Final Diagnosis -- BK virus nephropathy with diffuse tubular basement membrane C4d staining

DIAGNOSIS   BK virus nephropathy with diffuse tubular basement membrane C4d staining.


BK virus is a human polyomavirus that belongs to the family Polyomaviridae. It can be associated with BK virus nephropathy, which is a complication of excessive immunosuppressive therapy and can lead to premature graft failure 1, 2. The diagnosis of BK nephropathy relies on demonstration of the virus in tubular and/or Bowman's capsule epithelium using immunohistochemical stain and/or in situ hybridization. The differential diagnosis is acute cellular rejection and/ or chronic allograft nephropathy/ rejection. Rarely, BK nephropathy and acute cellular rejection can occur concurrently. The diagnosis of an accompanied rejection should only be made when specific signs of acute rejection, namely arteritis, fibrinoid arterial necrosis, or accumulation of the complement degradation product C4d along peritubular capillaries, are also observed 2, 3. Recently, Bracamonte et al and Hever et al demonstrated tubular basement membrane immune deposits in a subset of BK virus nephropathy patients 4, 5. Such deposits were associated with more active and severe course of the disease.

C4d is a single complement degradation product that was found to be associated with circulating donor specific antibodies when detected in peritubular capillaries 6. It is now well established as a marker for antibody-mediated rejection, and it can independently predict unfavorable graft outcome 7, 8. The significance of C4d staining in non-peritubular capillaries is still not well characterized. We found tubular basement membrane staining to be a rare phenomenon in paraffin embedded specimens. Such staining was only detected in 2/52 (4%) of allograft biopsies 9. Interestingly, one of the two biopsies with this staining pattern was associated with BK virus nephropathy.

We can speculate that potential immunoglobulin deposits observed in a subset of BK virus nephropathy cases could activate complement and lead to C4d deposition in tubular basement membrane. C4d staining was also observed in Bowman's capsule, which can also be infected by the virus 10. Finally, C4d staining in tubular basement membrane was not detected in patients with BK virus activation manifested by viruria or viremia but without BK virus nephropathy (unpublished observations). This suggests that C4d deposition may occur late in the course of the disease.

For now, and till a well organized study addressing this issue is published, we can say that C4d staining in tubular basement membrane especially if accompanied by Bowman's capsule staining should at least alert us to the possibility of BK virus nephropathy in renal transplant patients with graft dysfunction. This may be particularly important in consult cases, where information about PCR results for BK virus DNA is not always provided.


  1. Nickeleit V, Hirsch HH, Binet IF et al. Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease. J Am Soc Nephrol. 1999;10:1080-9.
  2. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006;6:2000-5.
  3. Nickeleit V, Singh HK, Mihatsch MJ. Polyomavirus nephropathy: morphology, pathophysiology, and clinical management. Curr Opin Nephrol Hypertens. 2003;12:599-605.
  4. Bracamonte E, Leca N, Smith KD et al. Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy. Am J Transplant. 2007;7:1552-60.
  5. Hever A, Nast CC. Polyoma virus nephropathy with simian virus 40 antigen-containing tubular basement membrane immune complex deposition. Hum Pathol. 2008;39:73-9.
  6. Collins AB, Schneeberger EE, Pascual MA et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol. 1999;10:2208-14.
  7. Racusen LC, Colvin RB, Solez K et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003;3:708-14.
  8. Feucht HE, Schneeberger H, Hillebrand G et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int. 1993;43:1333-8.
  9. Batal I, Girnita A, Zeevi A et al. Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney. Mod Pathol. 2008.
  10. Celik B, Randhawa PS. Glomerular changes in BK virus nephropathy. Hum Pathol. 2004;35:367-70.

Acknowledgment: We thank Dr. Parmjeet Randhawa for his support

Contributed by Hanady Zainah, MD and Ibrahim Batal, MD

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