BK Nephropathy: A Challenge in Renal Transplantation

US Pharm. 2008;33(6):HS-3-HS-9.

Polyomavirus infection is an emerging challenge wherein nephritis and graft loss may affect up to 10% of kidney-transplant recipients.¹ Two types of polyomaviruses in the Polyomaviridae family, BK and JC, appear to predominantly cause clinical disease in immunocompromised hosts. These are small, nonenveloped DNA viruses; however, they vary in their clinical manifestations of viral nephritis and viral encephalopathy, respectively. Primary infection with BK virus (BKV) is not well known, but is generally asymptomatic; it may be transmitted through ingesting contaminated water or food, via the respiratory system, transplacentally, or from donor tissue.^2-4 The virus remains latent in the renal epithelium and is activated during the immunocompromised state as a result of transplantation or increased immunosuppression. It may occur when the donor or recipient's tissue is infected. Donors with higher BKV titers have been shown to have an increased risk of causing BKV infection in recipients versus donors with lower titers; recipients who had BKV infection and received a kidney from the same donor have been shown to have identical BKV genotypes.^3,5,6

BKV was first recognized in a renal-transplant patient diagnosed with the disease in 1971 as a result of virus reactivation due to new potent immunosuppressive medications aimed at reducing acute rejection and improving allograft survival.⁷ BKV-induced interstitial nephritis (BK nephropathy) is not directly caused by one specific medication, but it has been reported in studies with drug regimens that include more intense immunosuppression with tacrolimus (TAC), mycophenolate mofetil (MMF), or the combination.^8-11 Reducing immunosuppression is the cornerstone of management, but the risk of predisposing patients to acute and chronic rejections must be considered. No approved antiviral medication is available, but leflunomide, cidofovir, IV immunoglobulin (IVIG), and fluoroquinolones have been used.^1,9

Clinical Risk Factors
BK nephropathy remains poorly understood despite its increasing incidence. Potent immunosuppression is believed to be the cause of the resurgence of BKV in kidney-transplant patients. Factors that may be associated with the risk of BK nephropathy include older age, male gender, white ethnicity, diabetes, renal-tissue injury from ischemia, presence of cytomegalovirus (CMV), acute rejection, and treatment with high-dose steroid pulses.^1,9 There have been 10 cases in which the absence of HLA-C7 allele (a genetic trait) was observed in donors and recipients with sustained BK viremia.³ The precise role of the HLA-C7 gene is unknown, but its absence may increase the risk that infection will advance to sustained viremia, a preceding factor in BK nephropathy.

Clinical Features
The clinical manifestation of BK nephropathy varies from the asymptomatic state of viremia to hematuria, ureteral stenosis, and interstitial nephritis. BK nephropathy closely simulates acute rejection in multiple reports where the onset of disease occurs at an average period of 10 to 13 months posttransplantation; however, onset of nephritis may occur early (six days posttransplantation) or be delayed (five years).^9,12-14 The first sign of BK nephritis is renal dysfunction (serum creatinine [SCr] >2.2 mg/dL), which correlates to a decline in long-term graft survival that may be accompanied by fever and a urinalysis consisting of decoy cells reflecting the disease state.^8,12 Recently, implemented routine surveillance measures such as posttransplant protocol biopsy also have detected BK nephritis in the absence of SCr elevation.^15,16

Diagnosis
Viral replication begins early after transplantation, and studies have suggested that BK viral infections progress through detectable stages: viruria, then viremia, and finally nephropathy.^17-20 Findings suggestive of interstitial nephritis in patients lead to a clinical suspicion of BKV infection, prompting laboratory tests to detect the presence of BKV. Although various laboratory tests exist (TABLE 1), the 2005 Consensus Conference states that a definitive diagnosis is established by renal-allograft biopsy.^1,21

Urine cytology remains the most common method to monitor and detect the presence of BKV after transplantation. It is a simple and inexpensive test for identifying patients at risk since asymptomatic shedding or urinary decoy cells usually foreshadow the development of BK nephropathy. However, acute cellular rejection, TAC nephrotoxicity, and acute tubular necrosis also may result in transient shedding of virus-infected cells.²¹ Thus, the elimination of decoy cells in the urine suggests active BKV infection but does not always confirm BK nephropathy. Patients demonstrating persistent viral cytopathic effects will need further tests.

Plasma polymerase chain reaction (PCR) studies to detect BKV DNA are more reliable as a clinical tool. This is because viremia (detectable virus in the plasma) is another clinical manifestation of BK infection that correlates closely with allograft involvement, where it is seen in nearly 100% of cases of BK nephropathy. ^22-24 Formulating an early diagnosis, determining clinical response to antiviral therapy, and monitoring for relapse are some of the advantages of utilizing PCR. Alternatively, evaluation of BKV DNA in the urine via quantitative PCR seems to be a viable detection method since the BKV load is 100-fold to 1,000-fold higher in urine than in plasma.²⁴ Urine BKV PCR, however, is a relatively expensive test without clear benefits over plasma BKV PCR.

Renal-allograft biopsy remains the gold standard for diagnosing BK nephropathy. BK nephropathy may be missed in one-third of biopsies due to the focal nature of early BK nephropathy; examination should therefore include two core biopsies, preferably of the medulla, where the virus is more likely to be present.^25,26 In cases where initial biopsy does not confirm BK nephropathy, preemptive treatment or repeat biopsy may be considered. Preemptive treatment should be reserved for patients with presumptive BK nephropathy, as defined by exhibition of characteristically high levels of BK replication (plasma BKV PCR load >10,000 copies/mL).^1,25

Treatment

Before treatment of BK nephropathy is commenced, allograft biopsy and quantification of baseline polyomavirus load in either urine or plasma should be performed to confirm the diagnosis, with subsequent monitoring every two to four weeks. The therapeutic goal of managing BKV infection is to eliminate the virus, avoid acute rejection, and preserve renal function. The principal treatment is to maintain a balance of immune suppression; inadequate control will result in rejection, and overimmunosuppression may lead to BK nephropathy (FIGURE 1). One strategy is to discontinue the antimetabolic agent (azathioprine or MMF) and reduce the calcineurin inhibitor; another is to switch from TAC to low-dose cyclosporine. Brennan et al demonstrated that preemptive withdrawal of MMF upon detection of viremia prevented BK nephropathy without acute rejection or graft loss.²⁷ Another study found that reducing the dose of calcineurin inhibitor, but not decreasing overall immunosuppression, was associated with recovery of renal function.¹² Interestingly, studies that incorporate steroid-withdrawal maintenance protocols seem to have a decreased incidence of patients developing BK nephropathy.^18,28 Since none of the therapies has proven efficacy, the cornerstone of treatment is to decrease maintenance immunosuppression. Adjuvant antiviral agents ( TABLE 2) may be considered in patients who present with progressive allograft dysfunction based upon small clinical case studies.²⁹

Cidofovir is approved as an IV treatment for CMV retinitis in AIDS patients. The use of cidofovir was initially explored in HIV-infected patients diagnosed with progressive multifocal leukoencephalopathy, which is a fatal demyelinating disease caused by polyomavirus infection. Limited studies exist on the use of cidofovir for BK nephropathy, and it is not known how cidofovir exerts anti-BKV activity. The case report by Keller et al showed BKV clearance and histologic improvement upon repeat biopsy in a renal-transplant recipient.³⁰

Therapeutic use of cidofovir is limited by its nephrotoxic effects, including proteinuria and renal failure. To reduce nephrotoxicity in BK nephropathy, cidofovir doses are five- to 10-fold lower than those given for CMV therapy. In a retrospective study, eight of 21 patients received adjuvant low doses of cidofovir (0.5-1.0 mg/kg for 4-10 weekly regimens) plus reduced immunosuppressive therapy and the other 13 were treated with reduced immunosuppressive therapy alone.³¹ The patients given adjuvant low-dose cidofovir therapy retained their allografts, whereas nine of the 13 who had reduced immunosuppressive therapy alone experienced graft loss.

Leflunomide is indicated for the treatment of patients with active rheumatoid arthritis. It is a prodrug with an active metabolite that has both antiviral and immunosuppressive effects that are thought to relate to its activity in BK nephropathy, but the exact mechanism of action remains unclear. In one report, treatment of 17 patients with leflunomide plus discontinuation of MMF and dose decrease of TAC led to a reduction in viremia and viruria without clinically significant adverse events.³² Patients were treated with loading doses of leflunomide 100 mg/day for five days and maintenance doses of 20 to 60 mg/day, with a target blood level of 50 to 100 µg/mL.³² Additionally, a prospective, open-label study of 12 patients reported that treatment consisting of reduced immunosuppression and leflunomide led to improved graft function (66.6%) and cleared BKV viremia (42%); it also produced anemia and mild thrombocytopenia (17%).³³ In both studies, it is unknown whether the decrease in viremia and viruria was caused by the use of leflunomide or by the decreased immunosuppression.^32,33

IVIG holds established indications for a number of autoimmune disorders and primary immune deficiencies through its immunomodulatory properties derived from macrophage inhibition. It is used in transplant patients to treat viral infection, but evidence of its efficacy is often lacking. IVIG has been used successfully to treat allograft rejection, and it may be effective for polyomavirus. Since it can be difficult to differentiate between rejection and BK nephropathy, it may be beneficial to use IVIG based upon plasma PCR. In a recent report, eight patients received IVIG 2 g/kg over five days in addition to a reduction in immunosuppressive therapy.³⁴ After a mean follow-up of 15 months, seven patients (88%) had functional grafts, but renal function remained impaired.³⁴ IVIG is a costly treatment that has significant side effects including allergic reactions, renal dysfunction, and thrombotic events, and in rare cases it can cause aseptic meningitis.

Fluoroquinolones are broad-spectrum antibiotics that inhibit bacterial DNA synthesis via the inhibition of two bacterial enzymes, DNA gyrase and topoisomerase IV. These medications may achieve high tissue concentrations, particularly in the renal tubulus, possibly as a result of inhibition of BKV T antigenñcoded helicase activity.²⁹ A study of 30 hematopoietic stem-cell transplant patients receiving ciprofloxacin 500 mg twice daily found that treatment reduced the urinary BKV load.³⁵ Fluoroquinolones are the most cost-efficient of the investigational agents, but their use is limited due to lack of data.

Screening
There are no definitive guidelines for screening patients to prevent BK nephropathy. Screening may help identify patients at risk for BKV replication and thus lead to targeted reduction of immunosuppression that can resolve the infection. Earlier diagnosis of BK nephropathy coincides with an increased success rate for treatment and decreased morbidity and mortality. This approach is effectively demonstrated by a study of 200 patients who were randomized to either TAC (n = 134) or cyclosporine (n = 66) and were monitored with PCR of blood and urine to help detect early viremia.²⁸ Viruria was highest with TAC/MMF (46%) and lowest with cyclosporine/MMF (13%).²⁸ The antimetabolite (MMF or azathioprine) was then discontinued, which led to resolution of viremia in 95% of patients without an increased risk of acute rejection, allograft dysfunction, or graft loss.²⁸

An international panel established screening recommendations for renal-transplant patients.¹ A positive screening result should be confirmed within four weeks and assessed by one of the quantitative assays (BKV DNA or RNA load in plasma or urine). If the adjunctive test is above threshold values, then allograft biopsy should be performed to definitively diagnose BK nephropathy. Despite the benefits of early detection, routine BKV screening becomes cost-effective only if the incidence of BK nephropathy exceeds 2.1% in a transplant center. ³⁶

Conclusion
BK nephropathy poses a significant complication for the posttransplant kidney recipient. Although modern immunosuppressive agents have greatly benefited this population, they have also led to increased rates of BK nephropathy. Screening may identify BKV replication in recipients, and targeted reduction of immunosuppression can resolve the infection; however, this method is reserved for transplant centers with a high incidence of BK nephropathy. Successful retransplantation has been achieved in patients with graft failure due to BK nephropathy. In a study involving five transplant centers, all 10 patients had good graft function with a mean SCr of 1.5 mg/dL after mean follow-up of more than 2 years.³⁷ Limited information exists on investigational antiviral agents; prospective, randomized, controlled clinical trials are needed to assess their efficacy and safety. BKV infection remains a challenge until reliable measures of immunosuppression or novel agents that specifically target the virus are available.

Pharmacists play an important role in the treatment of kidney transplantation and serve as part of a multidisciplinary team that counsels patients on all aspects of their medications. Clinical responsibilities include addressing compliance, adverse drug events, drug interactions, and appropriate dose adjustments. Additionally, pharmacists may have contact with these patients in the pharmacy and note that they are feeling unwell, a possible sign of rejection or BKV. Pharmacists should be aware of the signs and symptoms of rejection and BKV in order to direct the patient to seek immediate physician attention.

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