BK Virus Allograft Nephropathy: Unresolved Issues Complicate Diagnosis and Management

Gupta, Gaurav MD; Atta, Mohamed G. MD, MPH

doi: 10.1097/01.NEP.0000399784.15904.40
Grand Rounds

Gaurav Gupta, MD, is Senior Nephrology Fellow at Johns Hopkins University and will be starting as Transplant Nephrology Fellow there in July. Mohamed G. Atta, MD, MPH, a member of the Nephrology Times Editorial Board, is Associate Professor of Medicine in the Division of Nephrology at Johns Hopkins University School of Medicine.

Article Outline

BK virus has emerged as an important cause of graft loss in kidney transplant recipients. While surveillance strategies have increased early detection and, consequently, reduced graft loss, achieving a delicate balance in the use of potent immunosuppression remains key to preventing acute rejection and BK virus reactivation.

In the kidney transplant population, BK virus, a polyomavirus, first emerged as a clinical concern only in the mid-1990s, after the introduction of more potent immunosuppressive medications.

A significant correlation was observed between the emergence of the infection and of the immunosuppressive regimen containing lymphocyte-depleting agents for induction therapy followed by maintenance with calcineurin inhibitors (CNIs) and antiproliferative agents (mycophenolate mofetil, or MMF). At the current time, though, it seems more likely that the risk of BK virus reactivation relates to the total burden of immunosuppression, not to any one drug.

Although the majority of reactivation occurs in the first year posttransplant, BK virus nephropathy is a well-known cause of late allograft dysfunction. Risk factors for the condition include male gender, history of acute rejection, prolonged cold ischemia time, and degree of HLA mismatch.

A robust association has been demonstrated between BK virus nephropathy and recipient seronegativity at the time of transplantation, similar to the epidemiology of other opportunistic viruses—e.g., herpes viruses, Epstein-Barr virus, and cytomegalovirus.

Despite this known risk, testing for BK virus serostatus is not routinely performed, probably because seropositive renal transplant recipients can also develop BK virus nephropathy.

Thus, although the precise etiopathogenesis remains unclear, BK virus nephropathy likely arises from complementary determinants in the host, the allograft, and the virus, in the setting of immunosuppression. When BK virus nephropathy does occur, reported rates of graft loss have ranged from 10% to 80%.

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Diagnostic Dilemmas

The clinical presentation of BK virus nephropathy is typically asymptomatic and manifested only with a rise in serum creatinine. Rarely, fever, hematuria, cystitis, and hydronephrosis have been reported. Owing to this largely asymptomatic presentation, diagnosis of the condition can often be missed unless a high index of suspicion is maintained.

The “gold standard” test for the diagnosis of BK virus nephropathy remains the allograft biopsy. A biopsy provides excellent specificity, as well as the ability to diagnose other coexistent pathologies, such as acute rejection, drug toxicity, and recurrence of underlying disease.

However, sensitivity is low—approximately 60% to 70%—owing to the focal nature of BK virus nephropathy, which leads to sampling error. This error might be minimized by obtaining at least two biopsy cores, preferentially containing medullary tissues.1

The diagnosis is suggested by the presence of intranuclear polyomavirus inclusion bodies in tubular epithelial and/or glomerular parietal cells, which is often associated with acute tubular injury. The diagnosis needs to be confirmed by either in-situ hybridization for DNA/protein identification or by immunohistocytochemistry using an antibody directed against BK viral antigens.

Owing to the low sensitivity of renal allograft biopsy, various techniques have been advocated for early detection of BK virus reactivation. Urine cytology detects shedding of so-called “decoy cells”—-virally loaded epithelial cells. Although this technique is relatively cheap and has a negative predictive value close to 100%, it has a poor positive predictive value.

Accurate interpretation requires the services of a skilled pathologist who can distinguish viral infection from urothelial atypia. Further, based on morphologic features alone, one can not always distinguish between BK virus and other viral infections, including JC virus and adenoviruses.

Currently, most centers are using screening methods based on detection of BK viral DNA in plasma or urine by polymerase chain reaction (PCR).

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients recommends monthly plasma nucleic acid testing for the first three to six months posttransplant, and then every three months thereafter until month 12; in specific situations, such as unexplained rise in serum creatinine; and after treatment for acute rejection.2

An alternative and more cost–effective strategy suggested by the American Society of Transplantation guidelines is to perform urine PCR screening every three months in the first two years and then annually until the fifth year posttransplant.1 A urine PCR greater than 107 copies/mL triggers a plasma PCR.

Both sets of guidelines suggest a presumptive diagnosis of BK virus nephropathy if the BK viral load is greater than 104 copies/mL for more than three weeks. In the absence of a rise in creatinine, an allograft biopsy is typically not performed by most centers.

In our clinical experience, we have observed cases of BK virus nephropathy even after five years. Thus, we suggest indefinite annual screening for BK virus. Recent cost-effectiveness analyses suggest plasma only-based PCR testing for BK virus may be sufficient in most clinical settings.

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Management Strategies

Management of established BK virus nephropathy remains unsatisfactory because of the absence of effective, specific antiviral therapies.

Despite this issue, graft loss rates for the condition have fallen to less than 10% in recent reports. This is due to the institution of routine screening protocols at most major centers. Detection of persistent viremia is followed by preemptive reduction of immunosuppression.

Two strategies have been suggested and appear to be effective. The first and most commonly employed is dose reduction of the antiproliferative agent (MMF) followed by reduction of CNIs.3

The second strategy, which also appears to be effective, is dose reduction of CNIs followed by dose reduction of MMF. If viremia does not clear despite these measures, consideration needs to be given to discontinuation of mycophenolate mofetil.

For refractory BK virus nephropathy, various other drugs, including cidofovir, leflunomide, fluoroquinolones, and intravenous immunoglobulin, have been tried, with variable success. To date, no prospective studies have examined the efficacy of reducing immunosuppression versus alternative therapy strategies.

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Two Major Concerns

There are two major concerns with the current management of BK virus nephropathy. First, BK virus nephropathy and acute rejection can coexist on the same biopsy. The management of these difficult cases has not been standardized.

Second, preemptive reduction of immunosuppression for the treatment of BK virus nephropathy can exacerbate both acute and chronic rejection. Thus, prospective studies of combined virologic and immunologic monitoring are needed to assess which patients will progress to BK virus nephropathy so as to better provide guidance for safe reduction in immunosuppression.

Finally, recent reports suggest an association of BK virus nephropathy with the development of urogenital tumors. This issue needs further systematic study.

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Hirsch HH, Randhawa P, for the AST Infectious Diseases Community of Practice. BK virus in solid organ transplant recipients. Am J Transplantation 2009;9[suppl 4]:S136–S146.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplantation 2009;9[suppl 3]:S1–155.
Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplantation 2005;5:582–594.
© 2011 Lippincott Williams & Wilkins, Inc.