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Polyomavirus-associated Nephropathy in Renal Transplantation: Critical Issues of Screening and Management

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Polyomavirus-associated nephropathy (PVAN) is an emerging disease in renal transplant patients with variable prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases. Intense immunosuppression is viewed as the most important risk factor. However, the preferential manifestation in renal transplants as compared to other allografts or to autologous kidneys of other organ transplants suggests that organ determinants and immunologic factors synergize: Renal tubular epithelial cells and their compensatory proliferation to restore tubular integrity after immunologic, ischemic or toxic injury may provide the critical cellular milieu supporting polyomavirus replication while immune control is impaired due to maintenance immunosuppression, anti-rejection treatment and HLA-mismatches. Patient determinants (older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role. The definitive diagnosis of PVAN requires allograft biopsy which is, however, challenged by i) limited sensitivity due to (multi-)focal involvement (sampling errors); ii) varying presentations with cytopathic-inflammatory and/or fibrotic/scarring patterns; iii) coexisting acute rejection which is difficult to differentiate, but impacts on intervention strategies. Screening for polyomavirus replication in the urine and in the plasma complements allograft biopsy by high sensitivity and allows for noninvasive monitoring. Thus, we suggest a terminology similar to invasive fungal diseases where viruria (“decoy cells”) defines patients at risk (“possible PVAN”) who should be evaluated for plasma viral load. Increasing BK viremia (>10,000 copies/mL) or urine VP-1 mRNA (>6.5x105 copies/ng total RNA) load defines “presumptive PVAN” for which an intervention of reducing immunosuppression should be considered even if the diagnosis could not be confirmed by allograft biopsy (“definitive PVAN”). The response to intervention should be monitored using plasma DNA or urine mRNA load.

Introduction

The human polyomaviruses type 1 and type 2 were isolated in the early 1970s and named after the initials B.K and J.C. of the respective patients.1,2 However, the medical and scientific context was significantly different. For JC virus (JCV), the isolation was driven by a clear link to disease which followed the electron microscopic visualization of polyomavirus particles half a decade earlier in brain tissues from patients with progressive multifocal leucoencephalopathy (PML).2 In contrast, the discovery of BKV is more reminiscent of “chance favoring a prepared Polyomavirus and Human Diseases, edited by Nasimul Ahsan. ©2005 Eurekah.com.mind” when particles of polyomavirus-like morphology were noted in cytopathically altered urinary cells of a renal transplant patient with ureteric stenosis.1 The pathogenic role of BKV remained elusive, to the point that BKV was declared an orphan virus in search of a human disease. However, 25 years later, the salient feature of the initial isolation, namely “decoy cells” in the urine of a renal transplant patient has become a paradigm in the emerging PVAN.3-5 Less well known is the fact that four of todays cardinal features of PVAN in renal transplants have been published as early as 1978 by Mackenzie and coworkers, namely the shedding of decoy cells, the presence of viral inclusions in tubular epithelial cells in allograft biopsies, the erroneous interpretation of allograft dysfunction with infiltrates as acute rejection and the role of intense immunosuppression and its reduction, all of which can be gathered from the paper entitled “Human polyoma virus—a significant pathogen in renal transplantation“ and the appended discussion protocol.6,7 Subsequently, sporadic cases of PVAN in patients with complex immunodeficiencies or advanced HIV-disease were reported.8,9 Thus, the appearance of PVAN is remarkable after decades of virtual nondiagnosis in renal transplantation.3,4,10-12 Given the presumed coevolution of human polyomaviruses with humans and the basically unchanged seroepidemiology,13 the recent surge of PVAN points to new risk factors and critical, but as yet ill-understood, changes in our transplantation protocols.

Infection, Replication and Disease

The virological aspects of BKV, JCV and SV40 have been described in detail (see Chapters 1, 6, 20). BKV and JCV are specific for the human host and despite a high degree of genetic homology of >70% are independently transmitted from one another.13,14 Epidemiologic, clinical and virologic aspects suggest coevolutionary adaptation resulting from a long-standing virus-host interaction:9

  1. High prevalence of infection reaching 70-90% among adults;
  2. Low morbidity of primary infection;
  3. Latency in the renourinary tract as the epidemiologically most relevant site;
  4. Asymptomatic reactivation and shedding into the urine;
  5. Extensive dependence on host cell functions for viral gene expression and replication;
  6. Chimeric nucleosomes consisting of host cell histones and viral DNA which are even packaged into virions;
  7. Linkage of polyomavirus subtypes to defined human populations and their historic migration patterns across continents.9

Thus, polyomavirus genomes resemble (mini-)chromosomes, yet without access to their hosts' germline remain dependent on a minimal set of functions to reach out and colonize to the next generation by infection. In contrast, human exposure to the simian virus SV40 resulted accidentally from contaminated polio- and adenovirus vaccines in the 1960s. Significant spread of SV40 among humans is not supported by serological data, but a role in disease has been put forward by some.15 Possibly, accidental exposure may be ongoing in areas with significant contacts to macaques e.g., in animal parks in rural areas of developing countries.

Polyomaviruses are small nonenveloped viruses of 45nm diameter and establish a state of nonreplicative infection termed latency in urogenital epithelial cells. Switching to the replicative mode requires viral regulatory functions, most notably the large T-antigen encoded in the early gene region. The large T-antigen is a multifunctional protein which governs viral transcription and replication in concert with cellular factors by cross-talking to host cell proteins including transcription and replication factors, cell cycle proteins and DNA binding proteins (see Chapter 9). After replication of the viral double-stranded DNA genome of 5300 bp, the late genes encoding the viral capsid proteins VP1, VP2, and VP3 are expressed and transported to the nucleus for virion assembly. The agnoprotein may play a role in the early and in the late phase of viral replication and virion assembly. Release of infectious progeny requires host cell lysis. Thus, despite being relatively slowly replicating as compared to e.g., herpes simplex virus in epithelial cells, significant polyomavirus replication is lytic and hence cytopathic. Host cell lysis releasing viral and cellular constitutents may elicit nonspecific inflammatory responses and depending on the state of the immune system, a specific cellular and humoral immune response. Of note, polyomavirus infections have been associated with diverse disease pattern which involve either cytopathic, inflammatory, immunological or oncogenic pathologies (Table 1). The underlying mechanisms are not well understood, but may reflect differences in the time and load of infection, in the infected cell types and their state of differentiation as well as different individual immunogenetic background and/or their modification by inherited, acquired or therapeutic immune dysfunction.9

Table 1. Patterns of polyomavirus-associated disease.

Table 1

Patterns of polyomavirus-associated disease.

Thus, polyomavirus infection is defined as serological or virological evidence of virus exposure without distinguishing between replicating, latent or transforming patterns.9 Polyomavirus replication is defined as evidence for ongoing virus multiplication (synonymous with lytic infection) by detecting: infectious virus by cell culture; polyomavirus particles by electron microscopy; polyomavirus structural proteins by immunohistochemistry; messenger RNA expression of late genes (e.g., VP1); polyomavirus DNA in nonlatency sites (e.g., in plasma); cytological (e.g., decoy cells) or histological evidence for polyomavirus replication.9 If detected in a seronegative or a seropositive individual, polyomavirus replication is termed primary or secondary, respectively. Polyomavirus disease corresponds to histological evidence of polyomavirus-mediated organ pathology. Conceptually, cytopathic, cytopathic-inflammatory or immune reconstitution patterns are closely linked to significant polyomavirus replication which is most likely in patients lacking at one time specific immune effector cells e.g., in seronegative individuals or in patients with inherited, acquired or therapeutically induced immune dysfunction.9,16 In autoimmune disease, a pathologic immune response is triggered at some point by prior replication, but has become independently thereof.17 In oncogenic transformation, the replicative state of the host cell is uncoupled from virus induced host cell lysis.9,18 As discussed in more detail below, PVAN may present as cytopathic, cytopathic-inflammatory or immune reconstitution patterns.

Epidemiology

Following the inaugurating report by Randhawa and coworkers in 1995,3 a stepwise increase in PVAN has been observed from 1% in 1995 to 5% in 2001 (fig. 1).19,20 Other reports from 2002-2004 identified PVAN in 1% to 10% of renal transplant patients (mean 5.1%, median 4.5%, Table 2) which correspond well to Kaplan-Meier estimates of 8% for the incidence of PVAN (95% confidence interval 1% - 15%) described in a prospective study.21 The majority of cases occur within the first year posttransplantation, but approximately a quarter of cases are diagnosed later (fig. 2).9,21,31 Loss of renal allograft ranges from 10% - >80% of cases (Table 2).4,9,12,27,32 In transplant centers screening for polyomavirus replication in the urine, plasma or in protocol biopsies, the rate of graft loss seems to be lower.20,21,31,33-36

Figure 1. Increasing prevalence of PVAN from year 1995 to 2001 (data from ref.

Figure 1

Increasing prevalence of PVAN from year 1995 to 2001 (data from ref. 19).

Table 2. PVAN prevalence, drug use and outcome in reports 2002-2004.

Table 2

PVAN prevalence, drug use and outcome in reports 2002-2004.

Figure 2. Kaplan-Meier estimates of the incidence of polyomavirus replication (decoy-cell shedding), BK viremia and polyomavirus-associated nephropathy (PVAN) in renal transplant recipients (data from ref.

Figure 2

Kaplan-Meier estimates of the incidence of polyomavirus replication (decoy-cell shedding), BK viremia and polyomavirus-associated nephropathy (PVAN) in renal transplant recipients (data from ref. ).

Molecular studies indicate that most cases of PVAN are caused by BKV.21,30,33,34,37-40 A role for JCV and the simian virus SV40 has been suggested which may either act alone41-44 or in concert with BKV,28,45 and should be investigated further.

Risk Factors

The risk factors for PVAN in renal transplantation are still only incompletely understood. Appropriately sized prospective multi-center studies are lacking and the results of hitherto published reports are often contradictory. Most likely, PVAN results from multiple, partly complementing factors including determinants of the patient (age >50 years, male gender, negative BKV serostatus of recipient prior to transplantation, impaired BKV specific T-cell response, white ethnicity, cytomegalovirus coinfection, diabetes mellitus), of the allograft (HLA mismatches, prior episodes of acute rejection, calcineurin-inhibitor toxicity) and of the virus (new BKV serotypes, adaptive changes in immune and replicative control regions with presumably increased viral fitness) (Table 3). It is conceivable that these factors are modulated by immunosuppression, inflammatory response patterns, antiviral and antiproliferative activities e.g., cidofovir, immunoglobulins, and/or coinfections e.g., cytomegalovirus, JCV, SV40 (fig. 3).9 There is, however, general consensus that immunosuppression is the conditio sine qua non for PVAN. It has been noted4 that the emergence of PVAN coincided with the widespread use of tacrolimus (TAC) and mycophenolate mofetil (MMF).53 However, a proof of causality is lacking. Their different mode of action suggests that the intensity of immunosuppression rather than the specific agent is the most relevant factor.4,7,11,47,54 The role of the net state of immunosuppression is underscored by the fact that reducing, switching or discontinuing components of maintenance therapy represents currently the primary mode of intervention (see below). As a note of caution, this argument does not exclude drug-specific mechanisms promoting polyomavirus replication which act at different, yet synergizing levels and would be expected to respond also to this intervention. Almost all diagnoses of PVAN were made in patients receiving a triple therapy of four drug classes (calcineurin inhibitors, anti-metabolites, mTOR inhibitors and corticosteroids). In approximately 90% of patients reported to date, these triple combinations contained TAC or MMF (Table 2)9 which were used concurrently in >50% of the cases. Conversely, <10% of all reported cases of PVAN received triple immunosuppressive regimens that did not contain TAC or MMF.9 Of note, a recent retrospective histopathology study from India described 30 cases of PVAN in patients treated with triple combinations of cyclosporine (CyA), azathioprine (AZA) and prednisone (PRE).55 Yet, the type of polyomavirus involved and impact on allograft function is not known at present. Taken together, it is clear that PVAN can arise in patients not treated with TAC or MMF although less frequently,7,9 while an increased risk for sustained BKV viruria or for PVAN was reported for patients treated with triple combinations of TAC, MMF and PRE22,35 or with TAC trough levels higher than >8ng/mL.22

Table 3. Presumed risk factors for polyomavirus-associatedd nephropathy.

Table 3

Presumed risk factors for polyomavirus-associatedd nephropathy.

Figure 3. Determinants and modulators of PVAN.

Figure 3

Determinants and modulators of PVAN.

Using antilymphocyte preparations for induction was not significantly associated with BKV viruria, viremia or PVAN,4,21,56 or with histologically more severe PVAN.20 In this way, replication of polyomavirus and cytomegalovirus differ possibly reflecting viral differences in propensity to reactivate, in sites of latency and in immunological control. In contrast, antilymphocyte preparations were associated with an increased risk for polyomavirus replication when administered for the treatment of acute rejection episodes in patients receiving combination of TAC-AZA and/or CyA-MMF.4,21 The differential effect of antilymphocyte preparations for PVAN suggests a cofactorial role of tubular epithelial cell injury and regeneration, similar to animal models.7,16,57

Steroids may also increase the risk of polyomavirus replication when given as part of a triple combination46,58 or as intravenous bolus to treat rejection as long as maintenance immunosuppression is continued or intensified.4,12,21,59 This effect of steroids synergizes with the intensity of the maintenance immunosuppression and is potentially less relevant if coupled to decreased or modified maintenance immunosuppression.21,51,59 Of note, glucocorticoid response elements have been reported in the regulatory region of polyomaviruses60 suggesting a molecular explanation for an increased risk of replication in concert with immunosuppression.

Diagnosis

The diagnosis of PVAN requires the demonstration of polyomavirus induced cytopathic changes in tubular or glomerular epithelial cells (see Chapters 14, 15). The histopathological changes of PVAN are fairly characteristic, but should be confirmed with ancillary tests such as immunohistochemical detection of the large T-antigen which is most commonly used (see Chapter 14). The sensitivity and specificity of the histological diagnosis of PVAN is complicated by (i) the focality of renal involvement, particularly early in the disease (pattern A); (ii) a wide spectrum of associated changes, in particular inflammatory infiltrates which may be unspecifically elicited by tubular cell necrosis or result from virus-specific cellular immune responses and are difficult to differentiate from acute rejection (pattern B); (iii) by pronounced tubular atrophy and fibrosis of late stages (pattern C) where only few viral cytopathic changes are seen to the point where they may even be undetectable (false negative).31,37,61,62 Given the diverse determinants (fig. 3) and presentations of PVAN and confounding concurrent pathologies, hands-on stratification can be achieved by searching for BKV replication in urine. Because of its high negative predictive value, lack of detectable BKV replication in the urine practically excludes PVAN. Conversely, if BKV replication is detectable, the risk for PVAN is increased and further diagnostic studies are warranted. Thus, the hallmark of PVAN is that ongoing polyomavirus replication is detectable as BKV viremia, viruria and decoy cell shedding in all of these presentations.4,5,21,31,35,63 The limited sensitivity of allograft biopsy is also critical for the definition of “resolved PVAN” as the goal of any intervention. Therefore, resolution of PVAN not only requires the disappearance of the histological signs of active disease (e.g., viral replication, inclusions, necrosis, inflammatory infiltrates) and negative immunohistochemistry, but should also include negative results of the surrogate replication markers such as BKV viremia and viruria. Thus, we suggest a terminology similar to invasive fungal diseases where viruria (“decoy cells”) defines patients at risk (“possible” PVAN) who should be evaluated for plasma viral load. BKV replication above thresholds such as increasing BK viremia (>10,000 copies/mL) (fig. 4) defines “presumptive” PVAN for which an intervention of reducing immunosuppression should be considered, preferably with, but, due to the limited sensitivity, not dependent on prior histological confirmation (“definitive PVAN”) (Table 4). In summary, surrogate markers of polyomavirus replication complement the limited sensitivity of PVAN biopsy and allows for noninvasive monitoring.

Figure 4. BKV load in plasma of patients with PVAN-negative n=13) and positive (n=16) allograft biopsies (H.

Figure 4

BKV load in plasma of patients with PVAN-negative n=13) and positive (n=16) allograft biopsies (H.H. Hirsch, unpublished).

Table 4. Polyomavirus replication and PVAN diagnosis in renal transplantation.

Table 4

Polyomavirus replication and PVAN diagnosis in renal transplantation.

Polyomavirus replication can be demonstrated by several methods such as urine cytology (decoy cells), quantification of urinary BKV DNA or VP1 mRNA load,4,5,21,33,63 or electron microscopy for polyomavirus particles.5,64 The different screening methods have not been compared, but are assumed to be equivalent given sufficient local expertise. Because self-limiting (transient) polyomavirus replication has been observed in renal transplant patients,21,31,62 it is recommended that positive screening results are confirmed within four weeks, followed by adjunct quantitative diagnostic assays such as quantification of BKV DNA load in plasma (fig. 5)21,65,66 or VP1 mRNA load in urine.33 Detecting higher levels of BKV replication above empirically defined thresholds may provide specificity and specificity of >93% such as BKV VP-1 mRNA 6.5 x 105 copies/ng total RNA33 or BKV DNA load in plasma ≥10'000 copies/mL (fig.4, fig. 5).21,65 To monitor the course of disease, quantitative polyomavirus testing should be performed every 2-4 weeks until viral replication drops below the threshold or is no longer detectable. However, further interlaboratory and clinical validation of threshold values in plasma and urine is needed.

Figure 5. Screening and intervention.

Figure 5

Screening and intervention. (Modified after Hirsh et al. Transplantation 2005; in press.)

Intervention

At the present time, there is no approved treatment for PVAN. In the absence of safe, specific and efficacious antivirals, the current mainstay of intervention resides in the judicious reduction of immunosuppression similar to cytomegalovirus infection in the era before ganciclovir. As indicated above, most cases diagnosed with PVAN to date are on triple immunosuppressive maintenance combinations containing calcineurin inhibitors (TAC, CyA), antiproliferative agents (MMF, AZA), and corticosteroids (PRE), or more recently sirolimus (SIR).28,65 However, there are no prospective randomized trials evaluating the efficacy and safety of the different interventions. In principle, three different, but not exclusive modes have been reported which include reducing, switching and stopping immunosuppressive drugs (Table 5). It should be noted that these experiences are anecdotal and reflect individualized approaches to patients and cannot be generalized. More recently, switching to leflunomide, an inhibitor of pyrimidine synthesis and protein tyrosine kinase, or the newer derivative FK778 has been proposed as these immunosuppressive drugs have also anti-viral activity in vitro.68

Table 5. Modification of maintenance immunosuppression in renal transplant patients with PVAN.

Table 5

Modification of maintenance immunosuppression in renal transplant patients with PVAN.

A critical issue with regard to management is the diagnosis of acute rejection concurrently with PVAN. Although PVAN is generally considered a complication of intense immunosuppression, both disease entities may start focally and show different kinetics which may lead to concurrence. In addition, reconstitution of BKV-specific cellular immunity may be difficult to distinguish from, and in fact, trigger acute rejection.9 Given a bona fide diagnosis of PVAN and concurrent rejection, there is controversy regarding the use of antirejection treatment with steroids in this situation. Based on the initital experience it is clear that PVAN progression is frequently observed when anti-rejection treatment is administered and the maintenance immunosuppression is maintained or intensified.4,12,21,59 However, in some centers, a two-step protocol of antirejection treatment coupled to a reduction of maintenance immunosuppression has been successful.21,71 The sole reduction of maintenance immunosuppression in this situation seems to be particularly risky as it might precipitate severe rejection and premature graft loss. In general, the response to reduced immunosuppression seems to better when PVAN is diagnosed early, with only limited involvement20,21,25,31,36 which most likely also applies to the concurrence of PVAN and rejection.

Several drugs have polyomavirus-inhibitory activity in vitro, including cidofovir, leflunomide, and certain quinolone antibiotics. In the clinical situation, the use of these drugs was combined with reduced immunosuppression which limits the evaluation of their efficacy. Amantidine has been used in the treatment of PVAN without discernable effect.23,72 Cidofovir has a significant in vitro effect inhibiting nonhuman polyomaviruses. However, the pronounced nephrotoxicity limits its use particularly in renal transplantation. A number of patients have been treated with a combination of low-dose Cidofovir and reduced immunosuppression with variable results. In most published reports, its use was associated with a decrease in viremia, but viruria often persisted for prolonged times.73-75 Some patients have gone on to develop end-stage renal disease which may, however, be multifactorial. This off-label use of cidofovir is at a low dose of 0.25 mg/kg, administered every two weeks. The patients are usually premedicated, with increased intravenous fluids.73-75 Chandraker et al. have shown that the quinolones also have anti- polyomavirus activity in vitro, and observed resolution of BKV replication in vivo in some of 10 prospectively studied patients.76 Although the efficacy is less than requested for an antipolyomaviral agent, these data suggest that the BKV encoded helicase activity may represent a significant drug target for further development.

Retransplantation

There is only limited experience with regard to retransplantation of patients who have lost a previous graft due to PVAN. Based on the 15 cases reported to date, the recurrence may be more frequent compared to that seen in primary transplants (13% versus 8%).49,72,77-79 Although conclusive evidence is lacking, persistent polyomavirus replication in the urine and/or in the plasma in a patient undergoing retransplantation is viewed as increased risk for recurrence of PVAN. In these patients, reduction or discontinuation of immunosuppression should be considered unless this option is limited by other coexisting grafts (often pancreas). In patients on hemodialysis, administration of antiviral drugs (e.g., cidofovir) may be considered prior to retransplantation. Although tansplant nephroureterectomy does not appear to be required prior to retransplantation, this intervention should be considered in patients with persisting polyomavirus replication. Following retransplantation, the question arises whether or not the same immunosuppressive drugs and combinations can be used as for the primary graft. The data compiled in a multicenter survey by Ramos et at79 suggest that the same drugs can be used, but that intense immunosuppression should be avoided. Recommendations for screening and treatment of polyomavirus are the same as for patients with a first renal allograft.

Conclusion

The association of BKV with PVAN in renal transplant recipients emphasizes the role of allo-situation in addition to immunosuppression. Most likely, patient, organ and virus specific determinants interact in a complementary fashion and are subject to dose- and magnitude dependent modulators (e.g., immunosuppression). BKV screening of renal transplant patients is warranted to enable early diagnosis of “possible”, “presumptive” or “definitive” PVAN as well as of “resolved” PVAN after appropriate intervention. The detection of a plasma BKV DNA load or VP1 mRNA in the urine above thresholds should trigger allograft biopsy to confirm PVAN and exclude acute rejection. Antivirals or immunosuppressants with antiviral activity are interesting new avenues that remain to be explored. Large prospective studies are needed to identify risk factors and to evaluate intervention strategies for PVAN.

Acknowledgement

This work was supported in part by the Swiss National Fonds Grant 3200-62021 to HHH.

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