Nephropathology
   
Case 12
Diagnosis and discussion
 
     
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Diagnosis: BK virus associate interstitial nephritis

Are there concomitant acute cellular rejection, Banff type IB?

Interstitial nephritis associated to infection by Polyomavirus subtype BK (BKV) is a significant and growing problem in renal transplant recipients. BKV was first reported in 1971. I was isolation from the urine of a renal transplant recipient with the initials BK. Although the virus was considered to be rare, subsequent studies have estimated that 70% to 90% of the world's population have evidence of exposure to BKV. Because BKV is so widely distributed and infection may cause allograft loss, awareness of this complication is an essential element for successful management of the kidney transplant recipient.

It is estimated that BKV nephropathy affects up to 10% of renal transplant recipients and may lead to allograft failure in 50% to 80% of these patients. Median prevalence of BKV nephritis is 4.5% with a median graft loss of 44% Most cases are diagnosed in the firs post-transplant year, some cases are found in the second year. BKV associated nephritis is exceptional after two post-transplant years.

The presence of BK viruria in the setting of renal allograft dysfunction is of concern and must be addressed. A single, positive urine assay for BKV in an asymptomatic patient is usually of little consequence, and in that setting follow-up urinalysis is recommended. Hirsch and colleagues noted that repeated urine values > 107 copies/mL are associated with nephritis.

Recommended Screening Intervals (urine cytology and/or urine or serum PCR): Once every 3 months for the first 2 years post transplantation (others recommend monthly screening for first 6 months and once every 3-6 months thereafter for at least the first 2 years); once annually after the first 2 years post transplantation; at time of allograft dysfunction; at time of allograft biopsy; within 4 weeks after a positive result (for confirmation).

Figure 8. Decoy cells in urine from a kidney transplanted patients. BKV nephritis was demonstrated in a posterior graft biopsy. Papanicolau stain, X400.

Figure 9. Decoy cells showing intranuclear inclusions with gelatinous aspect, chromatin margination, and cyitoplasmic degeneration. Papanicolau stain, X400.

Figure 9. A cell with a well defined intranuclear inclusion not occuping the entire nucleus. See the aspect of the cytoplasm due to degenerative changes. Papanicolau satin, X600.

Our case demonstrates the ambiguity that often faces the clinician who must decide whether tubulitis seen in association with BKV infection represents infection, acute rejection, or a combination of these conditions. There is consensus that endarteritis, fibrinoid vascular necrosis, and glomerulitis (Banff type II and III) as well as C4d deposits along peritubular capillaries should be regarded as evidence of concurrent rejection. The diagnosis of tubulointerstitial rejection (Banff type I) is challenging since the inflammatory infiltrates may indicate a response to antigens of the virus and/or virus induced tubular cell necrosis and/or the allograft. The demonstration of lymphocytic infiltrates, marked tubulitis and tubular HLA-DR expression in areas lacking polyomavirus replication may support the diagnosis of Banff type I rejection. To enable meaningful comparisons, acute rejection episodes should be classified and reported according to the Banff criteria. In patients diagnosed with concurrent acute rejection, antirejection treatment should be considered followed by reducing immunosuppression 2 weeks later (Hirsch et al. Transplantation. 2005. [PubMed link]

One new feature that has emerged is that late graft fibrosis and scarring may be caused by polyomavirus, even though the virus is no longer demonstrable. The virus is cytopathic for the tubular cells and leads to characteristically destructive tubular lesions, with only tubular basement membrane remaining. The diagnosis is sometimes possible only by a review of prior biopsies. The process may be clinically silent: protocol biopsies have shown a subclinical incidence of BKV nephritis of 1.2%. Furthermore, BKV can affect the native kidneys of recipients of nonrenal allografts; only a few cases have been reported, but this may be in part due to a presumption of calcineurin inhibitors toxicity and a lack of renal biopsies in this setting.

A newly appreciated feature of BKV infection is that it may cause an immune complex deposition along the tubular basement membrane. This feature was described in
43% of cases in a series from Seattle and was the most common cause of IgG deposits in the tubular basement membrane of renal transplants (Colvin RB, Cornel LD. Current Diagnostic Pathology, 2007 [Full text link]). Granular IgG, C3 and C4d are focally present on immunofluorescence, and amorphous electrondense deposits on electron microscopy. The prognostic significance is not known, but it is unlikely to be beneficial. The deposits do not stain for the large T antigen by routine techniques (Colvin RB, Cornel LD. Current Diagnostic Pathology, 2007 [Full text link]). As the deposits may persist after the viral antigens become undetectable in the nuclei, the virus may perhaps trigger an autoimmune response to the tubular antigens.

See Poliomavirus infection in the chapter [Kidney allograft pathology - part 3] (Text and atlas. Only in spanish).

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Bibliography

  • Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79:1277-1286. [PubMed link]
  • Hirsch HH, Drachenberg CB, Steiger J, Ramos E. Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management. Adv Exp Med Biol. 2006;577:160-73. [PubMed link]
  • Colvin RB, Cornell LD. Renal transplant pathology: An update. Current Diagnostic Pathology 2007;13:15–24 [Full text link]
  • Buehrig CK, Lager DJ, Stegall MD, Kreps MA, Kremers WK, Gloor JM, Schwab TR, Velosa JA, Fidler ME, Larson TS, Griffin MD. Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy. Kidney Int 2003;64:665–73. [PubMed link]
  • Limaye AP, Smith KD, Cook L, Groom DA, Hunt NC, Jerome KR, Boeckh M. Polyomavirus nephropathy in native kidneys of non-renal transplant recipients. Am J Transplant 2005;5:614–20. [PubMed link]

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