NDT Advance Access originally published online on April 27, 2006
Nephrology Dialysis Transplantation 2006 21(7):2039-2040; doi:10.1093/ndt/gfl032
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Remission of polyomavirus-induced graft nephropathy treated with low-dose leflunomide
Email: sven.teschner{at}uniklinik-freiburg.deSir,
The incidence of polyomavirus (BK) induced allograft nephropathy (PVAN) has gained in clinical importance as a cause of renal graft dysfunction [1]. Treatment options are at present confined to reduction of immunosuppression with or without low-dose cidofovir [2]. Leflunomide is an immunosuppressive drug with in vitro and suspected in vivo antiviral potency and has been applied to PVAN with promising results [3].
Two living donor renal transplant recipients were diagnosed with PVAN, 117 and 70 days after transplantation, respectively [characteristics of patient 1/patient 2 respectively: age 39/51 years; renal disease: MPGN/IgA-nephritis; blood group donor/recipient: (0/0)/(A/0); CMV-serostatus donor/recipient: (+/+)/(–/–); HLA-mismatches: 3/4, cellular rejection episodes prior to PVAN: 2/1]. The diagnosis was confirmed by renal biopsy and positive quantitative BK RT–PCR (graded PVAN B/PVAN A according to [2]; 3.4 and 2.1 million copies/ml plasma, respectively). Preceding leflunomide therapy, immunosuppressive therapy was reduced and a course of immunoglobulins administered in patient 1 without effect within 3 weeks.
Immunosuppression was modified by discontinuation of mycophenolate, reduction of tacrolimus (target trough level: 4–6 ng/ml) and addition of leflunomide (Arava®, Sanofi-Aventis, Frankfurt/Main, Germany, 100 mg for 3 days, 20 mg thereafter). Patient 1 cleared the virus within 3 months. At present, 13 months after therapy initiation and 17.7 months after transplantation, serum creatinine values are stable (range: 2.7–3.3 mg/dl). After leflunomide initiation, viral load in patient 2 fell rapidly. On day 261 of leflunomide therapy, the PCR became and remained negative. Graft function stabilized (range 1.6–1.9 mg/dl, 10 months after leflunomide initiation, 12.8 months after transplantation). A retrospective analysis of archived plasma samples demonstrated viral loads as high as 350 million copies/ml without overt PVAN (Figure 1).
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We used a lower dose of leflunomide as in a previous report [3], which might account for the fact that no adverse reactions were observed. Lower dosing seems, nevertheless, to be effective (no graft rejection and negative PCR). Whether leflunomide exerts antiviral effects in vivo is still not known for certain and it may be possible that remission of PVAN is solely the effect of the reduced immunosuppression regimen. In this case, leflunomide seems at least to prevent graft rejections (none [3, this report] vs 15.3–25% [1,4]).
Important factors that need consideration seem to be close monitoring of tacrolimus trough levels (correlation of viral load with trough levels) and, in case of failing response to leflunomide, therapeutic drug monitoring of leflunomide [3].
In summary, leflunomide proved to be a safe and effective agent in the reported patients with PVAN.
1 Department of Medicine Renal Division University Hospital Freiburg Hugstetter Street 55 79106 Freiburg Germany2 Department of Virology University Hospital Freiburg Hermann-Herder-Street 11 79104 Freiburg Germany
Acknowledgments
The work was partially funded by a grant from Novartis, Germany.
Conflict of interest statement. The authors declare that no conflict of interest exists.
References
- 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
[Abstract/Free Full Text] - Hirsch HH, Brennan DC, Drachenberg CB et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplant 2005; 79: 1277–1286[CrossRef][Web of Science][Medline]
- Williams JW, Javaid B, Kadambi PV et al. Leflunomide for polyomavirus type BK nephropathy. N Engl J Med 2005; 352: 1157–1158
[Free Full Text] - Randhawa PS, Finkelstein S, Scantlebury V et al. Human polyomavirus-associated interstitial nephritis in the allograft kidney. Transplantation 1999; 67: 103–109[CrossRef][Web of Science][Medline]
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