Correspondence

Leflunomide for Polyomavirus Type BK Nephropathy

N Engl J Med 2005; 352:1157-1158March 17, 2005

Article

To the Editor:

Polyomavirus type BK nephropathy is an aggressively destructive disease occurring in up to 8 percent of patients with renal allografts,1,2 with rates of graft loss within one year of 30 to 65 percent.3,4 There is no therapy with proven efficacy. Leflunomide (Arava), approved for the treatment of rheumatoid arthritis, is an immunosuppressive drug, yet its active metabolite, A77 1726, has substantial antiviral activity in vitro and in animals.5

From July 2001 to April 2004, we used leflunomide as the initial antiviral therapy in 17 patients with biopsy-proven BK nephropathy. All but one of these patients was receiving tacrolimus, prednisone, and mycophenolate mofetil at the time of diagnosis. The mycophenolate mofetil was stopped, the tacrolimus was continued with target trough levels of 4 to 6 ng per milliliter, and the prednisone generally was continued without dose alteration. Leflunomide treatment consisted of a loading dose of 100 mg per day for five days and maintenance doses of 20 to 60 mg per day, with a target blood level of 50 to 100 μg per milliliter. Treatment was monitored by serial measurements of the viral load in blood and urine (by the polymerase chain reaction), measurements of serum creatinine, hematologic and liver function tests, measurement of A77 1726 in the blood, and repeated allograft biopsy when clinically needed.

All patients with blood levels of A77 1726 that remained above 40 μg per milliliter had either clearance of the virus or progressive reductions in the viral load in blood and urine (P<0.001) (Figure 1Figure 1Polyomavirus BK Load in Blood and Urine in 15 Patients with Blood Levels of A77 1726 That Remained above 40 μg per Milliliter.). Seven patients had complete clearance of the virus from the blood, and five of these patients had clearance from the urine as well. Viremia did not recur in the two patients who did not have complete clearance of the virus from the urine. Two of the 17 patients did not have blood levels of A77 1726 that remained above 40 μg per milliliter while they were receiving 60 mg of leflunomide per day, and both the histologic characteristics of the graft and the viral load failed to improve. In addition to continued treatment with leflunomide, a short course of cidofovir was given to these two patients. The viremia completely resolved in one, and the viral load has continued to fall in the other. Serum creatinine levels improved or stabilized in patients with therapeutic A77 1726 levels and, over time, did not change substantially from baseline. There were no clinically significant, dose-limiting changes in the hematocrit or white-cell counts. One patient had an elevation of serum alkaline phosphatase to five times the baseline value, requiring dose reduction.

Consistent with data demonstrating blockade of BK replication in vitro, blood levels of A77 1726 above 40 μg per milliliter appear to provide consistent control of the polyomavirus BK load in humans. Because of the wide variation among patients in the half-life of A77 1726, the known risk of toxic effects on the liver, and the requirement for doses that exceed recommendations for rheumatoid arthritis, this therapy should be monitored by frequent analysis of blood levels of the active metabolite and liver enzymes.

James W. Williams, M.D.
Basit Javaid, M.D.
Predeep V. Kadambi, M.D.
Daniel Gillen, Ph.D.
Robert Harland, M.D.
J. Richard Thistlewaite, M.D., Ph.D.
Marc Garfinkel, M.D.
University of Chicago, Chicago, IL 60637
jwilliam@surgery.bsd.uchicago.edu

Preston Foster, M.D.
Texas Transplant Institute, San Antonio, TX 78229

Walter Atwood, Ph.D.
Brown University, Providence, RI 02912

J. Michael Millis, M.D.
Shane M. Meehan, M.D.
Michelle A. Josephson, M.D.
University of Chicago, Chicago, IL 60637

5 References

1. 1

   Binet I, Neckeleit V, Hisrch HH, et al. Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation 1999;67:918-922
   CrossRef | Web of Science | Medline

2. 2

   Hirsch JJ, Knowles W, Dickermann M, et al. Prospective studies of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-496
   Full Text | Web of Science | Medline

3. 3

   Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999;67:103-109
   CrossRef | Web of Science | Medline

4. 4

   Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002;13:2145-2151
   CrossRef | Web of Science | Medline

5. 5

   Waldman WJ, Knight DA, Blinder L, et al. Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. Intervirology 1999;42:412-418
   CrossRef | Web of Science | Medline

Citing Articles (73)

Citing Articles

1. 1

   Mihir Raval, Alison Gulbis, Catherine Bollard, Ann Leen, Roy Chemaly, Elizabeth Shpall, Amit Lahoti, Partow Kebriaei. (2011) Evaluation and Management of BK Virus-Associated Nephropathy Following Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation 17:11, 1589-1593
   CrossRef

2. 2

   W James Chon, Michelle A Josephson. (2011) Leflunomide in renal transplantation. Expert Review of Clinical Immunology 7:3, 273-281
   CrossRef

3. 3

   Puneet Sood, Sundaram Hariharan. (2011) BK virus infection after renal transplantation. Dialysis & Transplantation 40:3, 102-107
   CrossRef

4. 4

   Katherine A. Barraclough, Nicole M. Isbel, Christine E. Staatz, David W. Johnson. (2011) BK Virus in Kidney Transplant Recipients: The Influence of Immunosuppression. Journal of Transplantation 2011, 1-9
   CrossRef

5. 5

   Abdelhamid Liacini, Mark E. Seamone, Daniel A. Muruve, Lee Anne Tibbles. (2010) Anti-BK Virus Mechanisms of Sirolimus and Leflunomide Alone and in Combination: Toward a New Therapy for BK Virus Infection. Transplantation 90:12, 1450-1457
   CrossRef

6. 6

   Hana Hakim, Jerry L Shenep. (2010) Managing fungal and viral infections in pediatric leukemia. Expert Review of Hematology 3:5, 603-624
   CrossRef

7. 7

   N. Ganguly, L.A. Clough, L.K. DuBois, J.P. Mcguirk, S. Abhyankar, O.S. Aljitawi, N. O'Neal, C.L. Divine, S. Ganguly. (2010) Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach. Transplant Infectious Disease 12:5, 406-411
   CrossRef

8. 8

   Sven Teschner, Volker Burst. (2010) Leflunomide: a drug with a potential beyond rheumatology. Immunotherapy 2:5, 637-650
   CrossRef

9. 9

   E. I. Anyaegbu, P. S. Almond, T. Milligan, W. R. Allen, S. Gharaybeh, S. I. Al-Akash. (2010) Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients. Pediatric Transplantationno-no
   CrossRef

10. 10

    Ilkka Helanterä, Adrian Egli, Petri Koskinen, Irmeli Lautenschlager, Hans H. Hirsch. (2010) Viral Impact on Long-term Kidney Graft Function. Infectious Disease Clinics of North America 24:2, 339-371
    CrossRef

11. 11

    Olwyn Johnston, Dharmvir Jaswal, John S. Gill, Steve Doucette, Dean A. Fergusson, Greg A. Knoll. (2010) Treatment of Polyomavirus Infection in Kidney Transplant Recipients: A Systematic Review. Transplantation 89:9, 1057-1070
    CrossRef

12. 12

    Carlos E. Araya, Eduardo H. Garin, Richard E. Neiberger, Vikas R. Dharnidharka. (2010) Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients. Pediatric Transplantation 14:1, 145-150
    CrossRef

13. 13

    H. H. Hirsch, P. Randhawa, . (2009) BK Virus in Solid Organ Transplant Recipients. American Journal of Transplantation 9, S136-S146
    CrossRef

14. 14

    Britta Höcker, Burkhard Tönshoff. (2009) Treatment Strategies to Minimize or Prevent Chronic Allograft Dysfunction in Pediatric Renal Transplant Recipients. Pediatric Drugs 11:6, 381-396
    CrossRef

15. 15

    (2009) Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. American Journal of Transplantation 9, S1-S155
    CrossRef

16. 16

    Harsharan K. Singh, B. Donna Thompson, Volker Nickeleit. (2009) Viral Haufen are Urinary Biomarkers of Polyomavirus Nephropathy: New Diagnostic Strategies Utilizing Negative Staining Electron Microscopy. Ultrastructural Pathology 33:5, 222-235
    CrossRef

17. 17

    Christine Materne, Jens Gerth, Undine Ott, Hermann-Josef Gröne, Gunter Wolf. (2009) Wechsel zwischen BK-Virus-Nephropathie und Abstoßung – der frustrane Verlauf einer Lebendnierenspende. Medizinische Klinik 104:8, 644-648
    CrossRef

18. 18

    Nicolae Leca. (2009) Leflunomide use in renal transplantation. Current Opinion in Organ Transplantation 14:4, 370-374
    CrossRef

19. 19

    Yi-Jung Li, Yung-Chang Chen, Ping-Chin Lai, Ji-Tseng Fang, Chih-Wei Yang, Yang-Jen Chiang, Sheng-Hsien Chu, Ming-Ju Wu, Ya-Chung Tian. (2009) A direct association of polyomavirus BK viruria with deterioration of renal allograft function in renal transplant patients. Clinical Transplantation 23:4, 505-510
    CrossRef

20. 20

    Jelle L. Epker, Paula van Biezen, Paul L.A. van Daele, Teun van Gelder, Ann Vossen, Jan L.C.M. van Saase. (2009) Progressive multifocal leukoencephalopathy, a review and an extended report of five patients with different immune compromised states. European Journal of Internal Medicine 20:3, 261-267
    CrossRef

21. 21

    L.P. Kihm, V. Schwenger, M. Zeier, C. Sommerer, C. Morath. (2009) Infektionen nach Nierentransplantation. Der Nephrologe 4:3, 239-249
    CrossRef

22. 22

    Emilio Ramos, Cinthia B. Drachenberg, Ravinder Wali, Hans H. Hirsch. (2009) The Decade of Polyomavirus BK-Associated Nephropathy: State of Affairs. Transplantation 87:5, 621-630
    CrossRef

23. 23

    Mengxi Jiang, Johanna R. Abend, Silas F. Johnson, Michael J. Imperiale. (2009) The role of polyomaviruses in human disease. Virology 384:2, 266-273
    CrossRef

24. 24

    Michael G. Ison, Michele Parker, Valentina Stosor, Dixon B. Kaufman. (2009) Development of BK Nephropathy in Recipients of Simultaneous Pancreas-Kidney Transplantation. Transplantation 87:4, 525-530
    CrossRef

25. 25

    Jodi M. Smith, Stanley C. Jordan. (2009) Intravenous immunoglobulin as treatment for BK virus: Nephropathy. Pediatric Transplantation 13:1, 11-13
    CrossRef

26. 26

    Meryl Waldman, Vickie Marshall, Denise Whitby, Jeffrey B. Kopp. (2008) Viruses and Kidney Disease: Beyond HIV. Seminars in Nephrology 28:6, 595-607
    CrossRef

27. 27

    Steven Chadban, Randall Morris, Hans H. Hirsch, Suphamai Bunnapradist, Wolfgang Arns, Klemens Budde. (2008) Immunosuppression in renal transplantation: some aspects for the modern era. Transplantation Reviews 22:4, 241-251
    CrossRef

28. 28

    Liwen Lim, Ian D. Kay, Silvano Palladino, James Flexman. (2008) Variability in patterns of BK viral load after renal transplantation. Diagnostic Microbiology and Infectious Disease 61:3, 302-308
    CrossRef

29. 29

    Takahito Moriyama, Andrey Sorokin. (2008) Repression of BK Virus Infection of Human Renal Proximal Tubular Epithelial Cells by Pravastatin. Transplantation 85:9, 1311-1317
    CrossRef

30. 30

    Ehab R. Saad, Barbara A. Bresnahan, Eric P. Cohen, Na Lu, Rimas J. Orentas, Brahm Vasudev, Sundaram Hariharan. (2008) Successful Treatment of BK Viremia Using Reduction in Immunosuppression Without Antiviral Therapy. Transplantation 85:6, 850-854
    CrossRef

31. 31

    Dechu P. Puliyanda, Mieko Toyoda, Avram Z. Traum, Francisco X. Flores, Stanley Jordan, Asha Moudgil, Michael J. G. Somers. (2008) Outcome of management strategies for BK virus replication in pediatric renal transplant recipients. Pediatric Transplantation 12:2, 180-186
    CrossRef

32. 32

    L K Dropulic, R J Jones. (2008) Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplantation 41:1, 11-18
    CrossRef

33. 33

    B. Sprangers, J. Pirenne, E. van Etten, Mark Waer, C. Mathieu, A.D. Billiau. 2008. Other Forms of Immunosuppression. , 333-349.
    CrossRef

34. 34

    John P. Vella, Mohamed H. Sayegh. 2008. Diagnosis and Management of Renal Allograft Dysfunction. , 994-1008.
    CrossRef

35. 35

    Karen D. Sims, Emily A. Blumberg. 2008. Prevention and Treatment of Infection in Kidney Transplant Recipients. , 1034-1046.
    CrossRef

36. 36

    J. Beimler. (2008) BK Virus-Nephropathie nach Nierentransplantation. Der Nephrologe 3:1, 14-21
    CrossRef

37. 37

    Suradej Hongeng, Samart Pakakasama, Ampaiwan Chuansumrit, Nongnuch Sirachainan, Thanyachai Sura, Artit Ungkanont, Suporn Chuncharunee, Saengsuree Jootar, Surapol Issaragisil. (2007) Reduced intensity stem cell transplantation for treatment of class 3 Lucarelli severe thalassemia patients. American Journal of Hematology 82:12, 1095-1098
    CrossRef

38. 38

    F. Ginevri, A. Azzi, H. H. Hirsch, S. Basso, I. Fontana, M. Cioni, S. Bodaghi, V. Salotti, A. Rinieri, G. Botti, F. Perfumo, F. Locatelli, P. Comoli. (2007) Prospective Monitoring of Polyomavirus BK Replication and Impact of Pre-Emptive Intervention in Pediatric Kidney Recipients. American Journal of Transplantation 7:12, 2727-2735
    CrossRef

39. 39

    Stanislas Faguer, Hans H. Hirsch, Nassim Kamar, Celine Guilbeau-Frugier, David Ribes, Joëlle Guitard, Laure Esposito, Olivier Cointault, Anne Modesto, Michel Lavit, Catherine Mengelle, Lionel Rostaing. (2007) Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transplant International 20:11, 962-969
    CrossRef

40. 40

    K.L. Womer, G. Guerra, K. Dibadj, Y. Huang, A. Kazory, B. Kaplan, T.R. Srinivas. (2007) Immunosuppression reduction for BK virus nephropathy: a case for caution. Transplant Infectious Disease 9:3, 244-248
    CrossRef

41. 41

    Hiroto Inaba, Deborah P. Jones, Lillian W. Gaber, Jerry L. Shenep, Sandra K. Call, Ching-Hon Pui, Bassem I. Razzouk. (2007) BK Virus-Induced Tubulointerstitial Nephritis in a Child with Acute Lymphoblastic Leukemia. The Journal of Pediatrics 151:2, 215-217
    CrossRef

42. 42

    Carlos A. Benavides, Vida B. Pollard, Shamila Mauiyyedi, Hemangshu Podder, Richard Knight, Barry D. Kahan. (2007) BK Virus???Associated Nephropathy in Sirolimus-Treated Renal Transplant Patients: Incidence, Course, and Clinical Outcomes. Transplantation 84:1, 83-88
    CrossRef

43. 43

    Supriya Maddirala, Jan V Pitha, Benjamin D Cowley, Lukas Haragsim. (2007) End-stage renal disease due to polyomavirus in a cardiac transplant patient. Nature Clinical Practice Nephrology 3:7, 393-396
    CrossRef

44. 44

    C. Morath, C. Sommerer, J. Schmidt, H. Krastel, V. Schwenger, M. Zeier. (2007) Infektionen nach Nierentransplantation. Der Nephrologe 2:3, 167-174
    CrossRef

45. 45

    Parmjeet Randhawa, Emilio Ramos. (2007) BK viral nephropathy: an overview. Transplantation Reviews 21:2, 77-85
    CrossRef

46. 46

    JogiRaju Tantravahi, Karl L. Womer, Bruce Kaplan. (2007) Why Hasn't Eliminating Acute Rejection Improved Graft Survival? ^*. Annual Review of Medicine 58:1, 369-385
    CrossRef

47. 47

    Christine Hanssen Rinaldo, Hans H Hirsch. (2007) Antivirals for the treatment of polyomavirus BK replication. Expert Review of Anti-infective Therapy 5:1, 105-115
    CrossRef

48. 48

    Laure Esposito, Hans Hirsch, Gr??goire Basse, Genevi??ve Fillola, Nassim Kamar, Lionel Rostaing. (2007) BK Virus???Related Hemophagocytic Syndrome in a Renal Transplant Patient. Transplantation 83:3, 365
    CrossRef

49. 49

    Millie Samaniego, Bryan N Becker, Arjang Djamali. (2006) Drug Insight: maintenance immunosuppression in kidney transplant recipients. Nature Clinical Practice Nephrology 2:12, 688-699
    CrossRef

50. 50

    Volker Nickeleit, Michael J. Mihatsch. (2006) Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat. Transplant International 19:12, 960-973
    CrossRef

51. 51

    Sonia Lin, Christopher J. Cosgrove. (2006) Perioperative Management of Immunosuppression. Surgical Clinics of North America 86:5, 1167-1183
    CrossRef

52. 52

    Regis A. Vilchez, Shimon Kusne. (2006) Molecular and clinical perspectives of polyomaviruses: Emerging evidence of importance in non-kidney transplant populations. Liver Transplantation 12:10, 1457-1463
    CrossRef

53. 53

    P. Randhawa, D. C. Brennan. (2006) BK Virus Infection in Transplant Recipients: An Overview and Update. American Journal of Transplantation 6:9, 2000-2005
    CrossRef

54. 54

    Gaurav Gupta, Ron Shapiro, Ngoc Thai, Parmjeet Singh Randhawa, Abhay Vats. (2006) Low Incidence of BK Virus Nephropathy After Simultaneous Kidney Pancreas Transplantation. Transplantation 82:3, 382-388
    CrossRef

55. 55

    Syed A Hussain, Sundaram Hariharan. (2006) BK virus infection after renal transplantation. Current Opinion in Organ Transplantation 11:4, 413-417
    CrossRef

56. 56

    Benjamin Bridges, Sarah Donegan, Ashraf Badros. (2006) Cidofovir bladder instillation for the treatment of BK hemorrhagic cystitis after allogeneic stem cell transplantation. American Journal of Hematology 81:7, 535-537
    CrossRef

57. 57

    R J Crew, G Markowitz, J Radhakrishnan. (2006) Therapeutic options in BK virus-associated interstitial nephritis. Kidney International 70:2, 399-402
    CrossRef

58. 58

    C.E.H. Barber, T.J.C. Hewlett, L. Geldenhuys, B.A. Kiberd, P.D. Acott, T.F. Hatchette. (2006) BK virus nephropathy in a heart transplant recipient: case report and review of the literature. Transplant Infectious Disease 8:2, 113-121
    CrossRef

59. 59

    M.A. Josephson, J.W. Williams, A. Chandraker, P.S. Randhawa. (2006) Polyomavirus-associated nephropathy: update on antiviral strategies. Transplant Infectious Disease 8:2, 95-101
    CrossRef

60. 60

    J. Trofe, H.H. Hirsch, E. Ramos. (2006) Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients. Transplant Infectious Disease 8:2, 76-85
    CrossRef

61. 61

    Robert J. Stratta, Michael S. Rohr, Aimee K. Sundberg, Alan C. Farney, Erica L. Hartmann, Phillip S. Moore, Jeffrey Rogers, Samy S. Iskandar, Michael D. Gautreaux, David F. Kiger, William Doares, Teresa K. Anderson, Gloria Hairston, Patricia L. Adams. (2006) Intermediate-Term Outcomes With Expanded Criteria Deceased Donors in Kidney Transplantation. Annals of Surgery 243:5, 594-603
    CrossRef

62. 62

    E. D. Han Lee, C. C. Kemball, J. Wang, Y. Dong, D. C. Stapler, K. M. Hamby, S. Gangappa, K. A. Newell, T. C. Pearson, A. E. Lukacher, C. P. Larsen. (2006) A Mouse Model for Polyomavirus-Associated Nephropathy of Kidney Transplants. American Journal of Transplantation 6:5p1, 913-922
    CrossRef

63. 63

    H. M. Wadei, A. D. Rule, M. Lewin, A. S. Mahale, H. A. Khamash, T. R. Schwab, J. M. Gloor, S. C. Textor, M. E. Fidler, D. J. Lager, T. S. Larson, M. D. Stegall, F. G. Cosio, M. D. Griffin. (2006) Kidney Transplant Function and Histological Clearance of Virus Following Diagnosis of Polyomavirus-Associated Nephropathy (PVAN). American Journal of Transplantation 6:5p1, 1025-1032
    CrossRef

64. 64

    M.E. Levi, N. Mandava, L.K. Chan, A. Weinberg, J.L. Olson. (2006) Treatment of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. Transplant Infectious Disease 8:1, 38-43
    CrossRef

65. 65

    Kristin Mekeel, Herwig-Ulf Meier-Kriesche, Bruce Kaplan. (2006) Are we making progress in kidney transplantation?. Current Opinion in Organ Transplantation 11:1, 1-6
    CrossRef

66. 66

    S Hariharan. (2006) BK virus nephritis after renal transplantation. Kidney International 69:4, 655-662
    CrossRef

67. 67

    Helio Tedesco Silva, Paula Pinheiro Machado, Claudia Rosso Felipe, Jose Osmar Medina Pestana. (2006) Immunotherapy for De Novo Renal Transplantation. Drugs 66:13, 1665-1684
    CrossRef

68. 68

    Gary Kunkel, Grant W Cannon. (2006) Leflunomide in the treatment of rheumatoid arthritis. Expert Review of Clinical Immunology 2:1, 17-31
    CrossRef

69. 69

    R. K. Avery. (2005) Bk Virus and Renal Dysfunction: Not Limited to Kidney Transplantation?. Clinical Infectious Diseases 41:12, 1726-1727
    CrossRef

70. 70

    Michael Boeckh, Veronique Erard, Danielle Zerr, Janet Englund. (2005) Emerging viral infections after hematopoietic cell transplantation. Pediatric Transplantation 9, 48-54
    CrossRef

71. 71

    Bryce A Kiberd. (2005) Screening to Prevent Polyoma Virus Nephropathy: A Medical Decision Analysis. American Journal of Transplantation 5:10, 2410-2416
    CrossRef

72. 72

    H. H. Hirsch, D. R. Snydman. (2005) BK Virus: Opportunity Makes a Pathogen. Clinical Infectious Diseases 41:3, 354-360
    CrossRef

73. 73

    Hans H. Hirsch, Daniel C. Brennan, Cinthia B. Drachenberg, Fabrizio Ginevri, Jennifer Gordon, Ajit P. Limaye, Michael J. Mihatsch, Volker Nickeleit, Emilio Ramos, Parmjeet Randhawa, Ron Shapiro, Juerg Steiger, Manikkam Suthanthiran, Jennifer Trofe. (2005) Polyomavirus-Associated Nephropathy in Renal Transplantation: Interdisciplinary Analyses and Recommendations. Transplantation 79:10, 1277-1286
    CrossRef