ACUTE INTERSTITIAL NEPHRITISDUE TO OMEPRAZOLE Omeprazole is a proton pump inhibitor utilized in the treatment of reflux esophagitis and ZollingerEllison syndrome [l]. It inhibits gastric acid secretion by altering the activity of H+/K+-ATPase in gastric parietal cells. While omeprazole has been shown to have slight advantage over Hz receptor antagonists in the treatment of gastric and duodenal ulcer, it is much more effective than these agents for the relief of symptoms and mucosal healing in patients with all grades of reflux esophagitis [1,2]. Maintenance therapy is often necessary because of the high rate of relapse in reflux esophagitis [3,4]. Omeprazole reportedly has relatively few side effects, which do not differ in frequency and severity when compared with those of Hz blockers [5]. We describe here what we believe is the first case of acute interstitial nephritis due to omeprazole. A 74-year-old woman was admitted to the University of Arizona Health Sciences Center because of acute renal failure. Her past medical history is remarkable for hypertension treated with amiloride and hydrochlorothiazide for several years. One year prior to admission, she experienced epigastric burning and underwent a barium esophagram that revealed prominent reflux esophagitis. She was initially treated with famotidine 20 mg/d, but developed recurrent esophageal ulceration with stricture. Six months prior to admission, she was prescribed omeprazole 20 mg/d, which was increased to 40 mg/d. She responded well and remained symptom-free for 3 months, at which time her dose was lowered to 20 mg/d. Two weeks prior to admission, she began to notice increasing generalized malaise, fatigue, and anorexia. She discontinued her amiloride and hydrochlorothiazide 5 days prior to admission without any relief of her symptoms. She presented to her physician and was admitted to the hospital after routine blood tests showed elevated blood urea nitrogen (BUN) and creatinine levels. Her BUN and creatinine before the initiation of omeprazole therapy were 6.8 mmol/L (19 mg/dL) and 90 pmol/L (1.2 mg/dL), respectively. On admission the patient was noted to have a blood pressure of 120/60 mm Hg with a heart rate of 70 in the lying position, which changed to 84/56 mm Hg with a heart rate of 110 in the standing position. She had good skin turgor and moist mucous membranes, and had no skin rashes or flank tenderness. Results of the balance of her physical examination were normal. Laboratory studies revealed the fol-
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lowing values: hematocrit, 33.2%; white blood cell count, 10,300/mm3 without eosinophilia; serum sodium, 136 mmol/L; potassium, 4.7 mmol/L; chloride, 103 mmol/L; carbon dioxide, 17 mmol/L; BUN, 30.1 mmol/L (84 mg/dL); creatinine, 540 pmol/L (7.2 mg/dL); calcium, 2.08 mmol/L (8.3 mg/dL); phosphate, 1.97 mmol/L (6.1 mg/dL); and albumin, 29 g/L (2.9 g/dL). A urinalysis revealed a pH of 6.5, a specific gravity of 1.006, trace protein, and 35 white blood cells per high-power field without renal tubular epithelial cells or red blood cells on microscopic examination. A Wright’s stain of urine sediment revealed 6% eosinophils. Renal ultrasonography showed no hydronephrosis. A 24hour urine protein collection demonstrated 741 mg of protein. The patient was diagnosed as having drug-induced acute interstitial nephritis. All of her medications were discontinued. The patient’s appetite improved, her orthostatic changes resolved, and she remained normotensive. She was discharged 6 days later without reinstitution of her previous medications, and follow-up as an outpatient revealed continually improving BUN and creatinine levels, which decreased to 5.7 mmol/L (16 mg/dL) and 113 Mmol/L (1.5 mg/dL), respectively, 5 weeks after discharge. Her eosinophiluria also resolved. Unfortunately, her symptoms of reflux esophagitis had returned. Therapy with omeprazole 20 mg/d was reinitiated. After two doses of omeprazole, the patient again developed generalized malaise, fatigue, and anorexia. Laboratory studies revealed a BUN of 6.1 mmol/L (17 mg/dL) and a creatinine of 166 pmol/L (2.2 mg/dL). A urinalysis showed pyuria with 16% eosinophils by Wright’s stain. The omeprazole was discontinued. Her symptoms resolved rapidly, and her renal function improved with a BUN of 5.3 mmol/L (15 mg/dL) and a creatinine of 285 pmol(l.6 mg/dL), 1 week after discontinuation of omeprazole. In the presence of a rapidly improving clinical picture, a renal biopsy was deemed clinically unnecessary. Drug therapy is the most common cause of acute interstitial nephritis [6]. A triad of fever, skin rash, and eosinophilia has been described as the classic presentation of drug-induced acute interstitial nephritis [7]; however, such typical signs are not always seen [6,8]. Eosinophiluria has been observed in 75% to 100% of the cases of acute interstitial nephritis and is considered a useful marker of druginduced acute interstitial nephritis [6,7,9]. Our patient presented in renal failure with eosinophiluria after taking omeprazole on a regular basis for 6 months. Her renal failure and eosinophiluria spontaneously resolved after discontinuation of the omeprazole, only to return again after two doses
Volume 93
when the omeprazole was restarted. Resolution of her renal failure and eosinophiluria again occurred after cessation of the medication. It is clear that omeprazole was the offending agent because amiloride and hydrochlorothiaxide were never reinitiated. Reviewing the literature, we have found only one report of renal failure associated with the use of omeprazole and that was in a patient who developed alkalosis and secondary renal failure after severe vomiting resulting from duodenal stenosis [lo]. It was believed that omepraxole was not responsible for the renal failure. We believe that our case is the first reported case of acute interstitial nephritis secondary to omepraxole. Since omeprazole is markedly superior to HZ blockers for the treatment of reflux esophagitis, and is currently the best available drug for patients with Zollinger-Ellison syndrome, it will soon become a mainstay in the treatment of acid-peptic diseases [l]. Physicians who prescribe omepraxole should be aware of the association of acute interstitial nephritis with omeprazole. STEPHEN J. RUFFENACH, D.O. MARKS. SISKIND, M.D. YEONC-HAU H. LIEN, M.D., Ph.D.
University
of Arizona Health Sciences Center Tucson, Arizona
1. Maton PN. Omeprazole.
N Engl J Med 1991; 324: 965-75. 2. Lundell L. Backman L. Ekstrom P, eta/. Omeprazole or high dose ranitidine in the treatment of patients with reflux esophagitis not responding to standard doses of Hz-receptor antagonists. Aliment Pharmacol Ther 1990; 4: 145-56. 3. Jansen JB. Lamers CB. Omeprazole in the short-term treatment of reflux esophagitis. Digestion 1989; 44 Suppl 1: 40-6. 4. Hetzel DJ, Dent J, Reed WD. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95: 903-12. 5. Arnold R, Koop H. Omeprazole: long-term safety. Digestion 1989; 44 Suppl 1: 77-86. 6. Linton AL, Clark WF. Driedger AA, Turnbull I, Lindsey RM. Acute interstitial nephritis due to drugs: review of the literature with a report of nine cases, Ann Intern Med 1980; 93: 73541. 7. Galpin JE, Shinaberger JH. Stanley TM, eta/. Acute interstitial nephritisdue to methicillin. Am J Med 1978; 65: 756-65. 8. Pusey CD, Saltissi D, Bloodworth L. Rainford DJ. Christie JL. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med 1983; 52: 194-211. 9. Nolan CR Ill, Anger MS, Kelleher SP. Eosinophiluria-a new method of detection and definition of the clinical spectrum. N Engl J Med 1986; 315: 1516-9. 10. Lloyd-Davies KA. Rutgersson K, Sdlvell L. Omeprazole in the treatment of Zollinger-Ellison syndrome: a 4 year international study. Aliment Pharmacol Ther 1988; 2: 13-22. Submitted
February
27, 1992, and accepted
in revised
form June 8, 1992
DISSEMINATEDMYCOBACTERIUMFORTUITUM DISEASEIN AN AIDS PATIENT Mycobacterium fortuitum is widespread in nature and represents the most prevalent nontuberculous mycobacterium isolated from environmental sources [l]. This rapidly growing mycobacterium
usually infects skin and soft tissue, but occasionally causes pulmonary, osteoarticular, or disseminated disease [2]. In contrast to other nontuberculous mycobacteria, rapidly growing organisms have been rarely reported in patients with the acquired immunodeficiency syndrome (AIDS) [3,4]. We present here a patient with AIDS who was successfully treated for disseminated M. fortuitum disease manifested by skin, soft tissue, and osteoarticular involvement. A 39-year-old homosexual man with AIDS was evaluated for fever, sweats, anorexia, weight loss, a pustular leg ulcer, and acute painful swelling of the right elbow. He was hospitalized a month earlier because of a presumptive episode of recurrent Pneumocystis carinii pneumonia that was successfully treated with a 3-week course of oral trimethoprim-sulfamethoxazole. On physical examination, he appeared cachectic and was sweating profusely. His temperature was 39”C, pulse 120/min, blood pressure 110/70 mm Hg, and respiratory rate 18/min. He had inflammation of the right elbow with limited range of motion because of extreme pain. A 1 X 2-cm, pustular lesion on the left pretibial area was noted. He also had two, 0.5 X 0.5~cm, tender, subcutaneous nodules on the left posterior thigh and behind the right knee without inflammatory changes in the overlying skin. His white blood cell count was 5,200/mm3 (79% segmented, 12% lymphocytes, 9% monocytes), hemoglobin 6 g/dL, hematocrit 18%, platelets 394,000/mm3, total protein 6.3 g/dL, and albumin 2.7 g/dL. The rest of his chemistry profile was normal. His chest roentgenogram was unchanged and showed increased interstitial markings. A bone scan revealed increased uptake in the right elbow, right third metacarpal bone, right shoulder, and left foot, all suggestive of bone infection; however, initial plain radiographs did not show bone abnormalities. The patient was treated empirically with intravenous vancomycin and ceftazidime for 10 days. Fever resolved, the joint and skin lesions improved, and the subcutaneous nodules disappeared. Meanwhile, culture of pus from the leg lesion yielded M. fortuiturn, which also had grown from several sputum and fecal specimens (for evaluation of transient diarrhea) that were collected during his most recent hospitalization. Mycobacterial cultures of blood and bone marrow remained negative. Antimicrobial susceptibility of the organism was determined by the disc-diffusion method [5]; the organism was sensitive to vancomycin, doxycycline, minocycline, amikacin, cefoxitin, and ciprofloxacin, but resistant to trimethoprim, sulfamethoxaxole, and ceftaxidime. No other potential pathogens were identified.
October
1992
The American
Journal
of Medicine
Volume
93
473
472
October 1992 The American Journal of Medicine
lowing values: hematocrit, 33.2%; white blood cell count, 10,300/mm3 without eosinophilia; serum sodium, 136 mmol/L; potassium, 4.7 mmol/L; chloride, 103 mmol/L; carbon dioxide, 17 mmol/L; BUN, 30.1 mmol/L (84 mg/dL); creatinine, 540 pmol/L (7.2 mg/dL); calcium, 2.08 mmol/L (8.3 mg/dL); phosphate, 1.97 mmol/L (6.1 mg/dL); and albumin, 29 g/L (2.9 g/dL). A urinalysis revealed a pH of 6.5, a specific gravity of 1.006, trace protein, and 35 white blood cells per high-power field without renal tubular epithelial cells or red blood cells on microscopic examination. A Wright’s stain of urine sediment revealed 6% eosinophils. Renal ultrasonography showed no hydronephrosis. A 24hour urine protein collection demonstrated 741 mg of protein. The patient was diagnosed as having drug-induced acute interstitial nephritis. All of her medications were discontinued. The patient’s appetite improved, her orthostatic changes resolved, and she remained normotensive. She was discharged 6 days later without reinstitution of her previous medications, and follow-up as an outpatient revealed continually improving BUN and creatinine levels, which decreased to 5.7 mmol/L (16 mg/dL) and 113 Mmol/L (1.5 mg/dL), respectively, 5 weeks after discharge. Her eosinophiluria also resolved. Unfortunately, her symptoms of reflux esophagitis had returned. Therapy with omeprazole 20 mg/d was reinitiated. After two doses of omeprazole, the patient again developed generalized malaise, fatigue, and anorexia. Laboratory studies revealed a BUN of 6.1 mmol/L (17 mg/dL) and a creatinine of 166 pmol/L (2.2 mg/dL). A urinalysis showed pyuria with 16% eosinophils by Wright’s stain. The omeprazole was discontinued. Her symptoms resolved rapidly, and her renal function improved with a BUN of 5.3 mmol/L (15 mg/dL) and a creatinine of 285 pmol(l.6 mg/dL), 1 week after discontinuation of omeprazole. In the presence of a rapidly improving clinical picture, a renal biopsy was deemed clinically unnecessary. Drug therapy is the most common cause of acute interstitial nephritis [6]. A triad of fever, skin rash, and eosinophilia has been described as the classic presentation of drug-induced acute interstitial nephritis [7]; however, such typical signs are not always seen [6,8]. Eosinophiluria has been observed in 75% to 100% of the cases of acute interstitial nephritis and is considered a useful marker of druginduced acute interstitial nephritis [6,7,9]. Our patient presented in renal failure with eosinophiluria after taking omeprazole on a regular basis for 6 months. Her renal failure and eosinophiluria spontaneously resolved after discontinuation of the omeprazole, only to return again after two doses
Volume 93
when the omeprazole was restarted. Resolution of her renal failure and eosinophiluria again occurred after cessation of the medication. It is clear that omeprazole was the offending agent because amiloride and hydrochlorothiaxide were never reinitiated. Reviewing the literature, we have found only one report of renal failure associated with the use of omeprazole and that was in a patient who developed alkalosis and secondary renal failure after severe vomiting resulting from duodenal stenosis [lo]. It was believed that omepraxole was not responsible for the renal failure. We believe that our case is the first reported case of acute interstitial nephritis secondary to omepraxole. Since omeprazole is markedly superior to HZ blockers for the treatment of reflux esophagitis, and is currently the best available drug for patients with Zollinger-Ellison syndrome, it will soon become a mainstay in the treatment of acid-peptic diseases [l]. Physicians who prescribe omepraxole should be aware of the association of acute interstitial nephritis with omeprazole. STEPHEN J. RUFFENACH, D.O. MARKS. SISKIND, M.D. YEONC-HAU H. LIEN, M.D., Ph.D.
University
of Arizona Health Sciences Center Tucson, Arizona
1. Maton PN. Omeprazole.
N Engl J Med 1991; 324: 965-75. 2. Lundell L. Backman L. Ekstrom P, eta/. Omeprazole or high dose ranitidine in the treatment of patients with reflux esophagitis not responding to standard doses of Hz-receptor antagonists. Aliment Pharmacol Ther 1990; 4: 145-56. 3. Jansen JB. Lamers CB. Omeprazole in the short-term treatment of reflux esophagitis. Digestion 1989; 44 Suppl 1: 40-6. 4. Hetzel DJ, Dent J, Reed WD. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95: 903-12. 5. Arnold R, Koop H. Omeprazole: long-term safety. Digestion 1989; 44 Suppl 1: 77-86. 6. Linton AL, Clark WF. Driedger AA, Turnbull I, Lindsey RM. Acute interstitial nephritis due to drugs: review of the literature with a report of nine cases, Ann Intern Med 1980; 93: 73541. 7. Galpin JE, Shinaberger JH. Stanley TM, eta/. Acute interstitial nephritisdue to methicillin. Am J Med 1978; 65: 756-65. 8. Pusey CD, Saltissi D, Bloodworth L. Rainford DJ. Christie JL. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med 1983; 52: 194-211. 9. Nolan CR Ill, Anger MS, Kelleher SP. Eosinophiluria-a new method of detection and definition of the clinical spectrum. N Engl J Med 1986; 315: 1516-9. 10. Lloyd-Davies KA. Rutgersson K, Sdlvell L. Omeprazole in the treatment of Zollinger-Ellison syndrome: a 4 year international study. Aliment Pharmacol Ther 1988; 2: 13-22. Submitted
February
27, 1992, and accepted
in revised
form June 8, 1992
DISSEMINATEDMYCOBACTERIUMFORTUITUM DISEASEIN AN AIDS PATIENT Mycobacterium fortuitum is widespread in nature and represents the most prevalent nontuberculous mycobacterium isolated from environmental sources [l]. This rapidly growing mycobacterium
usually infects skin and soft tissue, but occasionally causes pulmonary, osteoarticular, or disseminated disease [2]. In contrast to other nontuberculous mycobacteria, rapidly growing organisms have been rarely reported in patients with the acquired immunodeficiency syndrome (AIDS) [3,4]. We present here a patient with AIDS who was successfully treated for disseminated M. fortuitum disease manifested by skin, soft tissue, and osteoarticular involvement. A 39-year-old homosexual man with AIDS was evaluated for fever, sweats, anorexia, weight loss, a pustular leg ulcer, and acute painful swelling of the right elbow. He was hospitalized a month earlier because of a presumptive episode of recurrent Pneumocystis carinii pneumonia that was successfully treated with a 3-week course of oral trimethoprim-sulfamethoxazole. On physical examination, he appeared cachectic and was sweating profusely. His temperature was 39”C, pulse 120/min, blood pressure 110/70 mm Hg, and respiratory rate 18/min. He had inflammation of the right elbow with limited range of motion because of extreme pain. A 1 X 2-cm, pustular lesion on the left pretibial area was noted. He also had two, 0.5 X 0.5~cm, tender, subcutaneous nodules on the left posterior thigh and behind the right knee without inflammatory changes in the overlying skin. His white blood cell count was 5,200/mm3 (79% segmented, 12% lymphocytes, 9% monocytes), hemoglobin 6 g/dL, hematocrit 18%, platelets 394,000/mm3, total protein 6.3 g/dL, and albumin 2.7 g/dL. The rest of his chemistry profile was normal. His chest roentgenogram was unchanged and showed increased interstitial markings. A bone scan revealed increased uptake in the right elbow, right third metacarpal bone, right shoulder, and left foot, all suggestive of bone infection; however, initial plain radiographs did not show bone abnormalities. The patient was treated empirically with intravenous vancomycin and ceftazidime for 10 days. Fever resolved, the joint and skin lesions improved, and the subcutaneous nodules disappeared. Meanwhile, culture of pus from the leg lesion yielded M. fortuiturn, which also had grown from several sputum and fecal specimens (for evaluation of transient diarrhea) that were collected during his most recent hospitalization. Mycobacterial cultures of blood and bone marrow remained negative. Antimicrobial susceptibility of the organism was determined by the disc-diffusion method [5]; the organism was sensitive to vancomycin, doxycycline, minocycline, amikacin, cefoxitin, and ciprofloxacin, but resistant to trimethoprim, sulfamethoxaxole, and ceftaxidime. No other potential pathogens were identified.
October
1992
The American
Journal
of Medicine
Volume
93
473
