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Keywords:

  • BKV;
  • interstitial nephritis;
  • JCV;
  • PCR;
  • rejection;
  • viral load;
  • viral nephropathy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

Persisting polyomavirus replication is now widely recognized as a (re-)emerging cause of renal allograft dysfunction. Up to 5% of renal allograft recipients can be affected about 40 weeks (range 6–150) post-transplantation. Progression to irreversible failure of the allograft has been observed in up to 45% of all cases. The BK virus strain is involved in the majority of the cases. Risk factors may include treatment of rejection episodes and increasing viral replication under potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate. The diagnosis requires the histological demonstration of nuclear polyomavirus inclusions in affected tubular epithelial cells. Interstitial inflammatory infiltrates and fibrosis become more prominent in the persisting disease and may be difficult to distinguish from (coexisting) rejection. Detection of polyomavirus-inclusion bearing cells (‘decoy cells’) in the urine and quantification of BK virus DNA in the plasma have been proposed as surrogate markers for polyomavirus replication and allograft disease, respectively. Antiviral treatment is not yet established; however, reports of treatment with cidofovir are encouraging. Current management aims at the judicious modification and/or reduction of immunosuppression which, in view of preceding or concurrent rejection, is not without risk.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

‘…there were inclusion-like cells in the renal tubules, so that this might mimic a rejection episode… I think it is a very difficult clinical decision, and I am very glad I am a pathologist.’ (EFD Mackenzie)(1)

Viral infections in organ transplant recipients take place in the presence of immunologically ‘foreign’ graft tissues and iatrogenic suppression of the immune functions to prevent rejection. Allograft, immunosuppression and virus as well as the past immunological experience of the host are appreciated as qualitative and quantitative determinants for the viral pathogenesis with respect to time, manifestation and outcome (2). In the last 10 years, the most advanced concepts have been established for cytomegalovirus by a powerful interaction between pathologists, virologists and clinicians: prophylactic, preemptive or therapeutic interventions take into account the risk constellation of donor and recipient, the laboratory signs of infection and the clinical and histological definitions of disease against the background of the respective type of transplantation (3). In contrast, polyomavirus infections in transplant patients are not as well investigated, most likely a reflection of their generally low pathogenicity (4).

Virus and Host

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

The polyomaviruses type 1 (BK virus) and type 2 (JC virus) are small nonenveloped DNA viruses of 45 nm and seem to be well adapted to their human host. Primary infections occur typically without specific signs or symptoms in up to 90% of the population. Both types persist in the kidney as the principal site from where reactivation and asymptomatic shedding into the urine take place (5,6). Depending on the sensitivity of the laboratory test [polymerase chain reaction (PCR), urine cytology, tissue culture, electron microscopy], urinary shedding of polyomavirus has been detected in 0.5–20% of healthy individuals (7–9). Despite the presence of a specific cellular and humoral immune responsem (10), subtle changes in the host's immune system such as pregnancy or aging are associated with increases in polyomavirus shedding (11,12). The appearance of viral inclusion bearing cells, so-called ‘decoy cells’, in urine cytology smears represents a sign of elevated polyomavirus replication in the urogenital tract which is, however, not pathognomonic for renal involvement. Because polyomaviruses are nonenveloped, release of infectious progeny requires the lysis of the host cells. Consequently, polyomavirus replication is always associated with a cytopathic effect.

The type of immunological dysregulation and the type of virus seem to confer a certain organotropism of polyomavirus diseases. Thus, progressive multifocal leukoencephalopathy (PML) is caused by JC virus (13). PML is a rare complication in transplant patients, but affects 1–4% of HIV patients with the acquired immunodeficiency syndrome (14). BK virus, on the other hand, has been associated with hemorrhagic cystitis, a complication typically encountered in bone marrow transplantation (15), whereas ureteric stenosis and BK virus nephropathy were associated with renal transplantation (16). The organotropism is not well understood. A critical element might be tissue injury which could result from coinfection or immunological, drug-related, mechanical, or ischemic assaults (17,18). Subsequent repair processes and cell division in the presence of weakened immune functions might provide the necessary window for efficient polyomavirus replication. Conversely, certain continuously proliferating and differentiating cells like the urothelial cell layer may be more permissive to support polyomavirus replication even in the absence of significant injury and repair (Figure 1). Inflammatory processes may contribute to functional impairment as indicated by exacerbating signs and symptoms during immune reconstitution, e.g. following effective antiretroviral therapy in AIDS patients with PML (19,20). Renal failure due to nephritis or multiorgan failure due to nephritis, pneumonitis and encephalitis represent exceptional complications of persisting (high-level) polyomavirus replication in patients with primary (21) or acquired immunodeficiency syndromes (22,23), respectively.

image

Figure 1. BK virus nephropathy. Risk factors: maintenance immunosuppression (tacrolimus, mycophenolate, sirolimus); tub-ulus cell injury and regeneration; antirejection treatment; BK virus genotype; seropositive donor.

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Polyomavirus and Renal Transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

In renal allograft recipients, the clinical manifestations of polyomavirus infections range from asymptomatic replication in the urinary tract to complications such as ureteric stenosis, transient impairment of renal function, extensive viral nephropathy and irreversible graft failure. In a large prospective study of 496 renal allograft recipients over 6 months post-transplantation, serological evidence of infection with JC and BK virus was described in 10 and 22% of the patients, respectively, but without identifiable clinical consequences (24). While this supports the notion that polyomavirus infections in renal allograft recipients are mostly without complications, it cannot be excluded that the clinical manifestations and/or significant antibody changes had not yet developed, especially in the patients under more intense immunosuppression. In three studies with longer follow-up, 25% of 160 patients excreted ‘decoy cells’ in the urine. In 18% of these patients, ureteric stenosis was found, and 33% experienced varying degrees of graft dysfunction (1,25,26). Most of these symptomatic cases were attributed to the BK virus. In addition to rejection and steroid pulse treatment, mechanical and ischemic damage had been suggested as co-factors for ureteric stenosis (27).

Although renal allograft dysfunction was also noted in some of these early studies, direct histological evidence of allograft involvement was only described for one case by Mackenzie et al. in 1978 (1). In 1995, Randhawa and colleagues reported another case of renal allograft dysfunction with histologically manifest polyomavirus infection (28). This report and the description of four new cases (29,30)had significant impact as polyomavirus-associated allograft nephropathy had started to appear in other transplantation centers in North America and Europe.

Polyomavirus Nephropathy: Histological Presentation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

The clustering of cases in different centers greatly helped to elucidate the spectrum of the histological presentation of polyomavirus nephropathy (31–36). Immunohistochemistry using cross-reacting antibodies against the large-T antigen of the related simian polyomavirus SV40 has been instrumental for increasing the sensitivity and the specificity of the diagnosis. Electron microscopy and immunohistochemistry do not distinguish between BK and JC virus. Type-specific antisera may overcome this problem (37), but a rigorous side-by-side analysis has not been published to date. Due to their high genomic homology, even molecular techniques like in situ hybridization and polymerase chain reaction (PCR) have to be carefully targeted to discriminating gene sequences. Nevertheless, the results of four studies revealed that BK virus was responsible for the majority of cases of polyomavirus-associated allograft nephropathy (BK virus nephropathy) (37–40). Patients with concurrent cytomegalovirus infections have been described, but corresponding histological and immunohistochemical findings had not been detected in the respective allograft biopsies (35).

The typical signs of polyomavirus nephropathy consist of nuclear inclusions in tubular epithelial cells, often of an amorphous basophilic or eosinophilic ‘ground-glass’ type. Pronounced cytopathic changes include enlarged irregular nuclei and chromatin smudging (31–36). Cytopathically altered tubular epithelial cells may detach into the tubulus lumen, resulting in denuded patches of the basement membrane (Figure 2). Electron microscopic examination reveals dense assemblies or crystalline arrays of viral particles with a diameter of approximately 40–45 nm in the nuclei of affected tubular epithelial cells. Neutrophil, monocyte and lymphocyte cell infiltrates as well as signs of fibrosis have been found in persisting BK virus nephropathy; hence the term ‘interstitial nephritis’ has been used. The major differential diagnosis is rejection which may even coexist. Immunohistochemical demonstration of HLA-DR and C4d has been proposed as adjunct indicators of rejection (34,41,42). Among the infiltrating lymphocytes, a predominance of CD20-positive B-cells was observed, whereas TIA-1 positive lymphocytes (NK-cells and cytotoxic T cells) appeared to be reduced when compared with cases with acute rejection (36).

image

Figure 2. A: Urine cytology showing “decoy cells” with typical intranuclear viral inclusion bodies (arrows; Papanicolaou stain; ×400). B: Allograft biopsy showing viral inclusions in tubular epithelial cells with denudation of the tubular basement membrane (arrows; heamtoxylin and eosin stain, ×160). C: Allograft biopsy showing nuclear inclusions of tubular epithelial cells stained for polyomavirus large T-antigen (mouse monoclonal antibody with 3-amino-9ethylcarbazole as chromogen, hematoxylin as counterstain, ×100). The figures were reproduced with permission from ref. 38. Copyright © 2000 Massachusetts Medical Society. All rights reserved.

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Serial biopsies from individual patients indicated that early stages of polyomavirus nephropathy are confined to foci, mostly in the medulla, and lack inflammatory infiltrates (32,33,35). Repeat biopsies, often performed 3–6 months later, revealed more pronounced alterations with interstitial infiltrates and tubular atrophy in up to 80% of the biopsy areas. Late in the disease, fibrosis predominates, often with only few polyomavirus-infected cells. Based on a large series > 100 biopsies from 55 patients, Drachenberg et al. proposed four stages of BK virus nephropathy (early/noninflammatory; destructive/inflammatory; inflammatory/fibrosing; late sclerosing) (43).

(Re-)emergence and Risk Factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

Retrospective studies reported histological evidence of BK virus nephropathy in 1–5% of allograft biopsies and graft nephrectomies (4,31,32,34,39,44). It cannot be excluded that the increased awareness, the availability of immunohistochemical tools and improved biopsy techniques with more medullary tissues are confounding factors. However, BK virus nephropathy was virtually nonexistent in some centers before 1996, even when systematically re-examining all allograft biopsies from patients with documented shedding of ‘decoy cells’ since 1985 (33). Thus, the increasing number of cases with histologically manifest BK virus nephropathy suggests the presence of new risk factors.

As most patients had been treated with tacrolimus or mycophenolate mofetil, a crucial role of these potent new immunosuppressive drugs seemed likely (45). A recent case of BK virus nephropathy has occurred under treatment with sirolimus, cyclosporine and prednisone (46). However, BK virus nephropathy has been observed in patients not treated with tacrolimus or mycophenolate, albeit rarely (1,32,39). In most of the cases reported to date, recurrent rejection episodes, treatment with antithymocyte preparations and/or steroids and maintenance immunosuppression with tacrolimus- and/or mycophenolate-based regimens preceded the diagnosis of BK virus nephropathy (34,44,45). Our own prospective investigation indicates that the incidence of BK virus nephropathy is 5% among patients receiving tacrolimus- or mycophenolate mofetil-based immunosuppression. Hence, tacrolimus- and mycophenolate-containing immunosuppression seems to increase the risk, but is not sufficient for progression to BK virus nephropathy (Hirsch et al., unpublished results). Taken together, it seems reasonable to assume that a combination of possibly exchangeable risk factors promotes the pathogenesis of BK virus nephropathy (Figure 1). In analogy to well studied animal models (17,18), immunological injury of tubular epithelial cells due to rejection may provide regenerating host cells which are permissive for local or blood-borne polyomavirus infection and replication. Progression to full-blown nephropathy then occurs due the sustained paralysis of the specific immune function by antirejection treatments and tacrolimus- or mycophenolate-based regimens. A role of possibly more aggressive viral genotypes has been proposed as an additional pathogenetic factor (47–49). Transplantation of a kidney from a seropositive donor into a seronegative recipient might be a risk factor (50), but more than 80% of our patients with BK virus nephropathy have BK virus specific antibodies prior to transplantation (Hirsch et al., unpublished results).

Diagnosis and Management

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

Diagnosis requires allograft biopsy, not only to demonstrate the viral alterations, but also to rule out other, potentially coexisting pathologies such as rejection, drug toxicity, and recurrence of the underlying renal disease. Unless control biopsies were performed, early stages of BK virus nephropathy (no inflammatory infiltrates) were rarely found in the absence of other pathologies. Due to their focal nature and medullary localization, early stages can be easily overlooked unless immunohistochemistry is applied. These early stages are unlikely to explain significant functional abnormalities. Progression to relevant disease stages, however, may occur upon intensified immunosuppression, e.g. by the treatment of coexisting rejection. Conversely, more advanced stages of polyomavirus nephropathy with extensive allograft involvement, virally mediated tubular necrosis, varying inflammatory infiltrates and signs of fibrosis were more frequently diagnosed without concurrent pathologies, especially after successful antirejection treatment. Most cases of BK virus nephropathy have been diagnosed about 40 weeks post-transplantation (range 6–160) (32,33,35,43). The wide range of the time of manifestation may reflect differences in the type of injury and the corresponding antirejection treatment (44). Without appropriate intervention, allograft loss has been observed in up to 45% of all cases on average within 6 months of the histological diagnosis (4,34).

Although experience is limited, current management strategies aim at the judicious lowering of the dosage of the immunosuppressive maintenance therapy to allow immunological clearance of BK virus replication. This strategy was combined with switching to cyclosporine and azathioprine. The success of switching and/or lowering treatment supports a pathogenetic contribution of the intensity of the maintenance immunosuppression regime, although this by itself is not sufficient for the development of BK virus nephropathy. Individual cases support the view that early stages of BK virus nephropathy might be more readily reversible (38,46). Resolution of polyomavirus replication was documented even in cases diagnosed at a late fibrosing stage, but functional recovery was no longer observed (38). In cases of coexisting acute rejection, a two-step procedure of immediate antirejection treatment followed by reducing the maintenance immunosuppression might be indicated (31,41). It remains to be shown whether or not maintenance immunosuppression has to be re-increased once BK virus nephropathy is cleared from the graft.

More recently, antiviral treatment has been successfully used in three patients with BK virus nephropathy. Cidofovir, a potentially nephrotoxic cytidine analogue, was effective when administered at 20% of the dosage recommended for cytomegalovirus, without probenicid (51). All patients cleared BK virus from the urine 2–12 weeks after initiating therapy. In particular, patients with a history of aggressive rejection episodes are faced with an increased risk of entering a vicious cycle of repeated rejection, intensified immunosuppression and renewed progression of BK virus nephropathy. Thus, this significant observation on the effectiveness of cidofovir may indicate a potentially safe treatment alternative.

Non-invasive diagnostic tools have been evaluated for identifying patients at risk (screening). The detection of ‘decoy cells’ in the urine is a 100% sensitive sign of BK virus replication in the urogenital tract. The positive predictive value for BK virus nephropathy, however, is < 20% (38). Quantification of the number of ‘decoy cells’ per 10 high-powered fields has been reported to increase the specificity (43), but, in our hands at least, decreases the sensitivity to < 60%. In contrast, the detection of BK virus DNA in plasma by PCR was found to correlate closely with allograft involvement (sensitivity 100%, specificity 88%) (38). Allograft removal was followed by an immediate disappearance of BK virus DNA in plasma, indicating that viral replication in the allograft is the major source of BK virus DNA in the plasma (38). Changes in the immunosuppressive treatment were followed by corresponding changes in the BK viral load (40,46) Thus, monitoring of the BK viral load in plasma seems to be a suitable tool to tailor the necessary and sufficient duration of reduced maintenance immunosuppression to individual patients, particularly those with complex management strategies. Quantification of BK virus DNA in the urine might be an interesting alternative procedure. Because the BK virus load in the urine is 100- to 1000-fold higher than in plasma, threshold definitions might prove useful to distinguish significant from nonsignificant viral shedding. This could help to limit the time of intervention and, hence, the risk for recurrent rejection during transiently lowered immunosuppression, the toxicity and the risk for selecting viral resistance during antiviral treatment.

We currently screen patients for ‘decoy cells’ in the urine at routine visits. In fact, ‘decoy cells’ can easily be detected in native urinary sediments by phase contrast microscopy. When ‘decoy cell’ shedding persists, BK virus DNA should be searched for in plasma. Together, this represents a simple and cost-efficient way to identify patients at risk. Increasing BK viral loads in plasma suggest significant allograft involvement and should be confirmed by demonstration of BK virus nephropathy in the allograft biopsy. The effect of modified immunosuppression (or antiviral treatment) on the course of BK virus nephropathy should be monitored using the BK viral load as a surrogate marker for BK virus nephropathy (41,46) (Hirsch et al., unpublished data).

Perspective

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

The (re-)emergence of polyomavirus nephropathy in renal allograft recipients represents a pathogenetic, diagnostic and therapeutic challenge. In the past 3 years, significant progress has been made in elucidating the spectrum of the histopathological presentation as well as in identifying procedures for screening and monitoring. The development of diagnostic criteria should now be pursued which enable a standardized diagnosis, including the staging of BK virus nephropathy. This should provide an optimal starting point for prospective multicenter studies which are needed to identify risk factors and to evaluate intervention protocols. Long-term studies are needed to investigate the potential role of limited, but persisting, BK virus nephropathy in chronic allograft failure.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References

I would like to dedicate this review to Professor Dr Gilbert Thiel, former Head of the Division of Nephrology, Basel. I would also like to acknowledge the support of, and many fruitful discussions with, Drs Michael Mihatsch, Jürg Steiger, Volker Nickeleit, Michael Dickenmann, Michael Mayr, Lyndall Brennan and Thomas Klimkait, Basel, as well as the kind communication with Dr Parmjeet Randhawa, Pittsburgh, and Dr Sundaram Hariharan, Wisconsin. This work was supported by the Swiss National Fonds Grant 3200-62-02.00.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Virus and Host
  5. Polyomavirus and Renal Transplantation
  6. Polyomavirus Nephropathy: Histological Presentation
  7. (Re-)emergence and Risk Factors
  8. Diagnosis and Management
  9. Perspective
  10. Acknowledgments
  11. References
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