nephrol. dial. transplant. 2013 sharma 620 31

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Nephrol Dial Transplant (2013) 28: 620631

doi: 10.1093/ndt/gfs537

Advance Access publication 18 December 2012

BK polyoma virus nephropathy in the native kidney

Shree G. Sharma1,

Volker Nickeleit2,

Leal C. Herlitz1,

Anne K. de Gonzalez1,

Michael B. Stokes1,

Harsharan K. Singh2,

Glen S. Markowitz1

and Vivette D. DAgati1

1

Department of Pathology, Division of Renal Pathology, Columbia

University Medical Center, New York, NY, USA and2Department of Pathology, Division of Nephropathology, The

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence and offprint requests to: Shree

G. Sharma; E-mail: [email protected]

Keywords: acute renal failure, BK virus in native kidneys, BKvirus nephropathy, polyoma virus nephropathy, renal allo-graft dysfunction

A B S T R A C T

Background. While BK polyoma virus nephropathy (PVN) isa well-recognized cause of renal allograft dysfunction, PVN ofnative kidneys is likely under-recognized.Methods. We present the pathologic features, risk factors andoutcomes of eight cases of PVN in native kidneys.Results. The cohort included eight males aged 1673 years(mean 47.4) with an immunocompromised state (mean dur-ation 3.15 years) attributable to: hematologic malignancies(n = 6), for which three had undergone bone marrow trans-plant; lung transplant (n = 1) and combined tuberculosis anddiabetes (n = 1). Seven patients were receiving specific immu-nosuppressive therapies. Patients were biopsied for acutekidney injury (AKI) with rise in mean creatinine levels frombaseline 1.6 to 2.8 mg/dL. Pathology showed BK PVN withcharacteristic intranuclear inclusions staining positive forSV40 T antigen and negative for JC virus (JCV), with positiveserum and/or urine PCR for BK virus. One patient had focal

medullary JCV co-infection. Two patients also had renal infi

l-tration by chronic lymphocytic leukemia (CLL). Six patientsreceived specific therapy directed to PVN (cidofovir or leflu-nomide). Follow-up ranged from 2 to 20 (mean 10) months.Despite marked decrease in serum BK viral copy numbers,creatinine continued to rise in six cases (mean 3.7 mg/dL infour, requiring dialysis in two) and three patients died of ma-lignancy, opportunistic infection or renal failure. Advancedhistologic stage of PVN, ineffective antiviral therapy, co-mor-bidities and persistent immunocompromised state likely con-tributed to the poor outcomes.

Conclusion. A high level of suspicion in immunocompro-mised patients is needed to diagnose PVN in an early stagethat may respond more favorably to antiviral therapy.

I N T R O D U C T I O N

BK polyoma virus is the most common virus to infect therenal allograft and the most important viral etiology of graftdysfunction or loss. In the renal transplant recipient, pro-ductive polyoma virus infections mainly due to BK virus re-plication manifest as virally induced acute tubular injury,known as polyoma virus nephropathy (PVN) [13]. Stagingof PVN into early, florid and sclerosing disease phases mayhave prognostic value [4].

BK virus (BKV), so named after the initials of the firstpatient from which the virus was isolated in 1971 [5], is adouble-stranded DNA virus of the Polyomaviridae family.The two other family members are JC virus (JCV), which

causes progressive multifocal leukoencephalopathy (PML),and simian virus (SV)-40 virus, which entered the humanpopulation through contaminated polio vaccines and is a rarecause of nephropathy, central nervous system disease andneoplasms [68].

Although PVN was first reported in 1978 [9], it was notuntil the late 1990s that reports in the transplant populationspurred awareness of this entity [1, 2, 1012] and its risingincidence due to the widespread use of newer, more potentimmunosuppressive agents. The prevalence of PVN in renaltransplant patients varies from 1 to 5.5% and PVN has been

ORIGINAL

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detected 1.345.1 (mean 12.5) months after transplantation[13].

In the general population, 7090% of healthy individualscarry antibodies to BKV and have latent non-productive infec-tions in the urogenital tract [14]. Primary PV infections in im-munocompetent individuals typically occur early in childhood,followed by viral latency and the development of antibodies.The primary infection occurs as either a mild respiratory illnessor asymptomatic infection. The precise mode of transmission

of PV in the general population is unclear. In addition to res-piratory infection, feco-oral and transplacental routes of infec-tion may occur. PV has also been isolated from urine, semen,genital organs and skin biopsies [15].

Following primary infection, both BKV and JCV remainin a latent state in the urothelium and renal tubular epithelialcells, which is only detectable by molecular techniques [3].Reactivation of BK infection may occur under conditions ofdecreased host immunity such as diabetes, pregnancy or ma-lignancy, but reactivation in these settings is typically limitedto the urothelium, without productive intrarenal infection [1,16]. Most cases of PVN occur in renal transplant recipientstreated with immunosuppressive regimens to prevent allograft

rejection.Because of the potential for irreversible renal injury in PVN,

it is important to differentiate asymptomatic reactivation fromrenal parenchymal infection. There are various methods of di-agnosing PVN. The urine can be examined cytologically for thepresence of decoy cells (shed epithelial cells with intranuclearviral inclusions); however, this method cannot differentiateasymptomatic reactivation from PVN. Haufen testing, whichuses electron microscopy to detect cast-like viral aggregates inthe urinary sediment, is more specific for PVN [17]. PCR is auseful tool to detect the viral copy number in serum and/orurine [18]. A positive serum PCR is much more specific forPVN (the presence of >1 104 copies/mL has a positive predic-tive value of 5080%) [3, 19], whereas urinary PCR cannot dis-criminate lower urinary tract from renal parenchymal infection.The gold standard for the detection of intrarenal PV replicationis a renal biopsy showing the characteristic intranuclear viralinclusions by light microscopy and/or immunohistochemistry[4]. In addition to BKV, rarely JCV or SV40 may also be de-tected in PVN. Because the clinical presentation of PVN isnonspecific (varying degrees of renal failure without fever, leu-kocytosis, hematuria or proteinuria), diagnosis requires a highlevel of suspicion.

The vast majority of cases of PVN have been reported inrenal allografts. There are only rare instances of PVN in the

native kidney. Here, we report eight patients with PVN in thenative kidney and discuss the risk factors and outcomes.Because some of these patients have other intercurrent renalprocesses, we believe that PVN in the native kidney is likelyunder-recognized.

M A T E R I A L S A N D M E T H O D S

A retrospective review of renal biopsies examined at Colum-bia University and the University of North Carolina from

July 2004 to February 2012 identified seven biopsies and oneautopsy case of PVN in the native kidney. All cases hadcharacteristic intranuclear viral inclusions confirmed by posi-tive immunohistochemical staining for polyoma virus inrenal tubular nuclei using antibody to SV40 T antigen,(mouse monoclonal, Calbiochem). Because both BK and JCviral infections are SV40 positive, immunohistochemistry forJCV [20] (rabbit polyclonal antibody detecting residues 652672 of the JC-T antigen; kind gift of Dr H. Sawa, Japan) was

performed in seven of eight cases with residual paraffinsections.

The clinical histories, including presenting renal findings,systemic disease, laboratory data, medication history and out-comes, were obtained from the pathology request forms andby telephone interview with the treating physicians. All biop-sies were performed for indications of acute kidney injury(AKI). Biopsies were processed for light microscopy, immu-nofluorescence microscopy and electron microscopy accord-ing to the standard techniques, whereas the single autopsycase was studied by light microscopy only (Figure 1).

The biopsy scoring for polyoma viral load (pvl) levels andPVN disease stages followed suggestions of the Banff

Working Group on PVN. For pvl, the percentage of tubulesdemonstrating SV40 immunoreactivity was scored as: pvl.1,1% of tubules with viral replication; pvl.2, >1% to 10% oftubules; pvl.3: >10% of tubules [21]. PVN disease staging wasclassified as (A) PV replication with no or minimal tubularinjury; (B) severe PV-induced tubular injury or (C) PV repli-cation in the setting of severe (>50%) tubular atrophy andfibrosis [21].

R E S U L T S

Presenting clinical findings

In seven patients, a renal biopsy was performed for AKI(Table 1). The single autopsy case had mild elevation inserum creatinine. The mean age was 47.4 years (range 1673years). All of the patients were male. The majority were Cau-casians (six patients, 75%), one was African-American andone was Hispanic. Two patients had history of diabetes melli-tus and three had history of systemic hypertension. All eightpatients were immunosuppressed, either due to endogenousimmunocompromised state and/or ongoing exposure to oneor more immunosuppressive therapeutic agents. The cause ofimmunosuppression was hematologic malignancy in sixpatients, including three with chronic lymphocytic leukemia

(CLL), one with non-Hodgkins lymphoma (NHL), one withacute myeloid leukemia (AML) and one with chronicmyeloid leukemia (CML). Among this subgroup, three hadreceived bone marrow transplants requiring immunosuppres-sive therapy and three were being treated with immunosup-pressive agents directed to the hematologic malignancy. Onepatient had undergone bilateral lung transplant for cystic fi-brosis, requiring maintenance immunosuppressive therapy.In one patient, the immunocompromised state was attribu-table solely to tuberculosis and diabetes mellitus. Thus, atotal of four patients had undergone non-renal organ

B K P V N i n t h e n a t i v e k i d n e y

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transplantation, six had malignancies and seven were receiv-ing immunosuppressive therapies at the time of PVN diagno-sis. The mean duration of immunosuppressed state was 3.15years (range 110 years). Prior to the renal biopsy, sixpatients had experienced other opportunistic infections, in-

cluding tuberculosis (one patient), herpes zoster (onepatient), pulmonary nocardiosis (one patient), histoplasmosis(one patient), cytomegalovirus retinitis (one patient) and dis-seminated cytomegalovirus infection (two patients).

The mean serum creatinine at the time of presentationwas 2.8 mg/dL (range 0.84.5 mg/dL), which was increasedfrom a mean baseline serum creatinine of 1.6 mg/dL (range0.52.9 mg/dL). The mean serum creatinine at the time ofpresentation was 1.5 mg/dL in patients with Stage B diseaseversus 3.2 mg/dL for Stage C. No patient had nephrotic-rangeproteinuria, and the mean 24-h protein available in fourpatients was 0.8 gm (range 0.51.2 g). The urinary sediment

was active only in one patient, who had microhematuria andleukocyturia. Only one of the eight patients (the singlepatient so tested) had documented decoy cells on urinemicroscopy prior to biopsy.

Renal pathology

Viral inclusions were identifiable by light microscopy inthe nuclei of renal tubular epithelial cells in all eight casesand were also present within the glomerular parietal epi-thelial cells in one case. PVN was confirmed by positive SV40immunostain in all eight cases; one case showed a minor

component of JC co-activation limited to the medulla. Theviral inclusions were distributed in the cortex (eight cases)and medulla (five cases); (medulla was not sampled in threecases). Scores for pvl were pvl.2 in four cases and pvl.3 infour cases (Figure 2).

PVN stage was either B (two cases) or C (six cases). Dueto the relatively advanced PVN disease stages, interstitialinflammation was a common finding (Table 2), varying fromabsent (n = 1), to mild (n = 1), moderate (n = 2) and severe(n = 4). The inflammatory infiltrate was composed of mono-nuclear cells in all biopsies, with detectable plasma cells infour cases. Features of acute tubular injury were present in allbiopsied cases. Tubular atrophy and interstitial fibrosisranged from minimal (n = 1) to moderate (n = 4) to severe(n = 3). Two biopsies also had infiltration of the cortical par-enchyma by CLL (with 80 and 20% parenchymal involve-ment, respectively), which was confirmed by immunostaining

for CD20, CD5, CD79a, CD3 and CD138. The autopsy case,a 16-year-old male who had undergone bone marrow trans-plant for AML, was notable for virally induced severe acutetubular injury lacking significant interstitial inflammation,tubular atrophy or interstitial fibrosis, together with scatteredcalcified foci of histoplasmosis. No characteristic features ofcalcineurin inhibitor nephrotoxicity (such as isometrictubular vacuolization or arteriolar beaded medial hyalinosis)were identified in any patient receiving these agents.

Light microscopic examination showed histologically unre-markable glomeruli in all but three cases, including nodular

F I G U R E 1 : Light microscopic features of PVN: The top panel (from patient 1) illustrates the characteristic intranuclear viral inclusions ofPVN including groundglass appearance (A, arrow) or discrete amphophilic inclusions (B, arrow). Acute tubular injury and viral cytolysis areseen. There is adjacent interstitial expansion by edema and inflammation including mononuclear leukocytes and plasma cells with focaltubulitis (H&E, 400). The bottom panel (from patient 2) shows an example of Stage C, with extensive interstitial fibrosis and inflammation(C, H&E 200) and tubular atrophy [(D: periodic acid Schiff (PAS), 200]. Focal intranuclear inclusions are visible even at low power (C,arrow).

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Table 1. Clinical features, laboratory parameters and outcomes of eight patients with PVN in the nat

Case 1 Case 2 Case 3a Case 4 Case 5 Case 6

Age 66 66 16 73 53 17

Race Caucasian Hispanic Caucasian Caucasian Caucasian African-A

Gender M M M M M M

HTN Yes Yes Yes No No No

DM No Yes Yes No No No

Additional PMH CLL, HTN,TCCBladder

PulmonaryTB,HTN, CAD,COPD

AML CLL,HerpesZoster

NHL CML, GVH

CMVretinitis,DissCMV

Pulmonary

Immunosuppressed? Yes Yes Yes Yes Yes Yes

How? (a medicalcondition, drugs, etc.atthe time of biopsy)

CLL DM & TB AML, BMT CLL NHL,Rituximab,

CML, BM

IVIg 18months

Tacrolimus,MMF

Steroids Fludarabine,Ganciclovir

MMF, TacSteroids

Durationofimmunosuppression

CLL 1 0 years DMunknown,TB 9 months

AML 15months,Allo-BMT4months

S/P threecoursesofrituximabandfourcoursesoffludarabine(1 yearpriorto bx)

N HL4years

HaploidenBMT 2 y

Serum creatinine@time of bx

4.5 mg/dL 4.5 mg/dL 0.8 mg/dL 2.8 mg/dL 3.4 mg/dL 2.3 mg/dL

Baselineserumcreatinine (sCr)

1.2 mg/dL 2.5 mg/dL 0.5 mg/dL 1.5 mg/dL 2.9 mg/dL 1.1 mg/dL

Interval baselinesCr tobx 6 months 6 months 20 days 7 months 1 month 6 months

24-h Urine protein None UA: trace UA: 1+


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Initial post-biopsy follow-up:

Serum PCR for BK(copies/mL)

3 400 000 1 400 000 . 2 080 000 210 000 6 180 000

Urine PCR for BK(copies/mL)

>10 000 000 >10 000 0 00 . NA 7 900 000 000 1 557 500 0

Treatment for BK Yes No . Yes Yes Yes

Leflunomide No No . No No Yes

Cidofovir Yes No . Yes Yes No

IVIg Yes for CLL No . Yes No Yes for pa

Other ChlorambucilforCLL(afterbiopsy)

. . . . Was onnumerous(acyclovir,antifungal

GVHD,

Last follow-up:

Final serum creatinine Hemodialysis Hemodialysis . 5.2 mg/dL NA 3.1 mg/dL

Interval post-biopsy 3 months 3 months . 3 months NA 38 days

Change in serumPCRfor BK

NA NA . NA 412 (at5months)

359 000 (a

Change in urinePCRfor BK

NA NA . NA 300 000 (at5months)

NA

Comments 18 monthslaterPML/JC inCSF

Expired at18monthsfromcomplicationsofrenal failure

BKPVNfoundatautopsy,notprior

. Expired at18monthsfromNHLrelapse

Expired at2monthsfrMucormyc

AML, acute myeloid leukemia; BKPVN, BK polyoma virus nephropathy; BMT, bone marrow transplant; CLL, chronic lymphocytic leukemiadisease; CAD, coronary artery disease; CF, cystic fibrosis; DM, diabetes mellitus; Diss, disseminated; DLT, double lung transplant; GVHD, grHTN, hypertension; IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil; NHL, non-Hodgkins lymphoma; NA, not available;polyoma virus; PML, progressive multifocal leukoencephalopathy; Pul, pulmonary; TCC, transitional cell carcinoma; TB, tuberculosis; UA, uaCase 3 is an autopsy specimen.

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diabetic glomerulosclerosis (n = 1), mild diffuse diabetic glo-merulosclerosis (n = 1) and segmental membranous glomeru-lopathy (n = 1).

Immunofluorescence and ultrastructural examinations,performed in all cases but the autopsy case, showed noevidence of immune complex deposits in six of seven cases,

including both the glomerular and tubulointerstitial compart-ments. The single exception was the case with segmentalmembranous glomerulopathy, demonstrating subepithelialdeposits staining for IgG, kappa light chain, lambda lightchain and C3.

Outcome

Post-biopsy follow-up was available in all patients andranged from 2 to 20 months (mean 10 months). The biopsydiagnosis of PVN was accompanied by positive serum PCRfor BKV in all seven biopsied cases and by urine PCR per-formed in five cases. PCR was not performed in the autopsycase.

Specific treatment directed to PVN was given to sixpatients, including cidofovir (four patients) and leflunomide(two patients). Because the preservation of transplantedorgans was a priority, major reductions in immunosuppres-sive therapy were not made. In fact, in one patient (Patient 8)immunosuppression was increased due to the development ofgraft versus host disease. Post-treatment serum PCR was per-formed in four patients and showed a marked decrease in BKviral copy numbers at 7 weeks, 1 month, 5 months and 1year after initiation of treatment. Despite antiviral therapy insix patients and reductions in serum BK viral copy numbersin four, serum creatinine levels continued to rise in all six

biopsied patients with available data (with development ofend stage renal disease in two patients by 3 months post-biopsy, and rise in serum creatinine level to mean 3.7 mg/dL;range 3.15.2 mg/dL in the remaining four patients). Threebiopsied patients died. The patient with NHL died 18months post-biopsy from relapse of NHL. A patient withbone marrow transplant for CML died of mucormycosis 2months after renal biopsy. Of the two patients who becamehemodialysis-dependent 3 months post-biopsy, one expired18 months later of complications of renal failure and theother developed PML due to JCV (confirmed by JCV PCR

performed on cerebrospinal fluid) 18 months following renalbiopsy, without recovery of renal function (of note, thispatient had no evidence of JCV in the kidney by immunohis-tochemistry). The patient in whom PVN was an incidentaldiagnosis at autopsy succumbed to respiratory failure in thesetting of disseminated histoplasmosis and clofarabine-

induced capillary leak syndrome.

D I S C U S S I O N

Most cases of PVN are encountered in the renal transplant.Involvement of the native kidney by PVN is rare. BKV hasbeen reported to cause renal failure in native kidneys in im-munodeficient patients [22, 23] and in solid organ transplantpatients [1, 3, 2438], including cardiac [2530], lung [31],pancreas [32], liver [24, 33] and bone marrow transplants[3440]. PVN can develop in both auto- and allo-stem celltransplant recipients [25, 3440]. Table 3 summarizes theclinical features of the 18 biopsy-documented cases of BKPVN in the native kidney reported in the literature [ 22, 23,25, 26, 3032, 3442]. All 18 patients had an immunocom-promised state. Among this group, 14 patients had received anon-renal transplant, including 9 bone marrow or stem celltransplants, 3 heart, 1 lung and 1 pancreas transplant.Among the 14 transplanted patients, 7 had an underlying he-matologic malignancy. Of the four non-transplant patients,three had a hematologic malignancy (including two with anunderlying immunodeficiency state), and one suffered froman immunodeficiency syndrome. Outcomes were poor

despite use of antiviral therapy in 11 patients: nine patientsdied, eight had progressive renal failure and one had persist-ent renal insufficiency. Whereas some investigators have at-tempted to prospectively screen at-risk populations withheart [30, 43] or lung[44] transplants for BKV by urine and/or serum PCR and found incidences of viruria ranging from8 to 42%, only a renal biopsy can distinguish renal parenchy-mal from lower urinary tract infection. Better understandingof the incidence and risk factors for PVN outside the renaltransplant setting will be important as the number of non-renal organ transplants continues to rise.

F I G U R E 2 : Confirmation of PVN by immunohistochemistry: the same field from Patient 2 stained with H&E (A) and SV40 immunostain(B) shows atypical enlarged nuclei with strong SV40 immunoreactivity despite the presence of only subtle inclusions and marked acutetubular injury (400).


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Table 2. Renal biopsyfindings in eight patients with PVN in the native kidney

Case 1 Case 2 Case 3a Case 4 Case 5 Case 6

No. of glomeruli 31 14 >200 2 20 33

No. of globallysclerotic glomeruli

4 3 5 1 2 9

Interstitialinflammationb

Severe Severe None Moderate Severe Moderate

Componentsofinfiltrate

L L,M,Pl,N,E None L, M, Pl L, M,Pl, E

L

Tubular atrophyandinterstitial fibrosis

Severe(70%)

Severe (80%) Minimal (5%) Moderate (50%) Severe(60%)

Moderate (4

Viral inclusions inthecortex

Present Present Present Present Present Present

Viral inclusions inthe

medulla

Present NA NA Present Present NA

SV40 stain inthecortex

Present Present Present Present Present Present

SV40 stain inthemedulla

Present NA NA Present Present NA

JC stain in the cortex Neg Neg Neg Neg Neg Inadequatet

JC stain in themedulla Neg NA NA Rare focalpositive Neg Inadequatet

PV score 2 2 2 3 3 3

PVN stage C C B C C C

Histologicaldiagnosis(es)

(i) BKPVN(ii) CLL

(80%infiltration)

(i) BKPVN(ii)Nodulardiabetic

GS

(i) BKPVN (ii)Histoplasmosis

(i) BKPVNc(ii) CLL(20%infiltration)(iii)

Segmentalmembrano-usglomerulopathy

BKPVN BKPVN

aCase 3 is an autopsy specimen.bInterstitial inflammation was graded as: mild 50% of cortical parenchyma involved.cWith minor component of JC polyoma virus co-infection; rare focal staining seen only in the medulla.BKPVN, BK polyoma virus nephropathy; E, eosinophils; GS, glomerulosclerosis; L, lymphocytes; M, monocytes; N, neutrophils; NA, medull

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Table 3. Review of the clinical features, risk factors and outcome of 18 biopsy-documented cases previously reported in the literature

Referencenumber

No. ofbiopsydocumentedcases

Age(years)

Type oftransplant

Cause ofimmunosuppression

Duration ofimmunosuppression

ElevatedBKVPCR

[23] 1 6 None HyperimmunoglobulinMimmunodeficiency

>5 years Serum

[22] 1 5.5 None Cartilage hairhypoplasiaandHodgkins disease

>2 years Serum

[31] 1 40 Lung transplant

Chemotherapy forseminoma, Tx

15 months Serum

[34] 1 10 Auto-SCT Supratentorial PNET,chemotherapyand Tx

4 years Serum

[35] 2 10, 13 (i) UCBT(ii)Allo-SCT

(i) CML(ii) Fanconianemia

(i) 3.5 years(ii) 2years

(i) Serumandurine(ii) Serum

[36] 1 14 UCBT Secondary AML,chemotherapyand Tx

1 month Serum

[37] 1 28 HaploidenticalPBSCT

AML, chemotherapyand Tx

1 year Urine

[39] 1 57 Allo-SCT CLL, chemotherapy andTx

1 year Serum

[25] 2 59, 41 (i) Heart tx (i) Immunosuppressivetherapy, Tx

(i) 6.8 years (i) None

(ii) Auto-PBSCT

(ii) NHL,chemotherapy and Tx

(ii) 6.2 years (ii)Serumanurine

[41] 1 32 None AIDS- relatedplasmablasticlymphoma

>5 months None

[42] 1 59 None CLL 3 years None

[38] 1 50 Allo-SCT NHL, MDS,chemotherapy and Tx

>2 months Urine

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The present series describes the risk factors and clinicalcourse of PVN in the native kidney. All eight of our caseswere in an immunocompromised state, including sixpatients with hematologic malignancies, one with doublelung transplant for cystic fibrosis and one with diabetes andtuberculosis. In addition, three of the patients with hemato-logic malignancies had undergone bone marrow transplant(2 allo- and 1 haploidentical) for which they were receivingantirejection immunosuppressive therapy for up to 4 years.

The patients were all male, predominantly Caucasian, andvaried in age from young to elderly (mean 47.4 years, range1666 years). From these data and our review of 18 casesreported in the literature, we conclude that patients with he-matologic malignancies and non-renal organ transplants areparticularly at risk for development of PVN in the nativekidney.

AKI was the indication for renal biopsy in all seven biop-sied patients. In two cases, the kidneys also had renal infiltra-tion by CLL, which likely contributed to the renal failure.Renal failure due to involvement of the kidney by leukemicinfiltration has been reported rarely [45, 46] although 6090% of patients with CLL show leukemic infiltration of the

kidney on autopsy [42]. In these cases, the coexistence ofPVN can be easily overlooked due to the extensive interstitialinvolvement by neoplastic infiltrates, emphasizing the impor-tance of careful histologic search for intranuclear viralinclusions, with confirmation by SV40 immunostain.

There are four previous case reports of PVN in CLL [ 39,42, 47, 48]. In the report by Stoner et al. [48], in addition toPVN the patient with CLL developed disseminated BKV inthe lungs and brain. In the present series, Patient 1 with CLLrequired IVIg for hypogammaglobulinemia, which may havepredisposed him to infection. The other unusual feature inPatient 1 was the subsequent development of PML due toJCV. To our knowledge, this is the first reported case of apatient with PVN due to BKV who subsequently developedPML due to JCV. PML is a common opportunistic disease,and lymphoproliferative disorders were the most commonetiology of PML before the human immunodeficiency virus(HIV) era [49].

Our Patient 2, the only patient without hematologic malig-nancy or organ transplant, had both diabetes mellitus and tu-berculosis as potential predisposing conditions to animmunocompromised state, a combination that has not beenreported previously as associated with PVN. Of note, thepatient had received only 2 months of anti-tuberculoustherapy, which was discontinued 6 months prior to the diag-

nosis of PVN. Diabetes, which impairs immune function, hasbeen reported to increase the incidence of tuberculosis by 3-fold, such that diabetes now accounts for 8% of new cases oftuberculosis annually worldwide [50]. In addition, tuberculo-sis contributes to host immunosuppression by production ofunique phenolic glycolipids that promote anergy by blockingmacrophage phagosomal maturation [51].

Patient 7 also had diabetes in association with cystic fibro-sis and double lung transplant requiring immunosuppressivemedications, all of which may have contributed to the immu-nocompromised state. In the study by Schwarz et al. [52], a

[32]

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54

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renal biopsy was performed in 101 recipients of bonemarrow, liver, lung or heart transplants. PVN was detected inonly 1 (4%) of the 30 lung transplant recipients and none ofthe other organ transplant recipients underscoring the rarityof this complication.

Patient 5 had a 4-year history of low-grade NHL and hadreceived chemotherapy and radiation therapy for localizeddisease in the spine. This is the first report of PVN occurringin a non-transplant patient with low-grade NHL. Two casesof PVN have been reported in patients with NHL after receiv-ing autologous [25] or allogeneic [38] stem cell transplants.One case of PVN was reported in a patient with peripheralT-cell lymphoma [53]. PVN has also been reported in anHIV-infected patient with plasmablastic lymphoma [41].

The agents that are being used with limited success inPVN are leflunomide, cidofovir, fluoroquinoles and IVIg [15,54]. Six of our eight patients received antiviral therapydirected to PVN, including leflunomide in two patients andcidofovir in four. Because of concerns about organ transplant

viability, major reductions in immunosuppression were notmade. While four had improvement in viral load by serumPCR, renal function continued to decline, indicating thatPCR is not a reliable predictor of outcome. The poor out-comes in our cohort were likely multifactorial, including highPVN stage, ineffective antiviral therapy, persistent immuno-compromised state and other intercurrent renal processessuch as CLL infiltration or diabetic nephropathy. Two of ourpatients were PVN Stage B and six were Stage C, which arethe higher stages associated with greatest risk of renal allo-graft loss [3, 18] (Figure 3).

As the number of solid organ transplants continues torise, the incidence of renal dysfunction in this population hasalso increased [25, 55]. It will be important to distinguish therare development of PVN in this population from the morecommon situation of BKV activation. These outcome dataunderscore the importance of careful screening and promptuse of a renal biopsy for early detection of PVN involving thenative kidney in at-risk patients with hematologic malignan-cies and/or organ transplants who develop AKI. Ideally,monitoring of at-risk patients with urinary decoy-cell screen-ing, serum PCR assays for BKV and renal functional studiescoupled with the judicious use of renal biopsy are potentialstrategies for earlier detection. Greater awareness of thepotential development of PVN in the native kidney is neededto avoid under-recognition of this newly emerging entity.

C O N F L I C T O F I N T E R E S T S T A T E M E N T

None declared.

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