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The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.
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Micrograph showing a polyomavirus infected cell — large (blue) cell below-center-left. Urine cytology specimen.
The BK virus was first isolated in 1971 from the urine of a renal transplant patient, initials B.K. The BK virus is similar to another virus called the JCV since their genomes share 75% sequence similarity. Both of these viruses can be identified and differentiated from each other by carrying out serological tests using specific antibodies or by using a PCR based genotyping approach.
The BK virus rarely causes disease since many people who are infected with this virus are asymptomatic. If symptoms do appear, they tend to be mild: respiratory infection or fever. These are known as primary BK infections.
The virus then disseminates to the kidneys and urinary tract where it persists for the life of the individual. It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Typically, this is in the setting of kidney transplantation or multi-organ transplantation. Presentation in these immunocompromised individuals is much more severe. Clinical manifestations include renal dysfunction (seen by a progressive rise in serum creatinine), and an abnormal urinalysis revealing renal tubular cells and inflammatory cells.
It is not known how this virus is transmitted. It is known, however, that the virus is spread from person to person, and not from an animal source. It has been suggested that this virus may be transmitted through respiratory fluids or urine, since infected individuals periodically excrete virus in the urine. A survey of 400 healthy blood donors was reported as showing that 82% were positive for BK virus.
In some renal transplant patients, the necessary use of immunosuppressive drugs has the side-effect of allowing the virus to replicate within the graft, a disease called BK nephropathy. From 1–10% of renal transplant patients progress to BK virus nephropathy (BKVN) and up to 80% of these patients lose their grafts. The onset of nephritis can occur as early as several days post-transplant to as late as 5 years.
The cornerstone of therapy is reduction in immunosuppression. A recent surge in BKVN correlates with use of potent immunosuppressant drugs, such as tacrolimus and mycophenolate mofetil (MMF). Studies have not shown any correlation between BKVN and a single immunosuppressive agent but rather the overall immunosuppressive load.
The rationale behind using leflunomide in BKVN comes from its combined immunosuppressive and antiviral properties. Two studies consisting of 26 and 17 patients who developed BKVN on a three-drug regimen of tacrolimus, MMF, and steroids had their MMF replaced with leflunomide 20–60 mg daily. 84 and 88% of patients, respectively had clearance or a progressive reduction in viral load and a stabilization or improvement of graft function (7). In a study conducted by Teschner et al. in 2009, 12/13 patients who had their MMF exchanged with leflunomide cleared the virus by 109 days. In a case series, there was improvement or stabilization in 23/26 patients with BKVN after switching MMF to leflunomide.
There are no dosing guidelines for leflunomide in BKVN. Patient to patient variability has made dosing and monitoring of leflunomide extremely difficult.
A recent study from The Cleveland Clinic reported that BK viremia load > 185 000 copies/ml at the time of first positive BKV diagnosis - to be the strongest predictor for BKVAN (97% specificity and 75% sensitivity. In addition the BKV peak viral loads in blood reaching 223 000 copies/ml at any time was found to be predictive for BKVAN (91% specificity and 88% sensitivity .