- Email: [email protected]
Tetracycline-induced renal failure after dental treatment
CLINICAL PRACTICE
C A SE REPOR T
Tetracycline-induced renal failure after dental treatment Craig S. Miller, DMD, MS; Gary J. McGarity, PharmD, MPA
etracycline 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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ABSTRACT Background. Tetracyclines are broad-spectrum antibiotics used by dental practitioners in the treatment of periodontal disease. They generally are safe in adults. However, caution is advised in patients who have pre-existing kidney disease. Case Description. A 42-year-old woman with polycystic kidney disease received a prescription for tetracycline (250 milligrams, four times daily) after undergoing tooth extractions. She developed nausea, vomiting and diarrhea within days and end-stage renal disease within two weeks of taking the antibiotic. Hemodialysis was required to stabilize the patient’s condition. Use of the Naranjo nomogram demonstrated an association between the two events. Clinical Implications. This case illustrates the importance of obtaining a thorough medical history and understanding potential adverse drug effects before prescribing a common antibiotic. Key Words. Tetracycline; polycystic kidney disease; hemodialysis; renal toxicity. JADA 2009;140(1):56-60.
Dr. Miller is a professor, Oral Medicine Section, Department of Oral Health Practice, College of Dentistry, and Department of Microbiology, Immunology & Molecular Genetics, College of Medicine, University of Kentucky, 800 Rose St., Lexington, Ky. 40536-0297, e-mail “[email protected]”. Address reprint requests to Dr. Miller. Dr. McGarity is a clinical pharmacist, Veterans Administration Outpatient Pharmacy, Baton Rouge, La.
January 2009
Copyright © 2008 American Dental Association. All rights reserved. Reprinted by permission.
C L I N I C A L P R A C T I C E CASE REPORT
CASE REPORT
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 antibi-
otic. 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. DISCUSSION
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
ABBREVIATION KEY. BUN: Blood urea nitrogen. GFR: Glomerular filtration rate.
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times a day) administered to patients with renal Adverse drug reaction probability scale and patient’s impairment have resulted score.*† in hemodialysis and death, while dosages of less than TO ASSESS THE ADVERSE DRUG POSSIBLE SCORE PATIENT’S REACTION, ANSWER THE FOLLOWING SCORE 2,000 mg per day adminisYes No Unknown/ AND GIVE THE PERTINENT SCORE Not tered intravenously during Applicable pregnancy have resulted in Are There Previous Conclusive Reports +1 0 0 +1 severe hepatic toxicity and on This Reaction? death.15 Therefore, tetracyDid the Adverse Event Appear After the +2 −1 0 +2 clines must be administered Suspected Drug Was Administered? with great care, if at all, to Did the Adverse Reaction Improve When +1 0 0 0 patients with renal dysfuncthe Drug Was Discontinued or a Specific Antagonist Was Administered? tion. Untoward effects are related directly to the parDid the Adverse Reaction Reappear +2 −1 0 0 When the Drug Was Readministered? ticular tetracycline adminisAre There Alternative Causes (Other −1 +2 0 +2 tered, the dosage, duration Than the Drug) That Could on Their of therapy and extent of Own Have Caused the Reaction? renal disease before tetracyDid the Reaction Reappear When a −1 +1 0 0 cline exposure.16 Placebo Was Given? The mechanism of renal Was the Drug Detected in the Blood (or +1 0 0 0 Other Fluids) in Concentrations Known damage includes inhibiting To Be Toxic? protein synthesis and proWas the Reaction More Severe When the +1 0 0 0 voking a catabolic effect. Dose Was Increased or Less Severe Since the early 1950s, invesWhen the Dose Was Decreased? tigators have reported the Did the Patient Have a Similar +1 0 0 0 Reaction to the Same or Similar Drugs propensity for renal side in any Previous Exposure? effects.17-24 Was the Adverse Event Confirmed by +1 0 0 +1 Analysis. This patient any Objective Evidence? was not receiving treatTOTAL SCORE —‡ — — +6 ment for polycystic kidney * Probability categories: definite ≥ 9, probable 5 to 8, possible 1 to 4, doubtful ≤ 0. disease before the tetracy† Adapted by permission from Macmillan Publishers Ltd: Clinical Pharmacology & Therapeutics by cline exposure. At the time Naranjo and colleagues. ‡ Dash indicates not applicable. she received tetracycline therapy, she was being seen retained until about the fourth or fifth decade of by a cardiologist for mitral valve prolapse and a life.5 Clinical manifestations that usually result in general practitioner for treatment of hypertension patients’ seeking treatment and a subsequent and general medical care. Her most recent renal diagnosis include an abdominal mass, chronic function test was administered seven years before flank or back pain, gross hematuria, a urinary she received the tetracycline treatment. At that tract infection and renal calculi. 6 time, her serum creatinine level was 1.4 mg/dL Pharmacology. Tetracycline antibiotics, with and her weight was 107 pounds. the exceptions of doxycycline and perhaps The Cockcroft-Gault formula25 estimates creatiminocycline, can exacerbate renal impairment in nine clearance on the basis of the patient’s age, patients with pre-existing kidney disease, and weight and serum creatinine level. clinicians should not administer these drugs to creatinine clearance (mL per minute) = patients with renal impairment.7-14 These drugs are concentrated by the liver in the bile and (140 − age in yrs) (body wt in kg) ________________________________ 0.85, if female excreted by the kidneys and feces. Adverse effects 72 (serum creatinine, mg/dL) observed with tetracycline therapy include nausea, vomiting, diarrhea, photosensitivity, anaUsing this formula, we calculated the patient’s phylaxis, hematologic disorders and renal toxcreatinine clearance to be 44 mL/minute, indicating icity. Usual dosages (that is, 250 to 500 mg four moderately decreased renal function (glomerular fil-
TABLE
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C L I N I C A L P R A C T I C E CASE REPORT
tration 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 (Table28). 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. We considered the possibility of propoxyphene, acetaminophen or both contributing to the patient’s renal failure. Propoxyphene and its metabolite norpropoxyphene can accumulate in renal insufficiency, but they are associated with cardiac and central nervous system toxicities rather than nephrotoxicity.32 Acetaminopheninduced renal toxicity generally is accompanied by concomitant increases in serum hepatic transaminase levels and acute acetaminophen intoxication.33 In this case, the patient’s liver enzymes were within normal limits and there was no hint of excessive dosing. Although recall bias is possible, in response to specific questioning, the patient reported that she could not remember taking pain medication during this incident because dental treatment usually was not painful for her.
Finally, we ruled out a reversible type of Fanconi syndrome34,35 (that is, proximal tubular damage) induced by degraded products in outdated tetracyclines, because these toxic by-products develop only in hot, moist, acidic conditions, and because citric acid is no longer used in the production of tetracyclines.36 CONCLUSION
Because clinicians do not prescribe tetracycline hydrochloride as frequently as they have in the past, they may forget its propensity to cause renal toxicity in a patient with compromised renal function. For patients in whom renal impairment is a possibility, the dentist should consider antibiotics from other drug classes or prescribe doxycycline, given its lack of renal toxicity.37 If the clinician is considering prescribing tetracycline, he or she should consult with a nephrologist to determine the severity of the patient’s renal impairment and refer him or her for renal function tests (that is, BUN, serum creatinine, creatinine clearance or GFR), along with reducing the dosage and/or increasing the interval between doses.10,38-41 ■ Disclosures. Drs. Miller and McGarity both testified as plaintiff expert witnesses in litigation associated with the clinical circumstances of this case. 1. Pallasch TJ. Antibacterial and antibiotic drugs. In: Yagiela JA, Dowd FJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 5th ed. St. Louis: Mosby; 2004:643. 2. Ingman T, Sorsa T, Suomalainen K, et al. Tetracycline inhibition and the cellular source of collagenase in gingival crevicular fluid in different periodontal diseases: a review article. J Periodontol 1993;64(2): 82-88. 3. Raja K, Coletti DP. Management of the dental patient with renal disease. Dent Clin North Am 2006;50(4):529-545. 4. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350(2): 151-164. 5. Alpers CE. The kidney. In: Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders; 2005:962-965. 6. Horie S. ADPKD: a molecular characterization and quest for treatment. Clin Exp Nephrol 2005;9(4):282-291. 7. Lehne RA. Pharmacology for Nursing Care. 5th ed. St. Louis: Saunders; 2004:908. 8. Reddy J. Tetracycline antibiotics should be avoided in patients with renal disease. N Z Med J 1981;94(696):396. 9. Lew HT, French SW. Tetracycline nephrotoxicity and nonoliguric acute renal failure. Arch Intern Med 1966;118(2):123-128. 10. Svirsky JA, Nunley J, Dent CD, Yeatts D. Dental and medical considerations of patients with renal disease. J Calif Dent Assoc 1998; 26(10):761, 763-770. 11. Montgomery EH. Antibacterial antibiotics. In: Yagiela JA, Neidle EA, Dowd FJ, eds. Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis: Mosby; 1998:519. 12. Seymour RA, Heasman PA. Pharmacological control of periodontal disease, II: antimicrobial agents. J Dent 1995;23(1):5-14. 13. Curtis JR. Diseases of the urinary system. Drug-induced renal disorders: I. Br Med J 1977;2(6081):242-244. 14. Antonovych TT. Drug-induced nephropathies. Pathol Annu 1984; 19(part 2):165-196. 15. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 7th ed. Foster City, Calif.: Biomedical Publications; 2004:1080-1081. 16. Weinstein L. Antibiotics: the tetracyclines. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics: A Textbook
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of Pharmacology, Toxicology, and Therapeutics for Physicians and Medical Students. 4th ed. New York City: Macmillan; 1970:1253-1268. 17. Kapusnik-Uner JE, Sande MA, Chambers HF. Antimicrobial agents: tetracyclines, chloramphenicol, erythromycin, and miscellaneous antibacterial agents. In: Goodman LS, Gilman A, Hardman JG, Gilman AG, Limbird LE, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 9th ed. New York City: McGraw-Hill; 1996: 1123-1153. 18. Bihorac A, Ozener C, Akoglu E, Kullu S. Tetracycline-induced acute interstitial nephritis as a cause of acute renal failure. Nephron 1999;81(1):72-75. 19. George CR, Evans RA. Tetracycline toxicity in renal failure. Med J Aust 1971;1(24):1271-1273. 20. Kunin CM, Finland M. Restrictions imposed on antibiotic therapy by renal failure. Arch Intern Med 1959;104:1030-1050. 21. Kunin CM. A guide to use of antibiotics in patients with renal disease: a table of recommended doses and factors governing serum levels. Ann Intern Med 1967;67(1):151-158. 22. Phillips ME, Eastwood JB, Curtis JR, Gower PC, De Wardener HE. Tetracycline poisoning in renal failure. Br Med J 1974;2(5911): 149-151. 23. Shils ME. Renal disease and the metabolic effects of tetracycline. Ann Intern Med 1963;58:389-408. 24. Smythe WR, Bavaria JE. Tetracycline pleurodesis-associated acute renal failure. Chest 1993;104(4):1274-1276. 25. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41. 26. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139(2):137-147.
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27. Jackson EK. Drugs affecting renal and cardiovascular function. In: Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. New York City: McGraw-Hill; 2006:756. 28. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2):239-245. 29. Kunin CM. Nephrotoxicity of antibiotics. JAMA 1967;202(3): 204-208. 30. Breitenbucher RB, Crowley LV. Hepatorenal toxicity of tetracycline. Minn Med 1970;53(9):949-955. 31. Kovnat P, Labovitz E, Levison SP. Antibiotics and the kidney. Med Clin North Am 1973;57(4):1045-1063. 32. Quan DJ, Aweeka FT. Dosing of drugs in renal failure. In: KodaKimble MA, Young LY, Kradjan WA, Guglielmo BJ, Alldredge BK, Corelli RL, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:chap 34:22. 33. Reisner L, Koo P. Pain and its management. In: Koda-Kimble MA, Young LY, Kradian WA, Guglielmo BJ, Alldredge BK, Corelli RL, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:9-18. 34. Gross JM. Fanconi syndrome (adult type) developing secondary to the ingestion of outdated tetracycline. Ann Intern Med 1963;58:523-528. 35. Frimpter GW, Timpanelli AE, Eisenmenger WJ, Stein HS, Ehrlich LI. Reversible “Fanconi syndrome” caused by degraded tetracycline. JAMA 1963;184:111-131. 36. Whelton A. Tetracyclines in renal insufficiency: resolution of a therapeutic dilemma. Bull N Y Acad Med 1978;54(2):223-236. 37. Shuler CL, Bennett WM. Nephropathies due to drugs, chemicals, or physical agents. part 1: antimicrobial nephrotoxicity. In: Massry SG, Glassock RJ, eds. Massry and Glassock’s Textbook of Nephrology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:915. 38. Little JW, Falace DA, Miller CS, Nelson LR. Dental Management of the Medically Compromised Patient. 7th ed. St. Louis: Mosby Elsevier; 2008:187-189. 39. Kerr AR. Update on renal disease for the dental practitioner. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92(1):9-16. 40. Yagiela JA, Dowd FJ. Pharmacotherapeutics: the clinical use of drugs. In: Yagiela JA, Dowd FJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 5th ed. St. Louis: Mosby; 2004:51. 41. Wynn RL, Meiller TF, Crossley HL. Drug Information Handbook for Dentistry: Oral Medicine for Medically-Compromised Patients & Specific Oral Conditions. 11th ed. Hudson, Ohio: Lexi-Comp; 2006: 1467-1469.
January 2009
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C A SE REPOR T
Tetracycline-induced renal failure after dental treatment Craig S. Miller, DMD, MS; Gary J. McGarity, PharmD, MPA
etracycline 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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ABSTRACT Background. Tetracyclines are broad-spectrum antibiotics used by dental practitioners in the treatment of periodontal disease. They generally are safe in adults. However, caution is advised in patients who have pre-existing kidney disease. Case Description. A 42-year-old woman with polycystic kidney disease received a prescription for tetracycline (250 milligrams, four times daily) after undergoing tooth extractions. She developed nausea, vomiting and diarrhea within days and end-stage renal disease within two weeks of taking the antibiotic. Hemodialysis was required to stabilize the patient’s condition. Use of the Naranjo nomogram demonstrated an association between the two events. Clinical Implications. This case illustrates the importance of obtaining a thorough medical history and understanding potential adverse drug effects before prescribing a common antibiotic. Key Words. Tetracycline; polycystic kidney disease; hemodialysis; renal toxicity. JADA 2009;140(1):56-60.
Dr. Miller is a professor, Oral Medicine Section, Department of Oral Health Practice, College of Dentistry, and Department of Microbiology, Immunology & Molecular Genetics, College of Medicine, University of Kentucky, 800 Rose St., Lexington, Ky. 40536-0297, e-mail “[email protected]”. Address reprint requests to Dr. Miller. Dr. McGarity is a clinical pharmacist, Veterans Administration Outpatient Pharmacy, Baton Rouge, La.
January 2009
Copyright © 2008 American Dental Association. All rights reserved. Reprinted by permission.
C L I N I C A L P R A C T I C E CASE REPORT
CASE REPORT
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 antibi-
otic. 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. DISCUSSION
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
ABBREVIATION KEY. BUN: Blood urea nitrogen. GFR: Glomerular filtration rate.
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times a day) administered to patients with renal Adverse drug reaction probability scale and patient’s impairment have resulted score.*† in hemodialysis and death, while dosages of less than TO ASSESS THE ADVERSE DRUG POSSIBLE SCORE PATIENT’S REACTION, ANSWER THE FOLLOWING SCORE 2,000 mg per day adminisYes No Unknown/ AND GIVE THE PERTINENT SCORE Not tered intravenously during Applicable pregnancy have resulted in Are There Previous Conclusive Reports +1 0 0 +1 severe hepatic toxicity and on This Reaction? death.15 Therefore, tetracyDid the Adverse Event Appear After the +2 −1 0 +2 clines must be administered Suspected Drug Was Administered? with great care, if at all, to Did the Adverse Reaction Improve When +1 0 0 0 patients with renal dysfuncthe Drug Was Discontinued or a Specific Antagonist Was Administered? tion. Untoward effects are related directly to the parDid the Adverse Reaction Reappear +2 −1 0 0 When the Drug Was Readministered? ticular tetracycline adminisAre There Alternative Causes (Other −1 +2 0 +2 tered, the dosage, duration Than the Drug) That Could on Their of therapy and extent of Own Have Caused the Reaction? renal disease before tetracyDid the Reaction Reappear When a −1 +1 0 0 cline exposure.16 Placebo Was Given? The mechanism of renal Was the Drug Detected in the Blood (or +1 0 0 0 Other Fluids) in Concentrations Known damage includes inhibiting To Be Toxic? protein synthesis and proWas the Reaction More Severe When the +1 0 0 0 voking a catabolic effect. Dose Was Increased or Less Severe Since the early 1950s, invesWhen the Dose Was Decreased? tigators have reported the Did the Patient Have a Similar +1 0 0 0 Reaction to the Same or Similar Drugs propensity for renal side in any Previous Exposure? effects.17-24 Was the Adverse Event Confirmed by +1 0 0 +1 Analysis. This patient any Objective Evidence? was not receiving treatTOTAL SCORE —‡ — — +6 ment for polycystic kidney * Probability categories: definite ≥ 9, probable 5 to 8, possible 1 to 4, doubtful ≤ 0. disease before the tetracy† Adapted by permission from Macmillan Publishers Ltd: Clinical Pharmacology & Therapeutics by cline exposure. At the time Naranjo and colleagues. ‡ Dash indicates not applicable. she received tetracycline therapy, she was being seen retained until about the fourth or fifth decade of by a cardiologist for mitral valve prolapse and a life.5 Clinical manifestations that usually result in general practitioner for treatment of hypertension patients’ seeking treatment and a subsequent and general medical care. Her most recent renal diagnosis include an abdominal mass, chronic function test was administered seven years before flank or back pain, gross hematuria, a urinary she received the tetracycline treatment. At that tract infection and renal calculi. 6 time, her serum creatinine level was 1.4 mg/dL Pharmacology. Tetracycline antibiotics, with and her weight was 107 pounds. the exceptions of doxycycline and perhaps The Cockcroft-Gault formula25 estimates creatiminocycline, can exacerbate renal impairment in nine clearance on the basis of the patient’s age, patients with pre-existing kidney disease, and weight and serum creatinine level. clinicians should not administer these drugs to creatinine clearance (mL per minute) = patients with renal impairment.7-14 These drugs are concentrated by the liver in the bile and (140 − age in yrs) (body wt in kg) ________________________________ 0.85, if female excreted by the kidneys and feces. Adverse effects 72 (serum creatinine, mg/dL) observed with tetracycline therapy include nausea, vomiting, diarrhea, photosensitivity, anaUsing this formula, we calculated the patient’s phylaxis, hematologic disorders and renal toxcreatinine clearance to be 44 mL/minute, indicating icity. Usual dosages (that is, 250 to 500 mg four moderately decreased renal function (glomerular fil-
TABLE
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January 2009
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C L I N I C A L P R A C T I C E CASE REPORT
tration 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 (Table28). 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. We considered the possibility of propoxyphene, acetaminophen or both contributing to the patient’s renal failure. Propoxyphene and its metabolite norpropoxyphene can accumulate in renal insufficiency, but they are associated with cardiac and central nervous system toxicities rather than nephrotoxicity.32 Acetaminopheninduced renal toxicity generally is accompanied by concomitant increases in serum hepatic transaminase levels and acute acetaminophen intoxication.33 In this case, the patient’s liver enzymes were within normal limits and there was no hint of excessive dosing. Although recall bias is possible, in response to specific questioning, the patient reported that she could not remember taking pain medication during this incident because dental treatment usually was not painful for her.
Finally, we ruled out a reversible type of Fanconi syndrome34,35 (that is, proximal tubular damage) induced by degraded products in outdated tetracyclines, because these toxic by-products develop only in hot, moist, acidic conditions, and because citric acid is no longer used in the production of tetracyclines.36 CONCLUSION
Because clinicians do not prescribe tetracycline hydrochloride as frequently as they have in the past, they may forget its propensity to cause renal toxicity in a patient with compromised renal function. For patients in whom renal impairment is a possibility, the dentist should consider antibiotics from other drug classes or prescribe doxycycline, given its lack of renal toxicity.37 If the clinician is considering prescribing tetracycline, he or she should consult with a nephrologist to determine the severity of the patient’s renal impairment and refer him or her for renal function tests (that is, BUN, serum creatinine, creatinine clearance or GFR), along with reducing the dosage and/or increasing the interval between doses.10,38-41 ■ Disclosures. Drs. Miller and McGarity both testified as plaintiff expert witnesses in litigation associated with the clinical circumstances of this case. 1. Pallasch TJ. Antibacterial and antibiotic drugs. In: Yagiela JA, Dowd FJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 5th ed. St. Louis: Mosby; 2004:643. 2. Ingman T, Sorsa T, Suomalainen K, et al. Tetracycline inhibition and the cellular source of collagenase in gingival crevicular fluid in different periodontal diseases: a review article. J Periodontol 1993;64(2): 82-88. 3. Raja K, Coletti DP. Management of the dental patient with renal disease. Dent Clin North Am 2006;50(4):529-545. 4. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350(2): 151-164. 5. Alpers CE. The kidney. In: Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders; 2005:962-965. 6. Horie S. ADPKD: a molecular characterization and quest for treatment. Clin Exp Nephrol 2005;9(4):282-291. 7. Lehne RA. Pharmacology for Nursing Care. 5th ed. St. Louis: Saunders; 2004:908. 8. Reddy J. Tetracycline antibiotics should be avoided in patients with renal disease. N Z Med J 1981;94(696):396. 9. Lew HT, French SW. Tetracycline nephrotoxicity and nonoliguric acute renal failure. Arch Intern Med 1966;118(2):123-128. 10. Svirsky JA, Nunley J, Dent CD, Yeatts D. Dental and medical considerations of patients with renal disease. J Calif Dent Assoc 1998; 26(10):761, 763-770. 11. Montgomery EH. Antibacterial antibiotics. In: Yagiela JA, Neidle EA, Dowd FJ, eds. Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis: Mosby; 1998:519. 12. Seymour RA, Heasman PA. Pharmacological control of periodontal disease, II: antimicrobial agents. J Dent 1995;23(1):5-14. 13. Curtis JR. Diseases of the urinary system. Drug-induced renal disorders: I. Br Med J 1977;2(6081):242-244. 14. Antonovych TT. Drug-induced nephropathies. Pathol Annu 1984; 19(part 2):165-196. 15. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 7th ed. Foster City, Calif.: Biomedical Publications; 2004:1080-1081. 16. Weinstein L. Antibiotics: the tetracyclines. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics: A Textbook
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of Pharmacology, Toxicology, and Therapeutics for Physicians and Medical Students. 4th ed. New York City: Macmillan; 1970:1253-1268. 17. Kapusnik-Uner JE, Sande MA, Chambers HF. Antimicrobial agents: tetracyclines, chloramphenicol, erythromycin, and miscellaneous antibacterial agents. In: Goodman LS, Gilman A, Hardman JG, Gilman AG, Limbird LE, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 9th ed. New York City: McGraw-Hill; 1996: 1123-1153. 18. Bihorac A, Ozener C, Akoglu E, Kullu S. Tetracycline-induced acute interstitial nephritis as a cause of acute renal failure. Nephron 1999;81(1):72-75. 19. George CR, Evans RA. Tetracycline toxicity in renal failure. Med J Aust 1971;1(24):1271-1273. 20. Kunin CM, Finland M. Restrictions imposed on antibiotic therapy by renal failure. Arch Intern Med 1959;104:1030-1050. 21. Kunin CM. A guide to use of antibiotics in patients with renal disease: a table of recommended doses and factors governing serum levels. Ann Intern Med 1967;67(1):151-158. 22. Phillips ME, Eastwood JB, Curtis JR, Gower PC, De Wardener HE. Tetracycline poisoning in renal failure. Br Med J 1974;2(5911): 149-151. 23. Shils ME. Renal disease and the metabolic effects of tetracycline. Ann Intern Med 1963;58:389-408. 24. Smythe WR, Bavaria JE. Tetracycline pleurodesis-associated acute renal failure. Chest 1993;104(4):1274-1276. 25. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41. 26. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139(2):137-147.
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27. Jackson EK. Drugs affecting renal and cardiovascular function. In: Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. New York City: McGraw-Hill; 2006:756. 28. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2):239-245. 29. Kunin CM. Nephrotoxicity of antibiotics. JAMA 1967;202(3): 204-208. 30. Breitenbucher RB, Crowley LV. Hepatorenal toxicity of tetracycline. Minn Med 1970;53(9):949-955. 31. Kovnat P, Labovitz E, Levison SP. Antibiotics and the kidney. Med Clin North Am 1973;57(4):1045-1063. 32. Quan DJ, Aweeka FT. Dosing of drugs in renal failure. In: KodaKimble MA, Young LY, Kradjan WA, Guglielmo BJ, Alldredge BK, Corelli RL, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:chap 34:22. 33. Reisner L, Koo P. Pain and its management. In: Koda-Kimble MA, Young LY, Kradian WA, Guglielmo BJ, Alldredge BK, Corelli RL, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:9-18. 34. Gross JM. Fanconi syndrome (adult type) developing secondary to the ingestion of outdated tetracycline. Ann Intern Med 1963;58:523-528. 35. Frimpter GW, Timpanelli AE, Eisenmenger WJ, Stein HS, Ehrlich LI. Reversible “Fanconi syndrome” caused by degraded tetracycline. JAMA 1963;184:111-131. 36. Whelton A. Tetracyclines in renal insufficiency: resolution of a therapeutic dilemma. Bull N Y Acad Med 1978;54(2):223-236. 37. Shuler CL, Bennett WM. Nephropathies due to drugs, chemicals, or physical agents. part 1: antimicrobial nephrotoxicity. In: Massry SG, Glassock RJ, eds. Massry and Glassock’s Textbook of Nephrology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:915. 38. Little JW, Falace DA, Miller CS, Nelson LR. Dental Management of the Medically Compromised Patient. 7th ed. St. Louis: Mosby Elsevier; 2008:187-189. 39. Kerr AR. Update on renal disease for the dental practitioner. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92(1):9-16. 40. Yagiela JA, Dowd FJ. Pharmacotherapeutics: the clinical use of drugs. In: Yagiela JA, Dowd FJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 5th ed. St. Louis: Mosby; 2004:51. 41. Wynn RL, Meiller TF, Crossley HL. Drug Information Handbook for Dentistry: Oral Medicine for Medically-Compromised Patients & Specific Oral Conditions. 11th ed. Hudson, Ohio: Lexi-Comp; 2006: 1467-1469.
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