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• W2015396585 abstract "Background: Topiramate is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Calcium phosphate kidney stones have been observed with topiramate treatment, but a comprehensive elucidation of stone-risk profile was not reported previously. This study explores the relationship between topiramate treatment and propensity for kidney stone formation. Methods: Thirty-two topiramate-treated subjects and 50 healthy volunteers participated in a cross-sectional study in which serum chemistry test and 24-hour urine collection results were evaluated for stone risk. Furthermore, a short-term longitudinal study was conducted in 7 patients to assess stone risk before and 3 months after topiramate treatment. Results: Serum bicarbonate levels were lower with topiramate treatment. Urinary pH, urinary bicarbonate excretion, and fractional excretion of bicarbonate increased, whereas urinary citrate excretion was significantly lower (737 ± 329 versus 278 ± 226 mg/d; P < 0.001). Net acid excretion did not change. The relative saturation ratio for brushite increased with topiramate treatment (3.14 ± 1.69 versus 1.27 ± 1.26; P < 0.001) because of urinary alkalinization and decreased urinary citrate levels. Urinary saturation of undissociated uric acid decreased (41 ± 52 versus 76 ± 60 mg/d; P < 0.001). Conclusion: Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and increased urinary pH. These changes increase the propensity to form calcium phosphate stones. Background: Topiramate is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Calcium phosphate kidney stones have been observed with topiramate treatment, but a comprehensive elucidation of stone-risk profile was not reported previously. This study explores the relationship between topiramate treatment and propensity for kidney stone formation. Methods: Thirty-two topiramate-treated subjects and 50 healthy volunteers participated in a cross-sectional study in which serum chemistry test and 24-hour urine collection results were evaluated for stone risk. Furthermore, a short-term longitudinal study was conducted in 7 patients to assess stone risk before and 3 months after topiramate treatment. Results: Serum bicarbonate levels were lower with topiramate treatment. Urinary pH, urinary bicarbonate excretion, and fractional excretion of bicarbonate increased, whereas urinary citrate excretion was significantly lower (737 ± 329 versus 278 ± 226 mg/d; P < 0.001). Net acid excretion did not change. The relative saturation ratio for brushite increased with topiramate treatment (3.14 ± 1.69 versus 1.27 ± 1.26; P < 0.001) because of urinary alkalinization and decreased urinary citrate levels. Urinary saturation of undissociated uric acid decreased (41 ± 52 versus 76 ± 60 mg/d; P < 0.001). Conclusion: Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and increased urinary pH. These changes increase the propensity to form calcium phosphate stones. TOPIRAMATE (Topamax; Ortho-McNeil, Raritan, NJ)1Topamax (topiramate) package insert. Raritan, NJ, Ortho-McNeil Pharmaceuticals. Available at: www.topamax.com. Accessed July 12, 2006Google Scholar is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Topiramate exerts its effect through multiple pharmacological mechanisms.2DeLorenzo R.J. Sombati S. Coulter D.A. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons.Epilepsia. 2000; 41: S40-S44Crossref PubMed Scopus (130) Google Scholar, 3Gibbs J.W. Sombati S. Delorenzo R.J. Coulter D.A. Cellular actions of topiramate: Blockade of kainite-evoked inward currents in cultured hippocampal neurons.Epilepsia. 2000; 41: S10-S16Crossref PubMed Scopus (199) Google Scholar, 4Skradski S. White H.S. Topiramate blocks kainite-evoked cobalt influx into cultured neurons.Epilepsia. 2000; 41: S45-S47Crossref PubMed Scopus (101) Google Scholar, 5Shank R.P. Gardocki J.F. Streeter A.J. Maryanoff B.E. An overview of the preclinical aspects of TPM: Pharmacology, pharmacokinetics, and mechanisms of action.Epilepsia. 2000; 41: S3-S9Crossref PubMed Scopus (448) Google Scholar In vitro studies showed that 1 mechanism is inhibition of isoenzymes of carbonic anhydrase (CA), including CA type II and CA type IV, which are expressed in proximal and distal renal tubular cells.6Dodgson S.J. Shank R.P. Maryanoff B.E. Topiramate as an inhibitor of carbonic anhydrase isoenzymes.Epilepsia. 2000; 41: S35-S39Crossref PubMed Scopus (198) Google Scholar, 7Schwartz G.J. Olson J. Kittelberger A.M. Matsumoto T. Waheed A. Sly W.S. Postnatal development of carbonic anhydrase IV expression in rabbit kidney.Am J Physiol. 1999; 276: F510-F520PubMed Google Scholar, 8Brown D. Zhu X.L. Sly W.S. Localization of membrane-associated carbonic anhydrase type IV in kidney epithelial cells.Proc Natl Acad Sci U S A. 1990; 87: 7457-7461Crossref PubMed Scopus (133) Google Scholar, 9Brown D. Kumpulainen T. Roth J. Orci L. Immunohistochemical localization of carbonic anhydrase in postnatal and adult rat kidney.Am J Physiol. 1983; 245: F110-F118PubMed Google Scholar Several case reports described the association between topiramate treatment and the development of kidney stones.10Lamb E.J. Stevens P.E. Nashef L. Topiramate increases biochemical risk of nephrolithiasis.Ann Clin Biochem. 2004; 41: 166-169Crossref PubMed Scopus (48) Google Scholar, 11Kuo R.L. Moran M.E. Kim D.H. Abrahams H.M. White M.D. Lingeman J.E. Topiramate-induced nephrolithiasis.J Endourol. 2002; 16: 229-231Crossref PubMed Scopus (66) Google Scholar, 12Shorvon S.D. Safety of topiramate: Adverse events and relationship to dosing.Epilepsia. 1996; 37: S18-S22Crossref PubMed Scopus (211) Google Scholar, 13Eggener S. Kim S.C. User H.M. Pazona J. Nadler R.B. Urolithiasis associated with topiramate.Int Braz J Urol. 2004; 30: 29-30Crossref PubMed Google Scholar, 14Takhar J. Manchanda R. Nephrolithiasis on topiramate therapy.Can J Psychiatry. 2000; 45: 491-493PubMed Google Scholar However, this complication has not been well recognized by practicing physicians to inform patients of this risk, and, more importantly, the mechanism of stone formation largely is unknown. The widespread and escalating use of topiramate emphasizes the importance of considering the long-term impact of this drug on kidney stone formation. This circumstance prompted us to explore the effect of topiramate on acid-base profile, urinary chemistry test results, and urinary saturation of stone-forming salts in both a cross-sectional and a short-term longitudinal study. The study was composed of 2 different phases. Thirty-two subjects (30 women, 2 men) treated with topiramate were enrolled in the cross-sectional study. Seven subjects (6 women, 1 man) treated with topiramate were enrolled in the short-term longitudinal study in which subjects were evaluated before and 3 months after topiramate treatment. All subjects from both studies were referred from the Neurology Department, University of Texas Southwestern Medical Center, Dallas, TX. Control subjects in the cross-sectional study were healthy volunteers from an ongoing study of the Center for Mineral Metabolism and Clinical Research at the University of Texas Southwestern Medical Center. The first 50 consecutive female subjects were selected arbitrarily. None of the topiramate-treated subjects in the cross-sectional study or control subjects had a prior history of nephrolithiasis. Two women in the longitudinal study reported a past history of kidney stones. No one had primary hyperparathyroidism, gastrointestinal disease, or renal impairment (endogenous creatinine clearance < 60 mL/min [<1.00 mL/s]). No patient was administered alkali treatment or other CA inhibitors. Each subject signed an informed consent for the study that was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. All subjects were evaluated in the outpatient General Clinical Research Center. One 24-hour urine sample was collected under mineral oil while following a random outpatient diet in the cross-sectional study. In the longitudinal study, one 24-hour urine collection was obtained before and 1 collection was obtained 3 months after topiramate treatment. The 24-hour urine samples were analyzed for stone-risk factors and acid-base parameters,15Pak C.Y.C. Skurla C. Harvey J. Graphic display of urinary risk factors for renal stone formation.J Urol. 1985; 134: 867-870PubMed Scopus (75) Google Scholar including total volume, creatinine, sodium, potassium, calcium, phosphorus, oxalate, uric acid, chloride, citrate, sulfate, pH, ammonium, titratable acidity (TA), bicarbonate, and net acid excretion (NAE). From these measurements, relative saturation ratios (RSRs) of calcium oxalate and brushite (CaHPO4 · 2H2O) were calculated using the EQUIL2 program (University of Florida, Gainesville, FL).16Werness P.G. Brown C.M. Smith L.H. Finlayson B. EQUIL2: A basic computer program for the calculation of urinary saturation.J Urol. 1985; 134: 1242-1244Abstract Full Text PDF PubMed Scopus (441) Google Scholar The ratio of calculated activity product in a given urine sample and respective thermodynamic solubility product yields RSRs for which a value of 1 represents saturation, greater than 1 indicates supersaturation, and less than 1 indicates undersaturation. A fasting venous blood specimen was obtained for serum chemistry tests. Topiramate-treated subjects were instructed to hold their morning dose of topiramate until after the serum specimen was obtained. Serum chemistry test results were analyzed as part of a systematic multichannel analysis (General Clinical Research Center Core Laboratory using the SYNCHRON CX9 ALX system; Beckman Coulter Inc, Fullerton, CA). Urinary calcium was analyzed by means of atomic absorption spectrophotometry. Urinary citrate was quantified enzymatically by using reagents from Boehringer-Mannheim Biochemical (Indianapolis, IN). Urinary ammonium was determined by using the glutamate dehydrogenase method. Urinary sulfate was determined by using ion chromatography. Urinary TA was measured directly by using an automated burette end-point titration system (Radiometer, Copenhagen, Denmark) as milliequivalents of hydroxide ion required to bring urine pH to 7.4. Urinary bicarbonate was calculated from measured urinary pH and Pco2, and total milliequivalents of citrate were calculated from urinary pH and a pKa of citrate2−/citrate3− of 5.6. NAE was calculated as (ammonium + TA) − (bicarbonate + citrate); all expressed in milliequivalents. Net gastrointestinal absorption of alkali (NGIA) was calculated from the formula: NGIA = (urinary sodium + potassium + calcium + magnesium) − (urinary chloride + 1.8 × phosphorus), where electrolyte excretion is in milliequivalents per day, except for phosphorus, expressed as mmoles per day.17Sakhaee K. Williams R.H. Oh M.S. et al.Alkali absorption and citrate excretion in calcium nephrolithiasis.J Bone Miner Res. 1993; 8: 789-794Crossref PubMed Scopus (59) Google Scholar Nonparametric tests were performed because some variables had skewed distributions. The control and topiramate groups were compared in the cross-sectional study by using Wilcoxon rank-sum tests. Subjects’ baseline values before starting topiramate treatment were compared with those while on topiramate treatment in the longitudinal study with Wilcoxon signed-rank test. Results are expressed as mean ± SD. Statistical analysis was performed using SAS, version 9.1.3 (SAS Institute, Cary, NC). There were no statistically significant differences in mean age, weight, and body mass index (BMI) between topiramate-treated and control subjects. Mean age was 43 ± 12 years in both the topiramate and control groups. Mean weight was 69 ± 17 kg (BMI, 26 ± 7 kg/m2) in the topiramate group versus 74 ± 22 kg (BMI, 28 ± 7 kg/m2) in the control group (P = 0.240 for weight, P = 0.183 for BMI). Mean daily dose of topiramate was 139 ± 90 mg/d, and average duration of topiramate treatment was 12.2 ± 11.7 months. Compared with controls, topiramate-treated subjects had greater serum chloride levels (111 ± 3 versus 107 ± 3 mEq/L; P < 0.001; Table 1) and lower serum total carbon dioxide content (23.8 ± 2.0 versus 26.1 ± 2.1 mEq/L; P < 0.001) and serum potassium concentrations (4.0 ± 0.4 versus 4.2 ± 0.3 mEq/L; P = 0.025).Table 1Serum and Urinary Biochemistry Test Results in Cross-Sectional StudyControlTopiramatePSerum Sodium (mEq/L)138 ± 2139 ± 30.042 Potassium (mEq/L)4.2 ± 0.34.0 ± 0.40.025 Chloride (mEq/L)107 ± 3111 ± 3<0.001 Creatinine (mg/dL)0.8 ± 0.10.9 ± 0.1<0.001 Total carbon dioxide (mEq/L)26.1 ± 2.123.8 ± 2.0<0.001 Calcium (mg/dL)9.3 ± 0.49.2 ± 0.40.811 Phosphorus (mg/dL)3.2 ± 0.53.1 ± 0.40.423 Uric acid (mg/dL)4.6 ± 1.14.5 ± 1.00.996Urine Total volume (L/d)1.88 ± 1.081.79 ± 0.860.816 Sodium (mEq/d)139 ± 57134 ± 540.718 Potassium (mEq/d)51 ± 2147 ± 220.217 Calcium (mg/d)137 ± 89171 ± 590.009 Phosphorus (mg/d)712 ± 344724 ± 2450.537 Oxalate (mg/d)28 ± 1222 ± 60.004 Uric acid (mg/d)459 ± 152413 ± 1190.085 Chloride (mEq/d)137 ± 65122 ± 500.208 Creatinine clearance (mL/min)110 ± 3089 ± 230.001Urine acid-base pH6.14 ± 0.416.46 ± 0.40<0.001 Ammonium (mEq/d)25.4 ± 10.030.0 ± 14.00.118 TA (mEq/d)21.2 ± 11.413.9 ± 6.60.002 Bicarbonate (mEq/d)4.9 ± 4.910.0 ± 8.30.002 FEbicarb (%)1.3 ± 1.53.4 ± 2.8<0.001 Citrate (mg/d)737 ± 329278 ± 226<0.001 NAE (mEq/d)30.9 ± 21.629.8 ± 23.50.812 Sulfate (mmol/d)16.7 ± 7.414.4 ± 5.40.189 NGIA (mEq/d)24.8 ± 42.231.2 ± 24.10.641NOTE. The authors define hypocitraturia as 24-hour urinary citrate excretion less than 320 mg/d.32Nicar M.J. Skurla C. Sakhaee K. Pak C.Y. Low urinary citrate excretion in nephrolithiasis.Urology. 1983; 21: 8-14Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 33Preminger G.M. Sakhaee K. Skurla C. Pak C.Y. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis.J Urol. 1985; 134: 20-23Abstract Full Text PDF PubMed Scopus (154) Google Scholar, 34Pak C.Y. Prevention and treatment of kidney stones Role of medical prevention.J Urol. 1989; 141: 798-801PubMed Google Scholar Values expressed as mean ± SD. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; serum calcium in mg/dL to mmol/L, multiply by 0.2495; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum uric acid in mg/dL to mmol/L, multiply by 0.0595; urine calcium in mg/d to mmol/d, multiply by 0.02495; urine phosphorus in mg/d to mmol/d, multiply by 0.03229; urine uric acid in mg/d to mmol/d, multiply by 0.00595; urine oxalate in mg/d to μmol/d, multiply by 11.11; urine citrate in mg/d to mmol/d, multiply by 0.00521. Open table in a new tab NOTE. The authors define hypocitraturia as 24-hour urinary citrate excretion less than 320 mg/d.32Nicar M.J. Skurla C. Sakhaee K. Pak C.Y. Low urinary citrate excretion in nephrolithiasis.Urology. 1983; 21: 8-14Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 33Preminger G.M. Sakhaee K. Skurla C. Pak C.Y. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis.J Urol. 1985; 134: 20-23Abstract Full Text PDF PubMed Scopus (154) Google Scholar, 34Pak C.Y. Prevention and treatment of kidney stones Role of medical prevention.J Urol. 1989; 141: 798-801PubMed Google Scholar Values expressed as mean ± SD. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; serum calcium in mg/dL to mmol/L, multiply by 0.2495; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum uric acid in mg/dL to mmol/L, multiply by 0.0595; urine calcium in mg/d to mmol/d, multiply by 0.02495; urine phosphorus in mg/d to mmol/d, multiply by 0.03229; urine uric acid in mg/d to mmol/d, multiply by 0.00595; urine oxalate in mg/d to μmol/d, multiply by 11.11; urine citrate in mg/d to mmol/d, multiply by 0.00521. Urinary calcium excretion was greater in the topiramate-treated group compared with controls (171 ± 59 versus 137 ± 89 mg/d [4.3 ± 1.8 versus 3.4 ± 2.2 mmol/d]; P = 0.009). Urinary oxalate excretion was lower with topiramate treatment (22 ± 6 versus 28 ± 12 mg/d [0.24 ± 0.07 versus 0.31 ± 0.13 mmol/d]; P = 0.004). Twenty-four–hour creatinine clearance was lower in topiramate-treated subjects (89 ± 23 versus 110 ± 30 mL/min [1.48 ± 0.38 versus 1.83 ± 0.50 mL/s]; P = 0.001). The remaining urinary parameters were not different between the 2 groups. Mean urinary pH was higher in topiramate-treated subjects than controls (6.46 ± 0.40 versus 6.14 ± 0.41; P < 0.001; Table 1). Individual urinary pH values are shown in Fig 1. Seventy-eight percent of topiramate-treated subjects had a urinary pH greater than the mean urinary pH of 6.14 in the control group (Fig 1). Mean urinary ammonium excretion was slightly greater with topiramate treatment (30.0 ± 14.0 versus 25.4 ± 10.0 mEq/d; P = 0.118), and urinary TA was less with topiramate treatment (13.9 ± 6.6 versus 21.2 ± 11.4 mEq/d; P = 0.002). Urinary bicarbonate and fractional excretion of bicarbonate (FEbicarb) were greater in the topiramate group (10.0 ± 8.3 versus 4.9 ± 4.9 mmol/d; P = 0.002; and 3.4% ± 2.8% versus 1.3% ± 1.5%; P < 0.001, respectively). Mean urinary citrate excretion was lower with topiramate treatment (278 ± 226 versus 737 ± 329 mg/d [4.2 ± 3.5 versus 10.7 ± 4.8 mEq/d]; P < 0.001; Fig 1). Mean urinary NAE, urinary sulfate, and NGIA were not different between the 2 groups. Mean urinary saturation of calcium oxalate was not different between the 2 groups. However, mean urinary saturation of brushite was higher (3.14 ± 1.69 versus 1.27 ± 1.26; P < 0.001; Fig 2) and mean urinary undissociated uric acid content was lower with topiramate treatment than in the control group (41 ± 52 versus 76 ± 60 mg/d; P < 0.001). Average age of this cohort was 44 ± 15 (SD) years. After 3 months of topiramate therapy, subjects lost a mean of 4 kg of body weight (from 64 ± 8 to 60 ± 9 kg; P = 0.031; BMI, 22.5 ± 2.0 to 21.2 ± 2.4 kg/m2; P = 0.031). Subjects were prescribed topiramate dosages ranging from 50 to 200 mg/d, with a mean topiramate dosage of 107 ± 45 mg/d. Three months of topiramate treatment increased the mean serum chloride concentration (108 ± 2 to 111 ± 3 mEq/L; P = 0.016; Table 2) and decreased serum total carbon dioxide content (27.4 ± 1.7 to 24.7 ± 2.0 mEq/L; P = 0.031). No other measured serum chemistry test result changed with topiramate treatment compared with baseline. Urinary calcium and urinary oxalate excretion did not change significantly with topiramate treatment. Twenty-four–hour creatinine clearance decreased (103 ± 21 to 86 ± 16 mL/min [1.72 ± 0.35 versus 1.43 ± 0.27 mL/s]; P = 0.109). The remaining urinary chemistry test results were not significantly different with topiramate treatment.Table 2Serum and Urinary Biochemistry Test Results in Short-Term Longitudinal StudyBaselineTopiramatePSerum Sodium (mEq/L)139 ± 3141 ± 40.281 Potassium (mEq/L)4.3 ± 0.34.1 ± 0.60.703 Chloride (mEq/L)108 ± 2111 ± 30.016 Total carbon dioxide (mEq/L)27.4 ± 1.724.7 ± 2.00.031 Creatinine (mg/dL)0.9 ± 0.11.0 ± 0.10.125 Phosphorus (mg/dL)2.9 ± 0.43.2 ± 0.50.484 Uric acid (mg/dL)4.5 ± 0.94.7 ± 0.70.550Urine Total volume (L/d)1.84 ± 0.721.83 ± 1.150.406 Sodium (mEq/d)132 ± 66150 ± 630.281 Potassium (mEq/d)72 ± 4857 ± 340.703 Calcium (mg/d)170 ± 65206 ± 600.250 Phosphorus (mg/d)775 ± 322742 ± 2320.859 Oxalate (mg/d)25 ± 724 ± 90.844 Uric acid (mg/d)461 ± 142428 ± 950.297 Chloride (mEq/d)134 ± 62135 ± 640.938 Creatinine clearance (mL/min)103 ± 2186 ± 160.109Urine acid-base pH6.18 ± 0.426.76 ± 0.220.031 Ammonium (mEq/d)24.2 ± 9.530.0 ± 14.80.109 TA (mEq/d)19.3 ± 7.210.3 ± 2.90.016 Bicarbonate (mmol/d)6.8 ± 8.516.0 ± 11.40.016 FEbicarb (%)1.7 ± 1.65.0 ± 3.30.046 Citrate (mg/d)819 ± 342378 ± 2220.031 NAE (mEq/d)25 ± 2018 ± 260.813 Sulfate (mmol/d)16.4 ± 9.615.9 ± 6.90.531 NGIA (mEq/L)44.7 ± 41.848.6 ± 29.20.770NOTE. The authors define hypocitraturia as 24-hour urinary citrate excretion less than 320 mg/d.32Nicar M.J. Skurla C. Sakhaee K. Pak C.Y. Low urinary citrate excretion in nephrolithiasis.Urology. 1983; 21: 8-14Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 33Preminger G.M. Sakhaee K. Skurla C. Pak C.Y. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis.J Urol. 1985; 134: 20-23Abstract Full Text PDF PubMed Scopus (154) Google Scholar, 34Pak C.Y. Prevention and treatment of kidney stones Role of medical prevention.J Urol. 1989; 141: 798-801PubMed Google Scholar Values expressed as mean ± SD. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; serum calcium in mg/dL to mmol/L, multiply by 0.2495; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum uric acid in mg/dL to mmol/L, multiply by 0.0595; urine calcium in mg/d to mmol/d, multiply by 0.02495; urine phosphorus in mg/d to mmol/d, multiply by 0.03229; urine uric acid in mg/d to mmol/d, multiply by 0.00595; urine oxalate in mg/d to μmol/d, multiply by 11.11; urine citrate in mg/d to mmol/d, multiply by 0.00521. Open table in a new tab NOTE. The authors define hypocitraturia as 24-hour urinary citrate excretion less than 320 mg/d.32Nicar M.J. Skurla C. Sakhaee K. Pak C.Y. Low urinary citrate excretion in nephrolithiasis.Urology. 1983; 21: 8-14Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 33Preminger G.M. Sakhaee K. Skurla C. Pak C.Y. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis.J Urol. 1985; 134: 20-23Abstract Full Text PDF PubMed Scopus (154) Google Scholar, 34Pak C.Y. Prevention and treatment of kidney stones Role of medical prevention.J Urol. 1989; 141: 798-801PubMed Google Scholar Values expressed as mean ± SD. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; serum calcium in mg/dL to mmol/L, multiply by 0.2495; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum uric acid in mg/dL to mmol/L, multiply by 0.0595; urine calcium in mg/d to mmol/d, multiply by 0.02495; urine phosphorus in mg/d to mmol/d, multiply by 0.03229; urine uric acid in mg/d to mmol/d, multiply by 0.00595; urine oxalate in mg/d to μmol/d, multiply by 11.11; urine citrate in mg/d to mmol/d, multiply by 0.00521. Mean urinary pH increased with topiramate treatment (6.18 ± 0.42 to 6.76 ± 0.22; P = 0.031; Fig 3A; Table 2). Topiramate also increased urinary ammonium levels and decreased urinary TA. Urinary bicarbonate excretion and FEbicarb increased with topiramate treatment (6.8 ± 8.5 to 16.0 ± 11.4 mEq/d; P = 0.016 and 1.7% ± 1.6% to 5.0% ± 3.3%; P = 0.016, respectively). Urinary citrate excretion decreased with topiramate treatment (819 ± 342 to 378 ± 222 mg/d; P = 0.031 [12.1 ± 5.5 to 5.87 ± 3.5 mEq/d; P = 0.078]; Fig 3B). Mean urinary NAE, urinary sulfate, and NGIA did not change significantly with topiramate therapy. Topiramate treatment did not alter urinary saturation of calcium oxalate. However, urinary saturation of brushite increased with topiramate treatment compared with baseline (1.94 ± 1.34 to 4.41 ± 2.20; P = 0.016; Fig 4). Urinary undissociated uric acid content decreased from 68 ± 49 to 18 ± 8 mg/d (P = 0.031). The principal goal of this study is to explore the effect of topiramate treatment on acid-base profile and propensity for kidney stone formation. This is the largest cross-sectional study to date and the first comprehensive reporting of a longitudinal study that examined risk factors underlying the increased propensity for the development of nephrolithiasis with topiramate treatment. Topiramate treatment increases urinary bicarbonate excretion and urinary pH. In conjunction with the resultant hypocitraturia, urinary calcium phosphate supersaturation increases significantly. The decrease in urinary citrate excretion likely resulted in increased urinary ionized calcium levels from decreased citrate complexation of calcium. Hypocitraturia also could contribute directly to calcium phosphate crystallization because of the lack of inhibition of crystal growth and agglomeration of preformed crystals.18Pak C.Y.C. Citrate and renal calculi.Miner Electrolyte Metab. 1987; 13: 257-266PubMed Google Scholar Mean RSR for brushite in topiramate-treated patients was similar to that in an earlier study of a large group of patients with documented pure or mixed calcium phosphate stones.19Pak C.Y. Adams-Huet B. Elucidation of factors determining formation of calcium phosphate stones.J Urol. 2004; 172: 2267-2270Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Furthermore, the increase in RSR of brushite in this study also is consistent with an increased incidence of calcium phosphate stones in topiramate-treated patients observed in previous case reports.11Kuo R.L. Moran M.E. Kim D.H. Abrahams H.M. White M.D. Lingeman J.E. Topiramate-induced nephrolithiasis.J Endourol. 2002; 16: 229-231Crossref PubMed Scopus (66) Google Scholar, 13Eggener S. Kim S.C. User H.M. Pazona J. Nadler R.B. Urolithiasis associated with topiramate.Int Braz J Urol. 2004; 30: 29-30Crossref PubMed Google Scholar A decrease in urinary oxalate excretion was observed with topiramate treatment in the cross-sectional study. The exact mechanism underlying this effect remains uncertain. This may explain the lack of change in RSR of calcium oxalate despite greater urinary calcium excretion in topiramate-treated subjects. However, risk for calcium oxalate nephrolithiasis can still increase because calcium oxalate stones develop over Randall plaques, which are hydroxyapatite deposits in the basement membrane of the loop of Henle.20Coe F.L. Evan A. Worcester E. Kidney stone disease.J Clin Invest. 2005; 115: 2598-2608Crossref PubMed Scopus (559) Google Scholar Urinary undissociated uric acid content significantly decreased, principally because of the increase in urinary pH, which could decrease the propensity for pure uric acid stone formation (Fig 2). One case series reported similar observations of increased urinary pH and decreased urinary citrate excretion in 11 topiramate-treated subjects.11Kuo R.L. Moran M.E. Kim D.H. Abrahams H.M. White M.D. Lingeman J.E. Topiramate-induced nephrolithiasis.J Endourol. 2002; 16: 229-231Crossref PubMed Scopus (66) Google Scholar This is the first study to report significantly lower creatinine clearances in subjects on topiramate therapy in the cross-sectional and longitudinal trials. It is unknown whether decreased creatinine clearance is a result of decreased glomerular filtration or impaired renal tubular secretion of creatinine from a direct effect of topiramate on the proximal renal tubular cells. Studies using urinary or plasma clearance of filtration markers are required to assess glomerular filtration rate. Topiramate treatment caused a slight, but clinically significant, decrease in serum total carbon dioxide content, indicating systemic metabolic acidosis in both the cross-sectional and longitudinal studies. Hypocitraturia was the result of a prevailing systemic and perhaps renal proximal tubular intracellular acidosis.21Hamm L.L. Hering-Smith K.S. Pathophysiology of hypocitraturic nephrolithiasis.Endocrinol Metab Clin North Am. 2002; 4: 885-893Abstract Full Text Full Text PDF Scopus (84) Google Scholar, 22Aruga S. Wehrli S. Kaissling B. et al.Chronic metabolic acidosis increases NaDC-1 mRNA and protein in rat kidney.Kidney Int. 2000; 58: 206-215Crossref PubMed Scopus (98) Google Scholar, 23Melnick J.Z. Preisig P.A. Moe O.W. Srere P. Alpern R.J. Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia.Kidney Int. 1998; 54: 160-165Crossref PubMed Scopus (53) Google Scholar, 24Melnick J.Z. Srere P.A. Elshourbagy N.A. Moe O.W. Preisig P.A. Alpern R.J. Adenosine triphosphate citrate lyase mediates hypocitraturia in rats.J Clin Invest. 1996; 98: 2381-2387Crossref PubMed Scopus (76) Google Scholar, 25Jenkins A.D. Dousa T.P. Smith L.H. Transport of citrate across renal brush border membrane: Effects of dietary acid and alkali loading.Am J Physiol. 1985; 249: F590-F595PubMed Google Scholar Biochemical changes were not caused by the influence of dietary factors because no difference was found in NGIA absorption or urinary potassium, phosphorus, or sulfate levels between patients and control subjects and between subjects before or after topiramate treatment. Steady-state NAE was not altered by topiramate despite the decreased plasma bicarbonate concentration. The increased urinary ammonium levels and hypocitraturia likely offset the decreased urinary TA and increased bicarbonaturia. The mechanism of renal tubular acidification defect with topiramate in human subjects is not well studied. In a few case record studies,26Vainsel M. Fondu P. Cadranel S. Rocmans C. Gepts W. Osteopetrosis associated with proximal and distal tubular acidosis.Acta Paediatr Scand. 1972; 61: 429-434Crossref PubMed Scopus (47) Google Scholar, 27Ohlsson A. Cumming W.A. Paul A. Sly W.S. Carbonic anhydrase II deficiency syndrome: Recessive osteopetrosis with renal tubular acidosis and cerebral calcification.Pediatrics. 1986; 77: 371-380PubMed Google Scholar, 28Bregman H. Brown J. Rogers A. Burke E. Osteopetrosis with combined proximal and distal renal tubular acidosis.Am J Kidney Dis. 1982; 11: 357-362Google Scholar, 29Nagai R. Kooh S.W. Balfe J.W. Fenton T. Halperin M.L. Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: Pathogenesis of impaired acidification.Pediatr Nephrol. 1997; 11: 633-636Crossref PubMed Scopus (46) Google Scholar in subjects with inherited CA II deficiency, both proximal and distal renal tubular acidification defects were suspected. In a detailed study of a single patient with inherited CA type II deficiency, both proximal and distal renal tubular acidification defects were verified with alkali and acid loading.29Nagai R. Kooh S.W. Balfe J.W. Fenton T. Halperin M.L. Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: Pathogenesis of impaired acidification.Pediatr Nephrol. 1997; 11: 633-636Crossref PubMed Scopus (46) Google Scholar In our study, the distinction between proximal and distal renal tubular acidification defect could not be verified without provocative alkali and acid loading. Nonetheless, the presence of systemic metabolic acidosis, elevated FEbicarb, low urinary citrate excretion, and alkaline urine are suggestive of impairment in both proximal and distal renal tubular acidification mechanisms. Results of our study are consistent with previous studies of other potent CA inhibitors that affect the CA type II isoenzyme (eg, acetazolamide) that show hypocitraturia and elevated urinary pH.30Gordon E.E. Sheps S.G. Effect of acetazolamide on citrate excretion and formation of renal calculi Report of a case and study of five normal subjects.N Engl J Med. 1957; 256: 1215-1219Crossref PubMed Scopus (33) Google Scholar, 31Hanley T. Platts M.M. Observations on the metabolic effects of the carbonic anhydrase inhibitor diamox: Mode and rate of recovery from the drug’s action.J Clin Invest. 1956; 35: 20-30Crossref PubMed Google Scholar Whether topiramate directly affects renal citrate handling independent of alteration in acid-base status has not been studied. The current constellation of findings can be attributed to carbonic anhydrase inhibition in the kidney. In neurons, topiramate blocked the voltage-gated sodium channel, enhanced γ-aminobutyric acid–evoked currents, inhibited glutamate receptor activity, inhibited voltage-activated calcium channels, and modulated potassium.2DeLorenzo R.J. Sombati S. Coulter D.A. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons.Epilepsia. 2000; 41: S40-S44Crossref PubMed Scopus (130) Google Scholar, 3Gibbs J.W. Sombati S. Delorenzo R.J. Coulter D.A. Cellular actions of topiramate: Blockade of kainite-evoked inward currents in cultured hippocampal neurons.Epilepsia. 2000; 41: S10-S16Crossref PubMed Scopus (199) Google Scholar, 4Skradski S. White H.S. Topiramate blocks kainite-evoked cobalt influx into cultured neurons.Epilepsia. 2000; 41: S45-S47Crossref PubMed Scopus (101) Google Scholar, 5Shank R.P. Gardocki J.F. Streeter A.J. Maryanoff B.E. An overview of the preclinical aspects of TPM: Pharmacology, pharmacokinetics, and mechanisms of action.Epilepsia. 2000; 41: S3-S9Crossref PubMed Scopus (448) Google Scholar It is unknown what other effects topiramate has on renal epithelia in addition to CA inhibition. The low kidney stone incidence of 1.5% reported to date with topiramate treatment12Shorvon S.D. Safety of topiramate: Adverse events and relationship to dosing.Epilepsia. 1996; 37: S18-S22Crossref PubMed Scopus (211) Google Scholar may be an underestimation because of the short length of observation, as well as the lack of any ongoing kidney stone surveillance and data collection for this drug. Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and a significant increase in urinary pH. These changes increase the propensity to form calcium phosphate stones. Of note, 1 subject (administered 300 mg/d of topiramate) in the cross-sectional study developed a symptomatic calcareous kidney stone during the follow-up period. There is a legitimate concern for the occurrence of kidney stones with long-term topiramate treatment. Physicians who prescribe or care for patients treated with topiramate must be aware of an increased risk for nephrolithiasis. The authors thank the nursing staff of the outpatient General Clinical Research Center at the University of Texas Southwestern Medical Center for their assistance during this study and Beverley Adams-Huet, MS, for her expertise with statistical analysis." @default.
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