Title

Author(s)

Review on cytomegalovirus infection in renal transplant

recipients

Yeung, Ming-fong;

Citation

Issued Date

URL

Rights

2011

http://hdl.handle.net/10722/144856

Creative Commons: Attribution 3.0 Hong Kong License

Reviewoncytomegalovirusinfectioninrenaltransplantrecipients

By

DrYEUNGMingFong

Thisworkissubmittedto
FacultyofMedicineofTheUniversityofHongKong
Inpartialfulfillmentoftherequirementsfor
ThePostgraduateDiplomainInfectiousDiseases,PDipID(HK)

Date:29June2011

Supervisor:DrVCCCheng

Declaration

I,YEUNGMingFong,declarethatthisdissertationrepresentsmyownworkandthat
it has not been submitted to this or other institution in application for a degree,
diplomaoranyotherqualifications.
I,YEUNGMingFongalsodeclarethatIhavereadandunderstandtheguidelineon
What is plagiarism? published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.

Candidate: YEUNGMingFong

Signature:

Date:
29thJune,2011

Abstract
Cytomegalovirus infection (CMV) is the most important infection among various
common pathogens in post renal transplant recipients and it carries significant
morbidity and mortality. Most of the populations in Hong Kong are carrying CMV
immunoglobulin G in the body. Reactivation of latent CMV can be a result of
immunocompromise. Superinfection from another virus strain can also cause CMV
infection. Cytomegalovirus can modulate host immune system and induce allograft
rejection. Moreover, high risk group patient especially CMVseronegative recipient
receiving renal allograft from CMVseropositive donor should be identified and this
group of patients is warranted antiviral treatment. Because of morbidity related to
CMV and the ability of CMV to cause invasive disease in distant organs, early
detectionofviraemiaandinitiationofprompttreatmentasearlyaspossiblearethe
important steps for successful management and good prognosis of the disease.
Variouslaboratorydetectionmethodshavebeenusedandthosemethodswhichcan
yield rapid results are most preferred rather than histopathology. Various regimens
had been studied for CMV prophylaxis and preemptive therapy in the literature.
Adverse side effects associated with antiviral agents should also be considered
especiallyrenaldoseadjustmentshouldnotbeoverlooked. Thisisareviewofthe
3

basisofCMVinfectionafterkidneytransplantationandrelatedimportantissues.
1.0 Background
Renal transplantation is one of the wellestablished modes of renal replacement
therapyintheworldandconfersafewadvantagesoverothermodesofreplacement
therapy.Itoffersbetterrehabilitationandthebestqualityoflife,mostofthepatients
can seemingly lead life like normal person. Renal transplantation also has better
survivalfiguresoverotherreplacementtherapy.

However, despite continuous improvement in immunosuppressive regimen, better

graft preservation and surgical techniques, infection remains a significant cause of
morbidity and mortality after the patient receiving kidney transplant. Post renal
transplant patients are particularly at risk of infection because of their
immunecompromised state. The evaluation of infection risk and the attempt to
minimizepostrenaltransplantinfectionshouldbeginatapretransplantlevel,with
bothdonorandtherecipient.

Thisreviewwillconcentrateoncytomegalovirusinfectionwhichisawellrecognized
importantinfectioninpostrenaltransplantperiodthatcancausedirectandindirect
effectsresultinginspectrumofillnessrangingfromasymptomaticviraemiatofever
4

with neutropenia, graft failure and even invasive diseases in organs apart from the
kidneys.Thisinfectioncanresultinsignificantmorbidityandmortality.

2.0 Epidemiology
The seroprevalance of CMV ranges from 40% to 97%, depends on the population
screened, and increases with ages (1). In developed countries, about 70% of adults
haveasymptomaticlatentCMVinfection.InHongKong,morethan90%oftheadult
population has CMV immunoglobulin G (IgG) already in the body whereas in
newbornsaround95%(2).Incontrast,thereisonlyaround50%ofadultpopulation
hasCMVIgGintheirbodyinthepopulationinUnitedKingdom.Infact,mostofthe
dialysis patients have detectable immunoglobulin G to CMV. The CMV antibody
statusshouldbeascertained,andtheimportancewouldbediscussedfurtherbelow.

CMVcanbereactivatedifthepatientisimmunosuppressed.Atthesametime,CMV
is the most common viral infection after kidney transplantation. CMV infection
occursprimarilyafterthefirstmonthoftransplantationwithanestimatedincidence
of30%to78%ifantiviralprophylaxisisnotadministered,dependingontheserologic
status of the donor and recipient. Among all organ transplants, renal transplant
recipientshavethelowestriskforCMVdiseaseintheabsenceofantiviralprophylaxis
5

thanpancreasorkidneypancreastransplantrecipient.

3.0 Virology
Cytomegalovirus(CMV)wasfirstisolatedfromthesalivaryglandandkidneysoftwo
dyinginfantsandwasfoundtohavecytomegalicinclusionbodiesandthecaseswere
thus reported in 1956. Two other laboratories isolated CMV at approximately the
same time. Thus, CMV was initially called salivary gland virus or salivary gland
inclusion disease virus. In 1960, Weller et al. (3) proposed the use of the
cytomegalovirus.CMVwasfirstisolatedinarenaltransplantrecipientin1965(4).

Cytomegalovirusisthelargestmemberofthehumanherpesvirusgroupandisthe
largestknownvirustoinfecthumans.TheCMVgenomeisalinear,doublestranded
DNA molecule (230 Kbp) that has been completely sequenced and contains
nonoverlapping open reading frames for 230 proteins, many of which play a
significant role in downregulation of the immune response. It is classified as a
herpesvirus,togetherwithhumanherpesvirus6(HHV6)andHHV7.

4.0 ClinicalFeatures
Clinical presentation of cytomegalovirus (CMV) Infection can range from
6

asymptomatic viraemia to CMV syndrome often a flulike illness with fever,

malaise,myalgiasandfatigue,leukopenia,hepatitisandthrombocytopenia;toeven
invasive CMV disease with inflammation of distant organs systems or direct
involvementoftransplantedrenalallograft.

There is important distinction between CMV infection and CMV disease in the
terminology.

4.1 CMVinfection

Active CMV infection may be symptomatic or asymptomatic. It is characterized by

viralreplicationandsheddingwithaspecifichostcellularimmuneresponsetoCMV.
Primary CMV infection represents infection in the previously uninfected
seronegative host, whereas secondary CMV infection represents infection in a
previously infected seropositive host caused by either reactivation of latent
endogenousvirus,orsuprainfectionwithnewvirusstrain.CMVcanbetransmitted
bytherenalallograft,throughbloodproducts,orbysexualcontactandestablishes
lifelonglatencyafterprimaryinfection.

CMV infection is defined by detection of virus via culture,molecular techniques or

7

changesinserology.CMVInfectionisconsideredtobepresentifoneormoreofthe
followingfindingsarenoted(5):
1)seroconversionwiththeappearanceofantiCMVIgMantibodies;
2)afourfoldincreaseinpreexistingantiCMVIgGtiters;detectionofCMVantigens
ininfectedcells;3)detectionofCMVDNAemiabymoleculartechniques;and/or
4)isolationofthevirusbycultureofthethroat,buffycoat,orurine.

4.2 CMVDisease

CMVcanexertitsdirectviruspathology.CMV disease most commonly presents as

viraemic syndrome, manifested by fever, malaise, myalgia, leukopenia, deranged
liver function tests (mainly raised transaminases) and detection of CMV
antigenaemia. Unlike mononucleosis, it is rare to have enlarged lymph node or
atypical lymphocytes on blood film. Differential diagnoses needed to be consider
hereinsuchacontextofCMVsyndromeareotherinfections,graftrejection&drug
toxicities.

Onthecontrary,moreserioustypeofdiseasescausedbyCMViscalledinvasiveCMV
disease which presents as other organspecific involvement. These include
pneumonitis,pancreatitis,colitis,meningoencephalitis,andrarelymyocarditis(6,7,8).
8

PneumonitisisthemostseriousmanifestationofCMVdiseaseandischaracterized
by dyspnea, hypoxaemia, interstitial infiltrates, and detection of CMV antigens,
nucleic acids or inclusion bodies on bronchoalveolar lavage (BAL). CMV upper and
lower gastrointestinal diseases include oesophagitis, cholecystitis, duodenitis,
hepatitis and colitis. Diagnostic endoscopy can reveal solitary or multiple mucosal
ulcerations with haemorrhage. Tissue specimens should be stained for CMV using
immunofluorescent antiCMV antibody and examined for inclusion bodies. CMV
chorioretinitis, relatively common in patients with the acquired immunodeficiency
syndrome(AIDS),isararefeatureofCMVdiseaseintransplantrecipients.However,
progressive chorioretinitis, when it occurs, can become clinically apparent several
months after transplantation, even in patients without previous evidence of
symptomatic infection. It can be diagnosed by direct fundoscopy. Central nervous
systemCMVdiseaselikemeningitis,encephalitisandmyelitis,maybemoredifficult
to diagnose. Neurologic disease caused by other neurotropic opportunistic
pathogens, and drug toxicities, should be simultaneously investigated. Multiorgan
involvementcanbeobservedinthosepatientswithdisseminatedCMVdisease.

Studies had shown that CMV disease is associated with an increased overall
mortality. But moreover, asymptomatic CMV infection was even associated with
9

relativeriskofoverallmortalityof2.9(9).CMVinfectioninfacthaseffectofimmune
modulationandcausingdysregulationonthehostimmunesystem.Thiscanresultin
high chance of graft rejection. It has been postulated that CMV infection can
precipitatethedevelopmentofotheropportunisticinfection,whichinturncanagain
cause allograft dysfunction or rejection (10). Moreover, CMV can lead to the
developmentofposttransplantlymphoproliferativedisease(PTLD).

CMV is the single most important pathogen in transplant recipients due to both
directandindirecteffects(Table1).

Table1 DirectandindirecteffectsofCytomegalovirus(CMV)infection(11).

DirectEffectofCMVinfection
Fever

and

neutropenia

IndirectEffectofCMVinfection
syndrome Increases risk of secondary infection

(leukopenia,

bybacteria,fungi,andviruses

fever,myalgia,fatigue,thrombocytopenia,

hepatitis,nephritis)

Increasesriskofgraftrejection(12)

Myelosuppression

Pneumonia

IncreasesriskofPTLD
10

Gastrointestinal

invasion

with

colitis,

gastritis,

May increase risk of HHV6 and

ulcers,bleeding,orperforation

HHV7

Hepatitis

infection(1315)

Pancreatitis

Chorioretinitis

Indirect effects are often significant. CMV is capable of suppressing host immune
defenses, predisposing to secondary invasion by pathogens such as Pneumocystis
jiroveci,Candida,andAspergillusspecies,andsomebacterialinfections

One of the most controversial issues regarding CMV infection in renal

transplantationiswhetherthevirusitselfcancauseallograftdysfunction,orinother
words,CMVinducedrenaldisease.Renalfunctionmaydeteriorateinpatientswith
CMVinfectionbutfactorssuchasdecreasedrenalperfusion,acutetubularnecrosis,
and transplant rejection may be more important than a direct viral effect on the
kidney. There are reports describing the occurrence of a CMVinduced transplant
glomerulopathy(16,17).

11

Some other studies and report showed that CMV had been associated with both
atherosclerosis and chronic rejection. Chronic rejection is also known as chronic
allograftnephropathyandischaracterizedbyrenaltubulardysfunction&glomerular
diseases in which myointimal thickening is a form of atherosclerosis. Latent CMV
disease can occur especially of those with antiviral prophylaxis used. Also, latent
CMVdiseasehasbeenassociatedwithhigherchanceofdevelopingtransplantrenal
arterystenosis(TRAS)withamarkedlyincreasedrateofrestenosis(1200%higher)in
nontransplantseropositiveindividualscomparedwithseronegativeindividuals(18).

5.0 Riskfactorsanalysis
CMV infection can be acquired from the donor by the allograft, by blood products
transfusedfromaseropositivedonororbysexualcontact.CMVdiseasecandevelop
asaresultfromthereactivationofthelatentrecipientvirus,particularlyinpatients
who are immunosuppressed by multiple drug therapy posttransplant. Most CMV
disease develops between one to four months post renal transplant when
prophylaxis is not used and highest doses of immunosuppressive therapy are
receiving in this period. Patient at highest risk for developing CMV infection and
disease is CMVseronegative recipient (R) receiving an allograft from a
CMVseropositivedonor(D+);inotherwords,combinationofD+/Risofhighestrisk.
12


StudieshadshownthatprimaryCMVinfection(incombinationofD+/R),theriskof
developing CMV infection without CMV prophylaxis was 7088% while risk of
developingCMVdiseasewas5680%andthosepatientshad30%chancedeveloping
pneumonitis(16).ForthosecombinationofD/R+;i.e.CMVreactivation;theriskof
CMV infection was 020% without prophylaxis while CMV disease 027%. For the
combinationofD+/R+,itcanbeeitherreactivationoflatentCMVorsuprainfection
of a new virus strain, the risk of developing CMV infection without prior CMV
prophylaxiswas70%whileriskofCMVdiseasewas2739%andthosepatientshad
314%chanceofhavingpneumonitis(19,20).

Other high risk groups include those patients with CMV infection receiving
antilymphocyte preparation for induction or treatment of rejection. The uses of
OKT3 and high dose mycophenolate mofetil (MMF) are associated with increased
viral reactivation while calcineurin inhibitors (cyclosporine A, tacrolimus) are
associated with increased viral replication. Whether the donor is CMV seropositive
or seronegative, those previously CMV seropositive recipients who were taking
antirejection,antilymphocyteantibodiesplusconventionalimmunosuppressionlike
mycophenolatemofetil,theriskofdevelopingCMVdiseasewas65%(19).
13

6.0 Laboratorydiagnosis
Historically,tissueinvasiveCMVdiseasewasdiagnosedbyhistopathology,classically
bythepresenceofCMVinclusionbodies,butthisapproachcanbeassociatedwith
diagnosticdelayorsometimesinadequatespecimencollection.

DetectionofserumCMVimmunoglobulinIgMorIgGantibodiesbyimmunoassayis
usefulforpretransplantationscreeningoftheserostatusofboththedonorandthe
recipients.Itisalsousefulfordocumentationofseroconversionbutitisinsensitive
for the diagnosis of CMV disease. Detection of CMV IgG would means latent CMV
infection or the immune status of the donor or recipient. While detection of CMV
IgMwouldmeansrecentinfectionorreactivationofpreviousCMV).

Culturebased methods include conventional tissue culture, and shell vial

centrifugation and can be performed on blood, buffy coat blood fraction, urine ,
cerebrospinalfluid(CSF),respiratorysecretionandothertissuespecimens.

Noninvasivetestswhichyieldquickresultsaremostpreferred.Thetestmustbeable
14

to predict or to enable earlier diagnosis of CMV disease rather than CMV infection
and to monitor the progress of disease. Direct detection of antigens in neutrophils
with a monoclonal antibody against the CMV matrix protein pp65 has proved
particularly useful. This detection of CMV antigenaemia by a semiquantitative
fluorescent assay also is more rapid than traditional culture methods. Viral antigen
detectioncanalsobedoneintissuebiopsies.Thispp65antigenaemiaassaycanalso
beusedtomonitortheefficacyofantiviraltreatment.

CMV DNA detection is another quantitative method of diagnosing CMV disease

associatedwithviraemiaortomonitorresponsetoantiviraltherapy.Othermethods
for detection of CMV DNA or RNA have used labeled viral nucleic acid probes and
nucleic acid hybridization in body fluids or tissue specimens (21). A few studies,
thoughusingdifferentPCRtechniques,theyshowedremarkableagreement,witha
positivepredictivevalueofapproximately60%incorrelationofthe
presenceofCMVDNAwiththesubsequentdevelopmentofclinicaldisease(2224).

Clinical laboratories are rapidly adopting kitbased molecular technology for

diagnosisofactiveCMVdisease.KitsarebasedonPCRoronasolutionhybridization
capture assay (25). Technology based on nucleic acid sequencebased amplification
15

(NASBA),althoughpromising,isnotwidelyusedatthepresenttime.

7.0 Treatment
Effective antiviral agents for CMV prophylaxis and treatment have substantially
decreasedthemorbidityandmortalityassociatedwithCMVdisease.Currently,there
aretwoprincipalapproachesinhelpingpreventCMVdiseaseinpatientsundergoing
renaltransplantation.

Aprophylacticstrategyinvolvestheadministrationofantiviralagentstopatientsat
increased risk of developing CMV infection. In contrast, a preemptive strategy
involvesperiodicmonitoringforviremia,principallyusingpolymerasechainreaction
(PCR), to permit prompt interventional treatment after the detection of very early
systemicinfection.

Theapproachofuniversalprophylaxismaybemoreusefulforpatientsathighriskfor
CMVdisease,whereaspreemptivetherapymaybemoreusefulforpatientsatlowor
intermediateriskforCMVdisease.

Thereareafewpracticalpointstobeconsidered:
16

1) A CMVseronegative recipient who receive a CMV seropositive or a CMV

nontypeddonorisofhighestrisk.Theyshouldbegivenprophylactictreatment
foratleast3months.
2) CMVseropositive recipients who have received antiT lymphocyte antibody
treatmentcanbeconsideredtoreceiveprophylactictreatmentfor3months.
3) All patients should have surveillance for early detection of CMV disease after
transplantation.ThisincludesmonitoringoflevelofCMVpp65antigenaemiafor
at least 3 months and when clinically indicated. In recipients who are
CMVseronegativeinthefirstplace,serialserologicaltestingisindicatedtodetect
seroconversion.
4) PreemptivetreatmentshouldbeconsideredinasymptomaticpatientswithCMV
pp65 antigenaemia and a recent history of pulse steroid or antiT lymphocyte
therapy.

7.1 Prophylaxis
CMVprophylaxisintreatinghighriskpatientshadprovenitsefficacy.Inasystematic
review of 19 randomised clinical controlled trials of CMV prophylaxis in solid organ
transplant recipients, the author had demonstrated that compared to placebo,
prophylaxiswithacyclovir,ganciclovirorvalaciclovirwasfoundtohave significantly
17

reducedtherisksofCMVdiseasedevelopinginthetransplantrecipients(relativerisk
0.42, 95% CI 0.430.52), while CMV infection (relative risk 0.61, CI 0.48 0.77) and
allcausemortality(26).

Ganciclovir can be given by intravenous route or by oral route. Compared with

intravenous formulations, oral form of ganciclovir is substantially less bioavailable
(4% to 6% only) and achieves significantly lower serum level, but however it is of
easieradministration.Becauseofthelowbioavailability,relativelyhighdoseoforal
ganciclovirofupto1gtdsisrequired.Hibberdgroupdemonstratedthatganciclovir
wasassociatedat6monthswithasignificantlylowerincidenceofCMVinfection,14
vs33%incontrolgroup(27).

Aprospectivestudyof101highriskrenaltransplantrecipients,whowererandomly
assignedtoprophylactictherapywithoralgancicloviroracyclovir,foundsignificantly
fewerCMVinfectionsafterthreemonthsoftherapywithganciclovirinD+/R(54vs
0%),D+/R+,andD/R+patients(28).

Valganciclovir,theLvalineesterofganciclovir,isadministeredinthedoseof450mg
to900mgperdaybyoralrouteforCMVprophylaxisandproducessimilarareunder
18

the curve values to intravenous ganciclovir (5 mg/kg/day) and much higher values
than oral ganciclovir (3 g/day). In the phase III PV 16000 international,
doubledummy, doubleblinded trial of oral valganciclovirversus oral ganciclovirfor
thepreventionofCMVinfectionin364CMVD+/Rsolidorgantransplantrecipients
(including 120 renal transplant recipients) have been reported (29): those patients
wererandomlyassignedata2:1ratiotoreceiveoralvalganciclovir900mgperdayor
oralganciclovir1000mgTIDadministeredfor100days.Theresultwereonly0.8and
1.6 percent of patients in the valganciclovir and ganciclovir groups developed CMV
disease,respectively.Thisstudythereforedemonstratedthatvalganciclovirandoral
ganciclovirhavesimilarefficacy(29).

Valganciclovir is contraindicated in dialysis patient or patient with creatinine

clearanceoflessthan10ml/min.ThedosingforCMVprophylaxiswillbe900mgdaily
for90100dayswithadjustmentinpatientswithrenalimpairment.

Anecdotalexperience in treating refractoryCMV disease suggests that the addition

ofCMVhyperimmuneglobulin(CMVIG)orpooledintravenousimmunoglobulin(IVIG)
toganciclovirmayimprovetheclinicalresponse.

19

Patients with ganciclovirresistant CMV, although wellknown among HIVinfected

patients,havebeenreported.Foscarnetgivenintravenously60mg/kgQ8hfor2to3
weeksshouldbegivenwithdoseadjustmentinrenalimpairedpatients.Hydrationis
essential to avoid nephrotoxicity, and need to watch out for complications of
hypocalcemia,hypokalemiaandanaemia.

ProphylaxisregimenagainstCMVcanalsoprotectagainstotherhumanherpesvirus.
Subsequently, it may lead to fewer opportunistic infections. But however, how to
choosebetweenprophylaxisandpreemptivetherapy?Prolongedantiviralexposure
mayresultinresistance,thecostwillbehighanditmaydelaytheoccurrenceofCMV
disease.Butforpreemptivetherapy,therewillbefewerpatientsexposedtoantiviral,
thisdecreasedrugresistanceandalsodecreasetherecipientsfromdevelopingside
effectsofdrugs.

7.2 Preemptivetherapy
Asmentionedabove,aCMVseronegativerecipient(R)ofaCMVseropositivedonor
(D+)isatthehighestriskfordevelopingsubsequentCMVinfectionanddisease.After
transplantation, these recipients require preemptive antiviral therapy, typically for
100 days, and careful clinical and laboratory monitoring for evidence of CMV
20

viraemia. Recipients receiving antilymphocytic therapy may require prolonged

preemptiveantivirqaltherapy.AlthoughCMVpositiverecipients(D+/R+,DR+)have
a lower risk for CMV disease, a similar prevention strategy should be employed,
basedontheindividualriskfactorsandnetstateofimmunosuppression.

A preemptive strategy is based upon the idea that regular monitoring for any
evidence of CMV replication by use of laboratory assay such as PCR monitoring of
wholeblood.Thisallowsthedetectionofveryearlysystemicinfection.Thispermits
prompttreatment,whichmaylimitmorbidityandmortality.

Practically, in all cases of quantifiable CMV pp65 viraemia, the antimetabolite

immunosuppressives (namely, azathioprineor mycophenolate mofetil) should be
discontinuedorgivenlowereddose,atleastuntilviraemiaclears.Asymptomaticor
only mild disease is treated with valganciclovirfor a minimum of 21 days in clinical
practice.Thedurationwouldbelongerifnecessarytoclearthviraemia.Monitoring
of pp65 antigenaemia should be performed weekly to see the response of
preemptivetreatment.

7.3 TreatmentofCMVdisease
21

Therapy of CMV disease varies with the severity of the clinical manifestations. The
mononucleosislike syndrome may resolve without the administration of antiviral
drugs. A reduction in the overall level of immunotherapy is often recommended.
PatientswithhighCMVviralloads(e.g.>5x105copies/ml)orseveretissueinvasive
disease, and those who fail to achieve a reduction in viral load after 7 days of oral
valganciclovirshouldbeswitchedtointravenousganciclovir(5mg/kgevery12hours).
Thesepatientsshouldbemonitoredwithbloodviralloadatleastweeklyandantiviral
treatmentshouldbecontinueduntilthepp65antigenaemiabeingrenderednegative;
typicallyadurationoftreatmentof21days.

RenaltransplantrecipientswithongoingriskfactorsforCMVshouldbeconsideredto
receive longterm maintenance therapy with oral ganciclovir, or valganciclovir. The
mostfrequentsideeffectofganciclovirisleukopenia,whichisusuallyreversibleafter
stopping it. A mild elevation in the plasma creatinine level may also occur.
Crystalinducedacuterenalfailure,asseenwithacyclovir,appearstobeararewith
ganciclovir.

22


8.0 Conclusion
Cytomegalovirusinfectionisanimportantinfectioninpostrenaltransplantrecipients
and can cause significant morbidity and mortality to them. The importance of
screeningCMVseropositivityindonorandrecipientcouldhelpustoidentifythose
high risk cases of developing CMV disease. These prompt us to choose CMV
prophylaxisorpreemptiveregimen.CMVcausesimmunedysfunctionandcaninduce
allograft rejection. We need to check for CMV pp65 antigenaemia and closely
monitorpatientsifsuspectedtohaveCMVsyndrome/disease.Earlydetectionand
interventionshouldbewarrantedtogiveagoodprognosis.

23


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