Pediatr Transplantation 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12411
BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation Aksenova M, Tsetlina V, Gutovskaya E, Mitrofanova A, Balashov D, Maschan A. (2014) BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation. Pediatr Transplant, 00: 1–4. DOI: 10.1111/petr.12411. Abstract: We report the case of a seven-yr-old Caucasian girl who presented with progressive deterioration of renal function 13 months after HSCT for myelodysplastic syndrome. BK virus nephropathy was suspected and confirmed. After reduction of immunosuppression and treatment with IVIG, leflunomide, ciprofloxacin, and cidofovir, clearance of BK virus from blood was achieved, and further progression or renal failure was prevented. We believe that BK virus nephropathy should be considered in cases of renal function deterioration in all immunocompromised patients.
M. Aksenova1,2,*, V. Tsetlina3,*, E. Gutovskaya3, A. Mitrofanova4, D. Balashov3 and A. Maschan5 1
Nephrology Department, Research and Clinical Institute for Pediatrics, the Pirogov Russian National Research Medical University, Moscow, Russia, 2 Department of Clinical Diagnostics, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 3 Department of Hematopoietic Stem Cell Transplantation, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 4Department of Pathology, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 5Deputy Director for Science, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia Key words: BK virus nephropathy – BK polyomavirus – hematopoietic stem cell transplantation – renal insufficiency Marina Aksenova, Nephrology Department, Research and Clinical Institute for Pediatrics, Taldomskaya str.2, Moscow 125412, Russia Tel.: +7 495 4833653 Fax: +7 495 4833335 E-mail: [email protected] and Vera Tzetlina, Department of Hematopoietic Stem Cell Transplantation, The Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Samora Mashela str. 1, Moscow 117198, Russia Tel/fax: +7 495 6647085; E-mail: [email protected] *Co-lead authors with equal contributions. Accepted for publication 17 November 2014
Background
BKVN causes progressive kidney transplant injury in an estimated 1–10% of renal transplant Abbreviations: BKVN, BK virus nephropathy; CKD, chronic kidney disease; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; IVIG, intravenous immunoglobulin.
recipients (1–5), but is rarely diagnosed in cases of non-renal transplantation (6–10). In HSCT recipients, BK virus replication is commonly associated with hemorrhagic cystitis; its incidence in this population ranges from 5.7% to 7.7% (9, 11). BKVN after HSCT is a rare condition (8, 10, 11). Failure to recognize BK virus infection results in delay of diagnosis and treatment, and a poor prognosis. 1
Aksenova et al. Case report
The patient suffered from myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) first diagnosed at three yr of age. Allogenic HSCT from an HLA-10/10-matched unrelated donor was performed on the patient at six yr of age (June 28, 2012). The conditioning regimen consisted of equine antithymocyte globulin 50 mg/kg, treosulfan 42 g/m2, fludarabine 150 mg/m2, and melphalan 140 mg/m2. Graft manipulation included TCRab and CD19 depletion (transplant characteristics: nuclear cells – 6.3 9 108/kg, CD34+ cells – 8 9 106/kg, CD3+ cells – 19.9 9 106/kg, CD19+ cells – 4 9 104/kg, and TCRab cells – 2.9 9 105/kg). The patient received standard support therapy; prophylaxis against common post-transplant infections included fluconazole, azithromycin, acyclovir, and trimethoprim-sulfamethoxazole. GVHD prophylaxis consisted of tacrolimus (target blood concentration 7–12 ng/mL) and methotrexate 15 mg/m2 (at days 1, 3, 6, and 11 after HSCT). Engraftment was delayed (until day 26 after HSCT). Transplant function was good, and the patient had complete donor chimerism during the entire period of observation. At day 40 after HSCT, acute skin stage 3 GVHD (acute grade II GVHD) developed, which gradually turned into steroid-dependent chronic skin GVHD. Partial remission was achieved on prednisone 1 mg/kg/ day, tacrolimus, and mycophenolate mofetil 25 mg/kg/day. Extracorporeal photopheresis was started five months after HSCT with the intention of tapering the steroid dose and stopped nine months after HSCT because of ineffectiveness and poor toleration. Nonetheless, it proved possible to taper prednisone slowly, despite this problem. Ten months after HSCT, tacrolimus was substituted for methotrexate 10 mg/m2/wk and cyclophosphamide 200 mg/ m2/wk because of acute nephrotoxicity (reversible rise of serum creatinine to 0.9 mg/dL). The prolonged immunosuppression therapy caused delayed immune reconstitution: lymphocyte counts 12 months after HSCT remained severely suppressed (200–400 cells/lL), and CD3/4+ and CD19+ were absent. Because of a low serum IgG level (1.5–3.6 g/L), the patient received IVIG 400 mg/kg monthly. Serum creatinine level rose steadily between July 2013 (13 months after HSCT) and September 2013 (from 0.65 to 1.36 mg/dL). Urinary sediment was normal, there was no proteinuria, and ultrasound showed normal size and parenchymal echogenicity of both kidneys. Urine cell culture, and blood and urine CMV DNA tests were nega2
tive. Blood erythrocyte, platelet, and bilirubin levels, lactate dehydrogenase activity, and schistocyte count in a blood smear remained stable. Drug toxicity was suspected. Cyclophosphamide and methotrexate were stopped and dosages of all nephrotoxic drugs were reduced. But the serum creatinine level remained high. In November 2013, PCR for BK virus was performed for the first time. It revealed 6.7 9 106 copies/mL in urine and 2 9 106 copies/mL in the patient’s blood. BK nephropathy was suspected. Therapy was started with leflunomide 10 mg/day, ciprofloxacin 20 mg/kg/day, and repeated doses of IVIG 1000 mg/kg/wk. The patient underwent a diagnostic renal biopsy, which demonstrated classic findings of BKVN: severe tubulointerstitial injury, mild lymphocytic infiltration, and many tubular intranuclear inclusions, typical of BK polyomavirus (Fig. 1a), with immunostaining positive for SV40 T-antigen (Fig. 1b). Thus, BKVN was diagnosed. At that time, the patient’s immunosuppression was low and included prednisone 5 mg every other day (0.25 mg/kg/48 h). After three wk of treatment with leflunomide, ciprofloxacin, and repeated doses of IVIG, no change in BK viremia and no improvement of kidney function were observed. Cidofovir 0.5 mg/kg/wk was added. Despite the low dose of cidofovir, we observed an increase of the creatinine level to 1.58 mg/dL after the first infusion. Therefore, we decided to administer it every other week. After six wk of treatment (three cidofovir infusions), no BK virus was detected in blood, and the urine BK virus level declined to 0.012 9 106 copies/mL. By the completion of cidofovir therapy, the creatinine level had dropped to the pretherapy level. No other side effects were seen. Currently (seven months after BKVN diagnosis), the patient is stable. Unfortunately, she still has severe renal insufficiency (creatinine level 1.1–1.35 mg/dL, cystatin C—3–3.3 mg/L). BK viremia is absent, and BK viruria remains low. She continues to receive prednisone (0.5 mg/kg/day) because of mild chronic skin GVHD. Discussion
CKD after HSCT is not rare; its incidence is 18–66% (12). The exact etiology of most CKD in HSCT patients has not been identified, and drug nephrotoxicity is suspected in most cases. In view of the serum creatinine rise in our patient, in the absence of any other clinical or laboratory changes, toxic origin of her renal dysfunction was suspected. Cessation of cyclophosphamide
BK virus nephropathy in a child after HSCT (a)
(b)
Fig. 1. Renal biopsy of patient with BK virus nephropathy. (a) Mild inflammatory infiltrates in the interstitium, interstitial fibrosis, and tubular atrophy; many tubular epithelial cells have large, homogeneous, intranuclear inclusions (arrow) with a ground glass appearance, representing aggregations of viral particles in the nucleus (hematoxylin and eosin staining; magnification 9100). (b) A positive (arrow) immunohistological reaction with BK virus-specific determinants (immunoperoxidase staining against SV40 T-antigen, which cross-reacts with BK virus T-antigen; paraffin/ microwave techniques; magnification 9400).
and methotrexate and reduction of nephrotoxic drug doses had no effect on the serum creatinine level. BKVN is recognized as an important cause of allograft dysfunction and graft loss in renal transplant recipients. Despite the similar incidence of BK viruria/viremia, BKVN is much less common in the native kidneys of non-renal transplant recipients. The prevalence of BK viruria, BK viremia, and BK nephritis after renal transplantation is 30–40%, 10–40%, and 5–8%, respectively (1, 3, 11, 13). The rate of post-HSCT BK viruria is 50–100%, while BK viremia and BKVN have been observed in 15–23% and 1–2% of cases, respectively (2, 9, 11). These data support the role of organ determinants (prior kidney ischemia, kidney inflammation, donor–
recipient human leukocyte antigen mismatch) in the pathogenesis of BKVN after renal transplantation (2, 3, 13). In HSCT recipients, BK virus replication is commonly associated with hemorrhagic cystitis/hematuria. There are reports in the literature of several cases of acute kidney injury secondary to urinary tract obstruction by clots in the setting of BK virus-associated hemorrhagic cystitis, as well as a few cases of BKVN, in HSCT patients (8–10, 14). Despite decreasing renal function in the absence of other clinical signs, which is typical of polyomavirus-associated nephropathy, the diagnosis of BKVN in our patient was made late. Most cases of BKVN are preceded by an asymptomatic phase of persistent and significant viruria (>105 copies/mL followed by viremia within a few weeks) (2). Significant and sustained viremia (>5000 copies/mL plasma for three consecutive weeks) identifies patients with uncontrolled viral replication, potentially leading to renal parenchymal injury. Usually, appearance of viruria and viremia precedes the increase in serum creatinine by weeks or months (13). Therefore, screening for viral replication allows identification of patients at risk of developing BKVN. Renal transplant recipients are routinely screened for polyomavirus replication, but post-HSCT patients are not, although earlier detection of BKVN, prior to renal damage, and appropriate reduction of immunosuppressive therapy reduce the rate of progression to irreversible allograft failure in renal transplant recipients from >60% to 10–13% (13). Serologic testing of recipient and donor for BK virus is not done routinely. In contrast to renal transplant recipients, the role of initial BK virus antibody status of HSCT donors and recipients in the generation of BK viremia is not yet defined. In view of our patient’s age, it is likely that she had primary BK virus infection. Immunodeficiency due to a high level of immunosuppression led to uncontrolled BK virus replication (2 9 106 copies/mL in blood on initial BK-DNA PCR) and BKVN in our patient. Definitive diagnosis of BKVN requires renal biopsy. The typical lesion presents as patchy interstitial nephritis with characteristic intranuclear viral inclusions having a watery or finely granular appearance. Renal involvement may be focal in the earlier stages and may have predominant fibrotic with minimal inflammatory changes in the later stages of disease. Immunohistochemical staining for SV40 (large T-antigen) can be helpful in confirming the diagnosis. Electron microscopy reveals intranuclear viral particles approximately 40 nm in size (2, 13–15). This type 3
Aksenova et al.
of renal pathology, with the characteristic viral inclusions, was found in our patient by routine staining and confirmed by immunohistochemistry. Currently, there are no uniform guidelines for BKVN diagnostics and therapy following HSCT. A wide range of antivirals (cidofovir, leflunomide) and other agents (IVIG and fluoroquinolone antibiotics) have been proposed for the treatment of BKVN. But none has been shown to be effective in randomized controlled trials. Preemptive reduction of immunosuppression in renal transplant recipients with BK viremia seems to be the best approach to BKVN prevention and treatment (2, 3, 13, 16). Cessation of immunosuppression alone did not improve our patient’s renal function. To save the patient’s kidney function, we decided to use antiviral agents (leflunomide, ciprofloxacin, cidofovir) that were potentially toxic, but likely to be effective. As a result, we achieved BK clearance of blood and urine and stabilization of renal function. Unfortunately, kidney function did not improve. BKVN is characterized by high risk of progression to end-stage renal disease because tubulointerstitial damages persist after BK virus clearance (15). BK viremia level of 10 000 copies/mL is associated with poor renal outcome. In view of her prior high level of BK viremia and diffuse tubulointerstitial morphological renal change, the patient has an unfavorable renal prognosis. Renal transplantation has been successfully performed on patients with renal graft failure due to BKVN. The risk of BKVN recurrence is low, but should not be ignored (13). In conclusion, BKVN can occur in the native kidneys of pediatric non-renal transplant patients. Clinicians should be trained to suspect and consider BK nephropathy in the differential diagnosis of pediatric transplant patients with an elevated serum creatinine level and perhaps all immunosuppressed children. These patients may benefit from early detection of BK virus infection and careful modification of their immunosuppressive regimens for prevention of BKVN. Uniform guidelines for BKVN diagnostics and therapy following HSCT should be established on the basis of future controlled clinical trials. Acknowledgments We thank Dr. Marian Malone (Histopathologist, Great Ormond Street Hospital, London, UK) and Ashley Kilner
4
(Specialist Biomedical Scientist, Great Ormond Street Hospital, London, UK) for their technical assistance.
Conflict of interest
None declared. References 1. HIRSCH H, DRACHENBERG C, STEIGER G. Poliomaviruses and human diseases. In: Ahsan N, ed. Landes Bioscience, Georgetown; 2006: pp. 117–147. 2. COSTA C, CAVALLO R. Polyoma-associated nephropathy. World J Transplant 2012: 24: 84–94. € 3. JACOBI J, PRIGNITZ A, BUTTNER M, et al. BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition. BMC Nephrol 2013: 14: 207–220. € 4. HELANTERA€ I, SALMELA K, KYLLONEN L, et al. BK virus viremia in a well-HLA-matched kidney transplant population mainly on low-dose cyclosporine-based immunosuppression. Clin Transplant 2012: 26: E596–E601. 5. COMOLI P, CIONI M, BASSO S, et al. Immunity to polyomavirus BK infection: Immune monitoring to regulate the balance between risk of BKV nephropathy and induction of alloimmunity. Clin Dev Immunol 2013: 14: 1–6. € 6. MULLER A, BECK B, THEILEMANN K, et al. Detection of polyomavirus BK and JC in children with kidney diseases and renal transplant recipients. Pediatr Infect Dis J 2005: 24: 778–781. 7. SAHNEY S, YORGIN P, ZUPPAN C, CUTLER D, KAMBHAM N, CHINNOCK R. BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient. Pediatr Transplant 2010: 14: E11–E15. 8. VERGHESE P, FINN L, ENGLUND J, SANDERS J, HINGORANI S. BK nephropathy in pediatric hematopoietic stem cell transplant recipients. Pediatr Transplant 2009: 13: 913–918. 9. O’DONNELL P, SWANSON K, JOSEPHSON M, et al. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoetic stem cell transplants. Biol Blood Marrow Transplant 2009: 15: 1038–1048. € 10. STRACKE S, HELMCHEN U, von MULLER L, BUNJES D, KELLER F. Polyoma virus-associated interstitial nephritis in a patient with acute myeloic leukaemia and peripheral blood stem cell transplantation. Nephrol Dial Transplant 2003: 18: 2431–2433. 11. HAINES H, LASKIN B, GOEBEL J, et al. Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011: 17: 1512–1519. 12. SAWINSKI D. The kidney effects of hematopoietic stem cell transplantation. Adv Chronic Kidney Dis 2014: 21: 96–105. 13. DALL A, HARIHARAN S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008: 3(Suppl 2): S68–S75. 14. HARIHARAN S. BK virus nephritis after renal transplantation. Kidney Int 2006: 69: 655–662. 15. MENTER T, MAYR M, SCHAUB S, MIHATSCH MJ, HIRSCH H, HOPFER H. Pathology of resolving polyomavirus-associated nephropathy. Am J Transplant 2013: 13: 1474–1483. 16. IWAMOTO S, AZUMA E, HORI H, et al. BK virus-associated fatal renal failure following late-onset hemorrhagic cystitis in an unrelated bone marrow transplantation. Pediatr Hematol Oncol 2002: 19: 255–261.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12411
BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation Aksenova M, Tsetlina V, Gutovskaya E, Mitrofanova A, Balashov D, Maschan A. (2014) BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation. Pediatr Transplant, 00: 1–4. DOI: 10.1111/petr.12411. Abstract: We report the case of a seven-yr-old Caucasian girl who presented with progressive deterioration of renal function 13 months after HSCT for myelodysplastic syndrome. BK virus nephropathy was suspected and confirmed. After reduction of immunosuppression and treatment with IVIG, leflunomide, ciprofloxacin, and cidofovir, clearance of BK virus from blood was achieved, and further progression or renal failure was prevented. We believe that BK virus nephropathy should be considered in cases of renal function deterioration in all immunocompromised patients.
M. Aksenova1,2,*, V. Tsetlina3,*, E. Gutovskaya3, A. Mitrofanova4, D. Balashov3 and A. Maschan5 1
Nephrology Department, Research and Clinical Institute for Pediatrics, the Pirogov Russian National Research Medical University, Moscow, Russia, 2 Department of Clinical Diagnostics, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 3 Department of Hematopoietic Stem Cell Transplantation, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 4Department of Pathology, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 5Deputy Director for Science, the Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia Key words: BK virus nephropathy – BK polyomavirus – hematopoietic stem cell transplantation – renal insufficiency Marina Aksenova, Nephrology Department, Research and Clinical Institute for Pediatrics, Taldomskaya str.2, Moscow 125412, Russia Tel.: +7 495 4833653 Fax: +7 495 4833335 E-mail: [email protected] and Vera Tzetlina, Department of Hematopoietic Stem Cell Transplantation, The Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Samora Mashela str. 1, Moscow 117198, Russia Tel/fax: +7 495 6647085; E-mail: [email protected] *Co-lead authors with equal contributions. Accepted for publication 17 November 2014
Background
BKVN causes progressive kidney transplant injury in an estimated 1–10% of renal transplant Abbreviations: BKVN, BK virus nephropathy; CKD, chronic kidney disease; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; IVIG, intravenous immunoglobulin.
recipients (1–5), but is rarely diagnosed in cases of non-renal transplantation (6–10). In HSCT recipients, BK virus replication is commonly associated with hemorrhagic cystitis; its incidence in this population ranges from 5.7% to 7.7% (9, 11). BKVN after HSCT is a rare condition (8, 10, 11). Failure to recognize BK virus infection results in delay of diagnosis and treatment, and a poor prognosis. 1
Aksenova et al. Case report
The patient suffered from myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) first diagnosed at three yr of age. Allogenic HSCT from an HLA-10/10-matched unrelated donor was performed on the patient at six yr of age (June 28, 2012). The conditioning regimen consisted of equine antithymocyte globulin 50 mg/kg, treosulfan 42 g/m2, fludarabine 150 mg/m2, and melphalan 140 mg/m2. Graft manipulation included TCRab and CD19 depletion (transplant characteristics: nuclear cells – 6.3 9 108/kg, CD34+ cells – 8 9 106/kg, CD3+ cells – 19.9 9 106/kg, CD19+ cells – 4 9 104/kg, and TCRab cells – 2.9 9 105/kg). The patient received standard support therapy; prophylaxis against common post-transplant infections included fluconazole, azithromycin, acyclovir, and trimethoprim-sulfamethoxazole. GVHD prophylaxis consisted of tacrolimus (target blood concentration 7–12 ng/mL) and methotrexate 15 mg/m2 (at days 1, 3, 6, and 11 after HSCT). Engraftment was delayed (until day 26 after HSCT). Transplant function was good, and the patient had complete donor chimerism during the entire period of observation. At day 40 after HSCT, acute skin stage 3 GVHD (acute grade II GVHD) developed, which gradually turned into steroid-dependent chronic skin GVHD. Partial remission was achieved on prednisone 1 mg/kg/ day, tacrolimus, and mycophenolate mofetil 25 mg/kg/day. Extracorporeal photopheresis was started five months after HSCT with the intention of tapering the steroid dose and stopped nine months after HSCT because of ineffectiveness and poor toleration. Nonetheless, it proved possible to taper prednisone slowly, despite this problem. Ten months after HSCT, tacrolimus was substituted for methotrexate 10 mg/m2/wk and cyclophosphamide 200 mg/ m2/wk because of acute nephrotoxicity (reversible rise of serum creatinine to 0.9 mg/dL). The prolonged immunosuppression therapy caused delayed immune reconstitution: lymphocyte counts 12 months after HSCT remained severely suppressed (200–400 cells/lL), and CD3/4+ and CD19+ were absent. Because of a low serum IgG level (1.5–3.6 g/L), the patient received IVIG 400 mg/kg monthly. Serum creatinine level rose steadily between July 2013 (13 months after HSCT) and September 2013 (from 0.65 to 1.36 mg/dL). Urinary sediment was normal, there was no proteinuria, and ultrasound showed normal size and parenchymal echogenicity of both kidneys. Urine cell culture, and blood and urine CMV DNA tests were nega2
tive. Blood erythrocyte, platelet, and bilirubin levels, lactate dehydrogenase activity, and schistocyte count in a blood smear remained stable. Drug toxicity was suspected. Cyclophosphamide and methotrexate were stopped and dosages of all nephrotoxic drugs were reduced. But the serum creatinine level remained high. In November 2013, PCR for BK virus was performed for the first time. It revealed 6.7 9 106 copies/mL in urine and 2 9 106 copies/mL in the patient’s blood. BK nephropathy was suspected. Therapy was started with leflunomide 10 mg/day, ciprofloxacin 20 mg/kg/day, and repeated doses of IVIG 1000 mg/kg/wk. The patient underwent a diagnostic renal biopsy, which demonstrated classic findings of BKVN: severe tubulointerstitial injury, mild lymphocytic infiltration, and many tubular intranuclear inclusions, typical of BK polyomavirus (Fig. 1a), with immunostaining positive for SV40 T-antigen (Fig. 1b). Thus, BKVN was diagnosed. At that time, the patient’s immunosuppression was low and included prednisone 5 mg every other day (0.25 mg/kg/48 h). After three wk of treatment with leflunomide, ciprofloxacin, and repeated doses of IVIG, no change in BK viremia and no improvement of kidney function were observed. Cidofovir 0.5 mg/kg/wk was added. Despite the low dose of cidofovir, we observed an increase of the creatinine level to 1.58 mg/dL after the first infusion. Therefore, we decided to administer it every other week. After six wk of treatment (three cidofovir infusions), no BK virus was detected in blood, and the urine BK virus level declined to 0.012 9 106 copies/mL. By the completion of cidofovir therapy, the creatinine level had dropped to the pretherapy level. No other side effects were seen. Currently (seven months after BKVN diagnosis), the patient is stable. Unfortunately, she still has severe renal insufficiency (creatinine level 1.1–1.35 mg/dL, cystatin C—3–3.3 mg/L). BK viremia is absent, and BK viruria remains low. She continues to receive prednisone (0.5 mg/kg/day) because of mild chronic skin GVHD. Discussion
CKD after HSCT is not rare; its incidence is 18–66% (12). The exact etiology of most CKD in HSCT patients has not been identified, and drug nephrotoxicity is suspected in most cases. In view of the serum creatinine rise in our patient, in the absence of any other clinical or laboratory changes, toxic origin of her renal dysfunction was suspected. Cessation of cyclophosphamide
BK virus nephropathy in a child after HSCT (a)
(b)
Fig. 1. Renal biopsy of patient with BK virus nephropathy. (a) Mild inflammatory infiltrates in the interstitium, interstitial fibrosis, and tubular atrophy; many tubular epithelial cells have large, homogeneous, intranuclear inclusions (arrow) with a ground glass appearance, representing aggregations of viral particles in the nucleus (hematoxylin and eosin staining; magnification 9100). (b) A positive (arrow) immunohistological reaction with BK virus-specific determinants (immunoperoxidase staining against SV40 T-antigen, which cross-reacts with BK virus T-antigen; paraffin/ microwave techniques; magnification 9400).
and methotrexate and reduction of nephrotoxic drug doses had no effect on the serum creatinine level. BKVN is recognized as an important cause of allograft dysfunction and graft loss in renal transplant recipients. Despite the similar incidence of BK viruria/viremia, BKVN is much less common in the native kidneys of non-renal transplant recipients. The prevalence of BK viruria, BK viremia, and BK nephritis after renal transplantation is 30–40%, 10–40%, and 5–8%, respectively (1, 3, 11, 13). The rate of post-HSCT BK viruria is 50–100%, while BK viremia and BKVN have been observed in 15–23% and 1–2% of cases, respectively (2, 9, 11). These data support the role of organ determinants (prior kidney ischemia, kidney inflammation, donor–
recipient human leukocyte antigen mismatch) in the pathogenesis of BKVN after renal transplantation (2, 3, 13). In HSCT recipients, BK virus replication is commonly associated with hemorrhagic cystitis/hematuria. There are reports in the literature of several cases of acute kidney injury secondary to urinary tract obstruction by clots in the setting of BK virus-associated hemorrhagic cystitis, as well as a few cases of BKVN, in HSCT patients (8–10, 14). Despite decreasing renal function in the absence of other clinical signs, which is typical of polyomavirus-associated nephropathy, the diagnosis of BKVN in our patient was made late. Most cases of BKVN are preceded by an asymptomatic phase of persistent and significant viruria (>105 copies/mL followed by viremia within a few weeks) (2). Significant and sustained viremia (>5000 copies/mL plasma for three consecutive weeks) identifies patients with uncontrolled viral replication, potentially leading to renal parenchymal injury. Usually, appearance of viruria and viremia precedes the increase in serum creatinine by weeks or months (13). Therefore, screening for viral replication allows identification of patients at risk of developing BKVN. Renal transplant recipients are routinely screened for polyomavirus replication, but post-HSCT patients are not, although earlier detection of BKVN, prior to renal damage, and appropriate reduction of immunosuppressive therapy reduce the rate of progression to irreversible allograft failure in renal transplant recipients from >60% to 10–13% (13). Serologic testing of recipient and donor for BK virus is not done routinely. In contrast to renal transplant recipients, the role of initial BK virus antibody status of HSCT donors and recipients in the generation of BK viremia is not yet defined. In view of our patient’s age, it is likely that she had primary BK virus infection. Immunodeficiency due to a high level of immunosuppression led to uncontrolled BK virus replication (2 9 106 copies/mL in blood on initial BK-DNA PCR) and BKVN in our patient. Definitive diagnosis of BKVN requires renal biopsy. The typical lesion presents as patchy interstitial nephritis with characteristic intranuclear viral inclusions having a watery or finely granular appearance. Renal involvement may be focal in the earlier stages and may have predominant fibrotic with minimal inflammatory changes in the later stages of disease. Immunohistochemical staining for SV40 (large T-antigen) can be helpful in confirming the diagnosis. Electron microscopy reveals intranuclear viral particles approximately 40 nm in size (2, 13–15). This type 3
Aksenova et al.
of renal pathology, with the characteristic viral inclusions, was found in our patient by routine staining and confirmed by immunohistochemistry. Currently, there are no uniform guidelines for BKVN diagnostics and therapy following HSCT. A wide range of antivirals (cidofovir, leflunomide) and other agents (IVIG and fluoroquinolone antibiotics) have been proposed for the treatment of BKVN. But none has been shown to be effective in randomized controlled trials. Preemptive reduction of immunosuppression in renal transplant recipients with BK viremia seems to be the best approach to BKVN prevention and treatment (2, 3, 13, 16). Cessation of immunosuppression alone did not improve our patient’s renal function. To save the patient’s kidney function, we decided to use antiviral agents (leflunomide, ciprofloxacin, cidofovir) that were potentially toxic, but likely to be effective. As a result, we achieved BK clearance of blood and urine and stabilization of renal function. Unfortunately, kidney function did not improve. BKVN is characterized by high risk of progression to end-stage renal disease because tubulointerstitial damages persist after BK virus clearance (15). BK viremia level of 10 000 copies/mL is associated with poor renal outcome. In view of her prior high level of BK viremia and diffuse tubulointerstitial morphological renal change, the patient has an unfavorable renal prognosis. Renal transplantation has been successfully performed on patients with renal graft failure due to BKVN. The risk of BKVN recurrence is low, but should not be ignored (13). In conclusion, BKVN can occur in the native kidneys of pediatric non-renal transplant patients. Clinicians should be trained to suspect and consider BK nephropathy in the differential diagnosis of pediatric transplant patients with an elevated serum creatinine level and perhaps all immunosuppressed children. These patients may benefit from early detection of BK virus infection and careful modification of their immunosuppressive regimens for prevention of BKVN. Uniform guidelines for BKVN diagnostics and therapy following HSCT should be established on the basis of future controlled clinical trials. Acknowledgments We thank Dr. Marian Malone (Histopathologist, Great Ormond Street Hospital, London, UK) and Ashley Kilner
4
(Specialist Biomedical Scientist, Great Ormond Street Hospital, London, UK) for their technical assistance.
Conflict of interest
None declared. References 1. HIRSCH H, DRACHENBERG C, STEIGER G. Poliomaviruses and human diseases. In: Ahsan N, ed. Landes Bioscience, Georgetown; 2006: pp. 117–147. 2. COSTA C, CAVALLO R. Polyoma-associated nephropathy. World J Transplant 2012: 24: 84–94. € 3. JACOBI J, PRIGNITZ A, BUTTNER M, et al. BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition. BMC Nephrol 2013: 14: 207–220. € 4. HELANTERA€ I, SALMELA K, KYLLONEN L, et al. BK virus viremia in a well-HLA-matched kidney transplant population mainly on low-dose cyclosporine-based immunosuppression. Clin Transplant 2012: 26: E596–E601. 5. COMOLI P, CIONI M, BASSO S, et al. Immunity to polyomavirus BK infection: Immune monitoring to regulate the balance between risk of BKV nephropathy and induction of alloimmunity. Clin Dev Immunol 2013: 14: 1–6. € 6. MULLER A, BECK B, THEILEMANN K, et al. Detection of polyomavirus BK and JC in children with kidney diseases and renal transplant recipients. Pediatr Infect Dis J 2005: 24: 778–781. 7. SAHNEY S, YORGIN P, ZUPPAN C, CUTLER D, KAMBHAM N, CHINNOCK R. BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient. Pediatr Transplant 2010: 14: E11–E15. 8. VERGHESE P, FINN L, ENGLUND J, SANDERS J, HINGORANI S. BK nephropathy in pediatric hematopoietic stem cell transplant recipients. Pediatr Transplant 2009: 13: 913–918. 9. O’DONNELL P, SWANSON K, JOSEPHSON M, et al. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoetic stem cell transplants. Biol Blood Marrow Transplant 2009: 15: 1038–1048. € 10. STRACKE S, HELMCHEN U, von MULLER L, BUNJES D, KELLER F. Polyoma virus-associated interstitial nephritis in a patient with acute myeloic leukaemia and peripheral blood stem cell transplantation. Nephrol Dial Transplant 2003: 18: 2431–2433. 11. HAINES H, LASKIN B, GOEBEL J, et al. Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011: 17: 1512–1519. 12. SAWINSKI D. The kidney effects of hematopoietic stem cell transplantation. Adv Chronic Kidney Dis 2014: 21: 96–105. 13. DALL A, HARIHARAN S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008: 3(Suppl 2): S68–S75. 14. HARIHARAN S. BK virus nephritis after renal transplantation. Kidney Int 2006: 69: 655–662. 15. MENTER T, MAYR M, SCHAUB S, MIHATSCH MJ, HIRSCH H, HOPFER H. Pathology of resolving polyomavirus-associated nephropathy. Am J Transplant 2013: 13: 1474–1483. 16. IWAMOTO S, AZUMA E, HORI H, et al. BK virus-associated fatal renal failure following late-onset hemorrhagic cystitis in an unrelated bone marrow transplantation. Pediatr Hematol Oncol 2002: 19: 255–261.
