Int J Hematol (2010) 92:638–641 DOI 10.1007/s12185-010-0694-6
Acute renal failure associated with systemic polyoma BK virus activation in a patient with peripheral T-cell lymphoma Kazunari Aoki • Shinichi Kotani • Tatsuo Ichinohe Tadakazu Kondo • Takayuki Ishikawa
Received: 1 July 2010 / Revised: 27 August 2010 / Accepted: 13 September 2010 / Published online: 7 October 2010 Ó The Japanese Society of Hematology 2010
Abstract Renal dysfunction associated with polyoma BK virus (BKV) reactivation usually occurs in the setting of profound immunosuppression related to renal transplantation and hematopoietic stem cell transplantation. However, it has been rarely described as a complication during the course of conventional chemotherapy. Here, we report a case of BKV-associated acute renal failure developed in a patient suffering from refractory peripheral T-cell lymphoma, not otherwise specified. After repetitive cycles of salvage chemotherapy, the patient developed fever and urinary frequency, rapidly followed by anuria that necessitated the emergent institution of hemodialysis. Cytologic examination of the urine revealed the presence of decoy cells and positive immunostaining for polyomavirus simian virus 40 antigen. High levels of BKV were detected in urine and plasma with quantitative real-time polymerase chain reaction, strongly suggesting that his renal failure was due to polyoma virus-associated nephropathy. This rare complication should be kept in mind in case of unexplained renal failure developed in immunodeficient patients undergoing cytotoxic chemotherapy. Keywords Polyoma BK virus Urinary tract infection Acute renal failure Mature T-cell neoplasms Chemotherapy
K. Aoki S. Kotani T. Ichinohe (&) T. Kondo T. Ishikawa Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected]
1 Introduction Two types of polyoma viruses, BK virus (BKV) and JC virus, commonly remain latent in the renourinary tract after primary infection early in life. Latent BKV can be reactivated in immunosuppressed patients and cause diverse urinary tract disorders such as hemorrhagic cystitis, ureteric stenosis, renal dysfunction, and even multi-organ failure . Among these entities, polyoma virus-associated nephropathy (PVAN) is a well-known complication in the setting of profound immunosuppression related to renal transplantation and hematopoietic stem cell transplantation (HCT) [1–3]. However, it has been rarely described as a complication during the course of conventional chemotherapy. Here, we report a case of PVAN developed in a patient with mature T-cell neoplasm who underwent repetitive salvage chemotherapy for refractory disease.
2 Case report A 55-year-old Japanese male was found to have systemic lymphoadenopathy with thrombocytopenia and abnormal lymphocytes in peripheral blood. Bone marrow examination revealed proliferation of malignant lymphocytes that were strongly positive for CD2, CD3, CD5, CD52, and T-cell receptor-ab, and weekly positive for CD4 and HLA-DR, but negative for TdT, CD4, CD7, CD8, and CD10 by flowcytometric analysis. He was seronegative for human T-cell leukemia virus-I and diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) presenting with a leukemia picture. Although he was thereafter treated with three cycles of alternating hyperCVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with high-dose methotrexate
PTCL complicated with BK virus nephropathy
Fig. 1 Clinical course after CPT11 administration. CPT11 irinotecan, DEX dexamethasone, PSL prednisolone, CBDCA carboplatin, GEM gemcitabine, WBC white blood cell, LDH lactate dehydrogenase, CRE serum creatinine
and cytarabine , durable response was not obtained. He was then treated with each single cycle of EPOCH (etoposide, vincristine, doxorubicin, prednisolone, and cyclophosphamide) , DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) , and GDP (gemcitabine, dexamethasone, and cisplatin) as salvage chemotherapy ; however, abnormal lymphocytes never disappeared from his peripheral blood, and progressive disease was noted. He had no prior history of kidney dysfunction, and serum creatinine level was stable in the range 44.2–66.9 lmol/l (0.5–0.7 mg/dl) during these cycles of chemotherapy. Computed tomography at the time of initial presentation showed no abnormal lesions that might disturb the urine outflow. After 8 months from the diagnosis, he developed dyspnea and fever. His leukocyte count elevated to 11.4 9 109/l with 71% abnormal lymphocytes, and AST, ALT, and LDH elevated to 37, 59, and 717 IU/l, respectively. Computed tomography demonstrated bilateral ground-glass opacities and multiple small nodules in the lungs, pleural effusion, interlobular septal thickening, peribrochovascular interstitial thickening, mediastinal lymphadenopathy, and hepatosplenomegaly, which were diagnosed as the manifestations of systemic involvement of PTCL-NOS. A combination of CPT11 (30 mg/m2/day on days 1–3) and dexamethasone (10 mg/day on days 4–6) were administered as palliative chemotherapy. Thereafter, his respiratory symptoms subsided, and the repeated computed tomography revealed the improvement of the pulmonary infiltrates. On the 10th day after the start of chemotherapy, he developed urinary frequency and recurrent fever that did not ameliorate with the administration of broad-spectrum antimicrobial agents. Five days later, he
became anuric, and his serum creatinine level suddenly increased to 291.7 lmol/l (3.3 mg/dl) (Fig. 1). Obstructive nephropathy and acute tubular necrosis secondary to sepsis were excluded by ultrasonography and negative blood cultures. Possibility of acute uric acid nephropathy was also unlikely because his serum uric acid level was within normal range (4.6 mg/dl). Computed tomography showed neither renal enlargement nor intra-abdominal mass but ascites. He had no recurrence of pulmonary lesions and no increase in abnormal lymphocytes in peripheral blood with low leukocyte counts that had fallen to 0.5 9 109/l, Urinalysis at the onset of oligulia revealed mild proteinuria, an occasional white blood cell and red blood cell per high power field, and an occasional cast per low power field. Cytologic examination of the urine specimen revealed the presence of decoy cells, degenerate epithelial cells that all contained an enlarged nucleus with a single basophilic intranuclear inclusion, which were suggestive of BKV replication in the renourinary tract. With immunohistochemical staining, polyomavirus simian virus 40 (SV40) antigen was detected in the nuclear inclusions (Fig. 2). Analysis with real-time polymerase chain reaction (PCR) revealed high levels of BKV DNA in his urine ([5.0 9 107 copies/ml) and plasma (6.1 9 102 copies/ml), indicating systemic reactivation of BKV. A diagnosis of PVAN was strongly suspected although kidney biopsy was withheld because he had transfusion-refractory thrombocytopenia. Due to rapidly progressive anuria, hemodialysis was instituted 17 days after the start of the chemotherapy with a peak serum creatinine level of 636.5 lmol/l (7.2 mg/dl). Since then, he was unable to discontinue routine hemodialysis until the time he died of disease progression 3 months after the development of acute renal
K. Aoki et al.
Fig. 2 Cytologic examination of urine specimen. a The arrows indicate degenerate epithelial cells (‘‘decoy cells’’) that contained an enlarged nucleus with a single basophilic intranuclear inclusion. b Immunohistochemical staining of polyomavirus simian virus 40 (SV40) antigen. The cells positive for SV40 antigens are indicated by arrows
failure. Autopsy was not performed because his family did not give consent.
3 Discussion Primary BKV infection usually occurs during childhood at a median age of 4–5 years and is asymptomatic or associated with fever and mild upper respiratory symptoms [1, 8]. After primary infection, BKV enters a latent state and resides in renourinary tract as the principal site . Latent BKV can be reactivated and can lead to the emergence of kidney and urinary tract diseases in patients who are therapeutically immunosuppressed in the setting of organ transplantation or HCT. The prevalence of PVAN after kidney transplantation has been reported to be 1–7%, and persistence of PVAN was associated with irreversible kidney allograft failure in 10–100% . BKV viruria occurs in about 50% of HCT recipients and is associated with hemorrhagic cystitis and PVAN [1–3]. On the other hand, BKV-associated nephropathy as a complication after conventional chemotherapy is very rare, and only a few cases have been reported. Inaba et al.  reported biopsy-proven PVAN due to BKV in a 5-year-old girl treated for newly diagnosed acute lymphoblastic leukemia. During maintenance therapy for her leukemia, she developed fever and renal dysfunction associated with high levels of BKV DNA detected in her urine and plasma. Van der Bij et al.  also reported biopsy-proven PVAN due to BKV in a 57-year-old male with chronic lymphocytic leukemia who developed renal failure after receiving chemotherapy consisted of fludarabine and cyclophosphamide. Therefore, although it is very rare, PVAN can occur not only in HCT recipients but also in immunocompromised patients who had a history of repetitive cycles of chemotherapy. The definitive diagnosis of PVAN requires kidney biopsy, which typically reveals cellular necrosis of the tubules and collecting ducts, interstitial inflammation, and extensive BKV replication ; however, the sensitivity of
biopsy for PVAN is unlikely to be 100% because of sampling variability. Although the exclusion of other possible diagnosis such as renal infiltration of lymphoma and druginduced kidney injury was difficult because the preexisting thrombocytopenia precluded a kidney biopsy, the presence of BKV viremia and high levels of BKV viruria strongly suggested that rapidly deteriorating renal failure in this case was associated with BKV reactivation. Furthermore, typical urinary cytologic findings including positive immunostaining for SV40 further supports the development of PVAN. Although pulmonary symptoms and abnormal lymphocytes gradually improved after the administration of a salvage chemotherapy consisting of CPT11 and dexamethasone, his renal function continued to deteriorate, implying a low likelihood of development of infiltrative renal failure by a lymphoma. Viscount et al.  reported the utility of noninvasive tests for identifying renal transplant recipients with concurrent PVAN using biopsy-proven PVAN as a reference standard for definitive diagnosis. According to their report, the presence of decoy cells in the urine had 25% sensitivity and 84% specificity, while high levels of BKV viruria or BKV viremia were strongly associated with concurrent PVAN with more than 30% positive predictive value. There has been no consensus view with regard to appropriate antiviral therapy for BKV-associated nephropathy although the mainstay in the post-transplant setting is a prompt immunosuppressive dose reduction . Cidofovir, an antiviral agent approved for the treatment of cytomegalovirus, and leflunomide, an immunosuppressive agent commonly used in rheumatoid arthritis, may confer benefit in patients who did not respond to a reduction in immunosuppression alone, but the former often causes nephrotoxicity [14, 15]. Fluoroquinolone antibiotics have been suggested to be useful as prophylactic agents because it has in vitro antipolyomavirus activity . However, the efficacy of these drugs have not been tested in a randomized trial, and new antiviral drugs with more potent activity against BK virus with less toxicity are clearly needed.
PTCL complicated with BK virus nephropathy
In conclusion, the clinical course of this case suggests that acute renal failure associated with BKV reactivation can occur as a serious complication not only in HCT recipients but also in immunocompromised patients who have undergone repetitive cycles of chemotherapy. Since up to 90% of adults are seropositive for anti-BKV antibodies, patients with hematologic neoplasms who develop unexplained renal dysfunction during immunoablative chemotherapy should be screened for BKV reactivation using cytologic tests and quantitative PCR-based assays of urine and blood samples.
References 1. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3:611–23. 2. Shapiro S, Robin M, Esperou H, Devergie A, Rocha V, Garnier F, et al. Polyomavirus nephropathy in the native kidneys of an unrelated cord blood transplant recipient followed by a disseminated polyomavirus infection. Transplantation. 2006;82:292–3. 3. Lekakis LJ, Macrinici V, Baraboutis IG, Mitchell B, Howard DS. BK virus nephropathy after allogeneic stem cell transplantation: a case report and literature review. Am J Hematol. 2009;84:243–6. 4. Thomas DA, O’Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004;104:1624–30. 5. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol. 1993;11:1573–82. 6. Okamoto M, Maruyama F, Tsuzuki M, Nomura T, Miyazaki H, Wakita M, et al. Salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin’s lymphoma with a combination of dexamethasone, etoposide, ifosfamide and carboplatin. Rinsho Ketsuki. 1994;35:635–41 (in Japanese).
641 7. Baetz T, Belch A, Couban S, Imrie K, Yau J, Myers R, et al. Gemcitabine, dexamethasone and cisplatin is an active and nontoxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2003;14:1762–7. 8. Goudsmit J, Wertheim-van Dillen P, van Strien A, van der Noordaa J. The role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils. J Med Virol. 1982;10:91–9. 9. Inaba H, Jones DP, Gaber LW, Shenep JL, Call SK, Pui CH, et al. BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia. J Pediatr. 2007;151:215–7. 10. van der Bij A, Betjes M, Weening J, Cornelissen J, Mes T, Osterhaus A, et al. BK virus nephropathy in an immunodeficient patient with chronic lymphocytic leukemia. J Clin Virol. 2009;45:341–4. 11. Fishman JA. BK virus nephropathy—polyomavirus adding insult to injury. N Engl J Med. 2002;347:527–30. 12. Viscount HB, Eid AJ, Espy MJ, Griffin MD, Thomsen KM, Harmsen WS, et al. Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus-associated nephropathy. Transplantation. 2007;84:340–5. 13. Saad ER, Bresnahan BA, Cohen EP, Lu N, Orentas RJ, Vasudev B, et al. Successful treatment of BK viremia using reduction in immunosuppression without antiviral therapy. Transplantation. 2008;85:850–4. 14. Vats A, Shapiro R, Singh Randhawa P, Scantlebury V, Tuzuner A, Saxena M, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults. Transplantation. 2003;75:105–12. 15. Josephson MA, Gillen D, Javaid B, Kadambi P, Meehan S, Foster P, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81:704–10. 16. Leung AY, Chan MT, Yuen KY, Cheng VC, Chan KH, Wong CL, et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40:528–37.