Monday, January 6, 2014

BK nephropathy: Diagnosis and Management Update

The BK polyomavirus is a small, non-enveloped DNA virus, which is an ongoing concern for the transplant population as it primarily causes clinical disease in immunocompromised hosts, leading to BK-associated nephropathy (BKN) and graft loss.

Primary infection of BK virus is thought to occur early in childhood, commonly presenting as a viral respiratory infection. After that, BK virus remains latent in renal epithelial and lymphoid cells, where it can get re-activated in immunocompromised population.

Risk Factors include: 1- Degree of immunosuppression 2- Donor determinants (deceased donation, HLA-mismatches). 3- Recipient determinants (older age, male). 4- Re-transplantation due to BK virus graft loss

A definitive diagnosis of BKN requires analysis of tissue from renal biopsy (figure with positive staining for SV-40; courtesy of Dr Rennke). However, the diagnosis may be missed on biopsy since definitive lesions are focal in nature. Therefore, at least two biopsy cores should be taken and medulla ideally should be included in the sample. The suspicion of the diagnosis is supported by quantitative PCR for BK virus on urine and/or plasma.

Prevention of BKN is the cornerstone of routine screening. The two most commonly used ways of BK virus screening are blood and urine for viral DNA monitoring, monthly for the first 3-6 months, then every 3 months until the end of the first post-transplant year, and wherever there is an unexplained rise in the serum creatinine.

Based on retrospective studies, fluoroquinolones may have a role in the prevention, but are not effective for treatment. The mainstay of therapy is reduction in immunosuppressive medications, especially mycophenolic acid, followed by calcineurin inhibitors. If reducing immunosuppressive therapy is not effective, clinicians may try using adjunct medications with potentially antiviral action, even though the efficacy of the agents in vivo has not been demonstrated. These agents include: Intravenous immune globulin (IVIG), Leflunomide, and Cidofovir. None of them have been approved by the FDA for the treatment of BKN.

Kidney retransplantation after BKN yields satisfactory results and prior BK infection should not be a contraindication for re-transplantation. Note that extensive phase of aggressive immunosuppressive therapy post retransplant should be avoided, and close monitoring/screening for BK viral load is advisable.

Antiviral adjuvant agents for the treatment of BK associated nephropathy.

Major side effects
0.2-2.0 g/Kg IV
Renal dysfunction,  thrombosis
$$$$ (~$10-22K/dose)
Leflunomide# (Arava®)
LD*: 100 mg x 5 days
MD^: 20-60 mg daily
Peripheral neuropathy, bone marrow suppression, hepatitis
$$$ (~$2000/month)
Cidofovir (Vestide®)
0.25-1 mg/Kg every 1-3 weeks without probenecid
$$ (~$800/vial)

 *LD: Loading dose ^MD: Maintenance dose #Target blood levels: 40-100 ng/mL 

It is quite clear that prospective, multicenter, randomized clinical trials are needed to define the best strategy for immunosuppression reduction and also to investigate more antiviral agents based on the poor outcome of grafts after development of BK nephropathy.

 Brianne Ritchie, PharmD, MBA
 Sandra El Hajj, PharmD
Steven Gabardi, PharmD

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