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Published ahead of print on March 27, 2008
Clin J Am Soc Nephrol 3: 829-835, 2008
© 2008 American Society of Nephrology
doi: 10.2215/CJN.03930907
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Renal Transplantation

Higher Levels of Leflunomide Are Associated with Hemolysis and Are not Superior to Lower Levels for BK Virus Clearance in Renal Transplant Patients

Nicolae Leca*, Kimberly A. Muczynski*, Jonathan A. Jefferson*, Ian H. de Boer*, Jolanta Kowalewska{dagger}, Elizabeth A. Kendrick*, Raimund Pichler*, and Connie L. Davis*

* Department of Medicine, Division of Nephrology, and {dagger} Department of Pathology, University of Washington, Seattle, Washington

Correspondence: Dr. Nicolae Leca, University of Washington Medical Center, 1959 NE Pacific Street, Box 356521, Seattle, WA 98195. Phone: 206-543-0690; Fax: 206-685-8661; E-mail: nleca{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Background and objectives: Leflunomide use in renal transplantation has been increasing. Outcome correlation and safety data are still to be refined. The goals of this study were to report one center's experience with leflunomide, specifically the correlation of leflunomide levels with the outcomes of BK nephropathy and the observed toxic effects during the treatment with leflunomide.

Design, setting, participants, & measurements: Leflunomide was used in 21 patients with BK nephropathy. These patients were divided into two groups on the basis of the leflunomide levels achieved: Low-level group (<40 µg/ml) and high-level group (>40 µg/ml).

Results: During 13 mo of follow-up, there was no difference in the rate of serum BK viral clearance between the groups. There were three graft losses in the low-level group and one in the high-level group; however, creatinine levels were higher at the time of starting leflunomide in the low-level group. Leflunomide was also used in six patients with chronic allograft injury. No graft loss was observed during the follow-up period of 16 mo. Treatment with leflunomide seemed to be associated with a new toxicity, hemolysis, seen in four of the 27 patients so treated. Patients with hemolysis had high leflunomide levels (81.4 ± 14 µg/ml) and worsening allograft function. Two patients had histologic evidence of thrombotic microangiopathy, which led to graft loss in one patient.

Conclusions: The clinical correlation between leflunomide levels and outcomes needs to be further refined. This study described a possible association of leflunomide with thrombotic microangiopathy, especially at higher levels.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Leflunomide (Arava; Aventis Pharmaceuticals, Kansas City, MO) is an immunosuppressive drug that was approved for use for rheumatoid arthritis in 1998, with currently expanding use to other autoimmune disorders such as multiple sclerosis (1) and psoriatic arthritis (2). Leflunomide is also being prescribed off-label in solid-organ transplantation, where it provides a novel treatment strategy by combining immunosuppressive and antiviral effects.

The immunosuppressive effects of leflunomide are exerted through multiple mechanisms, and the drug has been used in experimental and clinical applications to prevent or treat rejection (3–6). Leflunomide blocks lymphocytic proliferation by reversible blockade of the mitochondrial dihydro-orotate dehydrogenase, an enzyme required for de novo pyrimidine synthesis (7–10). It also alters intracellular signaling of the T and B lymphocytes by interference with the function of multiple protein kinases, NF-{kappa}B, and other factors (5,11–16).

The mechanisms accounting for the antiviral effects of leflunomide have not been well delineated, and they seem to be independent of the effects on dihydro-orotate dehydrogenase. In cytomegalovirus (CMV) infection, leflunomide inhibits the viral tegumentation, but in BK infection, this does not apply, because the BK virus is not enveloped (17,18).

The targets of leflunomide dosing and/or level are not well established for clinical practice for either BK nephropathy (BKN) or rejection. The usual prescribed dosage for rheumatoid arthritis is 10 to 20 mg/d. Leflunomide is metabolized to its active ingredient, A77,1726 (teriflunomide), a malonitrilamide that is measured for the reported leflunomide level. The leflunomide dosage for the antiviral effect in renal transplantation has been inferred from its in vitro IC50 against viral replication. The current clinical practice is to target leflunomide levels in excess of 40 µg/ml. Published data suggest a possible worse outcome for patients who do not achieve such levels during the BKN treatment (19,20). For achieving levels higher than 40 µg/ml, leflunomide dosages that substantially exceed those used for rheumatic disorders are required for most patients. For rheumatoid arthritis, leflunomide level monitoring is not recommended and is not routinely performed.

The reported adverse effect profile of leflunomide includes predominantly diarrhea and rash, with potential for severe reactions including hepatotoxicity, pneumonitis, neurotoxicity, and bone marrow suppression in rare cases (21–28). No hemolysis-associated syndromes have been reported to date in humans in relation to the use of leflunomide.

In this article, we review our experience with the use of leflunomide, define the adverse effect profile that we have observed, and compare the outcomes of patients who had BKN and achieved levels higher or lower than 40 µg/ml. We describe for the first time a concerning association between the treatment with leflunomide and thrombotic microangiopathy (TMA).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 Disclosures
 References
 
Clinical Case
A 51-yr-old woman with ESRD secondary to polycystic kidney disease, sensitized secondary to pregnancies, received a renal transplant from her husband. Immunosuppression consisted of induction with anti-thymocyte globulin (Thymoglobulin; Genzyme, Cambridge, MA) and a maintenance regimen of tacrolimus (FK) and mycophenolate mofetil (MMF), without maintenance steroids. Her nadir creatinine was 1.2 mg/dl and increased to 1.7 mg/dl at 7 mo after transplant. Acute antibody-mediated rejection was diagnosed by C4d staining (Biogenesis, Ltd., England, UK) in the biopsy in association with peritubular capillary congestion and a high circulating level of a class II donor-specific antibody. Treatment with steroids, plasmapheresis, intravenous Ig (IVIg), and Rituximab (Genentech, San Francisco, CA) was followed by an improvement in creatinine to 1.5 mg/dl. Three months later, her creatinine increased to 2.1 mg/dl in context of a high serum BK viral load. Renal biopsy confirmed changes consistent with BKN manifested as a patchy inflammatory infiltrate with edema and tubulitis. The inflamed tubular segments showed enlarged nuclei with basophilic "ground-glass" intranuclear inclusions, which stained positive for the large T antigen (SV40; Lee Biomolecular Co., San Diego, CA). For treatment of BKN, leflunomide replaced MMF in the immunosuppressive regimen and the FK dosage was lowered to achieve levels of 5 ng/ml. Leflunomide dosage was titrated to achieve a level in excess of 40 µg/ml, and the highest documented level was 89 µg/ml, 6 wk after starting the treatment. Two weeks later, she presented with severe ecchymosis, an elevated creatinine at 3.8 mg/dl, thrombocytopenia (49,000/ml), undetectable haptoglobin, and a lactate dehydrogenase (LDH) level of 1436 U/L (normal range 0 to 190 U/L). FK level was 6 ng/ml. Renal biopsy revealed wide spread TMA involving all of the sampled glomeruli (Figure 1). C4d staining of the peritubular capillaries was negative, and the class II donor-specific antibody titer was very low. SV40 stain was positive. Leflunomide was stopped; however, the renal allograft function continued to worsen and the patient restarted dialysis 2 mo later.


Figure 1
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  		Figure 1. Glomerulus from a patient who was treated with leflunomide and had a microthrombus characteristic for thrombotic microangiopathy occupying the hilar region and extending to the peripheral capillary loops. Magnification, x400 (Jones Methenamine silver stain).

 
Patient Selection
With the approval from the institutional review board of the University of Washington, we reviewed the records of the kidney transplant recipients who received treatment with leflunomide. Clinical data were extracted, and clinical follow-up was included until December 2006. At our institution, leflunomide was prescribed for the treatment of BKN and for the treatment of increasing fibrosis and chronic inflammation secondary to previous acute rejection episodes, especially for those with intolerance to mycophenolic acid preparations.

The diagnosis of BKN was made on the basis of the histologic evidence of characteristic viral inclusions in tubular cell nuclei, confirmed by staining for SV40. BK viral DNA was detected by a PCR assay that amplifies a region of the large T antigen gene (29).

The severity of tubulointerstitial inflammation and fibrosis in BKN was graded semiquantitatively by two independent observers on a 0- to 3-point scale: 0 points, <10% tissue core area; 1 point, 10 to 25%; 2 points, 25 to 50%; and 3 points, >50%. The amount of immunohistochemical staining for SV40 was quantified by counting the number of positive epithelial cell nuclei in the biopsy and reported as number of positive cells per square millimeter of tissue.

Patients who received leflunomide for BKN were divided into two groups on the basis of their highest leflunomide levels during the entire duration of the treatment. The cutoff value for inclusion in the higher level group was 40 µg/ml. Clinical characteristics specifically determined for each patient included age, ethnicity, gender, cause of ESRD, retransplant status, type of transplant, HLA matching, CMV donor/recipient status, history of delayed graft function, creatinine levels, immunosuppression protocol, and history of rejection. The data collected at the time of BKN diagnosis included time after transplantation, serum creatinine, and BK viral load determined by PCR (29). The follow-up data included length of follow-up, treatment, serum creatinine, complete blood count values and peripheral smear, LDH, haptoglobin, CMV, graft and patient outcome, leflunomide levels, leflunomide dosage, and any documented adverse reaction during the treatment. Leflunomide assays were performed using HPLC/mass spectrometry (National Medical Services, Willow Grove, PA).

Treatment
The leflunomide dosage and target levels were individually determined for each patient by their transplant nephrologist. For both BKN and chronic allograft injury (CAI), leflunomide replaced MMF on the immunosuppressive regimen. Starting dosage for leflunomide included a loading dose (60 mg/d for 3 d). Maintenance was started with a dosage of 20 mg/d, which was then titrated on the basis of the levels. Leflunomide levels were checked monthly. Maintenance dosage did not exceed 60 mg/d. The targeted FK level was lowered to 5 ng/ml. The prednisone dosage was unchanged (5 to 10 mg/d).

In addition to leflunomide, some patients received other adjuvant therapies for BKN. These were initiated immediately upon histologic diagnosis of BKN and before starting leflunomide and included three to four infusions of cidofovir 0.35 mg/kg (n = 8) or low-sucrose IVIg 2 g/kg (n = 3).

Statistical Analyses
Categorical clinical characteristics and outcomes were compared using Fisher exact test. Continuous variables were compared using the t test (for normally distributed data) or the Wilcoxon rank-sum test (for skewed data). A significance level of P < 0.05 was used for all tests.

A Kaplan-Meier plot was used to summarize time to clearance of BK from serum, comparing the two groups of patients. Patients were considered at risk from the time starting leflunomide until serum BK virus levels were undetectable or until study end, with patients who experienced graft loss before viremia clearance considered to be at risk until study end. The time to the clearance of BK virus in the serum was compared by the attained leflunomide level using the log-rank test. Statistical comparisons were conducted using Stata statistical software (Stata 9; Stata Corp, College Station, TX).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 Disclosures
 References
 
Leflunomide Use for BK Nephropathy
Leflunomide was used for 21 patients with the diagnosis of BKN. Twelve patients did not achieve leflunomide levels in excess of 40 µg/ml at any time during the treatment, and nine patients had levels that exceeded 40 µg/ml. Table 1 shows the demographic, transplantation, and BKN characteristics of the two groups. No significant differences were observed for age, gender, ethnicity, cause of ESRD, previous transplant, pretransplantation panel reactive antibody, HLA mismatches, CMV donor/recipient status, CMV reactivation, induction or maintenance immunosuppression, or the incidence of rejection before the diagnosis of BKN. More living-donor transplants were performed in the group that achieved higher levels, and these patients achieved a significantly lower creatinine at nadir. The timing of BKN after transplantation and the peak BK viral loads by PCR were not different between the groups (P = 0.11, for peak BK viral load). The severity of BKN, measured by the number of positive SV40 cells per area and the degree of tubulointerstitial inflammation and fibrosis, was not different between groups. The average FK levels during the treatment with leflunomide were similar between groups. The number of patients who received adjunctive treatment with cidofovir or IVIg was not different between groups.


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  		Table 1. Demographic, transplant, and BKN characteristics of patients who were treated with leflunomide for BKNa

 
The dosage and levels of leflunomide were significantly higher in the group with leflunomide levels >40 µg/ml (Table 2). The duration of treatment with leflunomide calculated to the end of the follow-up period was not different between groups. The creatinine levels were significantly lower in the high-level group at nadir (P = 0.049), at diagnosis of BKN (P = 0.009), and at the end of the follow-up period (P = 0.5); however, the percentage changes from nadir creatinine at the diagnosis of BKN and from nadir to the end of the follow-up period were not different between groups.


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  		Table 2. Clinical outcomes of patients who were treated with leflunomide for BKN

 
The rate and timing of viral clearance in the serum by PCR was not different between the two groups (Figure 2). At the end of the study, the creatinine levels of the patients who cleared the BK virus from the serum were not significantly different between groups at 2.23 ± 0.76 versus 2.04 ± 0.23 mg/dl (P = 0.76).


Figure 2
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  		Figure 2. Plasma clearance of BK virus by PCR, by attained leflunomide level (P = 0.937 comparing groups).

 
There were three graft losses in the low-level group. One graft loss occurred 2 mo after treatment with leflunomide in the context of severe BKN. The other two graft losses occurred late, 12 and 24 mo after treatment with leflunomide, in the context of severe underlying tubular atrophy and chronic fibrosis, after clearance of the virus from the serum. In the high-level group, there was one graft loss, 4 mo after starting leflunomide, as a result of a severe TMA (see the Clinical Case section).

No CMV reactivation or disease was observed in any group before or after the diagnosis of BKN. Two patients in the high-level group had episodes of mild rejection with negative staining for SV40 at the time of clearing the BK virus in the serum. No rejection episodes were observed in the low-level group.

Leflunomide Use for CAI
Leflunomide was used in six renal transplant recipients with CAI changes represented by moderate to severe tubular atrophy and interstitial fibrosis in association with persisting interstitial inflammation. All six patients had preceding episodes of rejection; one patient had persistent antibody-mediated rejection treated with multiple cycles of plasmapheresis, IVIg, and rituximab. All six patients were receiving steroids, and leflunomide was used in combination with FK (mean level 6.4 ng/ml; range 5 to 9) for five patients and cyclosporine (level 150 ng/ml) for one patient. BK virus was negative in all patients by urine PCR.

The dosage of leflunomide was on average 29.2 ± 10.2 mg/d, and the average leflunomide level was 51.6 ± 28.9 µg/ml. The treatment with leflunomide was started on average 53 ± 45 mo after transplantation (range 21 to 144), and the duration of follow-up was on average 16 ± 10 mo (range 6 to 31).

Creatinine levels were statistically higher at the time of starting leflunomide (2.05 ± 0.68 mg/dl) when compared with the nadir level after transplantation (1.4 ± 0.49 mg/dl; P < 0.05). At the end of the follow-up period, the creatinine levels were higher (2.43 ± 0.74 mg/dl) but did not reach statistical significance when compared with the time of initiation of leflunomide therapy. No acute rejection episodes and no graft losses were observed during the duration of therapy.

Adverse Reactions Observed during Leflunomide Therapy
Adverse reactions were observed in nine of the 27 patients during the treatment with leflunomide. These included rash (n = 1), neuropathic-type pain (n = 1), mild elevation of transaminases (n = 1), pancytopenia (n = 1), and alopecia and malaise (n = 1). Hemolysis was present in four patients; two of them were receiving leflunomide for BKN and the other two for CAI. All patients with hemolysis had worsening allograft function and leflunomide levels >40 µg/ml (average 81.4 ± 14) at the time of hemolysis diagnosis. The incidence of hemolysis was 14.8% overall for the 27 patients who were treated with leflunomide and 28.6% for the 14 patients with leflunomide levels >40 µg/ml. Hemolysis was diagnosed on the basis of the presence of undetectable haptoglobin (<31 mg/dl), elevated LDH (718.7 ± 508 U/L), decreasing platelet numbers (83.7 ± 25 x 103/ml), anemia (hematocrit 29 ± 1.6%), and the finding of erythrocyte fragments in the peripheral smear for all four patients. Mean FK levels in the four patients with hemolysis was 6 ng/ml (range 5 to 7 ng/ml). Coombs test was negative. Bruising was the most frequent clinical symptom; however, no bleeding or thrombotic episodes were observed. Liver function test abnormalities did not occur. Three patients underwent a renal transplant biopsy at the time of diagnosis of the hemolysis. TMA lesions were observed in two of these patients.

Hemolysis was diagnosed in all four patients within the first 6 mo of leflunomide therapy. Specifically, these patients had no evidence of a positive C4d stain on biopsy. There was no evidence of other concurrent infections (viral or bacterial) at the time of hemolysis diagnosis. Leflunomide was stopped for two patients and reduced for the other two. Graft loss occurred in one patient despite discontinuation of the drug. One other patient had persistent renal dysfunction despite leflunomide discontinuation. Renal function improved in the other two patients upon reduction of leflunomide dosage (from 1.7 and 2.6 to 1.2 and 2 mg/dl, respectively). Laboratory abnormalities consistent with the diagnosis of hemolysis resolved upon discontinuation or reduction of the drug in all cases. The cause of renal disease of patients with hemolysis was polycystic renal disease (n = 2), type 1 diabetes (n = 1), and IgA nephropathy (n = 1). None of the patients had viral hepatitis. There was no history of recurrent thrombosis, anti-phospholipid antibody syndrome, or lupus. BP was well controlled in all patients.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 Disclosures
 References
 
In our experience with leflunomide for the treatment of BKN, patients who achieved a leflunomide level >40 µg/ml did not manifest an improved clinical outcome when compared with patients who achieved lower levels. Furthermore, we report four cases of hemolysis among patients who achieved leflunomide levels >40 µg/ml, the first such cases reported in the setting of leflunomide therapy. Our data differ significantly from the findings of Williams et al. (19) and Josephson et al. (20) that suggested a poorer outcome for patients who did not achieve a level >40 µg/ml during the treatment with leflunomide for BKN.

The beneficial effects of leflunomide in BKN are thought to be delivered by the antiviral as well as anti-inflammatory properties of the drug. To date, no clear correlation has been made between these effects and the in vivo leflunomide levels in humans. A target leflunomide level of 40 µg/ml has been suggested by extrapolating the in vitro effective concentrations against the CMV virus (17); however, it is possible that a lower level may be sufficient in vivo for the antiviral effect. In addition, the immunomodulatory effects of leflunomide, which may be particularly important in BKN, may be seen at drug exposures <40 µg/ml.

Difficulties with the clinical use of leflunomide are represented by the long serum half-life (15 d) of teriflunomide and the lengthy turnaround time of laboratory reporting. These characteristics and the high pharmacokinetic intersubject variability explain the wide differences observed in the leflunomide levels. The correlation between leflunomide dosage and levels was only moderate in our patients (r = 0.45 by Spearman rank-sum analysis).

We believe that leflunomide remains a potential effective therapy for BKN, but its particular properties make difficult the assignment of a "therapeutic" level and may explain the differences between our BKN outcomes and other studies (19,20). Leflunomide use for CAI has not been associated with an increased risk for rejection; however, the outcomes of therapy are difficult to interpret because of a small number of patients treated with multiple confounding factors.

The adverse effects that we observed during the treatment with leflunomide are similar to what has been reported previously in the literature. At higher levels, however, we observed a new toxicity associated with the leflunomide therapy: Hemolysis accompanied by evidence of TMA. Hemolysis can be clinically silent, and making the diagnosis requires a high index of suspicion. It is interesting that anemia has been consistently reported in the literature in association with the use of leflunomide, but further analysis into the cause of anemia is rare. Our data suggest that hemolysis may be playing an undiagnosed role. To date, the only reported association of leflunomide with hemolysis was found in a canine transplant model, particularly in dogs that were administered a higher dosage of leflunomide (30). We recommend obtaining a hemolysis panel (peripheral smear for red blood cell fragments, LDH, and haptoglobin) for patients who exhibit anemia and/or thrombocytopenia during the leflunomide treatment. A renal biopsy may be indicated to rule out TMA in patients who exhibit worsening renal function.

Although it is premature to draw the conclusion that leflunomide causes hemolysis and TMA directly, this drug has proven antiangiogenic properties mediated by inhibition of tyrosine kinases, as seen with its effect on the PDGF receptor (31). Leflunomide levels of 40 µg/ml also exceed the in vitro equivalent concentration required for tyrosine kinase inhibition (11–14,31). In addition, leflunomide has been shown to inhibit endothelial cell proliferation and organization of endothelial cells into capillary-like networks, suggesting a potential direct effect of leflunomide on endothelial cells (32).

In general, the mechanisms of de novo TMA after renal transplantation are not completely understood but are related most commonly to immunosuppressive agents such as cyclosporine, tacrolimus, and sirolimus, particularly when used in combination or in high dosages (33,34). TMA has also been described in association with viral infections, including CMV and BK (35–37). It is possible that the association of leflunomide with TMA may stem from a possible combined toxicity with the use of a calcineurin inhibitor, particularly in patients with a background of existing renal vasculopathy, as seen in both BKN and CAI. In our report, the FK levels of patients with hemolysis were relatively low and not different from patients without hemolysis.

Our study is subject to a number of limitations because of its observational design. First, the results could be confounded by differences in clinical characteristics between the groups; however, no features favoring the group that achieved levels <40 µg/ml were observed. Second, there may be unmeasured characteristics of the patients (e.g., differences in drug metabolism) or the impact of the adjuvant BKN treatments that may affect clinical outcomes. Third, no set protocol was used for treatment, follow-up, or evaluation of adverse effects, and it cannot be excluded that some outcomes were ascertained differently.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
Disclosures
 References
 
The correlation between leflunomide levels and the outcomes of BKN remains unclear. We question the need for dosage titration to achieve levels >40 µg/ml in patients who have BKN and exhibit a good clinical response at lower levels. We point out a possible association of leflunomide treatment with hemolysis and TMA, particularly at higher leflunomide levels. These data suggest that further studies should be performed to define the effectiveness of leflunomide in BKN and CAI and to determine whether lower target levels might minimize complications without decreasing the efficacy of leflunomide therapy.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
References
 
None.


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

See related editorial, "Leflunomide Therapy in Kidney Transplantation: Ready for Prime Time?" on pages 652–653.

Received September 19, 2007. Accepted February 13, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 

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