**3. BK polyomavirus infection and disease in humans**

Polyomaviruses are non-enveloped, double-stranded ubiquitous DNA viruses living in birds and mammals as natural hosts. The name indicates their ability to produce tumors (Greek poly- many, multiple; -oma, tumors), particularly in rodents and experimental models [46].

Seroprevalence in humans ranges from 20 to 90%, depending on the viral strain and patient age. It generally remains asymptomatic in the renourinary tract of healthy individuals, although may undergo periods of self-limiting transient asymptomatic activation with viruria and viremia, without causing disease [46]. However, in immunocompromised individuals, such as renal transplant recipients, it can be associated with various patterns of tissue injury, of which BK virus nephropathy is the most common.

Among approximately 18 polyomavirus strains, BK virus, JC virus, and simian virus (SV-40) have been considered to be pathogenic in humans. Infections with SV-40 were detected following the administration of contaminated polio vaccines in the late 1950s, without known clinical manifestation in humans [46].

BK virus was isolated in 1971 from a patient with ureteral stenosis after kidney transplantation and was named after the initials of the infected patient. Similarly, JC virus was named after a patient with progressive multifocal leukoencephalopathy. Both strains are characterized by productive viral infection with tissue injury, showing specific tropism for the renourinary tract or central nervous system [46, 47].

Recent studies have indicated that BK virus may be involved in the tumorigenesis of bladder carcinoma in renal transplant recipients and salivary gland inflammation and sclerosis in HIV patients [48, 49]. Trichodysplasia spinulosa-associated polyomavirus and Merkel cell carcinoma polyomavirus, recently detected new strains, may be related to proliferative lesions and neoplasms without productive viral replication [50].

#### **3.1 BK nephropathy**

PVN is a major causative agent in nephropathy after renal transplantation, affecting 1–10% of patients [51].

In the past, when immunosuppressive therapy was based mainly on cyclosporine, only sporadic PVN cases were reported. Although modern immunosuppressive drugs introduced after 1990 have enabled less rejection and improved allograft survival, they have been responsible for the occurrence of previously uncommon side effects, including PVN and hemorrhagic cystitis [47].

Before screening protocols for PV reactivation in renal transplant recipients were routinely used, PVN was usually diagnosed late after transplantation, in an advanced histologic stage, with chronic renal changes leading to allograft loss within 1 year in 50–90% of cases [4, 50]. Potential misdiagnosis of concurrent rejection resulting in increased immunosuppression might contribute to accelerated allograft failure.

#### **3.2 Features of BKN**

PVN is typically caused by the BK strain and only rarely by simultaneous activation of BK and JC viruses. The specific viral activation mechanisms remain unknown [47]. The transplant microenvironment may promote viral reactivation, because only sporadic detection of PV in native kidney of patients with other organ transplants or in immunodeficient patients has been reported [52, 53]. PVN also commonly occurs in patients with posttransplantation complications, including

#### **Figure 6.**

*Diagnosis of BK nephropathy: intranuclear viral inclusion bodies in tubular epithelial cells (A, HE, 200x), intracellular virions of 40–50 nm in diameter by electron microscopy (B, electron micrograph), intranuclear expression of SV-40 antigen in tubular epithelial cells (C) and/or epithelial cells of Bowman's capsule (D, both SV-40, 400x).*

delayed graft function and acute rejection. Other risk factors are male gender, older recipient age, diabetes, prolonged ureteral stent placement, smoldering subclinical graft inflammation, and/or abnormalities of dendritic cell and NK cell/T-cell activation. Relative over-immunosuppression by modern immunosuppressive drugs, though, is considered the main risk factor [47, 51, 54].

Polyomavirus infection represents serological or virological evidence of virus exposure without distinguishing among replicating, latent, and transforming patterns. Manifest viral disease is, however, defined as histological evidence of polyomavirus-mediated organ pathology and is mainly limited to immunocompromised patients, such as transplant recipients [47, 55, 56].

**51**

**Figure 7.**

*Viral Infections after Kidney Transplantation: CMV and BK*

Recognition of BKN is critical, since the proper therapy is reduction, rather than

In order to confirm intrarenal BKV replication, renal biopsy remains the gold standard for a definitive diagnosis of BKN [51]. A minimum of two cores including the medulla are recommended to make a correct diagnosis, since in the early stage, viral inclusions may be present only in the medulla [5, 51, 57]. However, characteristic viral inclusion and tubular injury might be focally observed in the biopsy

BKN is morphologically characterized by intrarenal viral replication, mainly in tubular epithelial cell nuclei (intranuclear inclusions), causing tubular injury, shedding of tubular epithelial cells, and cell lysis (**Figures 7** and **8**). On immunofluorescence, focal immune complex-type granular deposition of IG along the tubular basement membrane is sometimes found, indicating BK infection (**Figure 9**), although the biologic and clinical significance of this finding needs further evaluation [5].

Viral replication in tubular epithelial cells can induce various nuclear changes: an amorphous ground-glass inclusion body (type 1), a central irregular inclusion body surrounded by a halo (type 2), finely granular nuclear alterations (type 3), and vesicular changes with coarsely clumped viral inclusions (type 4) (**Figure 10**).

*BK virus nephropathy. Virally induced tubular epithelial cell injury and lysis in cortex (A, HE, 200x) and* 

*medulla (B, HE, 100x). Intranuclear viral inclusion bodies are observed (arrow).*

specimens, so PVN can be missed due to sampling error (**Figure 6**).

*DOI: http://dx.doi.org/10.5772/intechopen.86043*

*3.3.1 Morphological characteristics of BKN*

enhanced immunosuppression.

**3.3 Diagnosis of BKN**

Recognition of BKN is critical, since the proper therapy is reduction, rather than enhanced immunosuppression.
