CLINICAL
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TRANSLATIONAL RESEARCH
A Novel Treatment Regimen for BK Viremia Rumina A. Zaman,1 Robert B. Ettenger,1 Hay Cheam,1 Mohammed H. Malekzadeh,1 and Eileen W. Tsai1,2 Background. BK viremia, a prerequisite for BK virus nephropathy (BKVN), affects 5% to 16% of pediatric renal transplant recipients (PRTR). We evaluated the safety and efficacy of a novel approach to treating BK viremia using fluoroquinolones and leflunomide in PRTR. Methods. We studied 230 PRTR at Mattel Children’s Hospital, UCLA, who underwent renal transplantation between January 2003 and October 2010. Nineteen patients were found to have BK viremia. Ciprofloxacin was started when the BK viral load was greater than 625 copies/mL, and patients were switched to leflunomide if BK viral load did not decrease after 2 months of ciprofloxacin therapy. All patients underwent transplant kidney biopsy, and their estimated glomerular filtration rate (eGFR) and BK PCR was measured serially. The side effects of ciprofloxacin and leflunomide were recorded in each patient. Results. There was a significant decrease in BK viral load in patients treated with ciprofloxacin and leflunomide (P G 0.001) with only a small reduction in immunosuppression. BK viremia was associated with a significantly decreased eGFR (PG0.001), and treatment with ciprofloxacin and leflunomide was associated with improved eGFR (P G 0.001). This approach resulted in a BKVN rate of only 1%. Conclusions. This analysis demonstrates for the first time that, used in a stepwise fashion, ciprofloxacin and leflunomide are effective and safe treatments for BK viremia in PRTR. Keywords: BK nephropathy, Kidney dysfunction, Children. (Transplantation 2014;97: 1166Y1171)
lthough acute rejection rates have improved with newer immunosuppressive medications, BK viremia is emerging as a significant complication in pediatric renal transplant recipients (PRTR). BK viremia affects between 5% and 16% of PRTR (1, 2). BK viremia can progress to BK virus nephropathy (BKVN) in 2% to 8% of patients infected with the BK virus, leading to graft dysfunction in more than 50% of cases and graft loss in greater than 25% (3, 4). BK virus is a polyomavirus, which traditionally causes nephropathy in renal allografts as a result of reactivation of BK virus latent in renal tubular epithelium. In pediatrics, where young patients may be seronegative, this can present as a primary infection, presumably transmitted via respiratory or oral-enteric routes at peak ages of 2 to 5 years old.
A
This study was funded by Casey Lee Ball Foundation. The authors declare no conflicts of interest. 1 Mattel Children’s Hospital UCLA, Division of Pediatric Nephrology, Los Angeles, CA. 2 Address correspondence to: Eileen W. Tsai, M.D., Mattel Children’s Hospital UCLA, Division of Pediatric Nephrology, Box 951752, Los Angeles, CA, 90095-1752. E-mail: [email protected] R.A.Z. participated in research design, performance of the research, writing of the paper, and data analysis. R.B.E. participated in research design and writing of the paper. H.C. participated in research design and performance of research. M.H.M. participated in writing of the paper. E.W.T. participated in research design, writing of the paper, and data analysis. Received 15 April 2013. Revision requested 15 May 2013. Accepted 21 November 2013. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9711-1166 DOI: 10.1097/01.TP.0000441825.72639.4f
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Approximately 60% of children are BK virus seropositive by 10 years of age and 80% to 90% by adulthood (5, 6). In recent studies, BK seronegativity has been demonstrated to be an important factor in the generation of BK viremia (7). Newer immunosuppressive agents, such as tacrolimus and mycophenolate mofetil, and an increased overall intensity of immunosuppression have become the major risk factors for developing BKVN. Other potential risk factors for developing BKVN are age, white race, male sex, diabetes mellitus, BK serostatus (positive donor to negative recipient), HLA mismatch, and history of allograft rejection (7Y10). Pediatric specific risk factors may include BK virus antibody mismatch (seropositive donor organ into a seronegative patient), negative BK virus antibody (7Y9), and recipient age younger than 5 years. Currently, there is no agreed upon standard treatment of BK viremia or BKVN in renal transplant recipients, particularly in pediatric renal transplant recipients. Decreasing the amount of immunosuppression is often first line in patients with BK viremia (3, 4, 8, 10Y13). However, this reduction in immunosuppression may place patients at increased risk of acute rejection, particularly if the reduction is overly aggressive. Reduced immunosuppression in the treatment of BK viremia has been associated with an increased incidence of acute rejection episodes (14Y16). Other treatment options include cidofivir, intravenous immunoglobulin (IVIG), leflunomide, or fluoroquinolones (4, 8, 17Y25). Cidofovir is a cytosine nucleoside analog, which has in vitro activity against polyomavirus, but the efficacy of low-dose cidofovir in BKVN has also been questioned in Transplantation
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some reports (26). IVIG may have neutralizing antibodies, which can react against BK virus but may cause hemolytic anemia and is expensive and often limited in supply. Cidofovir can be profoundly nephrotoxic and may cause changes in renal function that can be confused with either BKVN and/or allograft rejection. Leflunomide and fluoroquinolones are two appealing therapeutic options to treat BK viremia as they have minimal nephrotoxicity. Leflunomide is a de novo pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory effects. The active metabolite, teriflunomide A771726, has been shown to have in vitro antiviral effects on BK viremia (19). It has been used for treatment of BKVN in adults (20) and in a small pediatric study (21). Therapeutic levels need to be monitored carefully. Main side effects of leflunomide include anemia and hepatic dysfunction. Fluoroquinolones have been shown to block DNA replication by interacting with the DNA-binding subunit of gyrase and shown to inhibit simian virus SV40 polyoma virus replication in vitro (22, 23). In small studies, fluoroquinolones have been shown to decrease BK viral load in adult renal transplant recipients (24, 25). To our knowledge, this has not been studied in pediatrics, in which BKV is more likely to be a primary infection. We were eager to identify the outcomes of BK infection in our patient population, using our novel approach. Therefore, the aim of our study was to understand the safety and efficacy of ciprofloxacin and leflunomide treatment for BK viremia and BKVN in PRTR in conjunction with preemptive BKV monitoring.
RESULTS Table 1 shows the demographic data for the PRTR who developed BK viremia. Nineteen of 230 patients (8%) developed BK viremia, and 3 of 230 patients (1%) developed TABLE 1. Demographic data and transplant characteristics n=230 Patients Patients developing without BKV BKV (n=211) (n=19) Median age in years at transplant (range) Sex (n): Male Female Ethnicity (n): White African American Hispanic Transplant donor type (n): Living Deceased Immunosuppression type (n): Steroid based Steroid-free ATG induction BKVN
14 (9, 16)
P
15 (11, 17) P=0.20 P=0.80
11 (58%) 8 (42%)
129 (61%) 82 (39%)
7 (37%) 3 (16%) 9 (47%)
78 (37%) 9 (4%) 128 (60%)
P=0.80 P=0.03 P=0.48
4 (21%) 15 (79%)
109 (52%) 102 (48%)
P=0.02
11 (58%) 8 (42%) 3 (16%) 3 (1%)
146 (69%) 65 (31%) 17 (8%) 0 (0%)
P=0.31 P=0.22 P=NS
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BKVN diagnosed by both characteristic cytopathic changes and positive SV40 staining on biopsy. The other 16 of 19 patients had no cytopathic changes and negative SV40 staining on biopsy. Age, sex, the use of anti-thymocyte globulin (ATG) induction, and steroid-based versus steroid-free immunosuppression were similar between both groups. Surprisingly, the median age of patients developing BK viremia did not significantly differ from patients without BK viremia; the median ages were 14 and 15 for patients with and without BK viremia, respectively. There was a significantly higher rate of BK viremia development among African American patients and those with deceased donor transplantation. Figure 1 shows the peak and post-BK viral loads of the 19 patients treated using a logarithmic scale. Utilizing our stepwise protocol, there was a significant reduction in the BK viral loads (PG0.001) in virtually all patients. A decrease in BK viral load was seen as early as within the first 2 weeks of ciprofloxacin therapy (data not shown). Fifteen patients were treated with a small reduction in immunosuppression, which included either lowering of CNI (1/15) or antimetabolite (14/15) by 30%. All 19 patients were begun on ciprofloxacin. Fourteen patients were treated with ciprofloxacin alone, 10 with immunosuppression reduction and 4 without; these 4 patients had no lowering of immunosuppression because previously, a reduction in immunosuppression had led to an increase in rejection. Five patients were switched from ciprofloxacin to leflunomide therapy when BK viral loads did not decrease after 2 months of ciprofloxacin and immunosuppression reduction (Fig. 2). The median BK peak viral load for those patients who responded to ciprofloxacin therapy was 11,700 copies/mL, whereas the median BK peak viral load for those patients switched to leflunomide was significantly higher at 184,000 copies/mL (Fig. 1, PG0.04). Approximately 74% (14/19) of patients were successfully converted back to their original immunosuppression without reemergence of BK; 26% (5/19) maintained on treatment for persistent low levels of viremia less than 1000 copies/mL. Figure 3 shows the eGFR prior to development of BK viremia, at the peak BK viral load, and 4 months posttherapy. There was a significant decrease in eGFR between the time when BK was first discovered and the time of the peak BK viral load (PG0.001). There was also a significant increase in eGFR from the time of peak BK viral load to 4 months after treatment of BK viremia commenced (PG0.001). However, there was an overall significant decrease in eGFR between development of BKV and 4 months posttreatment, as eGFR did not fully recover (P=0.003). The changes in eGFR were not significantly associated with CNI reduction. Table 2 shows the clinical time course and complications for patients developing BK viremia. The majority of patients 74% (14/19) developed BK viremia within the first year posttransplant at a median of 6.5 months posttransplant, whereas 26% (5/19) developed BK viremia after 1 year. In the three patients in whom BKVN occurred, the median number of months was 7 from the onset of BK viremia to the development of nephropathy. Overall, the patients received ciprofloxacin for a median of 13 months. Twenty-one percent (4/19) of patients had concomitant rejection during BK viremia associated with the reduction in their immunosuppression as described previously. Three of the
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FIGURE 1.
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Reduction of BK viral loads peak and posttreatment with ciprofloxacin and leflunomide. Patients included (n=19).
4 patients had acute cellular rejection, which resolved after treatment with steroid pulse, IVIG, and increasing calcineurin inhibition. One patient had both acute cellular and antibody mediated rejection, which improved after treatment with IVIG and reinstitution of MMF. We did not find a significant increase in the incidence of BK viremia between those who required high dose immunosuppression to treat acute rejection versus those who did not (data not shown). However, two of the three patients who developed BKVN had associated acute rejection episodes.
FIGURE 2.
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Sixteen percent (3/19) of patients with peak viral loads of 24,000, 660,000, and 670,000 copies/mL developed BKVN with an incidence in our total cohort of only 1%. Patients who developed BKVN were switched to leflunomide, and MMF discontinued with complete resolution of BKVN. There was no graft loss because of BK viremia or BKVN. Side effects of ciprofloxacin and leflunomide were minimal. One patient developed diarrhea, which resolved after ciprofloxacin dosing was reduced. Another patient had chronic abdominal pain which did not resolve after ciprofloxacin
Clinical course of patients with BK viremia. (n=19).
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FIGURE 3. Relationship between BK viremia and eGFR (ml/min/1.73 m2) before treatment, at peak viral load, and posttreatment. Patients included (n=19).
discontinuation. One patient had slightly elevated liver enzymes, which did not resolve after leflunomide discontinuation. No patient who received long-term ciprofloxacin developed drug resistant urinary tract infections or musculoskeletal problems that necessitated discontinuation of ciprofloxacin treatment.
DISCUSSION BK viremia has emerged as an important complication in pediatric renal transplantation. Since BK viremia is the precursor to BKVN, which may lead to allograft dysfunction and loss, it is important to identify BK viremia preemptively. Currently, there is no standardized screening protocol or treatment strategy for BK viremia in PRTR. Our data show that 8% of PRTR developed BK viremia, which is consistent with other pediatric studies (3, 4). Interestingly, only 1% of all PRTR in our total cohort developed BKVN, with no associated graft loss. This rate was lower than previous studies (3, 4, 8, 13). The lower rate of BKVN and 100% graft survival can most likely be attributed to our preemptive screening protocol for BK viremia and immediate treatment initiation at low BK viral loads. A study in a similar patient population conducted by Smith et al. used a less frequent TABLE 2.
schedule of monitoring and immunosuppression reduction as the primary treatment for BK viremia (8). They reported a 3.5% BKVN incidence in their total cohort population. Previous studies in transplantation have shown fluoroquinolones to be an effective prophylactic agent against BK viremia. In hematopoietic stem cell transplant recipients, ciprofloxacin prophylaxis significantly decreased BK viruria and rates of hemorrhagic cystitis (27). In a study with 10 adult renal transplant patients, a 10-day course of gatifloxacin without reduction in immunosuppression lowered BK viremia and BK viruria (24). Garbadi et al. did a retrospective analysis in 185 adult renal transplant patients and found that those who had a 1-month fluoroquinolone prophylaxis course after transplantation had significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone prophylaxis (25). In contrast, Koukoulaki et al. found that in 32 adult renal transplant recipients, a prophylactic course of ciprofloxacin was tried with no control group and showed a tendency for increased BK viremia and BK viruria peaking at 3 months posttransplant and then declining after (28). Our conservative use of ciprofloxacin along with preemptive screening is an effective way of reducing the rate of BK viremia without creating drug resistance, which is a
Clinical course and complications of patients developing BKV (n=19)
Median number of months to develop BKV post transplant (range) Median number of months of ciprofloxacin treatment (range) Median number of months posttransplant to develop BKN (range) Median number of months after BKV to develop BKN (range) Acute cellular rejection Acute cellular+antibody-mediated rejection BKN Graft loss
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6.5 13 18 7 3 1 3
(3, 12) (7, 18) (16, 24) (2, 11) (16%) (5%) (16%) 0
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limitation with the few studies that used prophylactic fluroquinolones. Although most of our patients had a significant decrease in BK viral load with ciprofloxacin and a concomitant small reduction in immunosuppression, 4 patients were successfully treated with ciprofloxacin alone. Approximately 21% of our patients developed acute rejection with modest lowering of immunosuppression. This is an experience that has been shared by others (14Y16). All episodes in our patients responded to conventional antirejection treatment. Recent studies report the successful use of preemptive immunosuppression reduction in adults with greater than 85% clearance of BK viremia (29Y31). However, these studies do report a 9% to 12% incidence of acute rejection in their patients (29Y31). Taken together, it is reasonable to suggest that careful monitoring and early treatment with ciprofloxacin alone may safely decrease BK viral load without experiencing acute rejection. However, a large randomized controlled trial is needed to validate this hypothesis. Early detection of BK viremia is an essential part of our treatment protocol. It has been established that early discovery of BKVN and prompt lowering of immunosuppression can forestall devastating effects on renal allografts (11). We are the first to show that such prompt diagnosis and a stepwise approach with anti-BKV therapy is successful in pediatric kidney transplantation, resulting in a very low incidence of BKVN. There are limited reports of the use of leflunomide for BKVN in PRTR (3). Consistent with our results, Araya et al. reported three pediatric patients with BKVN who failed cidofovir but responded to leflunomide with a subsequent decrease in BK viral load (21). Although the majority of patients had excellent initial eGFR, which could reflect overestimation from the Schwartz formula, there was a significant decrease in eGFR with development of BK viremia. This is to be expected, as BK viremia has been reported to cause graft dysfunction in up to 50% of cases and could reflect subclinical infection (3, 4, 8). There was also a significant increase in eGFR after successful treatment with ciprofloxacin or leflunomide, suggesting that early treatment may help recover graft function. Overall, there was a significant decrease in graft function between the time before onset of BK viremia and after successful treatment for BK viremia, which highlights the serious deleterious effects of BK viremia. Many other treatment options are nephrotoxic. In this setting, we have found that ciprofloxacin and leflunomide provide treatment for BK viremia and BKVN safely with few side effects. Understanding potential risk factors for developing BK viremia can help identify at-risk patients who may theoretically benefit from targeted ciprofloxacin prophylaxis. African Americans as well as those receiving deceased donor transplants had a significant higher incidence of BK viremia in our study for reasons which remain unclear; however, our numbers were limited, so these associations must be interpreted cautiously. NAPRTCS registry data has suggested that deceased donor transplants may have an increased risk of BK viremia because of higher incidence of rejection leading to a greater immunosuppression burden. Race did not pose a major risk factor for BK viremia (8). BK serostatus is also a potential risk factor for developing BK viremia (7, 8). However, checking serostatus before transplantation is not
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routine practice at most institutions. In light of the findings of Smith et al. (8) and Ginervi et al. (9), this practice may need to be reconsidered. On the other hand, in our study, the median age of our patients was 14 to 15 years old. This suggests the possibility that BK viremia may have been a reactivation of latent disease in a number of cases because most children are seropositive by 10 years of age. We acknowledge the limitations of our study, which include the fact that this is a retrospective analysis, that the sample size is relatively small, and that there was a concomitant small reduction in immunosuppression in some but not all patients. Directions for future trials would include designing a prospective trial where PRTR would be placed on ciprofloxacin prophylaxis posttransplant based on seronegativity of BK virus antibody to minimize drug-resistant infections and monitor for development of BK viremia. By measuring BK virus serostatus, we could also confirm whether patients had primary infection or reactivation of BK. Immunosuppression would not be lowered to hopefully minimize the rate of acute rejection. Instead, patients who did not respond within 2 months would be switched to leflunomide. Such a study could help establish whether ciprofloxacin alone can clear BK viremia and to identify cutoff points for BK viral loads as an indication to switch patients over to leflunomide.
MATERIALS AND METHODS Population This is a single-center retrospective cohort study of pediatric patients, younger than 21 years old, who underwent renal transplantation between January 2003 and October 2010 at Mattel Children’s Hospital, UCLA. All cases of BK viremia and BKVN were identified from a total cohort of 230 patients.
Immunosuppression Patients were induced with daclizumab or rabbit antithymocyte globulin and maintained on either steroid-based or steroid-free immunosuppression with tacrolimus and MMF. Maintenance immunosuppression at 6 months for steroid-based patients included prednisone dosing at 0.07 to 0.1 mg/kg/ day; by 4 months posttransplant, tacrolimus dosing targeted a 12-hr trough level of 8 to 12 ng/mL for the first 6 months and then 4 to 7 ng/mL thereafter; and MMF dosing was maintained at 300 to 450 mg/m2/dose twice daily.
Monitoring BK quantitative PCRs (copies/mL) were monitored monthly in the first 6 months after transplantation, every 3 months posttransplant during months 6 to 12, and yearly thereafter. Patients treated for BK viremia or BKVN were monitored every 2 to 4 weeks while on therapy. These studies were also obtained when clinical indications warranted. All patients had protocol allograft biopsies performed at 6 months, 1 year, and 2 years posttransplant as well as for clinical indication. SV40 staining was performed on both protocol and clinically indicated biopsies that were associated with BK viremia. BKVN was diagnosed by allograft biopsy with the identification of viral cytopathic changes in renal tubular epithelial cells and presence of BK virus in renal allograft biopsy tissue with positive SV40 immunohistochemistry staining (31, 32). Biopsies were classified using the Banff 2007 criteria as either acute cellular rejection, antibody mediated rejection, or no rejection (33).
Treatment Ciprofloxacin was started when patient’s BK viral load was greater than 625 copies/mL (lowest detectable load in our laboratory). Ciprofloxacin dosing was 10 to 15 mg/kg/dose up to 500 mg twice per day. Patients were deemed unresponsive to ciprofloxacin and switched to leflunomide, and MMF discontinued if their BK viral load did not decrease within 2 months of ciprofloxacin treatment. Leflunomide dosing consisted of a loading dose of 100 mg/1.73 m2/day for three days followed by maintenance therapy
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based on weight. For patients weighing 10 to 20 kg, leflunomide dose was 10 mg daily; for those weighing 20 to 40 kg, leflunomide dose was increased to 15 mg. For those greater than 40 kg, there was a leflunomide loading dose of 100 mg for 3 days and then 20 mg daily (21). Target leflunomide levels were 40,000 to 60,000 ng/mL. Estimated GFR (eGFR) by Schwartz formula was calculated using k (muscle factor)*height divided by serum creatinine (34). Ciprofloxacin and leflunomide side effects were serially followed at 4- to 8-week intervals. In the patients in whom immunosuppression was reduced, mycophenolate mofetil was lowered by no more than 30% at the onset of BK viremia (12). Only 1 of 15 patients who had been stable on methotrexate for Wegener granulomatosis had his tacrolimus lowered by no more than 30%. Ciprofloxacin and leflunomide were stopped and previous immunosuppression resumed once BK viral loads were not detected for three consecutive months. BK viral loads were checked quarterly thereafter to ensure that the BK viremia did not return.
Statistics Categorical variables were analyzed using the Fisher’s exact test. The t test or rank sum test was used to compare means of continuous variables. Differences were considered significant at PG0.05.
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AND
TRANSLATIONAL RESEARCH
A Novel Treatment Regimen for BK Viremia Rumina A. Zaman,1 Robert B. Ettenger,1 Hay Cheam,1 Mohammed H. Malekzadeh,1 and Eileen W. Tsai1,2 Background. BK viremia, a prerequisite for BK virus nephropathy (BKVN), affects 5% to 16% of pediatric renal transplant recipients (PRTR). We evaluated the safety and efficacy of a novel approach to treating BK viremia using fluoroquinolones and leflunomide in PRTR. Methods. We studied 230 PRTR at Mattel Children’s Hospital, UCLA, who underwent renal transplantation between January 2003 and October 2010. Nineteen patients were found to have BK viremia. Ciprofloxacin was started when the BK viral load was greater than 625 copies/mL, and patients were switched to leflunomide if BK viral load did not decrease after 2 months of ciprofloxacin therapy. All patients underwent transplant kidney biopsy, and their estimated glomerular filtration rate (eGFR) and BK PCR was measured serially. The side effects of ciprofloxacin and leflunomide were recorded in each patient. Results. There was a significant decrease in BK viral load in patients treated with ciprofloxacin and leflunomide (P G 0.001) with only a small reduction in immunosuppression. BK viremia was associated with a significantly decreased eGFR (PG0.001), and treatment with ciprofloxacin and leflunomide was associated with improved eGFR (P G 0.001). This approach resulted in a BKVN rate of only 1%. Conclusions. This analysis demonstrates for the first time that, used in a stepwise fashion, ciprofloxacin and leflunomide are effective and safe treatments for BK viremia in PRTR. Keywords: BK nephropathy, Kidney dysfunction, Children. (Transplantation 2014;97: 1166Y1171)
lthough acute rejection rates have improved with newer immunosuppressive medications, BK viremia is emerging as a significant complication in pediatric renal transplant recipients (PRTR). BK viremia affects between 5% and 16% of PRTR (1, 2). BK viremia can progress to BK virus nephropathy (BKVN) in 2% to 8% of patients infected with the BK virus, leading to graft dysfunction in more than 50% of cases and graft loss in greater than 25% (3, 4). BK virus is a polyomavirus, which traditionally causes nephropathy in renal allografts as a result of reactivation of BK virus latent in renal tubular epithelium. In pediatrics, where young patients may be seronegative, this can present as a primary infection, presumably transmitted via respiratory or oral-enteric routes at peak ages of 2 to 5 years old.
A
This study was funded by Casey Lee Ball Foundation. The authors declare no conflicts of interest. 1 Mattel Children’s Hospital UCLA, Division of Pediatric Nephrology, Los Angeles, CA. 2 Address correspondence to: Eileen W. Tsai, M.D., Mattel Children’s Hospital UCLA, Division of Pediatric Nephrology, Box 951752, Los Angeles, CA, 90095-1752. E-mail: [email protected] R.A.Z. participated in research design, performance of the research, writing of the paper, and data analysis. R.B.E. participated in research design and writing of the paper. H.C. participated in research design and performance of research. M.H.M. participated in writing of the paper. E.W.T. participated in research design, writing of the paper, and data analysis. Received 15 April 2013. Revision requested 15 May 2013. Accepted 21 November 2013. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9711-1166 DOI: 10.1097/01.TP.0000441825.72639.4f
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Approximately 60% of children are BK virus seropositive by 10 years of age and 80% to 90% by adulthood (5, 6). In recent studies, BK seronegativity has been demonstrated to be an important factor in the generation of BK viremia (7). Newer immunosuppressive agents, such as tacrolimus and mycophenolate mofetil, and an increased overall intensity of immunosuppression have become the major risk factors for developing BKVN. Other potential risk factors for developing BKVN are age, white race, male sex, diabetes mellitus, BK serostatus (positive donor to negative recipient), HLA mismatch, and history of allograft rejection (7Y10). Pediatric specific risk factors may include BK virus antibody mismatch (seropositive donor organ into a seronegative patient), negative BK virus antibody (7Y9), and recipient age younger than 5 years. Currently, there is no agreed upon standard treatment of BK viremia or BKVN in renal transplant recipients, particularly in pediatric renal transplant recipients. Decreasing the amount of immunosuppression is often first line in patients with BK viremia (3, 4, 8, 10Y13). However, this reduction in immunosuppression may place patients at increased risk of acute rejection, particularly if the reduction is overly aggressive. Reduced immunosuppression in the treatment of BK viremia has been associated with an increased incidence of acute rejection episodes (14Y16). Other treatment options include cidofivir, intravenous immunoglobulin (IVIG), leflunomide, or fluoroquinolones (4, 8, 17Y25). Cidofovir is a cytosine nucleoside analog, which has in vitro activity against polyomavirus, but the efficacy of low-dose cidofovir in BKVN has also been questioned in Transplantation
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some reports (26). IVIG may have neutralizing antibodies, which can react against BK virus but may cause hemolytic anemia and is expensive and often limited in supply. Cidofovir can be profoundly nephrotoxic and may cause changes in renal function that can be confused with either BKVN and/or allograft rejection. Leflunomide and fluoroquinolones are two appealing therapeutic options to treat BK viremia as they have minimal nephrotoxicity. Leflunomide is a de novo pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory effects. The active metabolite, teriflunomide A771726, has been shown to have in vitro antiviral effects on BK viremia (19). It has been used for treatment of BKVN in adults (20) and in a small pediatric study (21). Therapeutic levels need to be monitored carefully. Main side effects of leflunomide include anemia and hepatic dysfunction. Fluoroquinolones have been shown to block DNA replication by interacting with the DNA-binding subunit of gyrase and shown to inhibit simian virus SV40 polyoma virus replication in vitro (22, 23). In small studies, fluoroquinolones have been shown to decrease BK viral load in adult renal transplant recipients (24, 25). To our knowledge, this has not been studied in pediatrics, in which BKV is more likely to be a primary infection. We were eager to identify the outcomes of BK infection in our patient population, using our novel approach. Therefore, the aim of our study was to understand the safety and efficacy of ciprofloxacin and leflunomide treatment for BK viremia and BKVN in PRTR in conjunction with preemptive BKV monitoring.
RESULTS Table 1 shows the demographic data for the PRTR who developed BK viremia. Nineteen of 230 patients (8%) developed BK viremia, and 3 of 230 patients (1%) developed TABLE 1. Demographic data and transplant characteristics n=230 Patients Patients developing without BKV BKV (n=211) (n=19) Median age in years at transplant (range) Sex (n): Male Female Ethnicity (n): White African American Hispanic Transplant donor type (n): Living Deceased Immunosuppression type (n): Steroid based Steroid-free ATG induction BKVN
14 (9, 16)
P
15 (11, 17) P=0.20 P=0.80
11 (58%) 8 (42%)
129 (61%) 82 (39%)
7 (37%) 3 (16%) 9 (47%)
78 (37%) 9 (4%) 128 (60%)
P=0.80 P=0.03 P=0.48
4 (21%) 15 (79%)
109 (52%) 102 (48%)
P=0.02
11 (58%) 8 (42%) 3 (16%) 3 (1%)
146 (69%) 65 (31%) 17 (8%) 0 (0%)
P=0.31 P=0.22 P=NS
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BKVN diagnosed by both characteristic cytopathic changes and positive SV40 staining on biopsy. The other 16 of 19 patients had no cytopathic changes and negative SV40 staining on biopsy. Age, sex, the use of anti-thymocyte globulin (ATG) induction, and steroid-based versus steroid-free immunosuppression were similar between both groups. Surprisingly, the median age of patients developing BK viremia did not significantly differ from patients without BK viremia; the median ages were 14 and 15 for patients with and without BK viremia, respectively. There was a significantly higher rate of BK viremia development among African American patients and those with deceased donor transplantation. Figure 1 shows the peak and post-BK viral loads of the 19 patients treated using a logarithmic scale. Utilizing our stepwise protocol, there was a significant reduction in the BK viral loads (PG0.001) in virtually all patients. A decrease in BK viral load was seen as early as within the first 2 weeks of ciprofloxacin therapy (data not shown). Fifteen patients were treated with a small reduction in immunosuppression, which included either lowering of CNI (1/15) or antimetabolite (14/15) by 30%. All 19 patients were begun on ciprofloxacin. Fourteen patients were treated with ciprofloxacin alone, 10 with immunosuppression reduction and 4 without; these 4 patients had no lowering of immunosuppression because previously, a reduction in immunosuppression had led to an increase in rejection. Five patients were switched from ciprofloxacin to leflunomide therapy when BK viral loads did not decrease after 2 months of ciprofloxacin and immunosuppression reduction (Fig. 2). The median BK peak viral load for those patients who responded to ciprofloxacin therapy was 11,700 copies/mL, whereas the median BK peak viral load for those patients switched to leflunomide was significantly higher at 184,000 copies/mL (Fig. 1, PG0.04). Approximately 74% (14/19) of patients were successfully converted back to their original immunosuppression without reemergence of BK; 26% (5/19) maintained on treatment for persistent low levels of viremia less than 1000 copies/mL. Figure 3 shows the eGFR prior to development of BK viremia, at the peak BK viral load, and 4 months posttherapy. There was a significant decrease in eGFR between the time when BK was first discovered and the time of the peak BK viral load (PG0.001). There was also a significant increase in eGFR from the time of peak BK viral load to 4 months after treatment of BK viremia commenced (PG0.001). However, there was an overall significant decrease in eGFR between development of BKV and 4 months posttreatment, as eGFR did not fully recover (P=0.003). The changes in eGFR were not significantly associated with CNI reduction. Table 2 shows the clinical time course and complications for patients developing BK viremia. The majority of patients 74% (14/19) developed BK viremia within the first year posttransplant at a median of 6.5 months posttransplant, whereas 26% (5/19) developed BK viremia after 1 year. In the three patients in whom BKVN occurred, the median number of months was 7 from the onset of BK viremia to the development of nephropathy. Overall, the patients received ciprofloxacin for a median of 13 months. Twenty-one percent (4/19) of patients had concomitant rejection during BK viremia associated with the reduction in their immunosuppression as described previously. Three of the
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FIGURE 1.
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Reduction of BK viral loads peak and posttreatment with ciprofloxacin and leflunomide. Patients included (n=19).
4 patients had acute cellular rejection, which resolved after treatment with steroid pulse, IVIG, and increasing calcineurin inhibition. One patient had both acute cellular and antibody mediated rejection, which improved after treatment with IVIG and reinstitution of MMF. We did not find a significant increase in the incidence of BK viremia between those who required high dose immunosuppression to treat acute rejection versus those who did not (data not shown). However, two of the three patients who developed BKVN had associated acute rejection episodes.
FIGURE 2.
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Sixteen percent (3/19) of patients with peak viral loads of 24,000, 660,000, and 670,000 copies/mL developed BKVN with an incidence in our total cohort of only 1%. Patients who developed BKVN were switched to leflunomide, and MMF discontinued with complete resolution of BKVN. There was no graft loss because of BK viremia or BKVN. Side effects of ciprofloxacin and leflunomide were minimal. One patient developed diarrhea, which resolved after ciprofloxacin dosing was reduced. Another patient had chronic abdominal pain which did not resolve after ciprofloxacin
Clinical course of patients with BK viremia. (n=19).
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FIGURE 3. Relationship between BK viremia and eGFR (ml/min/1.73 m2) before treatment, at peak viral load, and posttreatment. Patients included (n=19).
discontinuation. One patient had slightly elevated liver enzymes, which did not resolve after leflunomide discontinuation. No patient who received long-term ciprofloxacin developed drug resistant urinary tract infections or musculoskeletal problems that necessitated discontinuation of ciprofloxacin treatment.
DISCUSSION BK viremia has emerged as an important complication in pediatric renal transplantation. Since BK viremia is the precursor to BKVN, which may lead to allograft dysfunction and loss, it is important to identify BK viremia preemptively. Currently, there is no standardized screening protocol or treatment strategy for BK viremia in PRTR. Our data show that 8% of PRTR developed BK viremia, which is consistent with other pediatric studies (3, 4). Interestingly, only 1% of all PRTR in our total cohort developed BKVN, with no associated graft loss. This rate was lower than previous studies (3, 4, 8, 13). The lower rate of BKVN and 100% graft survival can most likely be attributed to our preemptive screening protocol for BK viremia and immediate treatment initiation at low BK viral loads. A study in a similar patient population conducted by Smith et al. used a less frequent TABLE 2.
schedule of monitoring and immunosuppression reduction as the primary treatment for BK viremia (8). They reported a 3.5% BKVN incidence in their total cohort population. Previous studies in transplantation have shown fluoroquinolones to be an effective prophylactic agent against BK viremia. In hematopoietic stem cell transplant recipients, ciprofloxacin prophylaxis significantly decreased BK viruria and rates of hemorrhagic cystitis (27). In a study with 10 adult renal transplant patients, a 10-day course of gatifloxacin without reduction in immunosuppression lowered BK viremia and BK viruria (24). Garbadi et al. did a retrospective analysis in 185 adult renal transplant patients and found that those who had a 1-month fluoroquinolone prophylaxis course after transplantation had significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone prophylaxis (25). In contrast, Koukoulaki et al. found that in 32 adult renal transplant recipients, a prophylactic course of ciprofloxacin was tried with no control group and showed a tendency for increased BK viremia and BK viruria peaking at 3 months posttransplant and then declining after (28). Our conservative use of ciprofloxacin along with preemptive screening is an effective way of reducing the rate of BK viremia without creating drug resistance, which is a
Clinical course and complications of patients developing BKV (n=19)
Median number of months to develop BKV post transplant (range) Median number of months of ciprofloxacin treatment (range) Median number of months posttransplant to develop BKN (range) Median number of months after BKV to develop BKN (range) Acute cellular rejection Acute cellular+antibody-mediated rejection BKN Graft loss
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6.5 13 18 7 3 1 3
(3, 12) (7, 18) (16, 24) (2, 11) (16%) (5%) (16%) 0
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limitation with the few studies that used prophylactic fluroquinolones. Although most of our patients had a significant decrease in BK viral load with ciprofloxacin and a concomitant small reduction in immunosuppression, 4 patients were successfully treated with ciprofloxacin alone. Approximately 21% of our patients developed acute rejection with modest lowering of immunosuppression. This is an experience that has been shared by others (14Y16). All episodes in our patients responded to conventional antirejection treatment. Recent studies report the successful use of preemptive immunosuppression reduction in adults with greater than 85% clearance of BK viremia (29Y31). However, these studies do report a 9% to 12% incidence of acute rejection in their patients (29Y31). Taken together, it is reasonable to suggest that careful monitoring and early treatment with ciprofloxacin alone may safely decrease BK viral load without experiencing acute rejection. However, a large randomized controlled trial is needed to validate this hypothesis. Early detection of BK viremia is an essential part of our treatment protocol. It has been established that early discovery of BKVN and prompt lowering of immunosuppression can forestall devastating effects on renal allografts (11). We are the first to show that such prompt diagnosis and a stepwise approach with anti-BKV therapy is successful in pediatric kidney transplantation, resulting in a very low incidence of BKVN. There are limited reports of the use of leflunomide for BKVN in PRTR (3). Consistent with our results, Araya et al. reported three pediatric patients with BKVN who failed cidofovir but responded to leflunomide with a subsequent decrease in BK viral load (21). Although the majority of patients had excellent initial eGFR, which could reflect overestimation from the Schwartz formula, there was a significant decrease in eGFR with development of BK viremia. This is to be expected, as BK viremia has been reported to cause graft dysfunction in up to 50% of cases and could reflect subclinical infection (3, 4, 8). There was also a significant increase in eGFR after successful treatment with ciprofloxacin or leflunomide, suggesting that early treatment may help recover graft function. Overall, there was a significant decrease in graft function between the time before onset of BK viremia and after successful treatment for BK viremia, which highlights the serious deleterious effects of BK viremia. Many other treatment options are nephrotoxic. In this setting, we have found that ciprofloxacin and leflunomide provide treatment for BK viremia and BKVN safely with few side effects. Understanding potential risk factors for developing BK viremia can help identify at-risk patients who may theoretically benefit from targeted ciprofloxacin prophylaxis. African Americans as well as those receiving deceased donor transplants had a significant higher incidence of BK viremia in our study for reasons which remain unclear; however, our numbers were limited, so these associations must be interpreted cautiously. NAPRTCS registry data has suggested that deceased donor transplants may have an increased risk of BK viremia because of higher incidence of rejection leading to a greater immunosuppression burden. Race did not pose a major risk factor for BK viremia (8). BK serostatus is also a potential risk factor for developing BK viremia (7, 8). However, checking serostatus before transplantation is not
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routine practice at most institutions. In light of the findings of Smith et al. (8) and Ginervi et al. (9), this practice may need to be reconsidered. On the other hand, in our study, the median age of our patients was 14 to 15 years old. This suggests the possibility that BK viremia may have been a reactivation of latent disease in a number of cases because most children are seropositive by 10 years of age. We acknowledge the limitations of our study, which include the fact that this is a retrospective analysis, that the sample size is relatively small, and that there was a concomitant small reduction in immunosuppression in some but not all patients. Directions for future trials would include designing a prospective trial where PRTR would be placed on ciprofloxacin prophylaxis posttransplant based on seronegativity of BK virus antibody to minimize drug-resistant infections and monitor for development of BK viremia. By measuring BK virus serostatus, we could also confirm whether patients had primary infection or reactivation of BK. Immunosuppression would not be lowered to hopefully minimize the rate of acute rejection. Instead, patients who did not respond within 2 months would be switched to leflunomide. Such a study could help establish whether ciprofloxacin alone can clear BK viremia and to identify cutoff points for BK viral loads as an indication to switch patients over to leflunomide.
MATERIALS AND METHODS Population This is a single-center retrospective cohort study of pediatric patients, younger than 21 years old, who underwent renal transplantation between January 2003 and October 2010 at Mattel Children’s Hospital, UCLA. All cases of BK viremia and BKVN were identified from a total cohort of 230 patients.
Immunosuppression Patients were induced with daclizumab or rabbit antithymocyte globulin and maintained on either steroid-based or steroid-free immunosuppression with tacrolimus and MMF. Maintenance immunosuppression at 6 months for steroid-based patients included prednisone dosing at 0.07 to 0.1 mg/kg/ day; by 4 months posttransplant, tacrolimus dosing targeted a 12-hr trough level of 8 to 12 ng/mL for the first 6 months and then 4 to 7 ng/mL thereafter; and MMF dosing was maintained at 300 to 450 mg/m2/dose twice daily.
Monitoring BK quantitative PCRs (copies/mL) were monitored monthly in the first 6 months after transplantation, every 3 months posttransplant during months 6 to 12, and yearly thereafter. Patients treated for BK viremia or BKVN were monitored every 2 to 4 weeks while on therapy. These studies were also obtained when clinical indications warranted. All patients had protocol allograft biopsies performed at 6 months, 1 year, and 2 years posttransplant as well as for clinical indication. SV40 staining was performed on both protocol and clinically indicated biopsies that were associated with BK viremia. BKVN was diagnosed by allograft biopsy with the identification of viral cytopathic changes in renal tubular epithelial cells and presence of BK virus in renal allograft biopsy tissue with positive SV40 immunohistochemistry staining (31, 32). Biopsies were classified using the Banff 2007 criteria as either acute cellular rejection, antibody mediated rejection, or no rejection (33).
Treatment Ciprofloxacin was started when patient’s BK viral load was greater than 625 copies/mL (lowest detectable load in our laboratory). Ciprofloxacin dosing was 10 to 15 mg/kg/dose up to 500 mg twice per day. Patients were deemed unresponsive to ciprofloxacin and switched to leflunomide, and MMF discontinued if their BK viral load did not decrease within 2 months of ciprofloxacin treatment. Leflunomide dosing consisted of a loading dose of 100 mg/1.73 m2/day for three days followed by maintenance therapy
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based on weight. For patients weighing 10 to 20 kg, leflunomide dose was 10 mg daily; for those weighing 20 to 40 kg, leflunomide dose was increased to 15 mg. For those greater than 40 kg, there was a leflunomide loading dose of 100 mg for 3 days and then 20 mg daily (21). Target leflunomide levels were 40,000 to 60,000 ng/mL. Estimated GFR (eGFR) by Schwartz formula was calculated using k (muscle factor)*height divided by serum creatinine (34). Ciprofloxacin and leflunomide side effects were serially followed at 4- to 8-week intervals. In the patients in whom immunosuppression was reduced, mycophenolate mofetil was lowered by no more than 30% at the onset of BK viremia (12). Only 1 of 15 patients who had been stable on methotrexate for Wegener granulomatosis had his tacrolimus lowered by no more than 30%. Ciprofloxacin and leflunomide were stopped and previous immunosuppression resumed once BK viral loads were not detected for three consecutive months. BK viral loads were checked quarterly thereafter to ensure that the BK viremia did not return.
Statistics Categorical variables were analyzed using the Fisher’s exact test. The t test or rank sum test was used to compare means of continuous variables. Differences were considered significant at PG0.05.
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