BK virus
Encyclopedia
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
.
since their genome sequences share 75% homology. 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 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.
s has the side-effect of allowing the virus to replicate within the graft, a disease called BK nephropathy
.
It is thought that 1-10% of renal transplant patients progress to BK virus nephropathy (BKVN) and up to 80% of these patients are reported to have lost their grafts. The onset of nephritis can occur as early as several days post-transplant to as late as 5 years.
It is also associated with ureteral stenosis and interstitial nephritis
. In bone marrow transplant
recipients it is notable as a cause for hemorrhagic cystitis
.
and mycophenolate mofetil
(MMF). Studies have not shown any correlation between BKVN and a single immunosuppressive agent but rather the overall immunosuppressive load.
Other therapeutic options include Leflunomide
, Cidofovir
, IVIG
, and the fluoroquinolones. Leflunomide is now generally accepted as the second treatment option behind reduction of immunosuppression.
There are no dosing guidelines for leflunomide in BKVN. Patient to patient variability has made dosing and monitoring of leflunomide extremely difficult.
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...
family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
and the immunosuppressed
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
.
History
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 JCVJC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
since their genome sequences share 75% homology. 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.
Presentation
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.
Transmission
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.Immunosuppressant-induced susceptibility
In some renal transplant patients, the necessary use of immunosuppressive drugImmunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
s has the side-effect of allowing the virus to replicate within the graft, a disease called BK nephropathy
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
.
It is thought that 1-10% of renal transplant patients progress to BK virus nephropathy (BKVN) and up to 80% of these patients are reported to have lost their grafts. The onset of nephritis can occur as early as several days post-transplant to as late as 5 years.
It is also associated with ureteral stenosis and interstitial nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
. In bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
recipients it is notable as a cause for hemorrhagic cystitis
Hemorrhagic cystitis
Hemorrhagic cystitis or Haemorrhagic cystitis is diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage. The disease can occur as a complication of cyclophosphamide, ifosfamide and radiation therapy...
.
Diagnosis
This virus can be diagnosed by BKV blood & urine testing, in addition to carrying out a biopsy in the kidneys. PCR techniques are often carried out to identify the virus.Treatment
The cornerstone of therapy is reduction in immunosuppression. A recent surge in BKVN correlates with use of potent immunosuppressant drugs, such as tacrolimusTacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
and mycophenolate mofetil
Mycophenolate mofetil
Mycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
(MMF). Studies have not shown any correlation between BKVN and a single immunosuppressive agent but rather the overall immunosuppressive load.
- No guidelines or drug levels and doses exist for proper reduction of immunosuppressants in BKVN
- Most common methods:
- Withdrawal of MMF or tacrolimus
- Replacement of tacrolimus by cyclosporine
- Overall reduction of immunosuppressive load
- Some cyclosporine trough levels reported to be reduced to 100-150 ng/ml and tacrolimus levels reduced to 3-5 ng/ml
- Retrospective analysis of 67 patients concluded graft survival was similar between reduction and discontinuation of agents.
- Single center study showed renal allografts were preserved in 8/8 individuals managed with reduction in immunosuppression while graft loss occurred in 8/12 patients treated with an increase in therapy for what was thought to be organ rejection.
Other therapeutic options include Leflunomide
Leflunomide
Leflunomide is a medication of the DMARD type, used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.-Basic chemical, pharmacological, and marketing data:...
, Cidofovir
Cidofovir
Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...
, IVIG
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
, and the fluoroquinolones. Leflunomide is now generally accepted as the second treatment option behind reduction of immunosuppression.
Leflunomide in BKVN
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.
- Study of 26 and 17 patients were dosed between 20 mg/day and 60 mg/day with trough levels of 50-100 mcg/ml. Failure was seen in patients with leflunomide plasma levels <40 mcg/ml.
- One study of 21 patients found that low levels (<40 mcg/ml) and high levels (>40mcg/ml) had similar effects on the rate of viral clearance. Those with higher levels had more adverse events (hematologic, hepatic).
- In the study by Teschner et al., dosages and drug concentration showed no correlation with substantial variation from person to person.
- In the Teschner study, low drug concentrations were associated with decrease in viral load. This makes it difficult to determine whether or not reduction of viral load or addition of leflunomide was the cause for viral clearance.
Other treatment options
- Quinolone antibiotics: Ciprofloxaxin was shown to significantly lower viral loads but no data on survival and graft loss exist.
- Intravenous immunoglobulinIntravenous immunoglobulinIntravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
(IVIG) has use in the treatment of infection and allograft rejection – hard to distinguish - CidofovirCidofovirCidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...
has limited data and is highly nephrotoxic.
External links
- Overview of the BK virus
- MicrobiologyBytes: Polyomaviruses
- Reploeg, MD., Storch, GA., Clifford, DB., BK virus: A clinical review
- Blackwell Munksgaard, 2004. BK virus. American Journal of Transplantation.
- Katrien Blanckaert and An S. De Vriese, 2006. Nephrology Dialysis Transplantation, journal of the European Renal Association and the European Dialysis and Transplant Association