Leflunomide for Polyomavirus Type BK Nephropathy
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《新英格兰医药杂志》
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 1). 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.
Figure 1. Polyomavirus BK Load in Blood and Urine in 15 Patients with Blood Levels of A77 1726 That Remained above 40 μg per Milliliter.
Viral load was measured by the polymerase chain reaction. Because of the follow-up schedule, data are not available for the five-month point.
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
References
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.
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.
Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999;67:103-109.
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.
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.
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 1). 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.
Figure 1. Polyomavirus BK Load in Blood and Urine in 15 Patients with Blood Levels of A77 1726 That Remained above 40 μg per Milliliter.
Viral load was measured by the polymerase chain reaction. Because of the follow-up schedule, data are not available for the five-month point.
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
References
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.
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.
Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999;67:103-109.
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.
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.