Tetracycline antibiotics are broad-spectrum bacteriostatic agents that have been used by practitioners since chlortetracycline was introduced clinically in 1953.1 They are considered to be relatively safe for adults, except for those who are pregnant or who have renal impairment. Although not prescribed as frequently as in the past, tetracyclines remain available and are used in dental practice for the treatment of periodontal diseases, often at subtherapeutic dosages, because of their ability to inhibit replication of periodontal pathogens and matrix metalloproteinases that contribute to collagenolytic activity in the periodontal sulcus.2 In this article, we describe what is believed to be a case of tetracycline hydrochloride–induced renal failure after routine tetracycline therapy.
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CASE REPORT
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The patient was a 42-year-old woman being treated by her general dentist in preparation for a mandibular partial denture. Her medical history obtained on her first visit two years earlier indicated mitral valve prolapse, hypertension and polycystic kidneys. The mitral valve prolapse was without significant regurgitation. Maintenance medication therapy at the time of the visit included metoprolol extended release (150 milligrams daily), hydrochlorothiazide (12.5 mg daily) and cyproheptadine (4 mg) three times daily before meals as an appetite stimulant.
The initial diagnostic examination, which included intraoral radiographs and a panoramic radiograph, showed several amalgam restorations and four missing molars; the remaining mandibular molars had drifted and were tilted mesially into the edentulous spaces. Localized alveolar bone loss was evident interproximally at three maxillary sites and at one mandibular site. Caries was evident on the distal aspect of a maxillary premolar and a mandibular molar.
The initial therapy consisted of tooth extractions and a partial denture. Two years later, the dentist extracted three additional teeth. The dentist prescribed penicillin (250 mg) to be taken four times daily for seven days in conjunction with propoxyphene napsylate (100 mg) and acetaminophen (650 mg) tablets (12 in all), to be taken one every four hours as needed for pain. The dentist prescribed penicillin at more than one visit.
These medications did not cause any reported complications. One month later, the general dentist extracted two mandibular molars. Prescriptions included tetracycline (250 mg) taken four times daily for seven days and 12 propoxyphene napsylate (100 mg) with acetaminophen (650 mg) tablets taken one every six hours as needed for pain.
On the fifth day after the extraction, the patient visited her family physician with chief complaints of nausea, vomiting and diarrhea for which she received a prescription of promethazine (25 mg) to be taken orally every six hours as needed for nausea; she also was instructed to avoid dairy products for one to two weeks. Because the progress note in the medical record for this visit contained no reference to tetracycline, it appears that the patient failed to advise her physician of the recently prescribed antibiotic. At the same time, the physician apparently failed to question the patient regarding any new medications.
Twelve days after the extractions, the patient visited a hospital emergency department with increasing abdominal pain, nausea and diarrhea. During the evaluation, she revealed that she had received a prescription for tetracycline, which she took for two or three days. She then discontinued the therapy owing to the nausea; however, she continued to be symptomatic. Her vital signs included a blood pressure of 157/118 millimeters of mercury, a pulse of 128 beats per minute, a temperature of 99.8°F and an oxygen saturation of 97 percent. The initial laboratory test results were as follows: white blood cell count, 11,200 cells/cubic millimeter; hemoglobin, 9.4 grams/deciliter; hematocrit, 28.5 percent; international normalized ratio, 1.45; partial thromboplastin time, 38 seconds; sodium, 143 milliequivalents/liter; potassium level, 4.8 mEq/L; chloride, 112 mEq/L; bicarbonate, 10 mEq/L; glucose, 143 mg/dL; blood urea nitrogen (BUN), 134 mg/dL; serum creatinine, 13.4 mg/dL; calcium, 7.1 mg/dL; and albumin, 4.2 g/dL. The patient’s serum ferritin level was 401 nanograms/milliliter, while her liver enzyme and amylase levels were within normal limits. Several members of her family had polycystic kidney disease. She was admitted to a hospital with a diagnosis of end-stage renal disease, and maintenance hemodialysis was initiated. During the course of several days, the patient’s condition improved. However, to date, four years later, she continues to receive hemodialysis.
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DISCUSSION
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Polycystic kidney disease.
Adult polycystic kidney disease is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy renal parenchyma. This genetic anomaly occurs in approximately one in every 400 to 1,000 live births and in all races and ethnic groups.3 The disease most commonly is autosomal dominant, associated with mutations on genes located on chromosomes 16 and 4, but it also can be acquired as a consequence of aging and use of drugs and hormones.4 The disease progresses slowly, with cysts initially involving only segments of the nephrons, so renal function is
retained until about the fourth or fifth decade of life.5 Clinical manifestations that usually result in patients’ seeking treatment and a subsequent diagnosis include an abdominal mass, chronic flank or back pain, gross hematuria, a urinary tract infection and renal calculi. 6
Pharmacology.
Tetracycline antibiotics, with the exceptions of doxycycline and perhaps minocycline, can exacerbate renal impairment in patients with pre-existing kidney disease, and clinicians should not administer these drugs to patients with renal impairment.7–14 These drugs are concentrated by the liver in the bile and excreted by the kidneys and feces. Adverse effects observed with tetracycline therapy include nausea, vomiting, diarrhea, photosensitivity, anaphylaxis, hematologic disorders and renal toxicity. Usual dosages (that is, 250 to 500 mg four times a day) administered to patients with renal impairment have resulted in hemodialysis and death, while dosages of less than 2,000 mg per day administered intravenously during pregnancy have resulted in severe hepatic toxicity and death.15 Therefore, tetracyclines must be administered with great care, if at all, to patients with renal dysfunction. Untoward effects are related directly to the particular tetracycline administered, the dosage, duration of therapy and extent of renal disease before tetracycline exposure.16 The mechanism of renal damage includes inhibiting protein synthesis and provoking a catabolic effect. Since the early 1950s, investigators have reported the propensity for renal side effects.17–24
Analysis.
This patient was not receiving treatment for polycystic kidney disease before the tetracycline exposure. At the time she received tetracycline therapy, she was being seen by a cardiologist for mitral valve prolapse and a general practitioner for treatment of hypertension and general medical care. Her most recent renal function test was administered seven years before she received the tetracycline treatment. At that time, her serum creatinine level was 1.4 mg/dL and her weight was 107 pounds. The Cockcroft-Gault formula25 estimates creatinine clearance on the basis of the patient’s age, weight and serum creatinine level.
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Using this formula, we calculated the patient’s creatinine clearance to be 44 mL/minute, indicating moderately decreased renal function (glomerular filtration rate [GFR], 30 to 59 mL/minute). According to the National Kidney Foundation guidelines in effect at the time this patient was treated, she would have been classified as being at stage 3 of 5 (that is, moderately decreased renal function) for chronic kidney disease.26 The patient was receiving hydrochlorothiazide therapy at the time she was being treated with tetracycline. This provides putative support for a stage 3 classification, because thiazide diurectics are effective when the GFR is above 30 mL/minute.27
We used the Naranjo nomogram28 to evaluate the probability that the patient’s response to the tetracycline therapy was an adverse drug reaction (that is, a causal relationship). This nomogram is a validated instrument that can be applied systematically to evaluate the probability that an adverse reaction was caused by a single drug in question. This probability is based on a numerical score obtained from answers to 10 questions and is classified as definite, probable, possible or doubtful.
With the use of this methodology, a score of 6 of 13 (probable) was obtained (Table
28). The answer to question 10 was based on the evidence of nausea, increasing abdominal pain, vomiting, diarrhea, and significantly elevated BUN and serum creatinine levels in this patient, as has been documented in other patients with renal disease who received tetracycline therapy.8,9,13,18,19,22–24,29–31 In addition, a review of the patient’s medical records from her general practitioner failed to document any new onset of signs or symptoms related to progressing chronic kidney disease or the development or progression of uremia before administration of the tetracycline therapy.
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ABSTRACT
CASE REPORT
