Over the last decade, polyomavirus nephropathy (PVN) has emerged as an important cause of renal allograft dysfunction and graft loss. PVN occurs with a prevalence of 1%-8% in renal transplant recipients and is most commonly reported within the first 12 months posttransplant. The human polyomavirus, BK virus, is thought to be the primary etiologic agent of PVN. Risk factors for PVN are not well defined and are most likely a result of a complex interaction between multiple donor and recipient factors. Definitive diagnosis of PVN is made through histological assessment of a renal allograft biopsy. Recent studies have also evaluated noninvasive urine and serum markers for screening of BK virus replication and as adjunct tools in PVN diagnosis and monitoring. The principal treatment for PVN is immunosuppression reduction, but this must be balanced against the risks of rejection. If rejection occurs concurrently with PVN, a brief increase in immunosuppression to treat the rejection episode followed by a subsequent reduction in immunosuppression is recommended. No antiviral treatments for PVN have been approved by the Food and Drug Administration. Although the antiviral drug cidofovir has shown invitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Small series of patients treated with leflunomide and intravenous immune globulin therapy for PVN have also recently been reported. Retransplantation after graft loss due to PVN is feasible, but experience is limited. Current research is focusing on identifying PVN risk factors, refining screening, diagnostic and monitoring methods, and developing therapy for prophylaxis and treatment of PVN with the goals of decreasing the prevalence of PVN and improving allograft outcomes in renal transplant recipients diagnosed with PVN. This review will present recent advances in basic and clinical research related to PVN and renal transplantation.

Key words : BK virus, JC virus, Polyomaviruses, Renal transplantation, Retransplantation

Developments in surgical techniques and immunosuppressive regimens have allowed renal transplantation to evolve into an acceptable therapeutic option for patients with end-stage renal disease. Although vast progress has been made in renal transplantation, infectious complications in recipients remain a significant source of morbidity and mortality [1,2]. Over the last decade, polyomavirus nephropathy (PVN) has emerged as one of the more important causes of renal allograft dysfunction and graft loss.

Biology and Discovery of Polyomaviruses: Polyomaviruses are nonenveloped, double-stranded 45 nanometer DNA viruses that are ubiquitous in nature [3]. Although 13 distinct polyomaviruses are known to exist, only 3 species, [Simian virus 40 (SV40), JC virus (JCV), and BK virus (BKV)] have been shown to be associated with infections in humans [4]. SV40, JCV, and BKV are similar at the genomic level and share approximately 70%-75% homology with each other [5]. SV40 was initially discovered in rhesus monkeys in the 1960s and is believed to have been inadvertently transmitted to the human population through contaminated poliovirus vaccines administered to human populations from 1955-1963 [6,7]. JC virus (JCV) and BK virus (BKV) were both identified in 1971 and named after the patients’ initials in which they were first discovered. JCV was isolated from a patient with Hodgkin’s disease who died from progressive multifocal leukoencephalopathy [8], while BKV was found in a Sudanese renal transplant patient who presented with ureteral stenosis [9].

Routes of transmission of polyomaviruses have not been well defined. Although SV40 is thought to have been introduced to the human population through contaminated polio vaccines, studies have shown persons who have never been exposed to the vaccine to also have antibodies against SV40 [6,10]. BKV and JCV are thought to be acquired by primary infections in childhood through oral or respiratory routes [11]. Polyomaviruses have also been shown to be transferred to organ recipients through donor organs [12-14]. Similar to the prevalence of positive serologies for cytomegalovirus and Epstein-Barr virus, serologic studies have shown that up to 90% of adults in the United States and Europe have antibodies to BKV and JCV [5,15].

In the immunocompetent host, primary polyomavirus infections occur early in life and are usually asymptomatic. Once infected, the viruses persist indefinitely in various organs, including the kidneys. Approximately 50% of healthy native kidneys harbor latent BKV [16]. Asymptomatic transient reactivation may occur as viral shedding in the urine in 0.3% of immunocompetent patients [17] and 3.2% of pregnant women [18]. However, in immunocompromised hosts (such as organ and bone marrow recipients, and patients with cancers or human immunodeficiency virus infection), polyomaviruses can re-activate and cause overt disease. Moreover, SV40, BKV, and JCV have also been shown to be oncogenic in animal and laboratory models and are currently being investigated as potential cofactors for cancers in humans [6,19-26].

Polyomavirus disease presentation is in part dependent on the type of virus (SV40, JCV, BKV), and the underlying reason for the altered immune system. JCV is most commonly associated with progressive multifocal leukoencephalopathy in human immunodeficiency virus infected patients [27,28], while BKV is more frequently associated with the urogenital tract and usually presents as hemorrhagic cystitis in cancer and bone marrow transplant recipients [29-31], and ureteral strictures or nephropathy (PVN) in renal transplant recipients [32,33]. Rarely, polyomavirus infections can also result in multiorgan failure, as described in a report of a renal transplant recipient with fatal BKV-induced vasculopathy [34].

Limited data on PVN occurrence in the native kidneys of nonrenal transplant recipients are available [35-37]. One possible explanation for the low occurrence of PVN in the nonrenal transplant population was thought to be due to the fact that clinicians are less likely to consider PVN in nonrenal transplant recipients, and therefore it may be missed in these patient populations. A recent study, however, retrospectively evaluated the plasma of 51 heart, 45 liver, and 162 renal transplant recipients to evaluate the incidence of BKV viremia. Results found that 5% (8/162) of renal transplant recipients had BKV viremia with PVN. In contrast, BKV viremia was not found in any heart transplant recipient and was not found in 98% (44/45) of liver transplant recipients [38]. PVN was not identified in a pancreas alone transplant population either. The University of Maryland transplant program has found that 11% (4/38) of pancreas transplant alone recipients have evidence of polyomavirus reactivation by urine cytology, but this reactivation was not associated with renal impairment. Further studies are necessary to define the relationship of polyomavirus reactivation to PVN in nonrenal transplant recipients [37].

PVN Etiology: BKV is thought to be the primary polyomavirus responsible for PVN [39-41]. However, the occurrence and significance of SV40 or JCV coinfections with BKV in renal transplant recipients with PVN has not been wellstudied. More recent reports have identified the presence of SV40 [42] or JCV [43,44] in conjunction with BKV in renal transplant recipients affected with PVN. Moreover, JCV replication has also been identified in a subset of kidney specimens from patients with acquired immunodeficiency syndrome [45]. To date, however, the pathogenetic roles, if any, of JCV or SV40 in renal transplant recipients affected with PVN remain undefined and require further investigation.

Prevalence of PVN: Although BKV was first reported to be associated with infectious complications in a renal transplant recipient over 30 years ago [9], few additional cases of PVN in renal transplant recipients were reported in the 1970s and early 1980s [46,47]. In contrast, since 1995, a progressive increase in PVN has been observed, and the prevalence of PVN in renal transplant is currently reported to be between 1%-10% [33,44,48-64]. A recent prospective study of 78 renal transplant recipients found a Kaplan-Meier estimate for the incidence of PVN to be 8% (95% confidence interval 1%-15%) [65].

Reasons for the increased prevalence of PVN observed in the late 1990s are not well understood. The University of Basel diagnosed its first case of PVN in 1996 and subsequently confirmed that the diagnosis had not been missed in previous years by undertaking large scale rescreening of archived renal transplant biopsy material, thus supporting the observation that the prevalence of PVN has indeed increased over time [32]. Many reports attribute the increase in PVN prevalence to the incorporation of more-potent immunosuppressive agents, such as tacrolimus and mycophenolate, into transplant immunosuppressive drug regimens, which in turn may make patients more susceptible to opportunistic infections such as PVN. However, no prospective study to date has been able to identify one of these newer immunosuppressive agents as a cause of PVN [65,66]. A second reason may be that refined molecular and pathologic techniques for diagnosing PVN were not developed until recently, and therefore the diagnosis of PVN may have been missed in some centers in the past [54]. Thirdly, owing to increased reporting of PVN in the transplant literature, there is a heightened awareness of clinicians to consider this infectious complication as a diagnosis, particularly in a renal transplant recipient with allograft dysfunction. In summary, the increase in PVN prevalence is most likely multifactorial and further research is necessary to define specific risk factors.

PVN has been reported to occur between 2 to 60 months posttransplant, but is most commonly reported within the first 12 months posttransplant [16,57,63,67,68]. One early report described a bimodal distribution of PVN, with 50% of cases occurring 4-8 weeks after transplantation, with the remainder of the cases developing months to years after transplant [69]. However, these differences in PVN occurrences may be explained in part by differences in thresholds to perform renal transplant biopsies and varying levels of awareness for PVN.

The clinical significance of PVN derives from its association with renal allograft dysfunction and graft loss. A Kaplan-Meier analysis of graft survival in renal transplant recipients with PVN compared with contemporaneous recipients who did not develop PVN, found PVN markedly reduced renal allograft survival (P < 0.0001) [67]. Early reports of PVN patient outcomes were associated with graft loss rates of up to 45%-60% in PVN-affected patients [70,71]. With increasing awareness of PVN and improved diagnostic techniques, patients with PVN are being diagnosed at earlier stages of disease, while damage to the allograft may be more reversible [16,64]. As a result of earlier diagnosis of PVN, renal allograft loss rates reported in more recent experiences are decreasing to 10%-30% [44,61,65,72]. However, approaches are needed for PVN prevention, possibly through development of antiviral prophylactic approaches and identification of PVN risk factors.

Potential PVN Risk Factors: PVN risk factors are not well defined [33,48,49,52-55,57-63,65-67,70,73-76]. Analysis of risk factors are often based on small numbers of patients reported from various transplant centers. PVN-induced renal dysfunction and allograft loss are most likely a result of a complex interaction of multiple donor and recipient risk factors [16,39,76,77] (Table 1). Potential donor risk factors for PVN that have been evaluated include cold ischemia time, and cytomegalovirus status of the donor and the recipients, subsequent infections, and human leukocyte antigen mismatches. Thus far, cold ischemia time has not been found to be a risk factor for PVN [51,61,65,78]. Experimental data have shown that BKV can induce proliferation of human cytomegalovirus [79], however, clinical reports in renal transplant recipients have been conflicting [51,61,63-65,80]. When evaluating human leukocyte antigen mismatches, two studies showed a trend toward a higher number of human leukocyte antigen mismatches between donor and recipient in patients with PVN [56,65] with one of the studies also showing the number of human leukocyte mismatches to be significantly associated with BKV viremia (P < 0.01) [65]. In contrast, an analysis of 67 renal transplant recipients with PVN compared with 162 renal transplant recipients without PVN found no difference in the number of human leukocyte antigen mismatches [61]. Based on these findings, it is thought that the number of human leukocyte antigen mismatches may be a risk factor for BKV replication, but may not be a risk factor for PVN. Potential recipient risk factors for PVN have been reported to include: male gender [39,61,63], diabetes [44,68], older age (greater than 50 years) [61], Caucasian ethnicity [67] and BKV seronegativity prior to transplant [12,51]. Although a positive BKV serostatus pretransplant does not prevent polyomavirus replication or PVN [65], patients with a seronegative BKV status have been observed to have prolonged courses of viremia and PVN [39]. A study of 100 pediatric renal transplant recipients has also shown in a univariate analysis that seronegative BKV status, irrespective of the donor BKV status, was the most important predictor of BKV infection (P < 0.005) [51].

Several studies have attempted to identify individual immunosuppressive agents or specific combinations of immunosuppression as PVN risk factors. One of the major limitations of defining immunosuppressive risk factors has been the lack of standardized measurements available for analyzing cumulative immunosuppressive loads in renal transplant recipients. Nevertheless, intense immunosuppression represents a risk factor for PVN. Retrospective studies have shown PVN to occur under cyclosporine, tacrolimus, mycophenolate mofetil, and sirolimus-based immunosuppressive regimens [32,39,44,49,52,56,57,61,63,68,81]. In contrast, a recently published study from India of 414 screened renal allograft specimens performed from 1997-2002 from 321 renal transplant recipients on a combination of cyclosporine, azathioprine, and prednisolone for immunosuppression found the incidence of PVN to be 9.3%[82]. Moreover, prospective studies to date have been unable to identify antibody induction therapy, or any one maintenance immunosuppressive agent or immunosuppression combination as a risk factor for PVN [65,66]. A prospective, 2:1 randomized evaluation of renal transplant recipients receiving rabbit anti-thymocyte globulin and either tacrolimus (n = 32) or cyclosporine (n = 18) in combination with mycophenolate mofetil or azathioprine and corticosteroids, and a 43-week interim analysis showed no difference in the incidence of viruria or viremia between the tacrolimus and cyclosporine groups, and PVN was not observed in any patient [66]. This is the only study to date that has examined an early immunosuppression reduction for BKV viremia and viruria as a means for preventing PVN. A second prospective, single-center study followed 78 renal transplant recipients who were receiving immunosuppression which included tacrolimus (n = 37) or mycophenolate mofetil (n = 41). Urine was evaluated for the presence of decoy cells (expressed as the number of decoy cells per 10 high-power fields), and BKV viral loads were quantified in the plasma at 3, 6 and 12 months posttransplant, and whenever decoy cells were detected. Results showed that 10 patients had BKV viremia at a median of 23 (range 4-73) weeks posttransplant and 5 patients developed PVN at a median of 28 [8-86] weeks posttransplant. Kaplan-Meier estimates of the probability of decoy-cell shedding, viremia, and nephropathy were 30% (95% confidence interval 20%-40%), 13% (95% confidence interval 5%-21%), and 8% (95% confidence interval 1%-15%), respectively. In this prospective evaluation, PVN was not associated with any maintenance immunosuppressive regimen (tacrolimus, azathioprine and prednisone or cyclosporine, mycophenolate mofetil and prednisone), or antibody-induction therapy (antithymocyte globulin or interleukin-2 antibody preparations) [65].

As PVN is rarely reported in nonrenal allograft recipients [35-37], it is thought that risk factors other than immunosuppression alone are necessary for development of PVN. One prospective study has reported antirejection treatment with corticosteroids to be a significant risk factor for BKV replication and PVN [65], while several other reports have also noted an association of acute rejection episodes prior to PVN development [49,62,73]. This suggests that allograft injury, such as rejection, is an important determinant for PVN [39].

In summary, although intense immunosuppression seems to be a prerequisite for development of PVN, other factors such as renal allograft injury seem to make renal transplant recipients more susceptible to this infectious complication. Rather than one specific immunosuppressive agent, or combination, a “second hit”[16] involving a complex undefined interaction between several factors including immunosuppression, preexisting donor and recipient factors, and the presence of tubular injury (due to a combination of one or more events such as drug toxicity, ischemic injury, and rejection episodes and treatment) seem to play a role in the development of PVN in renal transplant recipients [16,32,39,76,77].

PVN Screening: PVN is most commonly recognized on a renal allograft biopsy prompted by evaluation following renal dysfunction. Unfortunately, in the majority of these cases, renal dysfunction is representative of a later stage of PVN [64,83]. More recently, it has been proposed that screening for BKV replication may identify patients at higher risk of developing PVN. Early identification of BKV replication prior to evidence of renal dysfunction would allow for earlier interventions, which may result in a decrease in the incidence and severity of PVN-induced renal complications. Due to the invasive nature of renal transplant biopsies, serum and urine assays such as viral quantization by polymerase chain reaction, urine decoy cell monitoring and anti-BKV serum antibodies, have been evaluated as a noninvasive means to identify patients at risk of PVN or for PVN diagnosis and monitoring [16,32,50,51,54,58,61,65-67,84-89] and several diagnostic algorithms have been proposed [16,32,55, 66,67,73,90]. Ding et al have proposed that detecting messenger RNA in the urine may be useful for PVN diagnosis. When using a cutoff value of 6.5 x 10⁵ BKV VP1 mRNA copy number per nanogram of total RNA, PVN was predicted with a sensitivity of 93.8% and a specificity of 93.9% [84]. Although BKV excretion in the urine can occur in 25%-44% of renal transplant recipients [3] (depending on whether urine cytology or polymerase chain reaction techniques are used) these events are usually transient and have been associated with causes such as drug toxicity and rejection [49,50].

Persistent decoy cell shedding (greater than 10 cells/cytospin or greater than 5 decoy cells per 10 high-power fields in cytology smears) has been found to be associated with PVN [32,83]. Ramos et al [67] recommend monitoring for decoy cells at 3, 6, 9, and 12 months posttransplant, and every 6 months thereafter in addition to initiating more intense monitoring during treatment of rejection episodes. Hirsch and Nickeleit et al have proposed an algorithm of PVN pathology where asymptomatic viral shedding is seen prior to early graft invasion with detectable viremia (greater than 7,700 copies/mL of BKV associated with PVN), followed by clinical graft dysfunction and the presence of histologic disease [32,58,65]. Likewise, Ramos et al [67] also recommend that a quantitative BKV serum load should be checked in the presence of viruria, and if serum BKV loads are greater than 10,000 copies of BK virus/mL an allograft biopsy should be performed for PVN. Although these assays are associated with high degrees of sensitivity and specificity, until further experience is gained with these methods, they are currently used only as adjuvant tools in diagnosing PVN and are utilized more widely in monitoring patients with PVN. The current gold standard for diagnosis of PVN remains the presence of microscopic histologic features of PVN in conjunction with the histologic demonstration of BKV in a renal transplant biopsy (see histologic diagnosis of PVN section below). Histologic Diagnosis of PVN: PVN diagnosis currently requires the presence of typical PVN histologic features (viral cytopathic effects in individual cells, tubulitis, mononuclear interstitial inflammation, and fibrosis) in conjunction with identification of BKV in renal allograft biopsy tissue [40,57,68,73,83]. Methodologies for identification of BKV on renal transplant biopsy include: immunohistochemistry using anti-polyomaviral antibodies (SV40 T antigen antibody), in situ hybridization (for BKV and JCV), or BKV polymerase chain reaction on the renal transplant biopsy [54,59,72,74,91]. More recently, Randhawa et al have developed methodology to measure BKV load in the renal transplant allograft, which may also be useful in early detection of PVN. Lower levels of BKV DNA were identified in biopsies performed before histologic development of PVN, and therefore may also have utility as a screening tool for PVN [72].

To further define the degree of PVN, Drachenberg et al have developed a 4-step pathologic grading system ranging from early to late PVN based on viral involvement, tubulitis, and inflammation [83]. As earlier diagnosis of PVN may be associated with better graft outcomes, surveillance renal transplant biopsies may be useful to identify diagnostic and prognostic markers for PVN. A report of 18 renal transplant recipients who were diagnosed with PVN through either surveillance biopsies posttransplant or nonsurveillance biopsies (performed for increasing creatinine), found that the surveillance biopsy group was more likely to have lower serum creatinines at diagnosis, 3 and 6 months postdiagnosis, have satisfactory graft function at 6 months postdiagnosis, and significantly lower chronic PVN scores. These differences were thought to be a result of earlier PVN diagnosis and reversible acute PVN damage [64].

A primary problem in treating PVN derives from the difficulties in distinguishing between the tubular lesions of acute rejection and the immune response to virally infected renal tubular epithelial cells, which are highly similar under routine histology staining techniques [16,92,93]. Inability to distinguish between acute rejection and antiviral immune responses may lead to inappropriate therapy such as anti-rejection treatment followed by a prolonged increase in immunosuppression which may result in worsening PVN and graft loss [68,91,94]. Moreover, some patients may present simultaneously with PVN and rejection. This problem is of particular importance as reductions in immunosuppression are a primary therapy for PVN in many centers. Research is underway to identify more specific histologic markers that may allow for differentiation between PVN and rejection. The expression of the major histocompatability complex class II (HLA-DR) molecules in tubular epithelial cells lacking polyomavirus replication has been proposed as an adjunct immunohistochemical marker of acute rejection [16]. Owing to the focal nature of PVN and the inherent possibility of biopsy sampling error, a negative biopsy may not rule out PVN. Therefore, although further research is necessary, it may be useful to evaluate biopsy results in conjunction with non-invasive markers such as serum and urine viral loads and urine decoy cells to detect early PVN.

Optimal methods for PVN screening, diagnosis, and monitoring have not yet been established. Viral assay results reported in the literature and commercial assays are not standardized and should not be compared with each other. To interpret patient results, the clinician must know what assay is being utilized and the specific range of values associated with that particular assay. It is hoped that with further research, refinement of diagnostic cutoff points may be identified to allow noninvasive blood and urine viral markers to play a more pivotal role in screening, diagnosing, and monitoring patients with PVN.

PVN Treatment
Prophylactic and therapeutic interventions for PVN are limited by our current understanding of PVN pathogenesis. Currently, antiviral drugs with specific activity directed at the polyomavirus life cycle are not available for prevention or treatment of PVN. Mechanisms for viral entry are not well understood. The majority of virions are thought to remain within the infected cell nucleus until released by cell lysis [15]. Moreover, polyomaviruses do not encode for viral DNA polymerases, but instead rely on host-cell enzymes [39]. Research is ongoing to determine potential therapeutic targets for PVN.

Polyomavirus Receptors: Human polyomavirus receptors may represent targets for therapeutic intervention to prevent and treat polyomavirusrelated diseases. Experimental evidence has shown that sialyated cell surface moieties serve as receptors for BKV, JCV and murine polyomaviruses [95101] while SV40 binds to the major histocompatability class I proteins [102,103] and ganglioside GM1 [104] to enter the target cell. JCV is internalized into the host cells via clathrin-dependent endocytosis [105,106], and chlorpromazine [107] and clozapine [108] have been found to inhibit this pathway. In contrast, SV40 and murine polyomaviruses utilize clathrin-independent entry mechanisms during productive infection. The uptake process for SV40 involves caveolae-mediated endocytosis, which is successfully inhibited by nystatin [109-113]. Interestingly, infection by murine polyomavirus is facilitated by either caveolar endocytosis [114] or by an alternative clathrin-, caveolin-1, and dynamin I-independent route dictated by the target cell type [115]. As for BKV, two studies report ultrastructural localization of virions in membrane-bound cytoplasmic structures, reminiscent of caveolae [34,40], however there is no conclusive experimental evidence characterizing the mechanism of BKV endocytosis into permissive cells.

Though the exact identity of the BVK receptor(s) is unknown, early work demonstrates that type-II gangliosides play an important role in the initial interaction between the virus and the permissive monkey kidney cells (Vero) as well as in the BKV hemagglutination of human type O red blood cells. Enzymatic removal of the surface sialic acid or the entire gangliosides was found to significantly inhibit infection of Vero cells by BKV [95,97]. Other studies have suggested membrane phopsholipids as a component of the BKV receptor [96]. Clearly a more-detailed analysis of polyomavirus receptors and their role as determinants of tropism, spread, and pathogenesis is needed prior to considering them as therapeutic targets for PVN.

Immune Responses and Reduction in Immunosuppression: Since PVN is an opportunistic infection, and there is no effective nonnephrotoxic antiviral agent available, the cornerstone of PVN treatment remains immunosuppression reduction to allow reconstitution of immune responsiveness to BKV with eventual infection resolution. PVN however, cannot be completely eradicated owing to viral latency in various tissues [41,116].

Recent studies of the cellular immunity against JCV have shown the presence of virus-specific CD8+ cytotoxic T lymphocytes in patients with progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy patients who had detectable JCV-specific cytotoxic T lymphocytes in their blood had a prolonged survival, whereas those who did not experienced progressive disease with a rapid fatal outcome [117,118]. Unlike JCV, nothing is known about the cellular immune response against BKV.

Reductions in immunosuppression should theoretically lead to better control of BKV replication, but it must be carefully balanced against the risks of rejection. Methods for reductions in immunosuppression vary greatly, and there are no randomized trials that have evaluated individual immunosuppressive reduction regimens [16,32,33,39,44,48,50, 52,57,61-64,66,76,81,85-87,90,91]. Early PVN studies where steroids or antilymphocyte therapy were employed were associated with significant graft losses [68,91,94]. More recent studies have shown that a brief increase in immunosuppression, followed by a subsequent decrease, may be the best way to manage rejection episodes occurring at or after PVN diagnosis [16,39, 65].

Therapeutic trials have been limited by small numbers of renal transplant recipients with PVN, lack of defined risk factors, and lack of nonnephrotoxic effective antiviral therapy. Retinoic acid, DNA gyrase inhibitors, and 5-bromo-2-deoxyuridine have been shown to inhibit polyomavirus replication in vitro but have not been successful in vivo [119-121]. An evaluation of Food and Drug Admin-istration-approved antiviral agents [ganciclovir, acyclovir, ribavirin, foscarnet, vidarabine (ARA-A), and cytarabine (ARA-C), and cidofovir] for in vitro activity against murine polyomaviruses and primate SV40 (but not BKV or JCV) found all antiviral agents ineffective except cidofovir [122]. Cidofovir, although associated with significant nephrotoxicity, has been used at lower doses to treat PVN in conjunction with reductions in immunosuppression [85-88]. The largest experience to date using cidofovir to treat PVN in renal transplant patients has been reported from the University of Pittsburgh (n = 16) [86,87]. Cidofovir was administered as 0.2-1mg/kg/dose every 1-4 weeks IV for a total of 1-7 doses (mean 2.7 doses per patient) without probenecid (to maximize excretion through the kidney affected with PVN) in conjunction with reductions in immunosuppression. The majority of patients [14/16 (88%)] showed clearance of BKV viremia, and most patients [15/16 (94%)] also had either a transient clearance or reduction in BKV viruria. Serum creatinine improved in 5 (31%) patients and stabilized in another 5 (31%) patients. Two (13%) patients experienced an increase in serum creatinine followed by stabilization, and the remaining 4 (25%) patients developed graft failure. Yet, several patients have experienced recurrent BKV viruria posttreatment. The authors conclude that cidofovir therapy may be beneficial in select patients, particularly those who have not responded to reductions in immunosuppression alone. Cidofovir has been used to treat BKV-induced hemorrhagic cystitis, but with mixed results [123-126]. A prospective study of cidofovir for the treatment of human immunodeficiency virus patients with JCV-induced progressive multifocal leukoencephalopathy did not show any benefit above that achieved with highly active antiretroviral therapy [127]. Larger patient populations and longer follow-up are necessary to assess the long-term risks and benefits of cidofovir in renal transplants with PVN.

Intravenous immune globulin (IVIG) has empirically been used for PVN treatment, but limited data exist to support its efficacy. Preliminary in vitro data from one group have shown IVIG to contain antibodies to BKV [128]. Based on this in vitro finding, IVIG has been administered at a dose of 500mg/kg/day for 7 days in conjunction with reductions in immunosuppression in 4 renal transplant patients with PVN. Two of 4 patients treated with IVIG and reductions in immunosuppression had clearance of BKV viremia and stabilization of serum creatinine at 12 to 19 weeks respectively. The other 2 patients treated with IVIG and reductions in immunosuppression had much shorter follow-up and still had BKV viremia at 4 weeks posttreatment. In comparison, two patients who received reductions in immunosuppression alone failed to clear BKV viremia by 45 weeks [129]. Further research with IVIG is necessary, as it also possesses efficacy in treating steroid-resistant rejections [130] and provides a potential treatment option for patients presenting with simultaneous rejection and PVN.

The investigational immunosuppressive malononitrilamide compound FK-778 [2-cyano-3-hydroxy-N-[4-(trifluoromethyl) phenyl]-2-hepten-6-yonic acid amide], a leflunomide analogue, has been shown to have in vitro activity against BKV and JCV, but is not yet Food and Drug Administration approved in the United States [131]. Based on these data, leflunomide has been used in limited clinical experiences for PVN treatment [132,133]. Its mechanism of action against polyomaviruses is unknown. Two renal transplant patients (one kidney alone, and one kidney-pancreas recipient) with PVN were treated with leflunomide (target blood levels of 60-90 mcg/mL) mycophenolate mofetil was discontinued, and tacrolimus was switched to cyclosporine (trough levels 250-350 ng/mL). BKV viremia was undetectable in both patients after 3 and 7 months of leflunomide therapy. The authors noted that the simultaneous antiviral effect and maintenance of global immunosuppression may be especially important in rejec-tion-prone kidney pancreas allograft recipients with PVN [132].

A second study of 6 renal transplant recipients with PVN also evaluated leflunomide as PVN therapy. At PVN diagnosis, BKV viremia was present in 4 of the 6 patients, and BKV viruria was present in 5 of the 6 patients. Upon PVN diagnosis, all 6 patients, who were maintained on tacrolimus, mycophenolate mofetil and prednisone-based immunosuppression were switched to a modified regimen where mycophenolate mofetil was replaced with leflunomide. A leflunomide loading dose of 100 mg/day for 3-5 days was followed by a daily maintenance dose of 40-60 mg/day. BKV viremia viral load measurement became undetectable in 4 patients, and BKV viruria showed significant reduction in 5 patients. Follow-up biopsies performed on the 2 patients with undetectable viral load at diagnosis showed partial resolution within 6 weeks of treatment. After a follow-up of 147 ± 67 days, none of the patients have had rejection or graft failure. The authors concluded that patients treated with leflunomide have responded with falling BKV loads and stable or improving renal function [133].

The effects of leflunomide and IVIG have been difficult to assess owing to their broad inclusion criteria, small sample sizes and lack of data in large randomized trials. Moreover, other reports have shown decreases or clearance of virus in the blood and urine with reductions in immunosuppression, particularly at early stages of PVN when allograft injury may be reversible [32,61,63,64,66,68,81, 90,134].

Retransplantation for PVN-Induced Graft Loss: Experience with retransplantation after renal allograft loss to PVN is limited. Issues to consider include: 1) the risk and incidence of recurrent PVN, 2) interval from PVN diagnosis to retransplant, 3) transplant nephrectomy prior to retransplantation, 4) influence, of donor/recipient serum anti-BKV antibody status, 5) immunosuppression, and 6) screening, prophylaxis, and treatment options for PVN recurrence.

Based on a summary of the currently published literature [135-139], 13 patients (8 kidney, 5 kidney pancreas) have undergone retransplantation for PVN- induced graft loss. PVN occurred in the primary transplanted kidney at a median of 14 (range 2-94) months posttransplant, and the time from graft loss to retransplantation was a median of 8 (range 1-60) months after PVN. Overall, 9 (69%) patients underwent transplant nephrectomy either prior to or at the time of retransplantation, and 7 (54%) patients received the same immunosuppressive regimen after retransplantation that they received with their primary transplant. Based on this literature, at a median follow-up of 24 (range 549) months after retransplant, 2 (15%) of the patients have experienced recurrent PVN at 8 and 15 months. Interestingly, both with recurrent PVN had their PVN-infected allografts removed prior to PVN recurrence [137,138].

Based on these experiences, PVN should not be considered a contraindication to retransplantation.

However, the occurrence of PVN after retransplant is higher (15%) than in the general transplant population (1%-10%). Patients should therefore be adequately informed of the potential risks of recurrent PVN in the retransplanted allograft prior to proceeding with transplantation. These data also show that PVN may recur despite removal of the primary infected allograft, and transplant nephrectomy may not be necessary prior to retransplantation. Time intervals between graft loss and retransplantation vary greatly (range 2-60 months), and no defined time period has been associated with the recurrence of PVN. However, in an effort to lower the risk of recurrent PVN, patients should have low to undetectable amounts of BKV in the serum and urine prior to retransplantation. Immunosuppression reduction or immunosuppression discontinuation should be considered to improve viral clearance prior to retransplantation. Patients may be maintained on the same immunosuppressive regimens as the primary transplant, but efforts should be made to avoid over-immunosuppression. Approximately 80% of the United States and European population have anti-BKV antibodies, thereby decreasing the feasibility of matching sero-negative anti-BKV serum antibody donors to patients retransplanted for PVN-induced graft loss. Moreover, it is not known if utilization of a sero-negative anti-BKV antibody donor will decrease the risk of recurrent PVN in patients with prior infection. Patients retransplanted for PVN-induced allograft loss should be monitored (BKV loads in serum, anti-BKV serum antibodies, BKV urine loads, decoy cells), and protocol biopsies to identify early PVN recurrence should be considered. If noninvasive markers such as BKV loads (serum, urine, biopsy) or decoy cells are found to be increasing, reductions in immunosuppression should be considered to prevent recurrent PVN. Further experience and longer follow-up to define risk factors for recurrent PVN and assess long-term outcomes in patients retransplanted for PVN-induced renal allograft loss.

Conclusions

PVN is occurring with increased frequency in the renal transplant population, and risk factors for BKV infection and PVN have not been well defined. The majority of patients are diagnosed via a renal allograft biopsy in the presence of renal dysfunction. Optimal prophylaxis or therapy for PVN has not been established. Owing to lack of effective antiviral therapies, the current standard for treatment of PVN is reductions in immunosuppression in an effort to achieve an immune response against BKV. When rejection presents simultaneously with PVN or occurs after PVN diagnosis, a two-step approach of initial increased immunosuppression to treat the rejection episode, followed by subsequent reductions in immunosuppression is recommended. Early reports of PVN reflected later stages of diagnosis, where reductions in immunosuppression were not as effective. As current screening, diagnostic, and monitoring techniques for PVN (serum and urine viral loads, urine decoy cells, and renal transplant biopsies) are refined, patients are likely to be diagnosed at earlier stages of BKV infection. Research focused on identifying PVN risk factors, and a nonnephrotoxic antiviral agent for prophylaxis and treatment of PVN may drastically decrease the prevalence of PVN and improve allograft outcomes in renal transplant recipients diagnosed with PVN.

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