Objectives: There is no active treatment for postrenal transplant BK virus-associated nephropathy proven to be effective so far. We assessed the effectiveness of actively treating this condition with combined leflunomide, intravenous immunoglobulin, and ciprofloxacin on long-term graft outcome compared with minimization of immunosuppressive drugs.

Materials and Methods: Kidney transplant re­cipients were screened for BK virus-associated nephropathy. Group 1 comprised 22 kidney trans­plant recipients with twice-positive BK virus polymerase chain reaction results in urine and blood. After diagnosis was confirmed with graft biopsy, antimetabolite (mycophenolate mofetil or aza­thioprine) was changed to leflunomide and intravenous immunoglobulin and oral ciprofloxacin were given. Group 2 comprised 33 BK virus-associated nephro­pathy patients treated conven­tionally with reduced immunosuppressive medications.

Results: Fifty-five patients were treated (38 males [69%], 28 patients [50.9%] with type 2 diabetes mellitus). Mean HLA antigen mismatches were 3.65, and 28 patients (50.9%) were HLA-Cw7 negative. All patients received induction therapy, 30 patients (55.6%) received thymoglobulin, and 29 patients (52.7%) received antirejection therapy before BK virus-associated nephropathy diagnosis. Maintenance immunosuppression was prednisolone in 53 patients (96.3%), mycophenolate mofetil (2 g daily) in 52 patients (94.5%), and tacrolimus in 28 patients (50.9%). Subsequent rejection episodes occurred in 38% of patients after diagnosis. Basal mean estimated glomerular filtration rate was 52.5 ± 25.5, which was reduced significantly to 38.1 ± 27.8 mL/min/1.73 m2 (P < .0001) at end of study but without significant differences between the groups (P = .08 and P = .17). Follow-up was 7.3 ± 4.99 years. Although no significant differences were shown in patient outcome, graft survival was significantly better in group 2 (P = .032).

Conclusions: Administration of 3 different anti-BK virus agents (leflunomide, intravenous immuno­globulin, ciprofloxacin) added no benefit to long-term outcome in patients with BK virus-associated nephropathy. Reduction of immunosuppressive medications appears to be a more effective treatment.

Key words : Allograft rejection, Polyomavirus, Renal transplant

Introduction

BK virus is one of the Polyomaviruses that is highly prevalent in human sera but may only cause clinical disease in immunocompromised patients.^1,2 BK virus-associated nephropathy (BKVAN) is a serious complication after kidney transplant that leads to graft dysfunction and loss.^1-5 It has variable prevalence (1%-10%) in kidney transplant recipients.^1,2 BK virus-associated nephropathy directly correlates with the intensity of immunosuppressive therapy. Because of the paucity of randomized controlled trials, a specific immunosuppressive drug or combination has not been proven to be associated with BKVAN.^1,2,4 Other potential risk factors include older and younger age, male sex, individuals who are categorized as white, total HLA antigen mismatch, absence of HLA-Cw7, zero HLA-DR mismatch, prior tubular injury, ureteral trauma, type 2 diabetes mellitus, delayed graft function, cytomegalovirus infection, treatment for acute rejection, and tacrolimus or mycophenolate mofetil treatment.^1,5,6 The diagnosis and monitoring of BKVAN in kidney transplant recipients are dependent on quantitative or real-time polymerase chain reaction (PCR) analyses for BK viral DNA of serum and urine.⁵ In addition, histologic diagnosis requires the presence of characteristic cytopathic changes and positive immunohistochemistry tests using antibodies directed specifically against BK or cross-reacting SV40 large T antigen.^7-9 Presumptive BK nephropathy is defined as sustained urine viral replication (more than 2 wk) and significant BK replication (plasma DNA PCR load > 10 000 copies/mL) with or without kidney dysfunction in the absence of definitive histologic evidence obtained by biopsy.⁷ The prevention and treatment of BKVAN in kidney transplant recipients are based on 2 principal approaches: (1) a screening and preemptive strategy that involves periodic monitoring for viremia to start early treatment once systemic infection is detected and (2) a treatment strategy that involves starting treatment only when proven by biopsy or after a presumptive diagnosis.^8-10 Leflunomide, intravenous immuno­globulin (IVIG), ciprofloxacin, and cidofovir have been investigated as active treatment modalities for BKVAN.^11-15 Unlike treatment for cytomegalovirus infection, there is not enough literature to support their use as a standard treatment for BKVAN.^11-27 The long-term combined effects of leflunomide, IVIG, and ciprofloxacin compared with the current practice of minimization of immunosuppressive drugs in treatment of patients with BKVAN have not been reported yet.

We aimed to assess the long-term efficacy and safety of actively treating patients with BKVAN with combined leflunomide, IVIG, and ciprofloxacin versus minimization of immunosuppressive therapy regarding graft and patient outcomes.

Materials and Methods

This is a longitudinal observational study of a cohort of kidney transplant recipients in our transplant center. The treatment protocol described here was approved prior to the beginning of the study by the local institutional ethical and scientific committees and is compliant with the guidelines of the Declaration of Helsinki.

Since 2002, kidney transplant recipients at our center are screened for possible BKVAN using qualitative and quantitative PCR analyses of urine and blood. Initially, patients had been screened for BK virus when unexplained graft dysfunction was noticed (> 20% of basal serum creatinine) or whenever graft biopsy was indicated. However, routine mass screening for all kidney transplant recipients has become available at our center since 2006, with patients screened for 2 years after transplant (at the time of transplant and then 1, 2, 3, 6, 9, 12, 18, and 24 months after transplant). BK viremia was considered significantly positive when it exceeded 10 000 copies/mL.

Kidney transplant recipients with twice positive viremia (at least 2 wk apart) underwent graft biopsy to confirm BKVAN. Patients with sustained significant viremia and negative cytopathic viral changes of BKVAN were treated as presumptive BKVAN.⁷ According to the type of treatment plan, the transplant patients with BKVAN were divided into 2 groups. Recipients in group 1 were actively treated with combined IVIG, leflunomide, and ciprofloxacin. Patients in group 2 served as historical controls; these patients received conventional treatment with minimization of immunosuppressive drugs. Group 1 patients were actively treated by changing antimetabolites (mycophenolate mofetil or azathioprine) to leflunomide (100 mg daily for 3-5 d followed by 20-40 mg daily), which was followed by a course of IVIG (2 g/kg, maximum 120 g divided over 5 d) and oral ciprofloxacin (500 mg twice per day for 4 wk) concurrently (Figure 1). Reduction of immunosuppressive therapy was implemented in group 2 patients by reducing steroid and anti­metabolite doses by 50%. Calcineurin inhibitors and sirolimus were maintained at low therapeutic trough levels in blood in both groups (levels of 50 ng/dL for cyclosporine and 4-5 ng/dL for tacrolimus and sirolimus). Our immunosuppression protocol consisted of induction antilymphocyte antibody with 5 daily doses of antithymocyte globulin at 1 mg/kg (rabbit derived, thymoglobulin; Sanofi-Aventis, Inc., Bridgewater, NJ, USA) or 2 doses of interleukin 2 receptor blocker (basiliximab; Novartis, Inc., Basel, Switzerland) based on immunologic risk stratification. Maintenance therapy consisted of prednisone, mycophenolate mofetil, and a calcineurin inhibitor. Sirolimus was given to patients who were stable with low immunologic risk and when conversion from a calcineurin inhibitor was applicable.

Acute cellular rejection was treated with intra­venous pulse steroid (methylprednisolone at 1 g daily for 3 d) and/or thymoglobulin (1 mg/kg daily for 7-10 d) for steroid-resistant rejection. Antibody-mediated rejection was treated with plasma exchange, 2 g/kg IVIG, and rituximab. All rejection episodes were diagnosed by biopsies and treated according to Banff criteria28 followed by gradual reduction of immunosuppressive drugs if BK viremia remained positive. Patients with intraepithelial lymphocytes and interstitial inflammation in the context of deteriorating graft function were treated as having acute rejection.23 Patients with definite or presumptive BKVAN and histologic evidence of rejection were treated with appropriate antirejection therapy followed by the BKVAN treatment as outlined for each group. According to histopathologic disease progression, BKVAN is classified into 3 patterns. Pattern A is defined as evidence of BKVAN with minimal inflammation. Pattern B is defined as BKVAN with focal or diffuse interstitial fibrosis and tubular atrophy. Pattern C is defined as BKVAN with significant graft sclerosis.28 Serial monitoring of graft function, blood counts, drug levels, and BK virus PCR results in urine and blood were done at 2 weeks, at 1, 2, and 3 months, and then every 3 to 6 months after the outlined treatments were started. Patients received a repeat BK virus PCR test of urine and blood and a repeat graft biopsy when an unexplained rise in serum creatinine levels (> 20% above baseline) was observed.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20, IBM Corporation, Armonk, NY, USA). Means were compared using paired sample t test, independent sample t test, analysis of variance, chi-square test, and Fisher exact test as appropriate. Results are shown as means ± standard deviation, with differences considered significant at P values ≤ .05. Survival functions were demonstrated using Kaplan-Meier estimator.

Results

Of the 2305 kidney transplant recipients being followed up in our center, we screened 1675 patients. Patients were highly compliant to the screening protocol as the samples were collected during the routine outpatient appointment visits (compliance rate was ≥ 90%). We identified 55 patients with BKVAN for more than 10 years (3.28%). Twenty-two patients received an active treatment protocol (Figure 1), with the remainder receiving conventional treatment. The demographic features of the 2 groups were comparable (P > .05; Table 1). The risk ratio with 95% confidence interval was > 1 for male sex, HLA-Cw7 locus negative recipients, those who received thymoglobulin induction, those who received prednisolone and mycophenolate mofetil maintenance therapy, and those with antirejection therapy before diagnosis of BKVAN (Table 1).

Significant viremia titers (> 10 000 copies/mL) for all patients were confirmed at the time of established BKVAN diagnosis. BK viremia titers were strongly positive at the time of diagnosis, which became negative in almost all of the patients by the end of the study (only 1 patient was still positive with insignificant titer; Table 2).

There were no significant differences between the groups regarding basal mean serum creatinine level and mean estimated glomerular filtration rate. Graft function was significantly deteriorated by the end of the study in both groups, as indicated by serum creatinine levels and estimated glomerular filtration rate results (Table 2). Patients in group 2 had better graft survival and longer duration of follow-up than patients in group 1, as estimated from time of transplant to the date of last follow-up (P = .032; Figure 2 and Table 2). Cytomegalovirus infection and other infections requiring hospitalization were comparable between the groups (P > .05; Table 2). Patient survival was comparable between the groups (P > .05; Table 2). Three patients in group 2 died from multiple severe infections. One patient in each group died at home with functioning graft.

Diagnosis of BKVAN was confirmed histo­pathologically in most patients. The 2 groups were comparable regarding histopathologic patterns of BKVAN (P > .05; Table 3). Pattern A was the most common in the biopsies of both groups (45.5%).

Table 4 shows that the 2 groups were comparable regarding rejection episodes before and after diagnosis of BKVAN (P > .05). Acute cellular rejection episodes were more significant in group 1. Mean duration of follow-up was more than 7 years (Table 2).

Discussion

Risk factors
Similar to that shown in the literature,^1,5,6 our BKVAN patients were at higher risk for BKV infection because they were mainly males, had type 2 diabetes mellitus, had high mean HLA antigen mismatch, and negative HLA-Cw7 locus (risk ratio and 95% confidence interval ≥ 1; Table 1). Although there was not a significant number of highly sensitized patients, our kidney transplant recipients received intensive immunosuppression therapy (in the form of thymoglobulin induction and a full dose of mycophenolate mofetil maintenance therapy, with > 50% of patients treated with tacrolimus, resulting in high risk ratio to develop BKVAN; Table 1). In addition, > 50% of patients received antirejection therapy before diagnosis of BKVAN (Table 1 and Table 4). Group 1 patients had numerically higher mean age and rejection episodes, which adversely affected their long-term graft outcome compared with group 2.

Screening and diagnosis
The key issue for better graft outcome in kidney transplant patients with BKVAN is early diagnosis by regular screening to avoid renal allograft loss.1,3,18 Some delay in treatment of patients with BKVAN was observed due to absence of mass screening, inadequate awareness of the disease during the first few years of the study, low titers of the first detected viremia in some patients, and prolonged time gap between the first detected viremia and the histopathologic evidence to confirm BKVAN (Tables 1 and 2).

Graft biopsy
Most patients (> 80%) started treatment after histo­pathologic evidence of BKVAN (Table 3). It was difficult to assess because there is no definite criteria to differentiate between cellular infiltrate of rejection and BKVAN.^23,27 Histopathology showed that most BKVAN biopsies displayed pattern A, with subsequent deterioration to patterns B and C in a lower number of biopsies. This can be explained by the heterogenous nature of the histopathologic abnormalities of BKVAN.^23-28 Most of the group 1 biopsies (52.8%) displayed pattern B or pattern C, which adversely affected graft outcome (Figure 2 and Table 3).

Graft function
Significant graft dysfunction at the time of diagnosis of BKVAN is a major risk factor for graft failure.^1,19 In Table 2, we demonstrated high basal serum creatinine levels and reduced estimated glomerular filtration rates in both groups, which was most likely due to the relative delay in BKVAN diagnosis and which adversely affected graft outcomes in all patients, especially those in group 1. Worse graft outcome in group 1 could be due to more adverse prognostic factors (more male patients, trend for more tacrolimus-based regimens, lower estimated glomerular filtration rate, more rejections, and more histologic pattern B). The graft function was significantly better in group 2 at 1 year (P = .001) and 3 years (P = .02) of follow-up (results not shown). However, this difference did not reach significance by the end of the study as the failed grafts (more in group 1) did not appear in the final estimation of serum creatinine and glomerular filtration rates (Figure 2 and Table 2). The disease had an aggressive course, resulting in graft failure in more than 40% of our kidney transplant recipients on long-term follow-up (Table 2). A similar finding was reported by Balba and associates, who showed that renal allograft loss from BKVAN has been estimated to occur in up to 50% of affected recipients despite reduction of immunosuppressive medications and clearance of viremia.²¹ Better results were reported by Brennan and associates, Hardinger and associates, and Menter and associates, which could be explained by shorter follow-up, fewer enrolled patients, and early diagnosis of the disease in their cohort of patients.^8,9,23

Associated infections
We found no significant differences between the 2 groups regarding associated infections to BK virus infection that required hospital admission (P > .05; Table 2). The incidence of cytomegalovirus infection requiring medical treatment was comparable to the reported incidence in the literature.²²

Rejection episodes
More than 50% of patients had biopsy-proven acute rejection before BKVAN diagnosis (Table 4). These were mainly acute cellular rejections, which were significantly higher in group 1. Currently, there are no morphologic features to distinguish acute cellular rejection from BKVAN with negative SV40 immuno­staining results.^24,26,29 This may lead to misdiagnoses of acute cellular rejection, aggressive immuno­suppression, and subsequently worse long-term graft outcome. It is also possible that some patients (especially in group 1) were having acute cellular rejection in addition to evolving BKVAN.^25,26 Treatment of BKVAN by either method (active treatment or minimization of immunosuppressive agents) is considered as low immunosuppressive therapies predispose patients to subsequent rejection episodes, as found in 38.1% of our patients after diagnoses of BKVAN. Total rejection episodes were numerically higher in group 1 before and after BKVAN diagnoses, which may be a reason for worse graft outcome compared with group 2.

Antiviral therapy
Along with minimization of immunosuppressive therapy, IVIG has been used for treatment of BKVAN due to its immunomodulatory and potential anti-BK virus properties.^11,30 Its high cost and the scarcity of supporting data on long-term benefits on graft survival in kidney transplant recipients with BKVAN limit its use as an active antiviral. As reported by Trofe and associates, we used IVIG as an antiviral and antirejection treatment for 1 patient in group 1 with established BKVAN (patient had type 2 diabetes mellitus and multiple infections) who developed suspicious acute rejection to avoid overimmuno­suppression.³¹ Our data showed that group 1 patients who received high-dose IVIG treatment did not gain any benefit and had worse graft outcome in long-term follow-up.

Leflunomide may be effective in vitro against BK virus, and it is used as an immunosuppressive agent more widely in patients with rheumatoid arthritis.^12,13,17 It has some limitations to its use in kidney transplant recipients due to unpredictable blood levels, difficulty in monitoring, and its weak immuno­suppressive effect. It was not effective in treating BKVAN in our cohort of patients.

Leung and associates have shown that the quinolones have antipolyomavirus activity in vitro and observed resolution of BK virus replication in vivo in some transplant patients.¹⁴ A recent prospective, multicenter, double-blind, placebo-controlled trial showed that administration of 500 mg daily of levofloxacin or placebo for 30 days resulted in an equivalent percent reduction in BK viral load at 1, 3, and 6 months and no difference in the graft outcome.³²

Cidofovir has a significant in vitro effect regarding inhibition of nonhuman Polyomaviruses.¹⁶ However, the pronounced nephrotoxicity limits its use, particularly in renal transplant recipients.^15,25

We tried to use a combination of nonnephrotoxic anti-BK virus drugs in group 1 to have the best cumulative antiviral activity and to have a comparison with immunosuppressive drug minimization in group 2. Recently, our group published 1-year results of the same protocol of management of BKVAN, which showed that active management was as effective as immunosuppressive drug minimization.33 In this report, we explored the long-term outcome of a greater number of patients with BKVAN. Our results did not support the hypothesis that combined treatment with leflunomide, IVIG, and ciprofloxacin are superior or even equal to the standard immuno­suppressive minimization strategy. Although this is a retrospective analysis, it is the first study to compare the long-term efficacy and safety of the 2 different treatment strategies of BKVAN on patient and graft outcomes.

Regular screening, less intensive immuno­suppressive therapy, and early intervention are advisable to obtain early diagnosis and to have better outcome of BKVAN.^5,8,18,20,31

In conclusion, the administration of 3 different anti-BK virus agents (ie, leflunomide, IVIG, and ciprofloxacin) added no benefit to the long-term outcome of patients with established BKVN. Treatment of BKVAN by reduction of immuno­suppressive medications alone appears to be more effective. Early diagnosis and tailoring of immuno­suppressive therapy might reduce the incidence of BKVAN and improve the clinical response to treatment.

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