What are the stages and management of BK virus-associated nephropathy (BKVAN)?

Classification and Staging of BK Virus-Associated Nephropathy (BKVAN)

BKVAN is classified into three distinct histologic stages (A, B, and C) based on the degree of tubular injury and fibrosis, with stage A representing early disease and stages B and C carrying significantly worse prognosis and risk of chronic allograft dysfunction. 1

Histologic Staging System

The morphologic classification of BKVAN progresses through the following stages:

• Stage A (Early BKVAN): Characterized by intranuclear viral inclusion bodies in epithelial cells with early tubular injury and minimal fibrosis 1
• Stage B (Intermediate BKVAN): More extensive tubular injury with developing interstitial inflammation and fibrosis 1
• Stage C (Late/Fibrotic BKVAN): Advanced disease with significant interstitial fibrosis and tubular atrophy, often resulting in chronic kidney dysfunction and end-stage renal disease 1

The clinical goal is to diagnose BKVAN in stage A to prevent progression to irreversible chronic renal injury. 1

Diagnostic Classification for Clinical Reporting

The American Society of Transplantation provides a two-tiered classification system:

1. BK Virus Infection (Without Nephropathy)

• BK viruria: Detectable BK viral DNA in urine by quantitative PCR 2, 3
• BK viremia: Detectable BK viral DNA in blood by quantitative PCR, which is more predictive of BKVAN than viruria alone 2, 3
• Both viruria and viremia can coexist 2

2. Proven BK Virus-Associated Nephropathy

Proven BKVAN requires renal biopsy demonstrating one of three histologic patterns WITH confirmatory testing: 2

• (a) Acute tubular necrosis-like picture with BK virus confirmation 2
• (b) Interstitial nephritis mimicking acute rejection with BK virus confirmation 2
• (c) Chronic allograft nephropathy pattern with BK virus confirmation 2

Confirmation must be obtained by electron microscopy, immunohistochemistry, or in-situ hybridization for BK virus. 2, 3 While intranuclear viral inclusions are usually present, their absence does not exclude BKVAN if confirmatory testing is positive. 2

Important Diagnostic Pitfall

In clinical practice, "presumptive BKVAN" is sometimes diagnosed when renal dysfunction and BK viremia coexist without histologic confirmation, but for standardized reporting (especially in clinical trials), these cases should be classified as BK viremia rather than proven BKVAN. 2 This distinction matters because biopsies can miss focal disease, but without tissue confirmation, the diagnosis remains presumptive. 2

Viral Load Thresholds and Their Limitations

• The American Society of Transplantation historically recommended a plasma BK viral load cutoff of ≥4 log10/mL (≥10,000 copies/mL) as presumptive BKVAN requiring immunosuppression reduction 4
• However, this cutoff significantly underestimates BKVAN diagnosis—in one study, 35% of biopsy-proven BKVAN cases had viral loads consistently below this threshold 4
• Using the 4 log10/mL cutoff, the sensitivity for detecting biopsy-proven BKVAN was only 64.5%, meaning over one-third of cases would be missed 4
• Patients with BKVAN and viral loads <4 log10/mL can still experience graft loss 4

Management Algorithm Based on Classification

For BK Viruria Only (No Viremia, Stable GFR)

• No treatment modification required 5
• Continue monitoring per protocol 5

For BK Viremia with Stable Renal Function

• Reduce mycophenolate mofetil by approximately 30% 5
• Monitor viral load and renal function closely 3

For BK Viremia with Declining GFR (>25% decline)

• Obtain kidney biopsy to confirm BKVAN 3, 5
• Reduce immunosuppression as first-line therapy—this is the only proven treatment according to current guidelines 6
• Consider calcineurin inhibitor discontinuation in severe cases 5
• Monitor for acute rejection, which occurs in 59-79% of patients after immunosuppression reduction 6

For >50% Decline in GFR at BKVAN Diagnosis

• This threshold correlates with significantly increased risk of graft loss despite treatment 5
• Aggressive immunosuppression reduction still warranted 5
• Consider adjunctive cidofovir therapy (0.25-1 mg/kg per dose every 2-3 weeks) 7
• Repeat biopsy if renal function deteriorates despite viral load reduction to differentiate BKVAN progression from acute rejection 6, 3

Monitoring Requirements

All kidney transplant recipients require routine quantitative BK viral load monitoring: 2, 3

• Monthly for first 6 months post-transplant 2, 3
• Months 9 and 12 post-transplant 2, 3
• Every 3 months during year 2 2, 3
• Annually thereafter 2, 3
• Additional testing for any unexplained creatinine rise ≥0.5 mg/dL 4