Diagnosis: BK virus nephropathy (BKVN)
Case Summary: Great work! Let’s take a deeper dive into BK virus nephropathy…
BK virus is a human polyomavirus which is highly prevalent in humans (60-80%), but only seems to lead to pathology in immunocompromised patients. The most common manifestation of disease from BK virus in kidney transplant patients is tubulointerstitial nephritis. Ureteral stenosis can also be seen with BK virus infection and the virus may cause hemorrhagic cystitis in bone marrow transplant patients. These clinical manifestations are likely a result of the virus persisting and replicating in renourinary epithelial cells.
There are several risk factors for BKVN, the most important of which being degree of immunosuppression. Some studies suggest an increased risk with tacrolimus as compared to cyclosporine, but BKVN has been observed with all types of regimens. Our patient is on a regimen of tacrolimus (calcineurin inhibitor), mycophenolate mofetil (anti-metabolite), and prednisone (corticosteroid).
The most common presentation of BKVN is that of our patient – an asymptomatic rise in serum creatinine. The urinalysis can be normal, or we may find pyuria, hematuria, or evidence of interstitial nephritis with renal tubular cells and/or casts. “Decoy cells”, named for their resemblance to renal carcinoma, with basophilic intranuclear inclusions on urine cytology, may provide evidence of BK infection, though sensitivity and specificity are low. BK viremia as detected by serum BK viral DNA PCR, on the other hand, has a higher sensitivity and specificity. However, BK viral DNA levels show a great deal of variation between assays. Thus, it is crucial to ensure that serial levels to monitor trends are checked at the same laboratory.
Unfortunately, the clinical presentation that most closely resembles BKVN in kidney transplant patients is allograft rejection. Given that their treatments are starkly different, it is imperative to perform a kidney biopsy to confirm the diagnosis. Histologic findings of BKVN often include interstitial nephritis and tubulitis (the presence of inflammatory cells in the tubular wall), which can also be seen in rejection. Characteristic intranuclear basophilic viral inclusions, as seen below, can help differentiate BKVN from rejection. (Of note, both CMV and human herpes simplex virus (HHSV) can also have viral inclusions, though CMV is more often cytoplasmic, and HHSV is both cytoplasmic and intranuclear.)
Immunohistochemistry (IHC) positivity for BK or the SV40 (simian virus) large T antigen can be performed, as shown below, to confirm polyomavirus nephropathy. Of note, the SV40 IHC stain will also pick up another polyomavirus family member JC virus – though JC virus nephropathy is rare. The significance of a positive SV40 stain in the absence of BK viremia or allograft dysfunction remains unclear.
Unfortunately, there has been no consistently effective antiviral therapy identified for BKVN. So, how do we manage this and prevent allograft loss? Most institutions take an approach of monitoring for evidence of viremia with screening BK viral DNA PCR during the early post-transplant period. If there is any evidence of allograft dysfunction, a kidney biopsy will be performed. Evidence of BKVN should prompt a quick response, as rates of premature graft failure are cited as high as 50% in these patients.
Detectable BK viral levels with or without allograft dysfunction should trigger a reduction in immunosuppression (the anti-metabolites azathioprine or mycophenolic acid are usually stopped first)! Remember that immunosuppression should strike a balance between infection and allograft rejection. If allograft dysfunction and viremia persist despite reduction of immunosuppression, institutions will often consider intravenous immune globulin (IVIG), cidofovir (carries significant risk of nephrotoxicity!), or leflunomide – though none are FDA-approved for this indication. If graft failure results, re-transplantation is typically deferred until BK viral DNA is undetectable.
For more, take a look here:
1. Jamboti JS. BK virus nephropathy in renal transplant recipients. Nephrology. 2016;21(8):647-654.
2. Sharma R, Tzetzo S, Patel S, Zachariah M, Sharma S, Melendy T. BK virus in kidney transplant: Current concepts, recent advances, and future directions. Experimental and Clinical Transplantation. 2016;14(4):377-384.