Ureteral Stents: A Risk Factor for Polyomavirus BK Viremia in Kidney Transplant Recipients Undergoing Protocol Screening

Ureteral Stents: A Risk Factor for Polyomavirus BK Viremia in Kidney Transplant Recipients Undergoing Protocol Screening N.F. Siparsky, L.F. Kushnir, M.H. Gallichio, and D.J. Conti ABSTRACT Background. Polyomavirus BK nephropathy (BKN) remains a common cause of early renal transplant dysfunction and graft loss. To date, little has been reported on the role, if any, of transplant ureteral stents in the development of polyomavirus BK viremia (BVK) and BKN. Methods. We performed a single-center, retrospective analysis of renal transplant recipients who underwent renal transplantation followed by monthly BKV screening at Albany Medical Center between January 1, 2006, and December 31, 2009. A transplant ureteral stent was placed at the discretion of the surgeon. The immunosuppression protocol employed for deceased donor and unrelated living -donor recipients was antithymocyte antibody induction with methylprednisolone, mycophenolate mofetil, tacrolimus, and sirolimus. Results. During the study period, 186 recipients were identified; 124 (67%) underwent intraoperative transplant ureteral stent placement, while 62 patients (33%) did not undergo stent placement. With our monthly screening protocol, we detected BKV in 32 of the 186 recipients (17%) following transplantation; 27 of the 32 (84%) viremic patients were stent recipients. In all patients who developed BKV, an immunosuppression dose reduction protocol was employed. Ureteral stent placement conferred a statistically significant elevated risk of developing BKV (odds ratio ⫽ 3.17, 95% confidence interval 1.16 – 8.70). Patient gender, age, ethnicity, diabetes status, and retransplant status were not statistically significant factors in the development of BKV. Conclusion. Our study demonstrated the elevated risk of BKV in recipients who undergo transplant ureteral stenting. Monthly BK polymerase chain reaction screening appears to be a useful tool for the early detection of BKV in this higher-risk group. olyomavirus BK, a member of the polyomavirus family, was first isolated in 1971 from the urine of a renal transplant recipient.1 Years later, BK emerged as the agent responsible for polyomavirus BK nephropathy (BKN) and was found to cause 10% to 15% of cases of graft dysfunction and graft loss.2 Today, the terms BK nephropathy and polyomavirus nephropathy are used synonymously in the literature. Recent studies suggest that the majority of the general adult population has been exposed to the BK virus. Most exposures occur in childhood, during which time the virus infects uroepithelial cells. In nonimmunosuppressed hosts, polyomavirus BK viremia (BKV) remains latent and asymptomatic,3 though a fraction of asymptomatic seropositive subjects (7%) shed virus into the urine.4 In states of immunosuppression, such as HIV infection,5 pregnancy, or

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kidney transplantation, BK virus is reactivated and infection can progress from viruria to viremia, followed by nephropathy.6 In 2009, an Organ Procurement and Transplantation Network registry analysis noted a rise in the rates of BKV and BKN despite efforts to increase awareness of BK infection. Efforts to eradicate this problem have included the identification of risk factors, early detection of BK From the Department of Surgery, Section of Transplantation, Albany Medical Center, Albany, New York, USA. Address reprint requests to David Conti, MD, Albany Medical College, Department of Surgery, Section of Transplantation, 47 New Scotland Ave, MC61GE, Albany, NY 12208. E-mail: contid@ mail.amc.edu

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0041-1345/–see front matter doi:10.1016/j.transproceed.2011.06.034

Transplantation Proceedings, 43, 2641–2644 (2011)

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viruria and BK viremia through screening, early diagnostic biopsy for allograft dysfunction, minimization of immunosuppression for biopsy-proven BKN, and the employment of pharmacotherapy.7 Noninvasive screening for BK viruria and/or BK viremia is not yet a universal practice. In centers that do not screen all recipients, emphasis has been placed on identifying risk factors for BKV infection and targeting screening to highrisk patients. Such risk factors include a higher degree of human leukocyte antigen mismatch, pediatric status, aggressive immunosuppressive regimen, BK virus mismatch between donor and recipient, and transplant ureteral stent use.8 In centers that routinely screen for BKV in their kidney transplant recipients, immunosuppression reduction protocols have been employed to eradicate BKV and prevent progression to BKN with success. We modeled our program’s universal BKV serum screening protocol on that reported by Brennan et al, though we employ a different immunosuppression regimen. The Brennan group employed a cyclosporine ⫹ prednisone ⫹ azathioprine/mycophenolate regimen, whereas we employed a tacrolimus ⫹ sirolimus ⫹ mycophenolate protocol.9 The primary purpose of this study was to determine the association between transplant ureteral stent use and BKV. We report the largest series to date demonstrating the relationship between transplant ureteral stenting and BKV. METHODS Participant Selection We conducted a retrospective chart review of all renal transplant recipients who were transplanted at our institution between January 1, 2006, and December 31, 2009. Patients who underwent living donor (unrelated; n ⫽ 22) and deceased donor (n ⫽ 164) renal transplantation were included. Living related donor recipients were excluded because they received a different immunosuppression regimen. All cases were performed by four surgeons. The decision to employ a transplant ureter stent was based on local operative findings and surgeon preference. Transplant ureteral stents were removed 6 weeks following transplantation. The demographics of the two groups based on stent placement are displayed in Table 1.

Immunosuppression Protocol Our immunosuppression protocol consists of induction therapy with antithymocyte globulin (Thymoglobulin) for living unrelated renal transplants and deceased donor renal transplants. Most Table 1. Patient Demographics Demographic Variable

Stent (n ⫽ 124)

No Stent (n ⫽ 62)

P Value

Average age Male Ethnicity White African-American Other Diabetes Retransplant status

48 (39%) 80 (65%)

51 (82%) 33 (53%)

.09 .14 .70

94 (76%) 18 (15%) 12 (10%) 46 (37%) 17 (14%)

50 (81%) 8 (13%) 4 (6%) 20 (32%) 5 (8%)

patients underwent an early steroid withdrawal with cessation of steroids at postoperative day 6. In most cases, maintenance immunotherapy consisted of mycophenolate mofetil (Cellcept), tacrolimus (Prograf), and sirolimus (Rapamune). In patients who were receiving steroids at the time of transplantation, suffered from delayed graft function, or whose underlying renal disorder was focal segmental glomerulosclerosis, oral steroid therapy was substituted for sirolimus.

Polyomavirus BK Viremia Screening and Treatment Protocol Beginning 1 month after transplantation, all renal transplant recipients underwent monthly serum BK polymerase chain reaction (PCR) measurement. Upon detection of BKV, which was defined as ⱖ2.7 log copies/mL, a repeat serum BK PCR was performed 2 weeks later. In cases where BKV was confirmed, a mycophenolate mofetil dose reduction of 50% was employed, followed by monthly serum BK PCR screening. Persistent BKV was defined as persistent PCR ⱖ 2.7 log copies/mL 4 months following mycophenolate mofetil dose reduction. Persistent BKV prompted discontinuation of mycophenolate mofetil.

Statistical Analysis The patient demographics, laboratory values, and donor history were compared between the stent and no stent recipients. A t test and chi-square test were used to compare means and proportions across categories. All statistical analyses were performed using Stata software version 11.1.

RESULTS Demographics

A total of 186 renal transplantations were performed at our institution by four surgeons during the study period. A transplant ureteral stent was inserted at the time of transplantation at the surgeon’s discretion. Of these, 124 recipients (67%) underwent intraoperative transplant ureteral stent insertion, while 62 recipients (33%) did not receive a stent. The demographics were similar in the two groups with respect to gender, ethnicity, diabetes status, and retransplant status (Table 1). Polyomavirus BK Viremia and Ureteral Stents

During the study period, 32 of 186 recipients developed BKV, resulting in a viremia rate of 17%. When stratified by the presence or absence of a transplant ureteral stent, 27 of 32 (84%) of the patients with BKV had a stent. In contrast, only 5 of 32 (16%) of the patients with BKV did not have a stent (Table 2). Ureteral stent placement conferred a statistically significant (P ⫽ .02) elevated risk of developing BKV (odds ratio ⫽ 3.17, 95% confidence interval 1.16 – 8.70). In all patients who developed BKV, an immunosuppression dose reduction protocol was employed to clear the BKV. No grafts were lost to BKN. One recipient underwent dose reduction for BKV and subsequently developed graft loss due to biopsy-proven rejection in the absence of BKN. Polyomavirus BK Viremia and Procurement Technique

.52 .26

The majority of our renal transplant recipients received a deceased donor allograft (n ⫽ 164). However, the recipient

RISK FACTOR FOR POLYOMAVIRUS BK VIREMIA

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Table 2. Recipient Results by Stent and BK Status (P ⴝ .02) BK Status

Stent (n ⫽ 124)

No Stent (n ⫽ 62)

BKV (⫺) BKV (⫹)

97 (78%) 27 (22%)

57 (92%) 5 (8%)

group was subdivided by allograft procurement type (Table 3) to ascertain whether or not a trend toward BKV (⫹) existed for recipients of allografts donated after cardiac death (DCD) compared to all others (donation after brain death, living unrelated donation). No statistically significant relationship was identified (P ⫽ .52) between recipients of DCD allografts BKV. DISCUSSION

The gold standard diagnostic study for BKN remains the invasive kidney transplant biopsy. In recent years, with advancements in molecular biology, BK PCR testing became widely available. In most cases, PCR screening for BK virus in the urine and/or blood allows for early detection of infection. With early intervention, progression of BKV to BKN can be largely avoided. Similarly, early detection and intervention can help to avoid invasive allograft biopsies. Our screening protocol takes advantage of the natural history of BK infection. In most transplant recipients, BK infection proceeds as follows: infection/reactivation ¡ viruria ¡ viremia ¡ nephropathy. In our institution, we screen transplant recipients monthly for BKV using serum BK PCR. When BKV is detected (ⱖ2.7 log copies/mL), a confirmatory serum BK PCR is performed within 2 weeks. In cases where BKV is confirmed, a mycophenolate mofetil dose reduction of 50% is employed, followed by monthly BK PCR screening. In recipients who suffer from persistent BKV, which we define as BK PCR ⱖ 2.7 log copies/mL for 4 months following mycophenolate mofetil dose reduction, we discontinue mycophenolate mofetil. Using this noninvasive method of screening, we detected BKV in 17% of our recipients during the 4-year study period. On further inspection, we observed a statistically significant difference in the rate of BKV detected in stented (22%) versus unstented (8%) recipients. In our analysis, ureteral stent placement conferred a statistically significant elevated risk (odds ratio 3.17) of developing BKV. Using this BKV screening protocol, we have virtually eliminated early graft loss due to BK infection in our program without the use of an invasive allograft biopsy. Using our BKV screening protocol, as well as our immunosuppression reduction protocol in recipients with PCRproven BKV, we did not lose any allografts to BKN. We lost one allograft (0.4%) during the study period as a result of our dose reduction treatment protocol. In that case, our stented recipient developed BKV 93 days after transplantation in the setting of normal allograft function. Several weeks following protocol dose reduction in immunosuppression, a rise in the recipient’s creatinine was noted. The recipient underwent an allograft biopsy, which demon-

strated acute cellular rejection without evidence of coexisting BKN. Ultimately, despite therapy for rejection, the patient resumed dialysis 3 years after transplantation; the graft was lost to biopsy-proven chronic allograft nephropathy in the absence of BKN. The rising incidence of BKV may be explained by a combination of several phenomena observed in recent years, including the increased use of potent immunosuppression, the increased use of transplant ureteral stenting, the transplantation of older recipients, and the increased use of organs procured in the setting of DCD. Thomas et al suggested that a two-hit model is necessary for BKV infection, wherein latent BK virus reactivates in the setting of immunosuppression (hit #1) and progresses to BKV/ BKN in the setting of further insult (hit #2).2 Though cold ischemia is not felt to influence this process per se, warm ischemia and ischemia-reperfusion injury have been shown to contribute to the inflammation associated with BK reactivation in a murine model.10,11 In the setting of inflammation and regeneration of the allograft uroepithelium in response to ischemia-reperfusion injury, ureteral stent placement may confer additional uroepithelial injury. In an in vivo pig model, most of the commonly used double-J ureteral stents were shown to negatively impact the lining of the ureter in which they dwell. Regardless of the individual stent’s biocompatibility profile, each of the many stents studied generated ureteral epithelial ulceration, epithelial hyperplasia, and inflammation.12 Similar findings have been noted in a canine model.13 Additional uroepithelial injury may worsen hit #2 and predispose the allograft to a higher risk of BK reactivation. Furthermore, following DCD procurement, the anticipated ischemia-reperfusion injury may be greater, potentially worsening hit #2. We were not able to demonstrate a significant difference in the BKV rate in DCD versus non-DCD allograft recipients (17% vs 18%). However, our volume of DCD recipients was small (n ⫽ 24), which may, in part, explain our inability to demonstrate a difference with our data. There are a number of limitations in this study. First, our patient population is a small one derived from a singlecenter experience, and our data were collected in a retrospective fashion. Patients were not randomized to receive stents. In fact, the surgeon’s decision to use a stent may have depended on variables suspected to contribute to hit #1 or hit #2, such as advanced recipient age, comorbid recipient medical conditions (such as prior steroid use or Table 3. Recipient Subgroup Analysis by Procurement (P ⴝ .52) BK/stent Status

DCD (n ⫽ 24)

Non-DCD (n ⫽ 162)

BK (⫺)/stent (⫺) BKV (⫹)/stent (⫹) BKV (⫺)/stent (⫹) BKV (⫹)/stent (⫺)

4 (17%) 4 (17%) 16 (67%) 0 (0%)

53 (33%) 23 (14%) 81 (50%) 5 (3%)

DCD, allografts donated after cardiac death.

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deconditioning), allograft procurement style (ie, DCD), and conditions around procurement (eg, long ischemia time). We were unable to demonstrate a statistically significant impact of recipient age or DCD procurement style on BKV. However, a randomized, prospective trial in a larger study group may be better powered to demonstrate these suspicions. Finally, we employ an uncommon maintenance immunosuppressive regimen, such that our results may not apply to the traditional dual- or triple-therapy recipient on tacrolimus, mycophenolate, and methylprednisolone. We suspect that the observed rising incidence of BKV/BKN in kidney transplant recipients is associated with the increased use of ureteral stents at the time of transplantation. We believe that this phenomenon may be the result of increased uroepithelial trauma seen in the setting of transplant ureteral stenting, which has become a more popular technique in recent years. Given the elevated risk of developing BKV in the setting of ureteral stent placement, we recommend routine BKV screening for all stented transplant recipients. REFERENCES 1. Mengel M, Marwedel M, Radermacher J, et al: Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant 18:1190, 2003 2. Thomas A, Dropulic L, Rahman M, et al: Ureteral stents: a novel risk factor for polyomavirus nephropathy. Transplantation 84:433, 2007

SIPARSKY, KUSHNIR, GALLICHIO ET AL 3. Petrov R, Elbahloul O, Gallichio M, et al: Monthly screening for polyoma virus eliminates BK nephropathy and preserves renal function. Surg Infect (Larchmt) 10:85, 2009 4. Egli A, Infanti L, Dumoulin A, et al: Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199:837, 2009 5. Manabe M, Yoshii Y, Mukai S, et al: BK virus-associated nephropathy in an HIV-positive patient with gingival plasmablastic lymphoma. Int J Hematol 92:208, 2010 6. Doerries: Human polyomavirus JC and BK persistent infection. Adv Exp Med Biol 577:102, 2006 7. Dharnidharka V, Cherikh W, Abbott K: An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation 87:1019, 2009 8. Yeo F, Yan C, Swanson S, et al: The prevalence of BK polyomavirus infection in outpatient kidney transplant recipients followed in a single center. Clin Transplant 22:532, 2008 9. Brennan D, Agha I, Bohl D, et al: Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 5:582, 2005 10. Kazory A, Ducloux D: Ureteral stent placement and BK virus allograft nephropathy in renal transplant recipients. Transplantation 85:657, 2008 11. Atencio I, Shadan F, Zhou X, et al: Adult mouse kidneys become permissive to acute polyomavirus infection and reactivate persistent infections in response to cellular damage and regeneration. J Virol 67:1424, 1993 12. Cormio L, Talja M, Koivusalo A, et al: Biocompatibility of various indwelling double-J stents. J Urol 153:494, 1995 13. Marx M, Bettmann M, Bridge S, et al: The effects of various indwelling ureteral catheter materials on the normal canine ureter. J Urol 139:180, 1988