Acute renal failure and nephrotic syndrome associated with zafirlukast therapy

Takanori Kumagai1, Yuichi Hori1, Yukiko Kishida2, Kazuhiro Yakumaru2, Takeshi Takahashi1 and Takashi Itou1

1Department of Nephrology 2Department of Pathology Tokyo Teishin Hospital Tokyo Japan Email: horiy-tky{at}umin.ac.jp

Sir,

Zafirlukast, a selective antagonist of the type 1 cysteinyl-leukotriene receptor, is used as an alternative therapy to low doses of corticosteroids for patients with mild persistent asthma [1]. For the first time, we herein report a case of acute renal failure and nephrotic syndrome following zafirlukast treatment in a patient with underlying Churg–Strauss syndrome (CSS).

Case. A 54-year-old man with late onset asthma and chronic sinusitis was referred for nephrology consultation because of a rapid increase in serum creatinine and nephrotic range proteinuria on December 3, 2001. He had been well until March 2000 when asthma developed. He was treated with bronchodilator but asthma attacks frequently occurred and i.v. corticosteroid followed by a short course of oral corticosteroid was required each time. On September 2000, he was noted to have an erythematous rash on his trunk. Blood tests revealed moderate eosinophilia (eosinophil 1534/mm3). Skin biopsy demonstrated a dermal infiltration of eosinophils and a deposition of eosinophil debris on collagen bundles, forming flame figures, which was characteristic of eosinophilic cellulitis, so-called Wells’ syndrome. These skin lesions were resolved by increasing doses of prednisolone up to 30 mg/day. Because of persistent asthma attacks, zafirlukast was initiated in October 19, 2001. He became aware of the oedema on upper eyelid and oliguria on November 28, 2001. Urinalysis demonstrated 3+ for protein and 2+ for haemoglobin. A 24 h urine collection yielded 8.8 g of protein. Serum chemistry panel revealed total protein 4.4 g/dl, albumin 2.3 g/dl, total cholesterol 369 mg/dl and creatinine 3.6 mg/dl. Serum antinuclear antibody, anti-glomerular basement membrane antibody and the antineutrophil antibody against myeloperoxidase and proteinase-3 were all negative. Zafirlukast was stopped and high dose oral prednisolone (60 mg/day) was commenced on admission. A renal biopsy performed on the third hospital day, revealed mild mesangial proliferation and mixed infiltration of small lymphocytes, neutrophils and eosinophils in ~10% of the tubulo-interstitial area (Figure 1A). There was no active vasculitis. Immunofluorescence studies were negative, and electron microscopy revealed fusion of foot processes and wrinkling of the glomerular basement membrane with no immune deposits (Figure 1B). Renal function became normal and proteinuria declined to 1 g/day after a month of the treatment. In November 2002, the dose of oral prednisolone was tapered to 5.0 mg/day and renal function remained normal and urinalysis showed +/– for protein.




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Fig. 1. Renal biopsy specimen. (A) Light microscopy demonstrated mixed infiltration of small lymphocytes, neutrophils and eosinophils into the tubulo-interstitial area. Haematoxylin and eosin, x200. (B) Electron microscopy showed foot process effacement of epithelial cells, x5000.

 
Discussion. According to the American College of Rheumatology criteria and reviews of Churg et al. [24], our case was compatible with pre-vasculitic phase CSS, including moderate to severe asthma, peripheral blood eosinophilia, paranasal sinus abnormality and extravascular eosinophils. In this patient with the underlying CSS acute renal failure and nephrotic syndrome developed a month after the administration of zafirlukast. The association of the zafirlukast with the renal disease was speculated. The common renal lesions of CSS are focal and segmental necrotizing glomerulonephritis. Renal failure is ordinarily uncommon in CSS, although described [5]. There has been some concern about leukotriene receptor antagonists being causative of CSS [6,7], but renal lesions of our case are unlike those of CSS. Our kidney specimen demonstrating interstitial cellular infiltration and extensive foot process effacement seems to resemble the renal injury associated with non-steroidal anti-inflammatory drugs (NSAIDs), which shows interstitial nephritis and nephrotic syndrome, most commonly presenting a histological pattern of minimal glomerular change disease [8,9]. Therefore, this pathological finding allowed us to consider that zafirlukast, in itself, might induce the nephrotic syndrome with renal failure by direct toxic effect. The mechanism of renal injury associated with NSAIDs is not precisely known but activated T cells are considered to play an important role in both interstitial nephritis and nephrotic syndrome [9]. The hypothesis is presented that cyclooxygenase inhibition by the NSAIDs results in the preferential conversion of arachidonic acid to leukotrienes, which can then activate T cells. While zafirlukast blocks the cysteinyl-leukotriene 1 receptor which transduces the effects of leukotriene C4, D4 and E4, it has no effect on the receptors for leukotriene B4 and may induce an imbalance in leukotrienes [10]. Both zafirlukast and NSAIDs act on metabolism of arachidonic acid and it is of interest that our kidney specimen resembled the NSAID-associated renal injury.

To our knowledge, whatever the mechanism of renal injury, we believe this is the first case of renal disease associated with zafirlukast therapy in a patient of asthma, especially underlying CSS and would suggest that clinicians should pay attention to renal function and proteinuria after commencing zafirlukast.

Conflict of interest statement. None declared.

References

  1. Georgitis JW. The 1997 Asthma management guidelines and therapeutic issues relating to the treatment of asthma. National Heart, Lung, and Blood Institute. Chest 1999; 115: 210–217[Abstract/Free Full Text]
  2. Masi AT, Hunder GG, Lie JT et al. The American College of Rheumatology 1990 criteria for the classification of Churg–Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: 1094–1100[ISI][Medline]
  3. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 1951; 27: 277–301[ISI]
  4. Churg A. Recent advances in the diagnosis of Churg–Strauss syndrome. Mod Pathol 2001; 14: 1284–1293[ISI][Medline]
  5. Gaskin G, Clutterback EJ, Pusey CD. Renal disease in the Churg–Strauss syndrome. Contrib Nephrol 1991; 94: 58–65[Medline]
  6. Knoell DL, Lucas J, Allen TN. Churg–Strauss syndrome associated with zafirlukast. Chest 1998; 114: 332–334[Abstract/Free Full Text]
  7. Wechsler ME, Finn D, Gunawardena D et al. Churg–Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000; 117: 708–713[Abstract/Free Full Text]
  8. Warren GV, Korbet SM, Schwartz MM, Lewis EJ. Minimal change glomerulopathy associated with nonsteroidal antiinflammatory drugs. Am J Kidney Dis 1989; 13: 127–130[ISI][Medline]
  9. Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol 1984; 4: 1–6[ISI][Medline]
  10. Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg–Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Safe 1999; 21: 241–251[ISI]




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