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Topiramate-induced renal tubular acidosis

2004; Elsevier BV; Volume: 116; Issue: 4 Linguagem: Inglês

10.1016/j.amjmed.2003.08.021

1555-7162

Hassane Izzedine, Vincent Launay‐Vacher, Gilbert Deray,

Ion Transport and Channel Regulation

Topiramate is a sulfamate-substituted monosaccharide derived from D-fructose recently introduced for use as adjunctive treatment for partial onset seizures and secondarily for generalized seizures in adults. Multiple mechanisms are thought to be related to its antiepileptic activity, including voltage-dependent blocking of sodium channels, potentiation of γ-aminobutyrate receptors, and glutamate receptor antagonization (1Shank R.P. Gardocki J.F. Streeter A.J. Maryanoff B.E. An overview of the preclinical aspects of topiramate pharmacology, pharmacokinetics, and mechanism of action.Epilepsia. 2000; 41: S3-S9Crossref PubMed Scopus (448) Google Scholar). We report a metabolic side effect of topiramate. A 35-year-old, 60-kg woman with a known seizure disorder was hospitalized in our department for persistent hypokalemia during the preceding 2 months despite oral potassium supplementation. The patient's history was notable for an intractable seizure disorder diagnosed in 1988. She had been taking carbamazepine for more than 5 years and topiramate (600 mg daily) was added 2 years before admission for breakthrough seizure activity. Vital signs were as follows: temperature, 36.6°C; heart rate, 89 beats per minute; respiratory rate, 20 breaths per minute; and blood pressure, 110/60 mm Hg. Results of physical and neurological examinations were normal. Serum chemistry values on admission were as follows: sodium, 140 mEq/L; potassium, 3 mEq/L (reference, 3.5 to 5 mEq/L); chloride, 113 mEq/L (reference, 98 to 106 mEq/L); uric acid, 2.1 mg/dL (reference, 2.52 to 6.72 mg/dL); bicarbonate, 16 mEq/L (reference, 25 to 35 mEq/L); anion gap, 11 mEq/L. Urinalysis revealed the following: pH, 8; sodium, 120 mEq/L/d; potassium, 75 mEq/L/d; chloride, 97 mEq/L/d; and negative glycosuria. A urine drug screening was negative for drug abuse. On day 3 after admission, topiramate concentration was 2.15 mg/L (reference, 2.25 mg/L). Topiramate treatment was maintained and potassium citrate was added. The biochemical picture of our patient was compatible with proximal renal tubular acidosis. The nonanion gap metabolic acidosis associated with a positive urine anion gap suggested that the metabolic acidosis was most likely the result of a renal tubular defect rather than a consequence of diarrhea. A distal acidification defect was strongly suspected because although the patient had a nonacute proximal renal tubular acidosis, she still had a urine pH of 8. Our hypothesis was supported by previous work showing that carbonic anhydrase inhibitors may interfere with H+ secretion by the distal tubule (2Weiner I.M. Diuretics and other agents employed in the mobilization of edema fluid.in: Gilman A.G. Rall T.W. Nies T.W. Goodman and Gilman's The Pharmacologic Basis of Therapeutics. 8th ed. Pergamon Press, New York1990: 713-731Google Scholar). In addition to its multiple antiepileptic activities, topiramate inhibits isoenzymes of carbonic anhydrase (3Dodgson S.J. Shank R.P. Maryanoff B.E. Topiramate as an inhibitor of carbonic anhydrase isoenzymes.Epilepsia. 2000; 41: 35-39Crossref Scopus (198) Google Scholar) in proximal renal tubules. Reduction in carbonic anhydrase activity impairs the exchange of H+ for Na+ in the proximal tubule, as well as the reabsorption of bicarbonate (HCO3−), and may result in nephrolithiasis, paresthesia, somnolence, and metabolic acidosis (1Shank R.P. Gardocki J.F. Streeter A.J. Maryanoff B.E. An overview of the preclinical aspects of topiramate pharmacology, pharmacokinetics, and mechanism of action.Epilepsia. 2000; 41: S3-S9Crossref PubMed Scopus (448) Google Scholar). In 15 patients treated with topiramate (4Tartara A. Sartori I. Manni R. Galimberti C.A. Di Fazio M. Perucca E. Efficacy and safety of topiramate in refractory epilepsy a long-term prospective trial.Ital J Neurol Sci. 1996; 17: 429-432Crossref PubMed Scopus (32) Google Scholar), the reported adverse events were nephrolithiasis in 1 patient, paresthesia in 1, somnolence in 1, and metabolic acidosis in 2. One patient with metabolic acidosis and altered mental status had to discontinue the drug after taking 800 mg/d for 4 months. Another acidotic patient without mental status changes continued therapy. As clinical experience with topiramate has accumulated, it is now clear that substantial metabolic acidosis may develop in patients over time (5Stowe C.D. Bollinger T. James L.P. Haley T.M. Griebel M.L. Farrar 3rd, H.C. Acute mental status changes and hyperchloremic metabolic acidosis with long-term topiramate therapy.Pharmacotherapy. 2000; 20: 105-109Crossref PubMed Scopus (31) Google Scholar, 6Wilner A. Raymond K. Pollard R. Topiramate and metabolic acidosis.Epilepsia. 1999; 40: 792-795Crossref PubMed Scopus (61) Google Scholar). In most cases, the metabolic acidosis was initially mild but worsened in acute stress situations, such as with infections or surgery. Most cases required withdrawal of the drug (7Ko C.H. Kong C.K. Topiramate-induced metabolic acidosis report of two cases.Dev Med Child Neurol. 2001; 43: 701-704Crossref PubMed Google Scholar). There was no apparent correlation between the topiramate dose and development of symptomatic metabolic acidosis in reported cases. Monitoring HCO3− levels, hematuria, and hypercalciuria before and during topiramate therapy may be indicated, especially in conditions that predispose to acidosis. In addition, chronic topiramate use may result in a distal tubular acidification defect, which in turn may lead to a higher risk of calcium phosphate nephrolithiasis. Physicians should be aware of this potential drug-induced metabolic acidosis and should give their patients appropriate recommendations to minimize the risk of stone formation. We recommend that all patients treated with combination therapy be treated with increased hydration.