Cytomegalic inclusions in pancreatic allograft after simultaneous pancreas-kidney transplantation: case report and literature review
ABSTRACT The incidence of cytomegalovirus (CMV) infection has increased inthe past years due to the use of more potent immunosuppressors,such as tacrolimus and mycophenolate. This is related to the earlypost transplantation period, when immunosuppressive regimenis more intense. Other well-known risk factors for CMV infectioninclude the serological status of donor (D) and recipient (R) and theuse of monoclonal or polyclonal antibodies for induction therapy or fortreating acute rejection. In the present study, it was reported a case ofan invasive CMV infection in the parenchyma of pancreatic allograftafter simultaneous pancreas-kidney transplantation. Upon diagnosis ofCMV infection, the patient also presented other clinical complicationsrelated to the transplant, such as bacterial and fungal infection, as wellas enteric fistula. The occurrence of invasive CMV infection is a rareevent, but it should be suspected if high risk factors for this infection arepresent or if there are concomitant clinical or surgical complications.Keywords: Cytomegalovirus infections; Pancreas transplantation;Kidney transplantation; Case reports
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ABSTRACT: Cytomegalovirus (CMV) infection is a common problem in solid organ transplant recipients. CMV infection of pancreas allografts is not, however, well described. We report the clinical presentation, histologic findings, treatment, and outcome in four patients with CMV allograft pancreatitis. These patients presented 18 weeks to 44 months after transplantation with elevated serum amylase and lipase and were suspected to have acute rejection. Percutaneous pancreas allograft biopsy specimens showed evidence of tissue invasive CMV infection. One patient had simultaneous CMV infection and acute rejection. Prolonged treatment with ganciclovir resulted in clinical and histologic resolution of the CMV disease. Rejection was successfully treated. Primary CMV infection in seronegative recipients seemed to be a risk factor. Three patients maintain normal allograft function; one patient lost function due to chronic rejection. The histology of tissue-invasive CMV pancreas allograft infection and its differentiation from acute rejection is described. Prompt diagnosis and prolonged therapy with antiviral agents can result in maintenance of allograft function.Transplantation 06/2000; 69(9):1968-71. · 3.78 Impact Factor
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ABSTRACT: The impact of tacrolimus (TAC), mycophenolate mofetil (MMF) and steroid immunosuppression on cytomegalovirus (CMV) infection in combination with ganciclovir prophylaxis in simultaneous kidney-pancreas transplantation (SKPT) has not been well studied. A retrospective analysis was made of 75 SKPTs performed between 1 January 1996 and 7 January 1999. All patients received ganciclovir for 3 months, but CMV donor (D)+ / recipient (R)- patients received ganciclovir for 6 months. 16/74 (22%) were CMV D+/R-, 25 (33%) D+/R+, 16 (22%) D-/R+, and 17 (23%) D-/R- (1 patient with unknown donor serology was excluded). The mean time to CMV infection was 198 days post-transplant. The incidence of either CMV infection or tissue invasive CMV disease was 16/74 (22%), including 9 (12%) with CMV infection and 7 (10%) CMV disease. The one-year patient, kidney, and pancreas graft survival rates were 91%, 89%, and 83%, respectively. The mean follow-up was 29 months (minimum of 12 months). CMV infection was not associated with an increased incidence of graft failure or mortality. The D+/R- group had the highest incidence of CMV infection (44%) compared with the other serologic groups (17%, P=0.02). Concurrent CMV and rejection occurred more frequently in the D+/R- than the other serologic groups (25% vs. 7%, P=0.03). The D-/R- group had the best outcomes, with no CMV infection, improved kidney graft survival at the end of follow-up (82% vs. 72%, P=0.04) and the highest event-free survival (no CMV infection, rejection, or graft loss) when compared to the other groups (76% vs. 33%, P<0.01). Compared to previous studies, ganciclovir prophylaxis delayed the onset and reduced the severity of CMV infection in patients receiving TAC, MMF, and steroids. Despite ganciclovir prophylaxis, CMV seronegative patients receiving CMV D+ organs had worse outcomes than seronegative recipients receiving CMV D- organs.Transplant Infectious Disease 03/2001; 3(1):8-15. · 1.98 Impact Factor
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ABSTRACT: Background. The relevance of cytomegalovirus (CMV) in simultaneous pancreas kidney (SPK) transplant recipients in the modern era of immunosuppression and antiviral therapeutics is largely unquantified. We sought to determine the risk factors of CMV disease and its impact on SPK transplant outcomes in recipients all receiving a consistent regime of maintenance immunosuppression and CMV prophylaxis. Methods. This is a retrospective, single center study of 100 consecutive SPK transplant recipients. All received maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. CMV prophylaxis consisted of a short course of parenteral gancyclovir followed by oral gancyclovir. Recipients at high-risk (D+/R-) for CMV also received CMV hyperimmune globulin. Multivariate analysis of risk factors for CMV disease and risk factors for adverse outcomes in SPK transplantation were determined. The effect of duration of prophylaxis on timing and severity of CMV disease in high-risk (D+/R-) SPK transplant recipients was also evaluated. Results. The actual 1-year rate of CMV disease was 17.0% (12.0% noninvasive, 5.0% tissue invasive); and according to donor and recipient CMV serological status was: D-/R+: 0%; D-/R-: 2.8%; D+/R+: 25.6%; and D+/R-: 40.6%. Multivariate analysis showed transplantation of organs from a donor with positive CMV serology to be predictive of CMV disease with a relative risk of 63.37 (P =0.0052). In the high-risk (D+/R-) subgroup, the duration of prophylactic therapy delayed onset of CMV disease, but had minimal effect on severity. Invasive CMV disease was an independent predictor of mortality but did not decrease kidney or pancreas allograft survival. Conclusions. Outcomes of SPK transplantation have improved in the current era of modern immunosuppression, yet CMV remains an important pathogen. The serological status of the organ donor and the duration of CMV prophylaxis are predictive of who and when CMV disease may occur. Nevertheless, new strategies that reduce risk and severity of CMV disease are still needed.Transplantation 12/2001; 72(12):1940-1945. · 3.78 Impact Factor
einstein. 2008; 6(4):481-4
Cytomegalic inclusions in pancreatic allograft after
simultaneous pancreas-kidney transplantation:
case report and literature review
Detecção de inclusões citomegálicas no enxerto pancreático após o transplante simultâneo
de pâncreas-rim: relato de caso e revisão da literatura
Érika Bevilaqua Rangel1, Irina Antunes2, Denise Maria Avancini Costa Malheiros3, Fábio Crescentini4, Tércio Genzini5,
Marcelo Perosa de Miranda6
The incidence of cytomegalovirus (CMV) infection has increased in
the past years due to the use of more potent immunosuppressors,
such as tacrolimus and mycophenolate. This is related to the early
post transplantation period, when immunosuppressive regimen
is more intense. Other well-known risk factors for CMV infection
include the serological status of donor (D) and recipient (R) and the
use of monoclonal or polyclonal antibodies for induction therapy or for
treating acute rejection. In the present study, it was reported a case of
an invasive CMV infection in the parenchyma of pancreatic allograft
after simultaneous pancreas-kidney transplantation. Upon diagnosis of
CMV infection, the patient also presented other clinical complications
related to the transplant, such as bacterial and fungal infection, as well
as enteric fistula. The occurrence of invasive CMV infection is a rare
event, but it should be suspected if high risk factors for this infection are
present or if there are concomitant clinical or surgical complications.
Keywords: Cytomegalovirus infections; Pancreas transplantation;
Kidney transplantation; Case reports
A incidência de infecção pelo citomegalovirus (CMV) vem aumentando
nos últimos anos devido ao uso de imunossupressores mais potentes,
como o tacrolimus e o micofenolato. Isso se aplica ao período logo após
o transplante, quando o regime imunossupressor é mais intenso. Outros
fatores de risco para infecção por CMV incluem o uso de anticorpos
monoclonais ou policlonais para tratamento de indução ou de rejeição
aguda, além de sorologia para CMV do doador (D) e do receptor (R). No
presente trabalho, relatou-se um caso de infecção invasiva por CMV
no parênquima do enxerto pancreático de um paciente submetido ao
transplante simultâneo de pâncreas e rim. Na ocasião do diagnóstico
da infecção por CMV, o paciente apresentava outras complicações
clínicas relacionadas ao transplante, como infecção bacteriana e
fúngica, além de fístula entérica. A ocorrência de infecção invasiva por
CMV no enxerto pancreático é um evento raro, mas deve ser suspeitada
quando os pacientes apresentam risco elevado para esta infecção ou
quando há várias complicações clínicas e cirúrgicas.
Descritores: Infecções por citomegalovirus; Transplante de pâncreas;
Transplante de rim; Relato de casos
The incidence of cytomegalovirus (CMV) infection after
simultaneous pancreas-kidney transplantation (SPKT)
ranges from 17 to 52%(1-3). CMV infection is associated
with an increased risk of acute rejection after SPKT; an
incidence of 66% of acute rejection was reported when
CMV infection was present, as opposed to 41% of acute
rejection when this infection is absent(2).
The serological status of donor (D) and recipient (R)
and the use of induction with monoclonal or polyclonal
Study carried out at Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
1 PhD; Nephrologist at the Pancreas-Kidney Transplantation Unit of Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
2 PhD; Nephrologist at the Pancreas-Kidney Transplantation Unit of Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
3 PhD; Pathologist at Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
4 Surgeon at the Pancreas-Kidney Transplantation Unit of Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
5 Master’s Degree; Surgeon at the Pancreas-Kidney Transplantation Unit do Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
6 Master’s Degree; Surgeon at the Pancreas-Kidney Transplantation Unit of Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.
Corresponding author: Érika Bevilaqua Rangel – Avenida Albert Einstein, 627 – Morumbi – CEP 05651-901 – São Paulo (SP), Brasil – Tel.: 11 5081-7034 – e-mail: email@example.com
There is no conflict of interest.
Received on Jan 7, 2008 – Accepted on Aug 11, 2008
einstein. 2008; 6(4):481-4
482Rangel ÉB, Antunes I, Malheiros DMAC, Crescentini F, Genzini T, Miranda MP
antibodies are the main risk factors for CMV infection
and disease(2-3). Transplantation of organs from a donor
with positive CMV serology is predictive of CMV
disease in recipients with negative serology (41%), and
the relative risk is of 63.4%(3). Although prophylaxis
with Gancyclovir® could decrease the incidence of
CMV infection, in the high risk (D+/R-) subgroup the
duration of prophylactic therapy delayed the onset of
CMV disease, but had minimal effect on its severity(3).
One case of CMV disease which was invasive in
pancreas allograft is reported, addressing its high
suspicion of diagnosis when other severe infection is
present after SPKT.
A 35-year-old black man, type-1 diabetic patient, on
insulin for 20 years and on hemodialysis for six years was
submitted to SPKT. The donor was a 41-year-old female
patient who presented ischemic stroke and was receiving
noradrenaline 0.39 mcg/kg/min. Cold ischemia time for
kidney allograft was nine hours and for pancreas allograft
was 13 hours. The pancreatic allograft exocrine secretion
was drained into the proximal jejunum via a side-to-side
duodenojejunostomy and insulin delivery was systemic.
Serologic status for cytomegalovirus was D+/R+.
Initial immunosuppressive regimen included tacrolimus
0.15 mg/kg/dose, mycophenolate sodium 1.44 g/day
and methylprednisolone (500 mg/day followed by
250 mg/day and 125 mg/day and then tapering doses of
prednisone 1 mg/day).
Although the cold ischemia time for kidney was
shorter, he presented delayed graft function and was
submitted to hemodialysis sessions during the first
week. Induction with thymoglobuline was initiated at
three doses of 100 mg every two days. Pancreas allograft
function was immediate.
On the ninth day, he presented an infection in the
dual-lumen hemodialysis catheter secondary to Candida
parapsilosis, and endovenous fluconazole 200 mg/day was
started. Transthoracic echocardiogram displayed a mass
of 2 versus 4 cm attached to the right atrium. Moreover,
blood stream infection attributed to Enterococcus faecium
was treated with vancomycin and the dose was adjusted
to kidney function. Wound infection by Enterobacter
cloacae was treated with imipenem.
On the 15th day, he presented enteric fistula and
was submitted to Roux-en-Y anastomosis. However, he
maintained abdominal drain with elevated drainage (600
to 1,900 ml/day) and amylase levels from drain ranged
from 3,150 to 16,424 U/l. On the 33rd day, the patient
was submitted to pancreas allograft removal due to
persistent enteric leak and to worsening of clinical and
hemodynamic parameters. He presented septic shock
secondary to pulmonary infection and died on the 41st
day. Histopathological analysis from pancreas allograft
revealed cytomegalic inclusions (Figures 1 to 3).
However, the CMV antigenemia was not available.
Figure 1. Viral cytopathic changes (arrows) in pancreatic parenchyma of
pancreas allograft associated with the presence of neutrophils and eosinophils
(hematoxylin-eosin, magnification X100)
Figure 2. Cytomegalic nuclear inclusions (arrow) in pancreatic parenchyma of
pancreas allograft associated with the presence of neutrophils and eosinophils
(PAS, periodic-acid-Schiff, magnification X400)
Figure 3. Cytomegalovirus (arrows) in pancreatic parenchyma of pancreas
allograft (immunohistochemistry, magnification X200)
einstein. 2008; 6(4):481-4
Cytomegalic inclusions in pancreatic allograft after simultaneous pancreas-kidney transplantation: case report and literature review 483
In the present study, it was reported a case of a male
patient submitted to SPKT and with high risk of
cytomegalovirus (CMV) infection (use of polyclonal
antibody and serological status D+/R+).
The incidence of CMV infection after organ
transplantation increased after the use of tacrolimus and
mycophenolate and led to several studies on prophylaxis
with Gancyclovir®, Valgancyclovir® or Acyclovir®(1-3).
The CMV infection is also significantly associated with
acute rejection, although not affecting patient and
allograft survivals(2). However, invasive CMV infection
is usually associated with higher mortality(3), as in the
Pancreatitis of pancreas allograft is a rare event
and may be associated with either acute or chronic
rejection(4). A correlation between pancreatitis of
pancreas allograft and CMV infection has not been well
established. However, pancreatitis could be related to
acute rejection(4), peripancreatic abscess(5) and enteric
perforation(6). In patients with multiple infections
after SPKT, either from bacterial or fungal etiology,
CMV infection may also be investigated because
these complications are compatible with an over-
immunosuppression condition. This suspicious should
be even greater in those patients with well-known risk
factors for CMV infection.
In the present case, the detection of cytomegalic
inclusions and the occurrence of pancreatic leak may
be an epiphenomenon. The pancreatic leak is usually
secondary to infection in the peritoneal cavity and
to peripancreatic sepsis(7). Patients usually present
persistent ileus, fever, abdominal pain, leukocytosis,
and tenderness between 7 and 14 days after surgery, as
observed in this case. The diagnosis of pancreatic leak
is made based on clinical parameters and by abdominal
ultrasound or computed tomography scan. Treatment
includes abdominal lavage, debridement of necrotic
peripancreatic fat, and antibiotics. Prolonged attempts
to treat with antibiotics may lead to fungal peritonitis.
If leakage occurs, an attempt at anastomotic revision is
warranted, but removal of the pancreas may ensue with
treatment failure. Complications requiring laparotomy
result in increased mortality(7), as observed in the
Another important point is the prophylaxis of
CMV infection. Its high cost is a matter of concern
and; therefore, is not routinely performed in most
Brazilian transplantation centers. The optimal
prophylaxis regimen for CMV infection after kidney
and/or pancreas transplantation remains unclear.
Recently, it was shown that three months of low-
dose Valgancyclovir® (450 mg/day) was as effective
as Gancyclovir® (3 g/day) for prophylaxis of CMV
disease after kidney pancreas-kidney transplantation
(2.9 versus 5.4%, respectively)(8). In accordance to
other studies, race/ethnicity, type of transplant, type
of antiviral prophylaxis, CMV serostatus, and use
of mycophenolate were all associated with risk of
developing CMV disease(8). Hence, the patient could
have had the benefit of CMV prophylaxis, inasmuch
as he was black, used polyclonal antibody and
mycophenolate and had positive serology for CMV
In regard to immunosuppressive regimen, the
incidence of CMV disease in the prednisone-free group
in comparison to steroid-treated group dropped from
36 to 18% only in recipients at highest risk (D+/R-
or D+R+) after SPKT(9). This could be also a useful
strategy in patients under high risk of CMV disease or
In the SPKT, the presence of multiple infections,
such as those of bacterial or fungal etiologies may be
associated with cytomegalovirus infection during the
early post-transplantation period, since this interval is
associated with an over-immunosuppression condition.
Invasive cytomegalovirus in pancreas parenchyma
allograft is a rare event, but it may be suspected in
patients at high risk of cytomegalovirus infection and
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al. Patterns of cytomegalovirus infection in simultaneous kidney-pancreas
transplant recipients receiving tacrolimus, mycophenolate mofetil, and
prednisone with ganciclovir prophylaxis. Transpl Infect Dis. 2001;3(1):
2. Ricart MJ, Malaise J, Moreno A, Crespo M, Fernández-Cruz L; Euro-SPK Study
Group. Cytomegalovirus: occurrence, severity, and effect on graft survival
in simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant.
2005;20 Suppl 2: ii25-32,ii62.
3. Kaufman DB, Leventhal JR, Gallon LG, Parker MA, Koffron AJ, Fryer JP, et al.
Risk factors and impact of cytomegalovirus disease in simultaneous pancreas-
kidney transplantation. Transplantation. 2001;72(12):1940-5.
4. Klassen DK, Drachenberg CB, Papadimitriou JC, Cangro CB, Fink JC, Bartlett
ST, et al. CMV allograft pancreatitis: diagnosis, treatment, and histological
features. Transplantation. 2000;69(9):1968-71.
5. Bäckman L, Brattström C, Reinholt FP, Andersson J, Tydén G. Development of
intrapancreatic abscess – a consequence of CMV pancreatitis? Transpl Int.
6. Jang HJ, Kim SC, Cho YP, Kim YH, Hans MS, Han DJ. Cytomegalovirus infection
of the graft duodenum and urinary bladder after simultaneous pancreas-kidney
transplantation. Transplant Proc. 2004;36(7):2200-2.
7. Zaman F, Abreo KD, Levine S, Maley W, Zibari GB. Pancreatic transplantation:
evaluation and management. J Intensive Care Med. 2004;19(3):127-39.
einstein. 2008; 6(4):481-4
484Rangel ÉB, Antunes I, Malheiros DMAC, Crescentini F, Genzini T, Miranda MP
8. Weng FL, Patel AM, Wanchoo R, Brahmbhatt Y, Ribeiro K, Uknis ME, et al. Oral
ganciclovir versus low-dose valganciclovir for prevention of cytomegalovirus
disease in recipients of kidney and pancreas transplants. Transplantation.
9. Axelrod D, Leventhal JR, Gallon LG, Parker MA, Kaufman DB. Reduction
of CMV disease with steroid-free immunosuppresssion in simultaneous
pancreas-kidney transplant recipients. Am J Transplant. 2005;5(6):