BK virus nephropathy in simultaneouspancreas kidney transplant: a potentiallypreventable cause of kidney allograft loss

Mujtaba M, Fridell J, Sharfuddin A, Kandula P, Yaqub MS, Phillips CL,Mishler D, Taber T. BK virus nephropathy in simultaneous pancreaskidney transplant: a potentially preventable cause of kidney allograftloss.

Abstract: More than half of the simultaneous pancreas kidney transplant(SPK) patients afflicted with BK virus nephropathy (BKVN) lose theirkidney allograft. Fear of pancreatic rejection limits the ability to reduceimmunosuppression; this may result in inadequate treatment of BKVN.This single-center retrospective review included 138 SPK patients whounderwent periodic BKV screening and were managed with IS reductionalone as a treatment of choice for BKVN.All patients underwent rabbit anti-thymocyte globulin (rATG) inductionand were maintained on tacrolimus/sirolimus or mycophenolate. Theincidence of BKVN was 4.4%. BKVN was diagnosed at a median of11 months; mean serum creatinine 2.1 mg/dL and the geometric meanBK serum viral load at diagnosis 1 758 000 DNA copies/mL. Mediantime to BKV clearance was 5.6 months; there was 96% reduction in themycophenolate dose, 100% reduction in sirolimus, and 40% reduction inthe tacrolimus blood level at BKVN clearance. No BKVN-related kidneyfailure was noted, and patients retained excellent kidney and pancreaticallograft function till last follow-up (43 months).BKVN in SPK is a potentially preventable cause of end-stage kidneydisease, and IS reduction alone is an acceptable treatment modality inSPK without a higher risk of kidney/pancreas allograft loss as long asclose monitoring can be ensured.

Muhammad Mujtabaa, JonathanFridellb, Asif Sharfuddina, PraveenKandulaa, Muhammad S. Yaquba,Carrie L. Phillipsa, Dennis Mishlera

and Tim Tabera

aDivision of Nephrology, Department of

Medicine, Indiana University School of

Medicine, Indianapolis, IN, USA and bDivision

of Transplant Surgery, Department of Surgery,

Indiana University School of Medicine,

Indianapolis, IN, USA

Key words: BK – pancreas transplant – kidney

transplant – kidney failure – pancreatic

function

Corresponding author: Muhammad A. Mujtaba,

MD, FASN, 550 N. University Blvd., University

Hospital, Indianapolis, IN 46074, USA

Tel.: 317-944-7534; fax: 317-948-3268;

e-mail: mmujtaba@iupui.edu

Conflict of interest: None.

Accepted for publication 20 October 2011

Polyomaviruses are common in the adult popula-tion with more than 80% of adults demonstratingserologic evidence of past exposure (1). In healthyindividuals, latent polyomavirus infection does notappear to result in any health consequences as thevirus can establish latency in the uroepithelium, ol-igodendrocytes, and mononuclear cells (2,3). Uri-nary shedding of virus has been detected in 0.5–20% of asymptomatic people (4,5).

Solid organ pancreas transplantation offers thepotential for euglycemia in patients with type 1diabetes mellitus and is most frequently performedin association with kidney transplantation forpatients with end-stage diabetic nephropathy. Thisprocedure can either be performed as a simulta-neous pancreas and kidney transplant (SPK) or astwo separate operations as a pancreas after kidneytransplant.

Polyomavirus-associated nephropathy, alsoknown as BK virus nephropathy (BKVN), hasbeen increasingly recognized as a significant,potentially reversible cause of graft failure in kidneytransplant recipients and is mainly attributed toimmunosuppression (6–9). BK virus is frequentlyassociated with interstitial nephritis and ureteralstenosis, potentially leading to kidney allograftlost. Early reduction of immunosuppression inpatients with BKVN has been associated withimproved prognosis (9,10).Although very well described in the isolated kid-

ney transplant literature, the incidence, outcomes,and treatment strategies for BKVN in the SPKpopulation is less well studied. In the few publishedstudies, the incidence of BKVN in SPK recipientsranged from 2.9% to 7.5%, and it has beendescribed as a leading cause of kidney allograft loss

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© 2012 John Wiley & Sons A/S

Clin Transplant 2012: 26: E87–E93 DOI: 10.1111/j.1399-0012.2012.01599.x

in the first two years post-transplant (11–13). Thereported kidney allograft loss rate from BKVN inSPK ranges from 43% to 89% (11–13). In thekidney transplantation literature, periodic screen-ing for BKV has been shown to significantly reducethe incidence of graft loss as it permits early detec-tion and intervention (8–10).At our center, we have been performing routine

periodic BKV screening in SPK patients. Ourtreatment protocol for SPK patients afflicted withBKVN has evolved from immunosuppressionreduction along with additional antiviral agent toimmunosuppression reduction alone since 2006.This study is a retrospective review of all SPKtransplants performed at a single center with theintention of determining the incidence of BKVNalong with the outcomes of our screening and man-agement strategy in terms of pancreas and kidneyallograft survival and functions. We have alsocompared our outcomes with the previouslyreported data.

Materials and methods

The medical records for all SPK transplantsperformed at Indiana University between January2006 and June 2010 were reviewed (n = 138). Datacame from the comprehensive transplant recipientregistry at our center. Inclusion criteria for thisanalysis included all transplant recipients undergo-ing SPK. BKVN was defined as quantitative poly-merase chain reaction (qPCR) >10 000 copies/mLof serum with a > 30% rise in serum creatininefrom baseline. The institutional review board ofIndiana University School of Medicine approvedthe study.All recipients were listed for transplantation at

Indiana University according to standard proce-dures and protocols as established by the UnitedNetwork for Organ Sharing (UNOS). Pancreasallografts were typically procured using an en-bloctechnique following aortic flush with preservationsolution and topical cooling with saline slush aspreviously described (14). The recipient operationwas performed through a midline incision. Thepancreas was routinely positioned with the tailtoward the pelvis and the head and duodenum ori-ented superiorly to facilitate the enteric anastomo-sis. Systemic venous drainage was performed tothe right common iliac vein or to the vena cava.Arterial perfusion of the allograft was routinelyestablished from the right common iliac artery,although on rare occasions where this vessel wasfound to be diseased or had been the site for arte-rial anastomosis for a prior transplant, the inflowwould be established either from the aorta or the

left common iliac artery. All SPK transplants wereperformed with ipsilateral placement of both thekidney and the pancreas to the right iliac vessels aspreviously described (15). Pulsatile perfusion wasused routinely for the kidney allograft portion ofthe SPK transplant regardless of the preservationsolution used for organ retrieval (16). All pancreasallografts were drained enterically using a stapledtechnique as described elsewhere (17). Routineimmunosuppression in all recipients consisted ofinduction with five doses of rATG (1 mg/kg/dose)and maintenance with tacrolimus (target troughlevel of 8–10 ng/mL) and sirolimus (target troughlevel of 3–6 ng/mL) (18,19). Steroids were exclu-sively used as a premedication for rATG and werediscontinued following induction in all recipients.In certain situations where the side effects of themaintenance immunosuppression were not welltolerated, mycophenolate mofetil (MMF) wasadded. All recipients received routine perioperativeantibiotics, prophylaxis against cytomegalovirus(CMV) with oral valganciclovir and prophylaxisagainst Pneumocystis jiroveci pneumonia with tri-methoprim and sulfamethoxazole (Septra) unlesscontraindicated. Systemic anticoagulation was notroutinely used unless the patient had a specifichistory of a coagulation disorder. Immediately fol-lowing surgery, all patients were started on aspirin.

BK virus screening

At our center, we routinely screen SPK patients forBK virus in the urine. Screening is carried outevery three months for the first two years andannually thereafter. All patients with a positive BKurine qPCR (urinary viral load > 10E7 viral copies/mL) receive a serum qPCR as well.

In addition to the above screening, urine andserum BKV qPCR is also included as a part ofthe evaluation process for any patient with anunexplained deterioration in kidney function.

Diagnosis of BKVN

BKVN was defined as qPCR of more than10 000 copies/mL of serum with a more than 30%rise in serum creatinine from baseline. Threepatients also underwent kidney allograft biopsythat was stained for simian virus 40 (SV 40) byimmunohistochemistry, and results were consistentwith BKVN diagnosis.

Statistical analysis

Electronic charts of these individual patientswith BKVN were reviewed to determine

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Mujtaba et al.

demographic data. Transplant characteristics(induction therapy, maintenance immunosuppres-sion, time to the diagnosis of BKVN, real-timemanipulation of maintenance immunosuppression,time to BKV clearance, and follow-up time) werenoted. Laboratory data were collected at differentpoint intervals. The collected variables includedserum creatinine (mg/dL), fasting blood glucose(mg/dL), hemoglobin A1C (%age), C-peptide (ng/mL), serum amylase (U/L), and serum lipase (U/L)level. Serum BKV qPCR blood was also monitoredat different time intervals until BKV clearance(defined as BK viral load < 5000 copies/mL ofblood). BK qPCR was performed by ViraCorLaboratories, Lee’s Summit, MO, USA, usingtheir standard techniques. Categorical variablesare reported as mean with standard deviation and/or median with range where specified.

Results

Six SPK recipients with BKVN were identified.Mean age at transplant was 46 years. All patientswere Caucasians. Five of six were men. Medianfollow-up was 42 (25–55) months. All patientsreceived r-ATG induction and were maintainedsteroid free. All patients had an excellent baselinekidney and pancreatic allograft function as shownin Tables 1 and 2.

The median time to BKVN diagnosis was 11(9–17) months. There was no episode of kidney orpancreas allograft rejection prior to BKVN diag-nosis. At BKVN diagnosis, the median 12-h troughtacrolimus level was 8.8 ng/mL, median 24-h sirol-imus trough level was 4.9 ng/mL, whereas themedian MMF dose was 1500 mg/d. Three patientswere on tacrolimus and MMF, two patients wereon tacrolimus and sirolimus, whereas one patientwas on tacrolimus, sirolimus, and MMF. At thetime of diagnosis, the median serum creatinine was2.1 mg/dL (Tables 1 and 2). The geometric meanBK serum viral load was 1 758 000 DNA copies/mL. The overall 4.5-year actuarial cumulative rateof BKVN was 4.3%.

All patients were managed with immunosup-pression reduction alone with close monitoring ofthe serum BK viral load and serum chemistries(every two wk). One patient (patient # 6) devel-oped septic shock and acute kidney failure soonafter BKVN diagnosis necessitating introductionof pressors and continuous kidney replacementtherapy. The follow-up kidney allograft biopsythree wk later for non-resolving acute kidney fail-ure revealed severe acute tubular necrosis. The kid-ney allograft loss in this patient was notattributable directly to BKVN as the immunohis- Table

1.Patie

ntdemographics,

immunosu

ppression,andkidneyfunctio

natdifferenttim

eintervals

Pt

Sex

Age

(yr)

Follow-up

(month)

NadirSCr

(mg/dL)

MaintenanceIS

atBKdiagnosis

BKonse

t

Post-Tx

(month)

SCrat

diagnosis

(mg/dL)

Tim

eto

BK

clearance

(month)

MaintenanceIS

atBKclearance

SCratBK

clearance

(mg/dL)

Kid/panc

rejectio

npost

ISreductio

n

SCratlast

follow-up

(mg/dL)

1M

41

55

1.8

Tac(9.0

+2.1

ng/m

L)/

(MMF)500mgBID/

Sir(4

+1.2

ng/m

L)

12

2.4

3.5

Tac(6.7

+0.9

ng/m

L)/

MMF250QD

2.0

No

2.2

2M

41

51

1.8

Tac(9.0

+2.5

ng/m

L)/

MMF1000mgBID

16

3.1

5.6

Tac(6.8

+2.5

ng/m

L)

1.7

No

2.5

3M

43

45

1.3

Tac(9.5

+1.7

ng/m

L)/

Sir(4.9

+0.9

ng/m

L)

11

1.8

9.8

Tac(5.4

+0.7

ng/m

L)

1.4

No

1.4

4M

48

40

0.9

Tac(7.6

+1.0

ng/m

L)/

Sir(6.0

+1.3

ng/m

L)

10

1.5

9.6

Tac(4.5

+1.0

ng/m

L)

1.3

No

1.1

5M

42

37

1.6

Tac(8.7

+0.9

ng/m

L)/

MMF1000mgBID

92.1

5.1

Tac(4.5

+0.3

ng/m

L)

1.8

No

1.5

6a

F39

25

1.3

Tac(8.0

+2.0

ng/m

L)/

MMF500BID

17

2.2

ESRDa

Tac,tacrolim

us;

Sir,sirolim

us;

MM,myc

ophenolate

mofetil.

aDeve

lopedse

ptic

shockso

onafterdiagnosisandwasstartedonCRRT,allograftkidneybiopsy

showedse

vere

acute

tubularnecrosis,

did

notregain

kidneyfunctio

n,pancreasallograftfunctio

nstable,patie

ntdata

notincludedin

follow-up.

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BK virus nephropathy in simultaneous pancreas kidney transplant

tochemistry staining for BK virus was negative onkidney biopsy. The real-time immunosuppressionintervention with the trend of serum BK qPCR inthe remaining five patients is demonstrated inFig. 1. Median time to BKVN clearance was5.6 months. Typically, the dose of MMF waseither reduced or stopped in a stepwise fashiondepending upon the serum BK viral load. Therewas overall 84% reduction in the group dose ofMMF from the time of BKVN diagnosis to BKVclearance. In one patient (patient #1), MMF hadto be re-introduced at 250 mg once daily for a one-time mild elevation in serum lipase, which normal-ized without a rebound in serum BK levels. Thisparticular patient had excellent pancreas andkidney allograft function at last follow-up of55 months post-BKV clearance. There was anoverall 100% reduction in the sirolimus and almost40% reduction in 12-h tacrolimus trough level inthe BKVN group from the time of diagnosis toclearance of BK. At last follow-up, four patientsare on tacrolimus monotherapy, and one patient ison tacrolimus and MMF 250 mg daily. To date,no biopsy-proven pancreatic or kidney rejectionevent has been observed during or after the treat-ment of BKVN. None of the patients receivedempiric treatment for clinical suspicion of pancre-atic or kidney allograft rejection either. Post-BKclearance, these patients are closely monitored withmonthly laboratories. So far, we have a medianpost-BK clearance follow-up of 24 (20–40) monthson these patients with excellent kidney and pancre-atic allograft function.

Discussion

SPK presents a unique scenario where the diagno-sis and therapy of BKVN can be a challengingproblem. Most experts agree that the overall

immunosuppression load rather than individualimmunosuppressive agents account for the inabil-ity of the host to mount an antiviral immuneresponse to BKV (8, 13, 20). The corner stone ofBKVN treatment is reduction in maintenanceimmunosuppression (9, 13, 21, 22). This strategy isespecially challenging in SPK patients as there is arisk for pancreatic allograft rejection, which canhave significant morbidity (23). This fear of pan-creatic allograft rejection indirectly may contributeto inadequate treatment of BKVN that can lead toa very high rate (43–89%) of kidney allograft lossin SPK patients (11–13). Very little is currentlyknown about the clinical course of disease in SPKrecipients, although the pancreas allograft is notthought to be vulnerable directly to BK virus infec-tion (12). To the best of our knowledge, this is theonly study in SPK patients to date that showsexcellent kidney outcomes without any compro-mise of pancreatic allograft function. Our patientdemographics, time to BKVN diagnosis, and theincidence of BKVN fall in the same range asreported by others (Table 3).

Several questions arise while approaching theBKVN diagnosis and subsequent management inSPK patients. For example: Would screening forearly viral replication benefit clinical outcomes?What is the ideal management of a patient withBKVN reduction of immunosuppression or earlyinstitution of antiviral therapy? Is there anincreased risk of pancreatic allograft rejection ifthe immunosuppression is reduced?

Clinically silent viruria usually precedes BKVN,thus allowing an opportunity for early identifica-tion of patients at risk for BKVN and creating awindow for pre-emptive measures (6, 8, 10, 20, 24).The presence of circulating virus in the blood isassociated with active nephropathy because virionsenter the circulation through peritubular capillaries

Table 2. Pancreatic and kidney allograft parameters along with immunosuppression

Parameter (median with range) At baseline At diagnosis At clearance At last F/U

Fasting blood sugar (mg/dL)a 87 (85–105) 92 (89–99) 90 (79–104) 83 (81–100)

A1C (%) 5.0 (4.9–5.7) 5.2 (5.1–6.1) 5.4 (5.2–6.2) 5.4 (5.2–6.4)

Serum amylase (U/L)b 81 (19–94) 98 (42–121) 100 (75–113) 70 (54–109)

Serum lipase (U/L)c 31 (25–78) 28 (16–77) 31 (15–91) 24 (22–63)

C-peptide (ng/mL) d 2.0 (1.5–2.7) 1.7 (1.7–3.2) 1.8 (1.4–3.2)

Serum creatinine (mg/dL)e 1.5 (0.9–1.6) 2.1 (1.5–3.1) 1.7 (1.3–2) 1.5 (1.1–2.5)

Prograf 12 h trough (ng/mL) 8.8 (7.6–9.5) 5.4 (4.5–6.8) 5.5 (4.7–6.5)

Sirolimus 24-h trough (ng/mL) 4.9 (4–6) 0 0

Mycophenolate (mg/dL) 1500 (1000–2000) 250 250

aReference range 70–99 mg/dL.bReference range 25–161 U/L.cReference range 22–51 U/L.dReference range 0.9–4.2 ng/mL.eReference range 0.6–1.4 mg/dL.

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Mujtaba et al.

following tubular damage. Although kidneyallograft biopsy is the gold standard for BKVNdiagnosis, detection of BKV DNA in plasma witha qPCR viral titer > 10 000 copies/mL has beenproposed as a surrogate marker for BKVN diagno-sis (6–8, 10, 25).

Our approach for BKVN screening in SPKrecipients has evolved into early detection by regu-lar screening for BK virus in the urine at threemonth intervals for the first two yr after transplan-tation and annually thereafter. The data recom-mending routine screening predominantly comefrom kidney transplantation where it is proven that

screening for BKV is cost-effective and has a signif-icant positive impact on kidney allograft survival(6, 7, 9, 24). Our study demonstrates a relativelyearly detection and a lower serum creatinine atBKVN diagnosis compared with other studies(Table 3) (11–13, 26). We attribute this to BKVscreening. It is more than likely that early detectionhas a significant impact on the kidney outcomes ofour patients.The present case series presents the largest expe-

rience with BKVN in SPK patients managed byimmunosuppression reduction alone with a follow-up of pancreatic allograft function. Our study

Table 3. Comparison with other published data

Parameter IUSMa UCSFb NMHc UPMCd

BK cases/no. SKPT (%) 6/138 (4.3) 9/146 (6.2) 9/205 (4.4) 7/243 (2.9)

Mean age at transplant (yr) 42 ± 5 38 ± 6 48 ± 5 40 ± 11

Male sex (%) 84 89 78 57

Follow-up (months) 43 (25–55) 35 (11–60) 36 (7–72) 43 (10–109)

Time to BK virus nephropathy

(BKVN) diagnosis (months)

11 (9–17) 12 (4–28) 20 (7–37) 19 (9–40)

Baseline serum creatinine (mg/dL) 1.4 ± 0.3 1.5 ± 0.4 1.1 ± 0.3 1.4 ± 0.4

Serum creatinine at BKVN diagnosis (mg/dL) 2.1 ± 0.5 3.5 ± 1.2 2.6 ± 0.4 2.4 ± 0.7

Kidney loss from BKVN (%) 0 55 89 43

Serum creatinine at last F/U (mg/dL) 1.7 ± 0.6 3.5 ± 1.2 ND 1.9 ± 0.3

Pancreatic rejection/allograft loss (%) 0 0 0 0

Use of cidofovir/leflunamide 0 44% 78% 86%

aIndiana University School of Medicine.bUniversity of California San Francisco.cNorth Western University Chicago.dUniversity of Pittsburgh Medical Center.

Fig. 1. Graph of blood BK viral load over time of simultaneous kidney and pancreas transplant patients managed by immunosup-pression reduction alone. Pt, patient; MMF, mycophenolate mofetil; Tac, tacrolimus; Sir, sirolimus. (A) MMF dose reduction,(B) MMF stop, (C) Tac reduction, (D) Sir dose reduction, (E) Sir stop, (F) MMF restart at lower dose. MMF resumed at lower dosein patient 1 for mild increase in serum lipase which normalized, and to date, patient has normal pancreatic allograft function withoutrecurrence of BK.

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BK virus nephropathy in simultaneous pancreas kidney transplant

shows that a careful, stepwise approach in immu-nosuppression reduction (Fig. 1) along with closemonitoring of kidney and pancreatic allograftfunction is safe and reliable as we did not observeany episode of pancreatic allograft loss duringimmunosuppression reduction for BKVN treat-ment or on long-term follow-up.Reports on BKVN in SPK show that a signifi-

cant number of patients were managed withcidofovir (Table 3). Data regarding the adminis-tration of cidofovir and leflunamide in the manage-ment of BKVN are also found in the kidneytransplantation literature (27, 28). We did not usecidofovir or leflunamide for the management ofthese SPK patients as all responded well to immu-nosuppression reduction alone. In our opinion,leflunamide and cidofovir should only be consid-ered if a reasonable attempt at immunosuppressionreduction fails to clear BKVN.Our study has the significant limitation that it is a

small single-center retrospective case series. Theadvantage of a single-center analysis is that donorand recipient management, immunosuppressionprotocols, and prophylactic therapies and screeningare homogeneous throughout the study population,allowing for legitimate comparisons between studysubjects. A large multicenter trial may be requiredto further strengthen and confirm our findings. Pro-spective trials are also required to determine theutility of BK virus screening in SPK transplanta-tion. Our approach can be used as a guideline forBKVN management in SPK patients as long asclose patient monitoring can be ensured.In summary, our study suggests that BKVN in

SPK recipients is a potentially preventable cause ofkidney allograft loss. Screening for BK virus inSPK recipients permits early detection and timelyintervention that in turn may result in an improvedkidney allograft survival. The study also suggeststhat, in our experience, immunosuppression reduc-tion alone is an acceptable modality for successfulBKVN management in SPK patients with excellentkidney and pancreatic allograft survival as long asthe patient can be monitored closely.

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