Increased propensity for calcium phosphate kidney stones with topiramate use

Abstract

Topiramate (TPM) is a neuromodulatory agent that was initially approved as an antiepileptic drug and is increasingly used in the treatment of a number of neurological and metabolic disorders. Among its various pharmacological actions, TPM has been shown to inhibit the activity of specific carbonic anhydrase enzymes in the kidney. This action is associated with the development of metabolic acidosis, hypocitraturia, hypercalciuria and elevated urine pH, leading to an increased risk of kidney stone disease. Despite the cautionary note in the package insert of TPM, the extent of these complications has not been fully explored. Few prescribing physicians are aware of these complications, underscoring the need for improved surveillance. Because the drug is among the most frequently prescribed agents in the US, more controlled studies are required to determine the prevalence of kidney stone disease among TPM users, and the optimal approach to prevent and treat nephrolithiasis in these individuals.

Renal Vulnerability to Drug Toxicity

“…Alkaline urine (pH Ͼ6.0) increases crystal precipitation within tubular lumens from drugs such as indinavir, oral sodium phosphate solution, and ciprofloxacin (23)(24)(25). In addition, drugs such as topiramate, zonisamide, and acetazolamide alkalinize the urine through inhibition of carbonic anhydrase and promote precipitation of calcium phosphate within tubules, thereby enhancing renal stone formation (26,27). The underlying genetic makeup of the host can also enhance renal vulnerability to potential nephrotoxins (28 -30).…”

Structure and Composition of Non-Infectious Phosphate Calculi Formed in Patients with Low and High Urinary Phosphate Concentrations

“…Using this method, we found that the mean concentrations of (free) calcium ions in group I and group II calculi were 0.24 mmol/L and 0.35 mmol/L, respectively. The percentages of total phosphorus at the given pH, calculated from the dissociation constants of phosphoric acid [13] and reported as 4 ions, were 31% and 4.6% in groups I and II calculi, respectively. Using the procedure described previously [14], we calculated that the supersaturation of urine with respect to carbonate hydroxyapatite was 6.0 for group I (the solubility product of hydroxyapatite containing 2.2 wt% carbonate was 1.17 × 10 −57 mol 9 /L 9 [15]) and 23.6 for group II (the solubility product of stoichiometric hydroxyapatite was 2.03 × 10 −59 mol 9 /L 9 [13]).…”

“…All stones containing calcium phosphate form in urine at higher pH [3][4][5][6]. In addition, hypercalciuria and hyperphosphaturia are often associated with phosphate stones [4,7].…”

“…In addition, hypercalciuria and hyperphosphaturia are often associated with phosphate stones [4,7]. Elevated urinary pH may be associated in some patients with renal tubular acidosis [8], but usually occurs in women without any clinical alterations [7].…”

Adverse Metabolic Effects of Antiepileptic Drug Treatment

“…In children, chronic metabolic acidosis may reduce growth rates. While the rate of kidney stones is estimated to be approximately 0.5 % in the general population, with some geographical variations, users of zonisamide and topiramate are found to have 1-4 % risk of developing nephrolithiasis, with men at greater risk than women (Vega et al, 2007). As with the effects of enzyme-inducing AEDs on the lipid profile, more studies are needed to elucidate more fully the clinical consequences of the drugs' effects on gonadal steroids.…”