Tubulointerstitial and Vascular Diseases of the Kidney
Section 6 -
Polyoma (BK) Virus Related Interstitial Nephritis
Donna J. Lager, M.D.
Matthew Lewin, M.D.
Case 5: Polyoma (BK) Virus Related Interstitial Nephritis
A 68 year old man with end-stage renal disease due to nephrosclerosis, received
a living related renal transplant. He received Thymoglobulin induction therapy, followed by Prograf,
CellCept and Prednisone. His post-operative course was complicated by a wound dehiscence; however serum
creatinine decreased to a baseline of 1.3 mg/dl. At about 4 months post-transplant, his serum creatinine
was noted to be elevated at 2.8 mg/dl.
Polyoma (BK) virus infection is a significant cause of renal allograft dysfunction and graft loss in
renal transplant patients. In 1971, BK virus was identified and named after the initials of the
transplant patient whose urine from which the virus was first isolated and described. BK virus is a
polyomavirus, which has a high seroprevalence (75%) and low morbidity in immune competent adults
worldwide. Primary infection is usually subclinical or an ill-defined "flu-like" illness. The urinary
tract is the principal site of latent infection.
In the late 1970s prior to cyclosporine use, BK virus was recognized to be a significant pathogen in
renal transplant patients and was implicated in ureteric stenosis, allograft dysfunction, and
polyomavirus associated nephropathy. After the introduction of cyclosporin A, induction treatment, and
routine ureteric stenting, these BK virus associated complications for practical purposes were no longer
encountered. In the Mid to late 1990s, with the introduction of newer immunosuppressive regimens
including tacrolimus and mycophenolate mofetil, BK virus re-emerged as an important cause of renal
allograft dysfunction. The University of Maryland Renal Transplant Program has had an increased
incidence of BK virus associated nephropathy from two cases per 188 renal transplants in 1995 (1%) to 23
cases per 396 renal transplants in 2001(5.81%). At the Basel University Hospital in Switzerland, there
were no cases of PVAN prior to January 1995; subsequently, 5 cases were diagnosed per 70 (7.12%) renal
transplants. The Mayo Clinic Rochester renal transplant program has also showed a steady increase in the
number of polyoma virus associated nephropathy (PVAN) cases according to the year of transplant.
Although the precise reason for the increase incidence of PVAN is not known, it is postulated that newer
immunosuppressive regimens and heightened awareness play key roles.
Clinical Presentation and Diagnosis/ Laboratory Findings:
In the population of patients with renal allografts, BK related problems have been discovered in
patients with increasing creatinine and in patients with stable creatinine undergoing protocol
surveillance biopsies. This demonstrates the spectrum of virus replication and related injury to the
kidney. Virally loaded urothelial "decoy" cells in the urine are a marker for BK virus activation and
replication. Decoy cells are not; however, diagnostic of polyomavirus associated nephropathy (PVAN).
Symptomless BK virus replication has been noted in 10-68% of renal transplants recipients and up to 62%
of immunocompetent individuals. A diagnosis of PVAN requires evidence of allograft dysfunction and
histologic confirmation of BK virus associated nephritis.
The histologic spectrum of PVAN is quite varied. The classic histologic finding is the presence of
virally infected tubular epithelial cells that are characterized by enlarged nuclei with smudgy
hyperchromatic chromatin, nuclear clearing, and basophilic nuclear inclusions. The infected cells are
often located in the deep cortex and the outer medulla. Associated tubulitis, tubule cell necrosis, and
interstitial inflammation are often seen. Mild or early cases may show only focal virally infected cells
within the deep cortex or medulla without significant associated inflammation. In advanced cases there
is often extensive interstitial fibrosis, scarring, and atrophic tubules making identification of
infected cells difficult. The histologic findings, including tubulitis and inflammation may be mistaken
for acute allograft rejection. Confirmation of PVAN is typically done with specially testing for the BK
Virus (In-situ hybridization, Immunohistochemistry, etc).
The differential diagnosis most commonly includes rejection. In the current mode of practice, testing
for BK virus should be performed when intense interstial lymphocytic infiltrates are observed to exclude
the possibility of PVAN. Often the question will be asked if two processes are present – rejection and
PVAN. This question is difficult to answer with certainty because morphologically these diseases
overlap, and both show tubulitis and interstitial infiltrates. If vascular intimal arteritis is observed
together with positive BK testing, both processes may then be diagnosed with more certainty.
Other viruses may affect the tubular epithelial cells including cytomegalovirus. Negative testing for
BK virus in the morphologic setting of cells demonstrating viral atypia/change may prompt testing for
other viral infections.
- Gardner SD, Field AM, Coleman MD and Hulme B: New human papovavirus (BK) isolated from urine after transplantation. Lancet 1:1253-1257, 1971.
- Hogan TF, Borden EC, McBain JA, Padgett BL and Walker DL: Human polyomavirus infections with JC virus and BK virus in renal transplant patients. Ann Intern Med 92:373-378, 1980.
- Hirsch HH, Knowles W, Dickenmann M et al.: Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488-496,2002.
- Ling PD, Lednicky JA, Keitel WA et al.: The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J Infect Dis 187:157-1580, 2003.
- Randhawa PS, Finkelstein S, Scantlebury V et al.: Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 67:103-109, 1999.
- Drachenberg RC, Drachenberg DB, Papadimitriou JC et al.: Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology. Am J Transplant 1:373-381, 2001.
- Binet I, Nickeleit V, Hirsch HH et al.: Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation 67:918-922, 1999.
- Buehrig CK, Lager DJ, Stegall MD et al: Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus- associated nephropathy. Kidney International 64:665-673, 2003.