Of grafts with function at 3 months after transplantation, actuarial survival of BK-positive grafts was significantly worse than that of BK-negative grafts (P<0.01, log-rank test), as shown in Figure 2. As noted above, there were seven graft losses in the BK-positive cohort. Four losses were related to BK infection, one loss was due to patient death, and two losses were due to acute rejection, unrelated to BK viremia. There were nine graft losses in the BK-negative cohort. Six losses were due to patient death, two losses were due to chronic rejection, and one loss was due to acute rejection resulting from medication noncompliance.
The mean estimated glomerular filtration rates (eGFR; Modification of Diet in Renal Disease study equation) of the BK viremia–positive and BK viremia–negative cohorts at 1, 3, 6, 9, and 12 months after transplantation are shown in Figure 3. At both 9 and 12 months after transplantation, the mean eGFR of the BK-positive group was lower than that of the BK-negative cohort (P=0.02). Additionally, 12 of 57 (21%) BK-positive grafts suffered marked (>25%) decline in eGFR from month 3 to the most recent follow-up compared with only 31 of 292 (11%; P=0.049) of BK-negative grafts over a similar period of time.
The principle finding of our study, in contradistinction to a number of recent reports of BK screening (8, 9), was that diagnosis of BK viremia, before clinical evidence of renal dysfunction, did not eliminate the risk of graft loss or dysfunction associated with BK nephropathy. In fact, once diagnosed with BK viremia, the risk of graft loss was increased and the quality of graft function was reduced compared with grafts of recipients free of BK viremia. Nevertheless, early diagnosis likely prevented many kidneys from progressing to BK nephropathy and graft loss. Certainly, the results suggest a better outcome compared with reports published before the era of prospective screening for BK viremia and viuria (7).
This report of 349 renal allograft recipients prospectively screened for BK viremia is among the largest studies presented to date. The incidence of BK viremia was 16%, comparable with other studies, and management by reduction in immunosuppression was consistent with current recommendations (10). The benefit of cidofovir remains unclear, because all recipients, in addition, had immunosuppression reduced. Most recipients were diagnosed early after transplantation, typically at 3 months, with a relatively low level of BK viremia and with renal function unchanged from baseline. Almost 50% of biopsies showed evidence of BK nephropathy and all positive biopsies were graded as showing mild to moderate degree of cellular infiltrate or fibrosis. There was an uncertain correlation between initial viral load and the presence of BK infection on biopsy. The mean viral load of recipients with a positive biopsy was significantly higher than that of recipients with negative biopsies. However, recipients with an initial viral load less than 100,000 copies/mL were equally likely to have a positive biopsy as recipients with initial viral loads more than 100,000 copies/mL. Risk of graft loss due to BK nephropathy was correlated with an initial viral load more than 100,000 copies/mL. Clearance of virus was more likely in recipients showing an early decline in viral counts.
Demographics of BK-positive and BK-negative recipients were generally similar, although, consistent with other published reports, older recipient age, receipt of a deceased donor, and the use of prednisone were all factors independently associated with BK viremia. Interestingly, in this study, we also found that Asian recipients were more likely to become BK viremia positive. Of importance, the actuarial graft survival of BK viremia–positive recipients was worse than that of the BK-negative cohort. Moreover, despite appropriate management, 4 of 57 such grafts were lost to causes related to BK nephropathy.
Although early graft function was similar between groups, by 9 months after transplantation, the mean eGFR of affected grafts was inferior to that of unaffected kidneys. Additionally, compared with BK-negative kidneys, a larger percentage of BK-positive grafts had suffered a decline in renal function at last follow-up. This reduction in renal reserve among the successfully treated cohort is likely a consequence of renal injury due to BK nephropathy. Because renal function at 1 year after transplantation has been correlated with long-term graft survival, it would suggest that, with longer follow-up, this group might suffer even more graft attrition compared with the unaffected cohort.
As with all retrospective single-center reviews, there are a number of limitations to this study. Although all recipients received a tacrolimus/mycophenolate-based immunosuppression protocol, 8% of recipients were prednisone-free and 6% of recipients received desensitization therapy before transplantation. Additionally, only 57% of recipients underwent renal biopsy after diagnosis of BK viremia. The use of cidofovir was, in part, based on the finding of BK nephropathy; thus, the treatment protocol was, to a degree, inconsistent.
As mentioned, the results herein are at odds with recent published reports describing superior outcomes using similar prospective screening protocols followed by immunosuppression minimization. In this regard, a publication by Schaub et al. describes a similar prospective screening protocol followed by reduction in immunosuppression. In their study of 203 patients, they found a 19% incidence of BK viremia, with 92% clearance of virus at last follow-up. There were no graft losses to BK nephropathy and a remarkable 100% death-censored graft survival at 3 years. In that study, monitoring was performed more frequently in the early posttransplantation period compared with our protocol, yet both the incidence of BK viremia and the immunosuppression reduction regimen were very similar to our report (9).
Similarly, Brennan et al. prospectively monitored 200 renal allografts recipients and described an 11% incidence of BK viremia. In that study, immunosuppression reduction consisted of complete withdrawal of the antimetabolite followed by reduction in the dose of calcineurin inhibitor as needed. They reported no graft losses to BK nephropathy and no impairment in renal function (8).
Similar to our own findings, a number of smaller single-center studies have recorded graft losses and impaired renal function despite the institution of screening protocols accompanied by immunosuppression reduction for BK viremia (7, 11, 12). Specifically, Vasudev et al. (13) reported a 36% graft loss due to BK nephropathy despite instituting screening for BK viremia followed by immunosuppression reduction.
Our data should thus raise a note of caution regarding the current optimism in the management of BK viremia and nephropathy. As a treatment algorithm, screening accompanied by immunosuppression reduction has resulted in improved outcomes but is not a panacea. We have followed currently recommended guidelines for the management of BK viremia but have not achieved the excellent published results described above. Arguably, results would have been improved with more frequent monitoring, yet the protocol outlined herein of testing at months 1, 3, 6, 9, and 12 and every 6 months is consistent with published Kidney Disease: Improving Global Outcomes guidelines. That protocol recommends screening for months 1 to 3 and then every 3 months until 1 year after transplantation (10).
Thus, in our view, the current treatment paradigm of viral monitoring followed by immunosuppression reduction does not appear adequate to manage what has become the most common viral infection in renal transplant recipients. Moreover, one must also take into account the enormous workload placed on a busy transplant program to effectively monitor all transplant recipients for BK viremia and appropriately manage immunosuppression reduction in affected recipients. Thus, it seems reasonable to focus on addressing possible modifiable risk factors, such as novel immunosuppression/antibiotic protocols to prevent the emergence of BK viremia. Based on data presented herein, and the work of others (1, 2), it could be recommended that a prednisone-free maintenance immunosuppression regimen would lower the risk of BK viremia. Similarly, there are data suggesting that both sirolimus and fluoroquinolones may prevent BK virus replication (14, 15). These are all interventions that should be explored to reduce the incidence of BK viremia.
In summary, a prospective screening protocol combined with immunosuppression reduction recorded improved outcomes for renal transplant recipients diagnosed with BK viremia compared with historical data. Nonetheless, BK-positive recipients had a greater risk of graft loss and, at 1 year after transplantation, impaired function compared with recipients free of infection. Future investigations should focus on more innovative practices to prevent BK viremia.
MATERIALS AND METHODS
This retrospective review of a single-center experience included 369 consecutive renal transplant recipients performed between August 2007 and July 2010. All subjects included in this review received a kidney-alone transplant and were followed for at least 3 months or until graft loss.
Subjects considered at high risk of acute rejection (African Americans, retransplantation, and highly sensitized recipients) received a 3-day course of rabbit antithymocyte globulin (thymoglobulin; Genzyme, Cambridge, MA) at a dose of 1.5 mg/kg per day beginning on the day of transplantation. All other subjects received 2.0 mg/kg daclizumab (Zenapax; Roche, Nutley, NJ) on the day of transplantation and on posttransplantation day 3. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisone. The dose of tacrolimus was adjusted to maintain a trough level of 8 to 10 ng/mL for the first 3 months after transplantation, tapered to 5 to 8 ng/mL thereafter. Mycophenolate mofetil was given at a dose of 1000 mg twice daily. Methylprednisolone (250 mg) was given on the day of transplantation, tapered to 25 mg by day 5 and then to 5 to 10 mg by 6 months after transplantation. By physician preference, a small number of patients were withdrawn from prednisone on posttransplantation day 6. This cohort was restricted to non–African-American recipients receiving a first transplant with a panel reactive antibody less than 20%. The protocol required thymoglobulin induction with complete steroid withdrawal at day 5 after transplantation. Additionally, a small group of living-donor recipients with pretransplantation donor-specific antibody received desensitization therapy that included intravenous immunoglobulin, rituximab, and plasmapheresis.
BK Viremia Testing
All recipients were tested for BK virus by serum polymerase chain reaction at months 1, 3, 6, 9, 12, 18, and 24 after transplantation. Additionally, BK viremia testing was performed for an unexplained rise in serum creatinine. A positive diagnosis of BK viremia required two tests showing more than 750 viral copies/mL. After diagnosis of BK viremia, recipients were tested on a monthly basis until disappearance of viremia. Viral clearance was defined as two consecutive monthly tests showing less than 750 viral copies/mL.
Most subjects who tested positive for BK viremia underwent renal biopsy to assess for evidence of BK nephropathy. At the introduction of the screening protocol, renal biopsy was performed selectively based on the individual preference of the treating physician. Because the biopsy data were reviewed, it became apparent that a large percentage of biopsies were positive for BK nephropathy. The protocol was then modified so that all patients with BK viremia underwent biopsy. Additionally, all recipients with an unexplained rise in serum creatinine underwent renal biopsy. Confirmation of BK nephropathy was performed using an immunoperoxidase stain for the simian virus 40 large T antigen. Nephropathy was graded as pattern A, B, or C based on the degree of tubulointerstitial inflammatory infiltrates and fibrosis (16).
Management of BK Viremia
Treatment of BK viremia consisted of concurrent reduction in the dosages of both tacrolimus and mycophenolate mofetil. The tacrolimus dose was targeted to a trough level of 4 to 6 ng/mL and the dosage of mycophenolate mofetil was reduced by 50%. Additionally, cidofovir was given every 2 weeks at a dosage of 0.5 mg/kg for recipients with either a high initial viral load or evidence of BK nephropathy on biopsy. Cidofovir treatment continued until clearance of virus but not longer than 6 months.
Statistical analyses were performed using JMP 9 (SAS Institute, Cary, NC). Recipient characteristics were categorized and compared using chi-square test or Fisher’s exact test to determine an association with BK development, with P<0.05 representing statistical significance. All factors found to approach significance (P<0.1) by univariate analysis were included in a nominal logistic fit model to determine independent risk factors associated with BK viremia. Graft survival was depicted using Kaplan–Meier curves and calculated using the log-rank test.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
BK viremia; Renal transplantation; Immunosuppression