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. Author manuscript; available in PMC: 2015 Aug 8.
Published in final edited form as: Transpl Infect Dis. 2015 Jun 26;17(4):536–543. doi: 10.1111/tid.12402

Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia

S Gabardi 1,2,3,4, S Ramasamy 2, M Kim 2,5, R Klasek 2, D Carter 2, MR Mackenzie 6, A Chandraker 3,4,7, CS Tan 4,6,8
PMCID: PMC4529764  NIHMSID: NIHMS699031  PMID: 25989423

Abstract

Introduction

Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression; but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN.

Patients and methods

A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN.

Results

Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312).

Conclusions

Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.

Keywords: BK virus, BKPyV viremia, polyomavirus, polyomavirus-associated nephropathy, renal transplantation, statins


One of the major causes of renal dysfunction and allograft loss among renal transplant recipients (RTR) is infection by human BK polyomavirus (BKPyV). Most immunocompetent individuals are BKPyV-antibody seropositive, with asymptomatic primary infection generally occurring during childhood. However, adverse sequelae from BKPyV are uncommon in patients with a competent immune system. In contrast, BKPyV in RTR may give rise to significant disease, including tubulointerstitial nephritis leading to polyomavirus-associated nephropathy (PyVAN) and ureteral stenosis. Following the onset of medical immunosuppression after transplantation, BKPyV reactivates from its latent state in tubular epithelial cells and is subsequently amplified in the urothelial cell layer (13). PyVAN can lead to an asymptomatic acute or slowly progressive allograft dysfunction (15). Studies have reported the incidence of BKPyV viremia to be as high as 29%, with peak viral loads (VLs) occurring at 3 months post transplant (6, 7). The onset of PyVAN generally occurs at nine to 12 months after transplantation (15). It is estimated that PyVAN affects up to 10% of RTR, frequently resulting in permanent allograft dysfunction or loss (2, 3). A relationship exists between the intensity of immunosuppression and development of BKPyV viremia and PyVAN (8). Several other recipient- and transplant-related risk factors have been reported, which include increased age, male gender, Caucasian race, diabetes mellitus, and acute rejection (911). Certain donor characteristics also influence the risk for BKPyV infection, including the presence of active BKPyV or cytomegalovirus infection, the number of human leukocyte antigen mismatches, female gender, and deceased donor transplant (911).

The American Society of Transplantation has issued guidelines for appropriate management of BKPyV in organ transplant recipients (8). These guidelines suggest that a reduction in the degree of immunosuppression should be considered in RTR with sustained BKPyV VLs (1, 4, 5, 8). However, in some patients receiving immunosuppressive regimens utilizing drug-minimization or withdrawal strategies, it may be impossible to reduce immunosuppression without increasing the risk of acute rejection. In these patients, along with patients with persistent high plasma BKPyV VLs despite reduced immunosuppression, the use of adjunctive pharmacologic agents with anti-BKPyV activity should be considered (8). The pharmacologic options for BKPyV treatment include intravenous immune globulin (IVIG), leflunomide, and cidofovir (3, 1214). Unfortunately, the data supporting these agents are comprised of retrospective analyses, individual case reports and small case-series.

Although existing evidence is limited, these current anti-BKPyV agents appear to have limited utility. Treatment with IVIG is associated with significant expense and lengthy infusions. IVIG also has the potential to induce nephrotoxicity; most commonly seen with the sucrose-containing formulations (13). Leflunomide is essentially a prodrug that is rapidly converted to its active metabolite, A77 1726. This metabolite displays significant inter-patient variability and a mean terminal half-life of 15 days. Monitoring of serum A77 1726 levels is recommended, but the limited availability and expense of doing so may preclude its use at some institutions. Leflunomide therapy is also associated with significant hematologic and hepatic adverse events (15). Cidofovir, a highly nephrotoxic antiviral, appears to have minimal in vitro activity against BKPyV (16, 17). Therefore, effective anti-virals against BKPyV are urgently needed.

In vitro data have demonstrated the potential benefits of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, better known as ‘statins,’ in the prevention of PyVAN (1820). The statins are frequently prescribed to RTR patients, where hyperlipidemia is reported to occur in nearly 65% of patients. Their pleiotropic effects may also positively impact the incidence of acute allograft rejection and survival (21). The newer statins, atorvastatin and rosuvastatin, can also decrease the expression of caveolin-1 (Cav-1), which could be crucial in preventing BKPyV entry into proximal tubule cells via the caveolar endocytosis pathway (18, 19, 22). To that end, Moriyama and Sorokin (20) evaluated in vitro the ability of pravastatin to interfere with BKPyV internalization through disruption of the caveolae. Human renal proximal tubular epithelial cells (HRPTEC) were incubated with BKPyV, with and without the presence of pravastatin. In pravastatin-treated cultures, the percentage of BKPyV-infected cells was significantly lower than in the HRPTEC that were incubated with BKPyV alone. Expression of Cav-1 was also significantly reduced by pravastatin. The researchers also evaluated the impact of adding pravastatin 3 days after HRPTEC were infected with BKPyV. They noted that adding pravastatin after the BKPyV infection provided no decrease in the percentage of infected cells. This study demonstrated that pravastatin prevents the progression of BKPyV infection in HRPTEC only if it is present before BKPyV exposure. These authors hypothesized that clinical management of BKPyV with statins may be beneficial, if statin therapy is initiated before or shortly after the finding of BKPyV viremia, in order to prevent progression to PyVAN (20).

Given this in vitro analysis, we attempted to test this hypothesis by evaluating the incidence of PyVAN in those RTR with BKPyV viremia either taking or not taking a statin for management of hyperlipidemia.

Materials and methods

Study design

A preliminary, single-center analysis of 194 consecutively transplanted patients initially evaluated the impact of statins on the occurrence of BKPyV viremia and subsequent PyVAN. This internal analysis consisted of 84 patients receiving statins post transplant, and 110 that were not. We saw no appreciable differences in the rates of BKPyV viremia (19.1% no statins vs. 26.2% statins; P = 0.296) or PyVAN (6.4% no statins vs. 13.1% statins; P = 0.136) in this cohort.

Based on these initial unpublished observations and the proposed mechanism of statins preventing BKPyV entry into proximal tubule cells, we decided to re-formulate our hypothesis to focus on statins’ ability to prevent PyVAN in patients with viremia, and invited a second center to participate in this analysis. This full analysis presented herein is a multicenter retrospective study of a consecutive cohort of patients undergoing renal transplant from July 1, 2005 through March 31, 2012. The study was designed to include patients 18 years of age or older and those with documented BKPyV viremia (VL > 500 copies/mL) within 1 year of transplantation. The analysis was based on intention-to-treat for prevention of PyVAN. The primary endpoint of this analysis was the incidence of PyVAN. Several secondary endpoints were also examined, including peak BKPyV VLs, need for leflunomide, continued viremia, BKPyV-induced graft loss, and renal function at 1 year.

This study was approved by each hospital’s institutional review board as a retrospective analysis; therefore, informed consent was not required. Inpatient and outpatient medical records, including clinic visit notes, laboratory data, and medication histories, were reviewed for demographics, transplant characteristics, laboratory results, BKPyV VLs, biopsy data, immunosuppressive therapies, and patient and allograft outcomes. Of note, all patients transplanted at our institutions continued to receive their long-term follow-up at our institutions.

Patients and intervention

In total, 68 patients met the inclusion criteria. The patients were separated based on pre-existing statin therapy at the time of BKPyV viremia diagnosis. Group I consisted of patients who were receiving a statin before the diagnosis of BKPyV viremia. Patients were included in this group regardless of the type and dose of statin prescribed. Overall, 13 patients in this group were receiving atorvastatin (median dose = 40 mg/day), 9 were receiving simvastatin (median dose = 40 mg/day), 8 were receiving pravastatin (median dose = 20 mg/day), and 2 received rosuvastatin (median dose = 12.5 mg/day). Statin doses were individualized to achieve low-density lipoprotein levels of <100 mg/dL, and may have changed after BKPyV viremia was discovered because of ineffectiveness in lipid lowering or adverse events. Group II had no exposure to any statin before or after the diagnosis of BKPyV viremia.

Clinical definitions

Clinical practice, with regard to the diagnosis and management of BKPyV viremia and PyVAN, was similar between the groups. A pre-emptive strategy to detect BKPyV DNA by utilizing blood polymerase chain reaction tests at 1, 3, 6, 9, and 12 months after transplantation was employed at each transplant center. However, other VL tests may have been added to some patients, based on clinical suspicion of BKPyV. Patients were considered to have BKPyV viremia if their VL was ≥ 500 copies/mL. In patients with BKPyV viremia, frequent VL monitoring occurred at the managing nephrologist’s discretion. In all cases, VL monitoring was continued until at least 3 consecutive negative VLs, or indefinitely in those patients unable to clear the viremia. The diagnosis of PyVAN was made by biopsy after immunostaining for polyomavirus antigens and/or based on pathologist-reported virus-mediated tubular epithelial cell damage and corresponding inflammation. Renal biopsies were only performed ‘for-cause,’ as neither institution mandated protocol biopsies in patients with BKPyV viremia. Follow-up days were censored for the last BKPyV VL completed.

All patients included in this analysis were followed in our clinics for at least 1 year. Mean follow-up time was 1428.0 ± 727.4 days in Group I and 1411.0 ± 680.7 days in Group II (P = 0.921).

Immunosuppressive regimen

Induction therapy was used in all patients, with either rabbit anti-thymocyte globulin (r-ATG) or basiliximab. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Most patients were eligible for early steroid withdrawal (ESW). The goal tacrolimus trough concentrations were 8–12 ng/mL for the first 6 months post transplant and 5–10 ng/mL thereafter. Doses of MMF were initiated at 2 g/day with a goal of maintaining this dose throughout the first 12 months, but dose adjustments were made in patients with severe myelosuppression or gastrointestinal intolerance. Methylprednisolone was initiated at a dose of 500 mg prior to graft reperfusion, followed by 200 mg given in 2 divided doses on postoperative day zero. Corticosteroid doses were quickly tapered over the first 5 postoperative days to prednisone 20 mg/day. In patients eligible for ESW, corticosteroids were completely withdrawn, once tacrolimus trough concentrations were ≥8 ng/mL. All patients receiving the ESW protocol had their corticosteroids completely withdrawn within 3 weeks of transplant. For patients that were maintained on corticosteroids, prednisone doses were lowered to a maintenance level of 2.5–5 mg/day by 2 months post transplant.

Intravenous pulse methylprednisolone (250–500 mg/day) for 3 days was used as initial treatment of biopsy-proven acute rejection (BPAR) Banff grade IIa or lower. Banff grade IIb or higher or steroid-resistant rejection was managed with r-ATG (1.5 mg/kg/day for 4–14 days). Antibody-mediated rejection (AMR) was treated at the discretion of the treating nephrologist. All patients with BKPyV viremia had a reduction in the degree of their immunosuppression; however, no set protocol was followed, and reduction was individualized in each patient’s case.

Statistics

Categorical variables were analyzed using the Fisher’s exact test and means of continuous variables were evaluated using the Student’s t-test. Differences were considered significant at P-values of < 0.05. GraphPad InStat 3.0 (GraphPad Software, San Diego, California, USA) was used to perform all statistical analyses.

Results

Patient characteristics

The baseline demographic data and transplant characteristics were similar between the 2 groups (Table 1), except for a higher number of diabetics in Group I (n = 15 [46.9%] vs. Group II = 6 [16.7%]; P = 0.009). The type and degree of immunosuppression were also similar between the groups, as were the transplant-related outcomes (Table 2). In terms of post-transplant outcomes, the incidence of BPAR, steroid-resistant rejection, and AMR were equivalent between the groups.

Table 1.

Demographic data and transplant characteristics

Group 1
(n = 32)
Group 2
(n = 36)
P-value

Age (yrs; mean ±SD) 56.7 ± 10.9 51.5 ± 11.1 0.056

Recipient male gender 24 (75.0%) 25 (69.4%) 0.787

Race
   Asian 2 (6.3%) 1 (2.8%) 0.598
   Black 4 (12.5%) 12 (33.3%) 0.051
   Hispanic 2 (6.3%) 3 (8.3%) 1.000
   Caucasian 23 (71.8%) 19 (52.8%) 1.000
   Other 1 (3.1%) 1 (2.8%) 0.136

Previous transplant 5 (15.6%) 10 (27.8%) 0.257

Diabetes mellitus 15 (46.9%) 6 (16.7%) 0.009

Living donor 17 (53.1%) 18 (50.0%) 0.813

ECD* 8 (25.0%) 9 (25.0%) 1.000

Donor age (yrs) 47.5 + 15.6 47.2 + 15.1 0.937

Donor male gender 16 (15%) 15 (41.7%) 0.626

Donor race 0.618
   Black 1 (3.1%) 3 (8.3%)
   Non-Black 31 (96.9%) 33 (91.7%)

Cold ischemic time (minutes) 491.8 ± 538.4 496.5 ± 499.6 0.971

Warm ischemic time (minutes) 35.2 ± 11.2 36.1 ± 8.5 0.713

Number of HLA mismatches 3.7 ± 2.1 4.1 ± 1.8 0.401

DGF** 7 (21.9%) 9 (25.0%) 0.780
*

Expanded criteria donor (ECD): any deceased donor > age 60 yrs or a donor > 50 yrs with 2 of the following: a history of hypertension; a terminal serum Cr >1.5 mg/dL; or death from stroke.

**

Delayed Graft Function (DGF): the need for hemodialysis within the first 7 days post renal transplant.

Yrs, years; SD, standard deviation; HLA. human leukocyte antigen; Cr, creatinine.

Table 2.

Immunosuppression and transplant outcomes

Group I
(n = 32)
Group II
(n = 36)
P-value

Pre-transplant desensitization* 3 (9.4%) 4 (11.1%) 1.000

Induction therapy 1.000
   r-ATG 23 (71.9%) 25 (69.4%)
   Basiliximab 9 (28.1%) 11 (30.6%)

ESW 25 (78.1%) 22 (61.1%) 0.189

mToR conversion prior to BKPyV viremia diagnosis 2 (6.3%) 5 (13.9%) 0.434

BPAR 4 (12.5%) 8 (22.2%) 0.353

Steroid-resistant cellular rejection 1 (25%) 0 (0%) 0.333

AMR 2 (6.3%) 5 (13.9%) 0.434

Time (days) to BKPyV viremia diagnosis after transplant 119.3 ± 83.0 143.1 ± 80.1 0.234

Graft loss 6 (18.8%) 5 (13.9%) 0.744

Patient death 3 (9.4%) 3 (8.3%) 1.000

Follow-up (days) 1428.0 ± 727.4 1411.0 ± 680.7 0.921
*

Desensitization: patients with anti-donor antibodies receive a regimen of plasma exchange and intravenous immunoglobulin (IVIG) prior to transplantation.

r-ATG, rabbit anti-thymocyte globulin; ESW, early steroid withdrawal; mToR, mammalian target of rapamycin inhibitor (i.e., sirolimus, everolimus); BKPyV, human BK polyomavirus; BPAR, biopsy-proven acute rejection; AMR, antibody-mediated rejection.

Frequency of PyVAN

All patients in both groups were initially managed for their BKPyV viremia with a reduction in the degree of immunosuppression. In patients with persistent viremia or rising VLs despite reduced immunosuppression, leflunomide therapy was considered (Group I = 15 [46.9%] vs. Group II = 15 [41.7%]; P = 0.807). Overall, the incidence of PyVAN was numerically lower in patients receiving a statin, but this did not reach statistical significance (Table 3; Group I = 9 [28.1%] vs. Group II = 15 [41.7%]; P = 0.312). The mean peak blood BKPyV VLs were also not statistically different between the 2 groups. Approximately 16% of patients continued to have BKPyV viremia on follow-up, regardless of whether they were on a statin or not. The incidence of BKPyV-associated graft loss and renal function did not significantly differ between the groups.

Table 3.

Human BK polyomavirus (BKPyV)-related cutcomes

Group I
(n = 32)
Group II
(n = 36)
P-value
Primary endpoint
PyVAN 9 (28.1%) 15 (41.7%) 0.312
Secondary endpoints
Days from BKPyV viremia diagnosis to PyVAN 36.8 ± 33.6 (n = 9) 40.6 ± 44.3 (n = 15) 0.827
Peak mean BKPyV viral load (copies/mL) 932,370 ± 2,748,182 5,305,304 ± 27,083,417 0.367
Need for leflunomide due to progression of BKPyV viremia 15 (46.9%) 15 (41.7%) 0.807
BKPyV-induced graft loss 4 (12.5%) 4 (11.1%) 1.000
Continued viremia at conclusion of analysis 5 (15.6%) 6 (16.7%) 1.000
Mean eGFR by MDRD calculation of last five follow-up visits (mL/min/1.73 m2) 45.3 ± 15.8 39.1 ± 13.4 0.085

PyVAN, polyomavirus-associated nephropathy; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.

Moriyama and Sorokin (20) speculated that high concentrations of pravastatin were needed to prevent BKPyV infection in HPRTEC; therefore, we analyzed our patients that were receiving the maximum recommended statin dose of 80 mg/day. Overall, 6 patients were using this high dose. In these patients, 2 cases of PyVAN occurred, compared with 22 cases in the remaining 62 patients (P = 1.000). Given that the ability of pravastatin to prevent nephropathy may not be a class effect, we evaluated the incidence of PyVAN in the 8 patients treated with pravastatin vs. all others. This subgroup analysis revealed 4 cases of PyVAN in pravastatin-treated patients vs. 20 cases in the remaining 60 patients (P = 0.439).

Lastly, in vitro data demonstrate that both atorvastatin and rosuvastatin have the ability to decrease Cav-1 expression, which should help prevent entrance of BKPyV into proximal tubule cells. Therefore, we also preformed a subgroup analysis looking specifically at the 15 patients receiving either atorvastatin or rosuvastatin. In these patients, 3 developed PyVAN, compared with 21 cases in the remaining 53 patients (P = 0.225).

Discussion

BKPyV continues to be a major problem in renal transplantation. Approximately 10% of RTR develop PyVAN, with half of these patients progressing to irreversible allograft dysfunction (8). Pre-emptive strategies involving early virus detection and reduced immunosuppression have proven beneficial in a small number of patients (8). However, there is a paucity of data evaluating the effectiveness in anti-BKPyV therapies in patients with established BKPyV viremia. Given the statins’ in vitro anti-BKPyV properties, as well as their high prevalence among RTR, these agents would be ideal in the management of BKPyV infections (18, 19, 22).

As stated above, several patient characteristics have been identified with increased incidence of BKPyV viremia and may impact rates of PyVAN. The prevalence of these characteristics was similar between the 2 groups, with the exception of the statin-treated group had more patients with diabetes. The degree of post-transplant immunosuppression has also been described as a risk factor for development of BKPyV. In our analysis, r-ATG induction therapy was used most frequently in both groups. In terms of maintenance immunosuppression, tacrolimus trough concentrations and MMF daily doses were nearly identical at months 3, 6, and 12 post transplant. Also, a similar percentage of patients in each group received an ESW protocol. The incidence of BPAR and AMR was comparable between the groups. These data confirmed that both groups were relatively comparable, in terms of risk for viremia and subsequent progression to PyVAN.

To our knowledge, this is the first clinical analysis of statin therapy for the prevention of PyVAN. As explained earlier, our initial evaluation of a cohort of nearly 200 patients either taking or not taking statins after renal transplant did not show a benefit of statins in prevention or BKPyV viremia or PyVAN. Given this initial result, we decided to further evaluate the impact of statins on preventing PyVAN in only those patients with viremia. Despite the ability of statins to prevent Cav-1 expression and development of BKPyV infection in vitro, our analysis showed no beneficial effects of statin therapy, when dosed for lipid-lowering effects, on rates of PyVAN in RTR with BKPyV viremia. This finding could be the result of several reasons. First, in the in vitro analysis by Moriyama and Sorokin (20), the peak pravastatin serum concentrations needed to prevent BKPyV infection were several-fold higher than those achieved with recommended cholesterol-lowering statin doses. The mean daily dose of the statins in our analysis was 33.9 ± 24.8 mg. This lower dose may have been a major factor in the lack of clinical response to the statins. On the basis of this information, we evaluated the impact of high-dose (80 mg/day) statin therapy. This subgroup analysis also revealed no beneficial effect in preventing PyVAN. We also evaluated the impact seen in only those patients receiving pravastatin, as well as those receiving either atorvastatin or rosuvastatin. No statistically significant differences were seen when comparing these subgroups to the other patients.

We acknowledge the limitations of our study. Data were collected in a retrospective manner. Both groups had a small sample size. Reduction in immunosuppression was implemented as primary therapy for the BKPyV viremia in all patients. However, we were not able to quantify the degree of reduction in each patient, which may have impacted the rates of PyVAN development. Also, diagnosis of PyVAN was made only after a biopsy, and biopsies were only performed for cause (i.e., rise in serum creatinine, decreased urine output, etc.). Therefore, cases of subclinical PyVAN may have been missed in both groups. Overall, the daily doses of the statins were low, and neither serum or tissue concentrations of these agents were available in any of the patients evaluated in this analysis.

This analysis revealed that statin therapy, when used at doses necessary for cholesterol-lowering, in RTR with BKPyV viremia, had no impact on the incidence of PyVAN, BKPyV peak VL, BKPyV-induced graft loss, or allograft function. This finding was true regardless of the dose of the statin or the individual agent chosen. Given the in vitro data, and lack of effective alternate anti-virals against BKPyV, further studies are warranted looking at higher statin doses, specifically for the management of BKPyV and prevention of progression to PyVAN.

Abbreviations

AMR

antibody mediated rejection

BKPyV

human BK polyomavirus

BPAR

biopsyproven acute rejection

Cav-1

caveolin-1

ESW

early steroid withdrawal

HMG-CoA

3-hydroxy-3-methyl-glutaryl-CoA

HRPTEC

human renal proximal tubular epithelial cells

IVIG

intravenous immune globulin

MMF

mycophenolate mofetil

PyVAN

polyomavirus-associated nephropathy

r-ATG

rabbit anti-thymocyte globulin

RTR

renal transplant recipients

VL

viral load

Footnotes

Author contributions: S.G.: Participated in research design, performance of the research, data analysis, and writing of the paper; S.R., M.K., R.K., and D.C.: Participated in the performance of the research; M.R.M.: Participated in the performance of the research and data analysis; A.C.: Participated in research design and data analysis; C.S.T.: Participated in research design, performance of the research, data analysis, and writing of the paper.

Conflict of interest: All authors declare no potential conflicts of interest.

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