tient survival [18,19], as well as cost and quality of life
benefits [20] compared to a preemptive strategy, the lat-
ter may be appropriate for patients at risk for CMV dis-
ease with contraindications to oral valganciclovir therapy
[17,21]. In such an approach, monitoring of the serum C-
MV PCR is conducted at regular intervals (often weekly) to
detect infections before tissue-invasive disease results
[17]. Most CMV infections occur in the first few months
after transplantation, or the first few months after CMV
prophylaxis is stopped [22].
Treatment of CMV disease usually includes stopping
lymphocyte-depleting therapy, reducing the dose of other
immunosuppressive medications, and instituting antiviral
therapy [14,17]. During treatment, the PCR is followed
to verify that the virus is responding to the drug. In rare
cases, primarily occurring in donor-positive to recipi-
ent-negative transplants, there have been antiviral-resis-
tant CMV strains, with reported adverse outcomes [14,
17].
This case has some notable limitations. No effort was
made to establish a histologic diagnosis or conduct im-
munofluorescence, as the patient improved briskly with
valganciclovir. Additionally, it is impossible to defini-
tively exclude culture-negative septic arthritis, a transient
EBV mononucleosis, or systemic CMV viremia that
“overflowed” into the joints. However, the patient’s
monoarticular pain, joint effusion, and the positive syno-
vial fluid PCR indicate that the synovium was a focus (if
not the only focus) of viral replication. Furthermore, the
synovial fluid characteristics such as neutrophilic pre-
dominance are consistent with previous biopsy-proven
cases of CMV arthritis. Serum sickness was unlikely
based on the asymmetry, severity, and rapidity of the
arthritis, the lack of rash or fever, and recurrence of
symptoms without further drug exposure. Though the
CMV PCR was not impressively high, we believe that
may have to do with acquisition and handling; CMV is
the best explanation for the clinical scenario.
In summary, we have reported a case of CMV-induced
oligo-arthritis that followed aggressive immunosuppres-
sion for treatment of acute rejection of a kidney allograft.
This disease may have been prevented, or diagnosed ear-
lier, through the use of chemoprophylaxis or preemptive
screening. Oral valganciclovir is an effective treatment
for CMV disease, and other treatment considerations
were reviewed.
3. Author Contributions
Richard Fuquay and James Cooper participated in the
preparation of the manuscript.
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