HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: CJN.01050308v1 3/3/652    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mannon, R. B. Search for Related Content PubMed PubMed Citation Articles by Mannon, R. B. Related Collections Related Article

Leflunomide Therapy in Kidney Transplantation: Ready for Prime Time?

Transplantation Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence: Dr. Roslyn B. Mannon, Transplantation Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC 1450, CRC 5-5750, Bethesda, MD 20892. Phone: 301-594-7886; Fax: 301-451-6989; E-mail: rozm{at}mail.nih.gov

	Introduction

Top Introduction Disclosures References

 
BK polyomavirus has become a scourge in kidney transplantation, mediating graft loss with progressive tubular cell death and interstitial inflammation and fibrosis (1). In the setting of immunosuppression, the virus reactivates, replicating along the tubular epithelium, spreading to other uninfected tubules, entering the tubular lumen after cell lysis, and eventually entering the bloodstream through destruction of peritubular capillaries (2). Whereas viruria is common, viremia occurs in only 13% of recipients, and nephropathy in 8% (3). Once a diagnosis is established by transplant biopsy and viral load measurements, the primary treatment strategy is immunousuppressive withdrawal (4). Disease that is more fully progressed may be unresponsive to any manipulation. Adjuvant therapies have included intravenous immune globulin, quinolones, and cidofovir, all with varying results (5). Center-specific experiences have been reported, but there are no definitive treatments.

Leflunomide is an immunosuppressive agent approved for use in rheumatoid arthritis. Metabolized by the liver, the active metabolite A77 1726 blocks tyrosine kinase activity as well as pyrimidine synthesis. Leflunomide also has antiviral activity against cytomegalovirus replication in vitro and in rodent models. Although limited, initial experience in kidney transplant recipients demonstrated significant interpatient variability in drug levels and anemia while facilitating calcineurin inhibitor withdrawal (6). Based on this immunosuppressive profile and the potential to halt BK activity, leflunomide has entered into practice for BK nephropathy. The initial report in 17 kidney transplant recipients in place of mycophenolate mofetil demonstrated a drop in viral loads by 2 to 3 logs when A77 1726 levels were more than 40 µg/ml (7). Graft loss or bone marrow suppression was not reported. Treatment of an additional 13 patients at this center with targeted levels at 50 to 100 µg/ml or used in combination with cidofovir resulted in consistent reduction in viral loads when levels were greater than 35 µg/ml (8). Graft loss was 15%, lower than seen in other reports, with 2 patient deaths due to cardiovascular complications. However, levels of A77 1726 varied considerably among recipients on 20 to 60 mg daily, doses often in excess of those recommended for rheumatoid arthritis. Less optimistic results were recently reported in a small, prospective open label study in which viral clearance was only 42% with significant toxicity to discontinue the drug in 17% of recipients (9).

Is leflunomide ready for prime time in the treatment of BK polyomavirus nephropathy? In this issue of CJASN, Leca et al. (10) retrospectively review leflunomide usage in recipients with BK nephropathy as well as TA/IF. Patients received doses averaging from 33 mg/d ("low level" <40 µg/ml; n = 12) to 48 mg/d ("high level" >40 µg/ml; n = 9), based on levels monitored monthly. In both groups, the rate and timing of viral clearance and the rate of graft loss were similar. Serum creatinine was indeed lower in the high level group, despite more frequent rejection episodes. Moreover, adverse events in all patients were common. In particular, hemolytic anemia occurred in 29% of all patients, particularly in high-level recipients. Thrombotic microangiopathy was seen in two recipients, one of whom eventually lost her graft. Potential contributing factors, such as donor alloantibody, infection, or tacrolimus, were not apparent, leaving the association with leflunomide. Speculated potential mechanisms include direct endothelial cell effects or via inhibition of tyrosine kinases. Alternatively, vascular endothelium damaged directly by the virus (11) and perhaps in combination with the drug could have led to endothelial cell activation.

Transplantation has always contained special challenges, with the recognition that risk is acceptable if the overall outcome is improved. Presently, there is no effective antiviral agent for BK infection. The acceptance of leflunomide therapy as effective antiviral and anti-inflammatory has been based on limited published clinical experience and limited unpublished experience. As frustrating a disease as BK nephropathy is, we must recognize that current strategies reported in the literature have ill defined efficacy and safety in larger transplant populations under varying conditions. Clearly, there are several concerns with the use of leflunomide in kidney transplant subjects. Studies in individuals with renal failure, the population often targeted for therapy, are incomplete (6). There is wide interpatient variation in pharmacokinetics making predictable dosing difficult (6,8). Moreover, the antiviral activity measurements are limited and not optimally assayed. Using total DNA copy number measured by polymerase chain reaction, the effective concentration 50 (EC₅₀; drug concentration in which viral load is reduced by 50%) is 11.3 ± 2.8 µg/ml (40.7 µM) with a 50% inhibitory concentration (IC₅₀) measured as a 50% reduction in housekeeping gene expression is 39.7 ± 6.9 µg/ml (147 µM), resulting in a relatively low selectivity index of 3.8 ± 0.8 (12). Similar semiquantitative measurements using immunofluorescence of late viral protein VP-1 suggest an IC₅₀ of 40 µM (8). However, more robust quantitative methodologies using hemagglutination or virion quantitation by in situ hybridization (13) have not been undertaken. With the broad range of effects of this drug, we need to more completely understand the specific mechanisms of its antiviral activity. The onus is now on our community to derive better strategies, be they direct antiviral agents or indirect strategies of immune monitoring, to intercept infection before full disease manifestation.

	Disclosures

Top Introduction Disclosures References

 
None.

	Acknowledgments

 
This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. The author wishes to thank Dr. Eugene Major for his critical review of this manuscript.

	Footnotes

 
Published online ahead of print. Publication date available at www.cjasn.org.

See related article, "Higher Levels of Leflunomide Are Associated with Hemolysis and Are not Superior to Lower Levels for BK Virus Clearance in Renal Transplant Patients," on pages 829–835.

	References

Top Introduction Disclosures References

 

1. Bohl DL, Brennan DC: BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol2 [Suppl 1]:36 –46,2007[CrossRef]
2. Imperiale MJ, Major EO: Polyomaviruses. In: Fields Virology, 5th edition, edited by Knipe DM, Howley PM, Philadelphia, Lippincott Williams and Wilkins,2007 , pp2265 –2298
3. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J: Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med347 :488 –496,2002[Abstract/Free Full Text]
4. Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, Torrence S, Schuessler R, Roby T, Gaudreault-Keener M, Storch GA: Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant5 :582 –594,2005[CrossRef][Medline]
5. Rinaldo CH, Hirsch HH: Antivirals for the treatment of polyomavirus BK replication. Expert Rev Anti Infect Ther5 :105 –115,2007[CrossRef][Medline]
6. Williams JW, Mital D, Chong A, Kottayil A, Millis M, Longstreth J, Huang W, Brady L, Jensik S: Experiences with leflunomide in solid organ transplantation. Transplantation73 :358 –366,2002[Medline]
7. Williams JW, Javaid B, Kadambi PV, Gillen D, Harland R, Thistlewaite JR, Garfinkel M, Foster P, Atwood W, Millis JM, Meehan SM, Josephson MA: Leflunomide for polyomavirus type BK nephropathy. N Engl J Med352 :1157 –1158,2005[Free Full Text]
8. Josephson MA, Gillen D, Javaid B, Kadambi P, Meehan S, Foster P, Harland R, Thistlethwaite RJ, Garfinkel M, Atwood W, Jordan J, Sadhu M, Millis MJ, Williams J: Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation81 :704 –710,2006[CrossRef][Medline]
9. Faguer S, Hirsch HH, Kamar N, Guilbeau-Frugier C, Ribes D, Guitard J, Esposito L, Cointault O, Modesto A, Lavit M, Mengelle C, Rostaing L: Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transpl Int20 :962 –969,2007[CrossRef][Medline]
10. Leca N, Muczynski K, Jefferson J, de Boer I, Kowalewska J, Kendrick E, Pichler R, Davis C: Higher levels of leflunomide are associated with hemolysis and are not superior to lower levels for BK virus clearance in renal transplant patients. Clin J Am Soc Nephrol3 :829 –835,2008[Abstract/Free Full Text]
11. Petrogiannis-Haliotis T, Sakoulas G, Kirby J, Koralnik IJ, Dvorak AM, Monahan-Earley R, DE Girolami PC, DE Girolami U, Upton M, Major EO, Pfister LA, Joseph JT: BK-related polyomavirus vasculopathy in a renal-transplant recipient. N Engl J Med345 :1250 –1255,2001[Free Full Text]
12. Farasati NA, Shapiro R, Vats A, Randhawa P: Effect of leflunomide and cidofovir on replication of BK virus in an in vitro culture system. Transplantation79 :116 –118,2005[CrossRef][Medline]
13. Hou J, Major EO: The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol4 :451 –456,1998[Medline]

This Article Full Text (PDF) All Versions of this Article: CJN.01050308v1 3/3/652    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mannon, R. B. Search for Related Content PubMed PubMed Citation Articles by Mannon, R. B. Related Collections Related Article