Does Varenicline Induce Acute Interstitial Nephritis

To the Editor: A 64-year-old man with a history of chronic renal insufficiency secondary to hypertension and remote postoperative kidney injury was referred to an outpatient nephrology clinic after developing acute on chronic renal insufficiency. His baseline serum creatinine level in February 2007 was 1.4 mg/dL (to convert to μmol/L, multiply by 88.4) but had risen to 2.6 mg/dL by October 2007. The patient reported development of chills with a low-grade fever starting in May 2007. Results of urinalysis were positive for leukocytes with leukocyte casts but negative for any eosinophils or bacteria. Bilateral renal ultrasonography revealed normal cortical thickness and echogenicity with no sign of hydronephrosis. A 24-hour urine collection revealed a total protein value of 714 mg/24 h. The patient's serum creatinine level continued to increase; thus, an ultrasonography-guided renal biopsy was scheduled. Pathologic study revealed diffuse tubulointerstitial mononuclear cell infiltrates associated with severe tubulitis, consistent with acute interstitial nephritis (AIN) (Figures ​(Figures11 and ​and2).2). Moderate interstitial fibrosis and tubular atrophy were also present, but glomerulonephritis was not evident. FIGURE 1. Diffuse tubulointerstitial mononuclear cell infiltrates (periodic acid-Schiff stain, original magnificatio×10). FIGURE 2. Higher magnification highlighting the tubulointerstitial mononuclear cell infiltrates and severe tubulitis (periodic acid-Schiff stain, original magnificatio×20). The differential diagnosis included autoimmune AIN, infectious AIN, idiopathic AIN, and, of course, drug-induced AIN. The patient's white blood cell count was normal. Because of his age and medical history, an autoimmune disease was not suspected. Thus, his medication regimen was reviewed. Only 2 drugs were thought to be likely causes: omeprazole and varenicline (Chantix, Pfizer). Omeprazole has been reported to be a potential cause of AIN1; however, our patient had been taking this medication for several years with no known complications. He began taking varenicline in March 2007, seven months before presentation. Although no case reports have described varenicline-induced AIN, the patient's low-grade fevers and malaise for several months, in addition to the laboratory findings of mild proteinuria and sterile pyuria with leukocyte casts, renal biopsy indicating acute interstitial inflammation, and the timeline of varenicline initiation, pointed to this drug as the cause of his AIN. The patient immediately discontinued use of varenicline and took oral prednisone, 60 mg/d, for 10 days. Three weeks later, his serum creatinine level was 1.8 mg/dL, which was considered his new baseline level. After a detailed search of the literature, including both MEDLINE and PubMed, we found no case reports of varenicline-induced AIN. There are a few possible reasons why no cases have been published previously. First, AIN may be an exceedingly rare adverse effect of varenicline and thus not clinically important when weighed against the risks of smoking. Second, clinicians may not consider varenicline as a possible cause of AIN, and thus when a patient develops AIN while taking this drug, the clinician simply overlooks the relationship. Third, varenicline-induced AIN may be seen only in patients with underlying renal insufficiency, similar to our patient. Regardless of why no cases have been previously reported, the evidence in this case strongly implicates varenicline as the cause of the patient's AIN.