BK Virus–Associated Nephropathy in a Patient With AIDS

CASE REPORTS BK Virus–Associated Nephropathy in a Patient With AIDS William R. Sukov, MD,1 Matthew Lewin, MD,1 Sanjeev Sethi, MD, PhD,1 Thomas A. Rakowski, MD,2 and Donna J. Lager, MD1 The BK virus is a ubiquitous member of the group of human polyoma viruses that commonly is reactivated in the setting of immunosuppression related to renal transplantation, which results in tubulointerstitial nephritis and allograft dysfunction. BK virus–associated nephropathy occurring in association with human immunodeficiency virus infection and acquired immunodeficiency syndrome (AIDS) was reported only rarely. We describe the case of a 43-year-old man with AIDS presenting with nonoliguric renal failure. The renal biopsy specimen showed tubulointerstitial nephritis and renal tubular cell changes consistent with BK viral inclusions. Results of in situ hybridization for BK viral DNA were positive and showed tubular cell intranuclear inclusions. To our knowledge, this represents the third case of AIDS-associated BK virus–associated nephropathy diagnosed by means of biopsy. Am J Kidney Dis 51:e15-e18. © 2008 by the National Kidney Foundation, Inc. INDEX WORDS: BK virus; human immunodeficiency virus (HIV); acquired immunodeficiency syndrome (AIDS); interstitial nephritis.

T

he BK virus, with JC virus, comprises the group of human polyoma viruses. Seropositivity for BK virus typically occurs in early childhood, with a peak seroprevalence range at that age of 60% to 100%, and antibody titer typically persists throughout life.1,2,3 After the primary infection, the virus may remain latent in various organs, with the kidney the most common site of latent infection, where the virus shows tropism for the renal tubular epithelium.1-5 Reactivation of BK virus can occur in association with immunosuppression of various types, including immunosuppressive therapy after organ and bone marrow transplantation, chemotherapy, and human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).1,6-10 The urinary tract is the most commonly reported site of involvement by BK virus reactivation.2,3,6,7,11-13 Kidney infection by BK virus is by far most common in the setting of kidney transplantation.8,9,12,14-16 In patients with other causes of immunosuppression, an association between BK virus reactivation and nephropathy is much less frequent.3 Patients with AIDS previously were shown to have increased BK virus levels in blood and urine relative to patients without HIV infection.17-21 Postmortem studies showed BK viral infection of the renal tubular cells with consequent cytopathic changes in patients with clinical evidence of BK viral infection in other organ systems, but no sign of renal dysfunction.10,19,22-24 However, descriptions of

clinically apparent nephropathy resulting from BK viral infection in patients with AIDS were limited to case reports.20,25 We describe the case of a 43-year-old patient with AIDS presenting with acute nonoliguric renal failure who was found on renal biopsy to have tubulointerstitial nephritis secondary to BK virus infection. We also present a review of the literature with regard to AIDS-associated BK virus–associated nephropathy (BKVAN) diagnosed by means of renal biopsy.

CASE REPORT The patient was a 43-year-old indigent African-American man with AIDS who presented with nonoliguric acute renal failure. Although previously prescribed antiretroviral therapy for HIV infection, he had not used his medication for several years. His CD4-positive lymphocyte count at presentation was 2.0 ⫻ 103/␮L (2.0 ⫻ 109/L). Additionally, he had an ongoing Mycobacteria kansasii pulmonary infection; however, he did not use the prescribed medications. At presenta-

From the 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; and 2Virginia Hospital Center, Arlington, VA. Received August 20, 2007. Accepted in revised form November 20, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.11.030 on March 3, 2008. Address correspondence to Donna J. Lager, MD, Department of Laboratory Medicine and Pathology, Hilton 10-18, 200 First St SW, Rochester, MN. E-mail: lager.donna@ mayo.edu © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5104-0034$34.00/0 doi:10.1053/j.ajkd.2007.11.030

American Journal of Kidney Diseases, Vol 51, No 4 (April), 2008: pp e15-e18

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Figure 1. (A) Tubular epithelial cells with nuclear inclusions as indicated by the arrows (hematoxylin and eosin; original magnification ⫻400). (B) Positive staining of tubular epithelial cell nuclei (BK virus in situ hybridization; original magnification ⫻400). (C) Intranuclear inclusion (electron microscopy; original magnification ⫻7,400). (D) BK viral particles in intranuclear inclusion (electron microscopy; original magnification ⫻66,000).

tion, serum creatinine level was 6.3 mg/dL (557 ␮mol/L), and creatinine clearance was less than 10 mL/min (⬍0.17 mL/s), whereas 5 months before presentation, serum creatinine level was 1.1 mg/dL (97 ␮mol/L). Toxicology screen was positive for cocaine, and he admitted to long-term cocaine use. Serological studies for antineutrophil cytoplasmic antibodies, anti–glomerular basement membrane antibodies, and hepatitis had negative results, and complement levels were normal. A renal biopsy was performed. On light microscopy, 1 core of renal cortex and medulla was available for examination and contained 8 glomeruli. Glomeruli showed slight enlargement without a significant increase in mesangial matrix or cellularity (Fig 1A). The interstitium showed a focal mild increase in fibrosis, slightly more prominent in the subcapsular region. Additionally, areas of fibrosis were accompanied by interstitial edema and a mixed inflammatory infiltrate. Many tubules in the edematous areas showed dilatation with epithelial flattening. Numerous tubular cells contained enlarged hyperchromatic nuclei with pale basophilic or eosinophilic intranuclear inclusions (Fig 1A). The deeper cortical tubules appeared dilated with an attenuated epithelium, and intraluminal cast material was present.

In situ hybridization for BK virus was performed on formalin-fixed paraffin-embedded renal biopsy material. A BK complementary DNA probe labeled with biotin and appropriate negative probe were applied to the tissue, followed by antibodies to streptavidin-alkaline phosphatase. In situ hybridization results for BK virus were positive in numerous tubular cells, highlighting the intranuclear inclusions seen on light microscopy (Fig 1B). Immunofluorescence histological examination showed faint mesangial staining for C3 and nonspecific tubular basement membrane and capillary wall staining for albumin. Stains for immunoglobulin A, immunoglobulin G, immunoglobulin M, C1q, fibrinogen, ␬, and ␭ were negative. On electron microscopy, glomeruli showed a mild increase in mesangial matrix without significant hypercellularity. There were a few segmentally distributed mesangial and paramesangial and rare subepithelial electrondense deposits. Glomerular capillary basement membranes appeared normal. Occasional endothelial cell tubuloreticular inclusions were present. Podocytes showed mild segmental foot-process effacement. Tubules showed focal nuclear enlargement with electron-dense intranuclear inclusions. Higher magnification showed the inclusions to

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Table 1. Clinical and Pathological Findings in 3 Patients With HIV/AIDS and BK Virus–Associated Nephropathy Patient No. CD4 Cell Serum and Count Creatinine Reference Age (y) Sex (⫻109/L) (mg/dL)

120

36

M ⬍50

9.7

225

31

M

0.01

NP

3 (present patient)

43

M

2.0

6.3

Medications

Renal Biopsy Findings

Zidovudine, fluconazole, Tubulointerstitial nephritis, pentamidine tubular epithelial BK viral inclusions Stavudine, lamivudine, Tubulointerstitial nephritis, indinavir tubular epithelial BK viral inclusions None Tubulointerstitial nephritis, tubular epithelial BK viral inclusions

Follow-up (mo) Final Disposition

1

3

8

Death from unrelated cause Continued renal impairment Dialysis dependence

Note: To convert serum creatinine in mg/dL to ␮mol/L, multiply by 88.4. Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; NP, not provided by case report.

be composed of numerous viral particles characteristic of polyoma virus (Fig 1C and D). The patient rapidly progressed to end-stage renal disease and became hemodialysis dependent. Highly active retroviral therapy also was started.

DISCUSSION Epidemiological studies based on seropositivity showed BK virus to be ubiquitous, infecting 50% to 90% of a given population at some time during childhood. After the primary infection, BK virus may persist indefinitely in the latent state. The most common location of latent infection is the urogenital tract, specifically, urothelial and renal tubular epithelial cells. During conditions of immunosuppression, reactivation of the latent virus may occur.1-5 Most significant complications associated with reactivation of latent BK viral infection occur as a result of immunosuppressive therapy in renal transplant recipients. Whether representing a primary infection or reactivation of the latent virus, the typical genitourinary BK virus infection in immunosuppressed patients shows a clinically silent course, often manifest only as decoy cells detected by using urine cytological examination. BK viral infection in the urinary tract can present clinically as hematuria, acute hemorrhagic cystitis, ureteric stenosis, and BKVAN. BKVAN affects up to 10% of renal transplant recipients, with subsequent graft loss in 1% to 10% of these patients.2,3,6,7,11-13,26 Although BKVAN is a well-established complication associated with renal allograft transplantation, BKVAN in the context of other immuno-

compromised states is less well defined, particularly in patients with HIV infection and AIDS. Previous studies showed BK virus to be present at high levels in blood and urine of patients with HIV/AIDS relative to immunocompetent patients.1,10,18 Additionally, BK virus and cytopathic effects of infection were shown in the renal tubular epithelium in postmortem examinations of patients with AIDS who died of pulmonary or central nervous system effects of BK virus.10,19,21,24 However, few cases of BKVAN associated with HIV/AIDS were reported in the literature. We identified only 2 previous case reports of BKVAN confirmed by using renal biopsy.20,25 The clinicopathologic findings of these previous cases, as well as those of the present case, are listed in Table 1. All reports involved men with AIDS based on previous AIDS-defining illness who presented with acute renal failure and no history of renal impairment. By means of renal biopsy, all patients showed the typical pathological changes of BKVAN; namely, tubulointerstitial nephritis with a predominantly mononuclear cell inflammatory infiltrate, renal tubular dilatation, and renal tubular cell pleomorphism with occasional intranuclear inclusions. All biopsy specimens showed BK virus in tubular epithelial cells. Of the 2 patients with follow-up (patient 2 and the present patient), renal function failed to return to normal after the initial diagnosis. Although the 2 previously reported patients were receiving HIV therapy, their CD4 counts, as well as that of the present patient, were extremely low. From an immunologic perspective, we can

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only speculate about whether BKVAN would become more likely in the setting of a very low CD4 cell count. Interestingly, a recent study indicated that HIV-1 viral proteins Tat and Vpr may enhance BK viral transcription, suggesting that high HIV viral loads also may act synergistically with the immunosuppressed state to enhance BK viral infections.27 In summary, we present a case of AIDS-associated BKVAN diagnosed by means of renal biopsy and provide a review of the literature. We suggest that although more common in the setting of renal transplantation, BKVAN should be considered in other immunocompromised patients, including those with HIV/AIDS, especially in the setting of extremely low CD4 cell counts.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.

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