Chronic overdose of leflunomide inducing interstitial nephritis

Sir,

Leflunomide (LFM) is one of the relatively new drugs in the treatment of rheumatoid arthritis (RA) [1]. It has been reported as causing anaphylaxis, hepatic failure, Stevens–Johnson syndrome and toxic epidermal necrolysis [2], but never as causing renal tubulointerstitial disease. We report a case of a man who was taking a higher dose than prescribed of LFM (equivalent to 34 mg/day) and developed acute on chronic reversible renal impairment secondary to interstitial nephritis.

Case. A 70-year-old male patient was diagnosed at the age of 55 with chronic active RA. He was tried on many medications including anti-inflammatory drugs, steroids, weekly intramuscular gold injections and finally oral methotrexate (stopped due to elevated liver enzymes). The patient had another disease flare up and was started on LFM 100 mg loading dose for two doses and 10 mg/day for maintenance. The initial response was modest, so the LFM dose was increased to 20 mg per os per day. The patient was reviewed every 3 months and it was noted that his creatinine was increasing gradually from a baseline of ~140 mol/l to 287 mol/l over 2 years. The baseline creatinine was elevated because of uncontrolled hypertension. The patient was reluctant to bring his medication to clinic, but when he finally brought his regular prescription, it became clear that he was taking LFM 100 mg once a week in addition to his 20 mg daily maintenance dose. This equated to an average of 34 mg of LFM/day for the past 26 months. His other medications were bumetanide, furosemide, atenolol, aspirin, amiodarone and lisinopril. Urinalysis showed low-grade proteinuria and negative urine sediment, and renal ultrasound was normal. Because of continuously rising creatinine, a renal biopsy was performed and revealed patchy chronic tubulointerstitial nephritis (non-eosinophilic), 10% glomerulosclerosis and hypertensive vascular changes with no immunoglobulin deposition (see Figure 1). LFM was stopped immediately and he was started on daily 20 mg prednisolone, mainly to control his RA and for the possible benefit from steroids, although the evidence for this in the literature is weak. Plasma creatinine started to decrease after 1 month and returned to 160 mol/l (close to the patient's baseline) after 5 months. No other drug changes were made.



View larger version (135K):
[in this window]
[in a new window]
 
Fig. 1. Microscopy of the renal biopsy. Masson Trichrome x200. The arrow points to an area of scarring and interstitial fibrosis with a chronic inflammatory cell infiltrate.

 
Comments. RA, a chronic systemic inflammatory disease, affects, in addition to the joints, many vital organs such as the eyes and the heart. Severe kidney disease in patients with RA is rare, and most commonly is either secondary amyloidosis or membranous/analgesic nephropathy as a side effect of medications (gold, penicillamine, non-steroidal anti-inflammatory drugs, acetaminophen, mesalazine and cyclosporine). RA itself, as opposed to the effects of systemic inflammation or drug toxicities, is rarely known to cause primary interstitial disease, although focal glomerulonephritis is not an uncommon finding [3].

LFM has, in contrast to many disease-modifying agents in rheumatoid disease, no known renal side effects. LFM has been incriminated once as causing IgA glomerulonephritis [4] and anti-glomerular basement membrane disease [5] in two RA patients, but not interstitial nephritis. Many other drugs can cause interstitial nephritis, but this patient was not taking any of them (e.g. non-steroidals or acetaminophen).

Our patient was on a higher dose than that which is generally prescribed for RA patients (the patient was on 34 mg/day for 26 months; maximum recommended dose is 20 mg/day), and his creatinine started to increase 1 year after the drug was introduced and returned to baseline 5 months after LFM was withdrawn (positive dechallenge). This, and the previous safety record for LFM, suggests that the interstitial nephritis was related to the chronic overdosage which persisted for many months especially as LFM has a very long half-life lasting for 15 days. Furthermore, the time course of the deterioration in renal function was very long, which argues against an idiosyncratic response.

The patient had uncontrolled hypertension which was the cause of his initial elevated creatinine. In addition, the renal biopsy showed mainly interstitial fibrosis and minimal glomerulosclerosis which is a typical lesion in hypertension-induced renal dysfunction.

Steroids are not proven in uncontrolled trials to be efficacious in the treatment of interstitial nephritis. The evidence for their benefit comes from two small trials where they induced quicker recovery, lower creatinine on follow-up, and less interstitial fibrosis in repeat renal biopsy [6,7].

This case emphasizes the importance of physicians supervising the treatment of patients having a precise knowledge of the type and dosage of drugs their patients are actually taking.

Conflict of interest statement. None declared.

Ali A. Haydar1, Nabil Hujairi1, Bruce Kirkham2, Robert Hangartner3 and David J. A. Goldsmith1

1Renal and Transplantation Unit 2Rheumatology Department 3Histopathology Department Guy's and St Thomas’ Hospitals London UK Email: david.goldsmith{at}gstt.sthames.nhs.uk

References

  1. Silva HT, Gao W, Shorthouse RA et al. Transplant Proc 1997; 29: 1292–1293[CrossRef][ISI][Medline]
  2. Lacy C. Drug Information Handbook. Lexi-Comp, Inc., USA; 1989
  3. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 1995; 38: 242–247[ISI][Medline]
  4. Kemp E, Nielsen H, Petersen LJ et al. Newer immunomodulating drugs in rheumatoid arthritis may precipitate glomerulonephritis. Clin Nephrol 2001; 55: 87–88[ISI][Medline]
  5. Bruyn GA, Veenstra RP, Halma C, Grond J. Anti-glomerular basement membrane antibody-associated renal failure in a patient with leflunomide-treated rheumatoid arthritis. Arthritis Rheum 2003; 48: 1164–1165[CrossRef][ISI][Medline]
  6. Galpin JE, Shinaberger JH, Stanley TM et al. Acute interstitial nephritis due to methicillin. Am J Med 1978; 65: 756.[ISI][Medline]
  7. Kida H, Abe T, Tomosugi N et al. Prediction of the long-term outcome in acute interstitial nephritis. Clin Nephrol 1984; 22: 55[ISI][Medline]




This Article
Extract
FREE Full Text (PDF)
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 ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Haydar, A. A.
Articles by Goldsmith, D. J. A.
PubMed
PubMed Citation
Articles by Haydar, A. A.
Articles by Goldsmith, D. J. A.