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Urolithiasis With Topiramate in Nonambulatory Children and Young Adults
Urolithiasis With Topiramate in Nonambulatory Children and Young Adults Monisha Goyal, MD*, Richard I. Grossberg, MD†, Mary Ann O’Riordan, MS*, and Ira D. Davis, MD* Urolithiasis occurs infrequently in the pediatric population, where metabolic factors play a primary role in the pathogenesis of stone formation. Topiramate, an antiepileptic drug, is associated with a kidney stone in 1.5% of patients in published clinical trials. However, this risk may be much higher in certain populations with multiple preexisting risk factors. We performed a retrospective review of all nonambulatory and neurologically impaired individuals in a long-term care facility. Three groups were involved: those with no exposure to antiepileptic drugs, those on antiepileptic drugs other than topiramate, and those who had been treated with topiramate. Thirteen of 24 (54%) individuals on topiramate monotherapy or polytherapy developed clinical evidence of urolithiasis after a mean duration of 36.4 months. Our results suggest that nonambulatory and neurologically impaired individuals in a longterm care facility appear to be at higher risk of developing kidney stones with topiramate than previously reported. Ó 2009 by Elsevier Inc. All rights reserved. Goyal M, Grossberg RI, O’Riordan MA, Davis ID. Urolithiasis with topiramate in nonambulatory children and young adults. Pediatr Neurol 2009;40:289-294.
Introduction Pediatric urolithiasis occurs infrequently, with a prevalence varying from 1 in 1000 to 1 in 7600 hospital admissions in American children [1]. Male predominance was reported in some pediatric series, and stones occur most often in Caucasian children [2,3]. The recurrence of stones is common, and many predisposing factors often coexist in the pediatric age group [4,5].
From the *Pediatric Neurology Department, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio; and †Hattie Larlham Center for Children with Disabilities, Mantua, Ohio.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.11.004 0887-8994/09/$—see front matter
Stone formation results from supersaturation of urine, leading to crystallization. Biochemical factors pose an increased risk for stone formation, and include increased urinary excretion of calcium, uric acid, or oxalate. Inhibitors of stone crystal growth include increased urinary levels of magnesium or citrate. In addition, increased urinary sodium excretion is associated with increased urinary calcium excretion, whereas an alkaline urinary pH predisposes patients to the formation of calcium-containing stones. Over the past few decades, the etiology of stones has shifted from predisposing infections to metabolic causes [6]. Stones containing calcium account for 60-90% of all stones and indicate a metabolic etiology. Only 2-20% of analyzed stones are composed of struvite or ammonium-magnesium phosphate, and are associated with urinary tract infections. However, multiple factors may be prognostic of stone formation, including abnormal renal morphology, anatomic and functional abnormalities such as a neurogenic bladder, metabolic derangements, decreased activity level, and predisposing genetic factors. Diet and fluid intake may also influence the risk of kidney stones, with hypercalciuria as the common pathway leading to calcium stone formation [6]. Certain therapies, such as loop-diuretics (e.g., furosemide), a ketogenic diet, and carbonic anhydrase inhibitors (e.g., acetazolamide), are associated with an increased risk of nephrolithiasis. Topiramate, a broad-spectrum antiepileptic drug, is a weak carbonic anhydrase inhibitor. Although the incidence of kidney stones with topiramate was 1.5% in clinical trials [7], this incidence has not been assessed in subpopulations that may already manifest preexisting risk factors for stone formation, such as immobilization, a neurogenic bladder, and urinary tract infections. Our objective was to estimate the frequency of stones in nonambulatory, medically fragile children and young adults
Communications should be addressed to: Dr. Goyal; Pediatric Neurology Department, Rainbow Babies and Children’s Hospital; University Hospitals of Cleveland; 11100 Euclid Avenue, M/S 6090; Cleveland, OH 44106-6090. E-mail: [email protected] Received July 22, 2008; accepted November 3, 2008.
Goyal et al: Urolithiasis With Topiramate 289
receiving topiramate and with severe mental retardation and developmental disabilities. We also attempted to identify predisposing clinical factors for stone development in this patient population. Methods A retrospective chart review was performed of all individuals (n = 127) at the Hattie Larlham Center for Children with Disabilities, a long-term care facility for our population of interest. All individuals who had been treated with topiramate, alone or in combination with other antiepileptic drugs, comprised the topiramate group (n = 24). Patient data were collected from January 1, 2005 to December 31, 2007. Two control groups were created. The first (n = 22) consisted of all patients who were not on any antiepileptic medication for at least 2 years. Because the long-term use of some antiepileptic drugs was associated with osteomalacia and sometimes urolithiasis [8-10], a second control group (n = 23) was created from the remaining pool of 80 patients at the Hattie Larlham Center. This group included all patients who had characteristics similar to those in the topiramate group in regard to sex, race, pathology, mean ages within 4 years, and a similar number of antiseizure medications. Recorded parameters included sex, age, race, duration and dose of topiramate, concomitant medications, radiologic studies, diet (including calcium, vitamin D, sodium, protein, and fluid intake), and other risk factors, such as renal anomalies and urinary tract infections. We defined urolithiasis (i.e., a stone disease anywhere in the urinary tract system, from the kidney to the urethra) according to evidence of stones, either in radiologic studies or by the presence of stone fragments in diapers. Stones in diapers were initially identified by the direct-care staff, who change diapers on a regular basis at the facility, and were later confirmed by the nursing staff. Metabolic studies included serum electrolytes, urinalysis, alkaline phosphatase, and parathyroid hormone. Because our patient population was in diapers, random urine studies, rather than a 24-hour collection of urine from catheterized bladders, were collected and analyzed for calcium, creatinine, sodium, oxalate, citrate, uric acid, phosphorus, and magnesium. These urine studies were only performed in individuals with evidence of stone disease while on topiramate [11-15]. Urinary solute-to-creatinine ratios, including urate, oxalate, and citrate, were calculated as detailed elsewhere [11,14,16,17]. Treatment and any complications from stones were also recorded. This study was approved by the Institutional Review Boards of both the Hattie Larlham Center for Children with Disabilities and the University Hospitals of Cleveland.
Statistical Methods Variables are described overall and by relevant groups. Continuous variables are described with means and standard deviations when the departure form normality was not great. Medians and ranges are used when sample sizes are very small, and normality cannot be ascertained. Analysis of variance was used for continuous measures in three-group comparisons. The P value from the generalized F test is reported in the tables. Post hoc pairwise analyses were performed as appropriate. Fisher’s exact test was used for nominal variables. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC). The level of significance was set at 0.05.
Results The results are summarized in Table 1. Of 126 individuals (aged 4-45 years) residing at the Hattie Larlham Center for Children with Disabilities, 24 (19%) were treated with topiramate. The etiology of developmental disabilities varied from unknown to perinatal insults such as hypoxic-ischemic injury and stroke, and neurodevelopmental disorders such as Rett syndrome.
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All individuals were nonambulatory and had fixed dietary and fluid intake. Among the three groups, mean fluid intake ranged from 45-50.6 cm3/kg/day, mean protein intake ranged from 1.35-1.65 g/kg, mean total daily calcium intake (including diet and supplementation) varied between 17041809 mg, mean sodium intake was 43.7-58.6 mg/day, and vitamin D intake ranged from 787.5-876.3 IU/day. No patients were receiving diuretics, a ketogenic diet, or other carbonic anhydrase inhibitors such as zonisamide, which are associated with an increased risk for stones. Although statistical significance among the three groups was achieved in some dietary parameters (e.g., protein intake), this finding was not considered clinically significant. High protein intake is a risk factor for stone formation and, in fact, the highest protein intake was recorded in the first control group, on no antiepileptic drugs. Serum chemistries, however, revealed statistically significant higher serum chloride and lower serum bicarbonate values in the topiramate-treated group (P = 0.03 and < 0.001, respectively). Mean urinary pH was also nominally higher in this group compared with the two control groups, but did not reach statistical significance (P = 0.48). In the topiramate-treated group, one individual was previously diagnosed with a horseshoe kidney, without urinary outflow obstruction. Eight had a history of recurrent urinary tract infections, whereas each of the two control groups had only two individuals with urinary tract infections (P = 0.02). None had a family history or known genetic condition predisposing to urolithiasis. Stone fragments were evident in the diapers of 13 of 24 individuals (54%) on topiramate. No stone fragments occurred in any individuals in the two control groups. The incidence of stone fragments in the topiramate group was statistically significant (P < 0.001), compared with either control group. Radiologic confirmation with renal sonography or abdominal/pelvic computed tomography was achieved in 7 of 13 patients (54%). In four, stones were not evident according to ultrasound or computed tomography. Two of 13 did not undergo any radiologic studies because of unexpected death. Calcium-containing stones were evident in all four patients undergoing stone analysis. Calcium stones containing 90% calcium phosphate and 10% calcium oxalate were evident in two patients. In the other two patients, analysis revealed a mixed composition, including calcium phosphate (30%) and struvite (70%) in one patient. In the other patient, analysis on two different occasions showed calcium phosphate (95%) and struvite (5%) initially, and 3 years later, calcium phosphate (30%), calcium oxalate (10%), and struvite (60%). Data on the topiramate group are further summarized in Tables 2 and 3. Three of 13 individuals who developed stones were on topiramate monotherapy. Age at onset of stones ranged from 11-29 years. The average duration of topiramate therapy was 36.4 months (range, 1-84 months). The dose varied from 3.2-25.7 mg/kg/day (mean, 7.9 mg/kg). The topiramate dose is reported as mg/kg/day because many patients were in the adult age range, but their weight was more appropriate for the pediatric age group. Seven of
Table 1. Results: Demographic and clinical characteristics Control Group 1: No AEDs (n = 22)
Control Group 2: Nontopiramate AEDs (n = 23)
Topiramate Group (n = 24)
P-Value
12/10 20 (91%) 18.1 (5.6) 36.2 (12.1) 2 0
11/12 22 (96%) 21.0 (5.2) 41.9 (6.0) 2 0
11/13 20 (83%) 21.3 (6.4) 42.0 (9.5) 9 13
0.87 0.43 0.13 0.07 0.02 <0.001
50.6 (14.2) 32-82 1.65 (58) 1.0-3.3 1704 (498.9) 640-2475 58.6 (25.3) 27-106 876.3 (288.1) 256-1320
45 (11.4) 17.1-78.6 1.35 (0.28) 0.85-1.97 1765 (405) 775-2575 45 (24) 7-105 831 (183) 463-1156
46.7 (9.5) 31.7-70.8 1.35 (0.33) 0.86-2.5 1809 (451.7) 1245-2747 43.7 (16.7) 13.8-76.3 787.5 (236.1) 474-1345
0.27
101.9 (3.6) 91-110 26.2 (4) 19-43
101.9 (3.4) 95-107 26.3 (2.5) 20-31
100.6 (3.2) 91-105 28.3 (5.0) 20-43
103.4 (3.7) 96-110 23.9 (2.7) 19-29
0.03
n = 42 7 (8.2) 5-8.5
n = 11 6.9 (0.6) 6-8
n = 12 6.8 (0.9) 5-8
n = 19 7.2 (0.8) 5-8.5
Total (n = 69) Male/female Race: Caucasian (%) Mean age, yr (S.D.) Mean weight, kg (S.D.) Urinary tract infections Kidney stones Diet ad fluid intake Mean fluid, cm3/kg/day (S.D.) Range Mean protein, g/kg (S.D.) Range Mean calcium, mg (S.D.) Range Mean sodium, mEq (S.D.) Range Mean vitamin D, IU (S.D.) Range Serum chemistries Mean chloride, mmol/L (S.D.) Range Mean bicarbonate, mmol/L (S.D.) Range Urinalysis Mean pH (S.D.) Range
34/36 62 (90%) 20.2 (5.9) 40.1 (9.8) 13 13 47.4 (11.9) 17-82 1.5 (43) 0.85-3.3 1761.1 (448) 640-2747 48.9 (22.9) 7-106 830.3 (238) 256-1345
0.02 0.74 0.05 0.46
<0.001
0.48
Abbreviation: AEDs = Antiepileptic drugs
13 patients with stones had a history of urinary tract infections, compared with 1 of 11 patients without stones. Metabolic studies, as summarized in Table 3, were not performed in all patients in the topiramate-treated group. Seven died of complications from their underlying medical condition, and four were weaned off topiramate before all laboratory data were obtained. The fractional excretion of sodium and the median urine solute-to-creatinine ratios calculated for calcium, uric acid, oxalate, magnesium, citrate, and phosphorus are presented in Table 3. The difference in solute ratios within the topiramate-exposed group with and without stones did not reach statistical significance for any solute. However, the median calcium-to-creatinine ratio was higher than normal in the cohort with stones, consistent with hypercalciuria. The oxalate and magnesium ratios were elevated in all patients on topiramate (>0.013:1 and 0.09:1, respectively). Hypocitraturia with decreased median citrate-to-creatinine ratios was evident in both subgroups. Fractional excretion of sodium values of <1% were indicative of a prerenal etiology rather than renal or postrenal injury. Seven of 13 patients were weaned off topiramate, and two were treated with citrate supplementation. Two patients underwent lithotripsy for persistent stones. One failed lithotripsy, and needed two percutaneous nephrostomies for
stone removal. Urosepsis and retroperitoneal bleed requiring transfusion complicated lithotripsy in another patient.
Discussion Eighty percent of all urinary tract calculi in North America are calcium-containing stones, usually a mixture of calcium oxalate and calcium phosphate, and are associated with metabolic factors. Stones attributable to infection are the second most common form, typically comprising 2-20% of the total, and contain an organic matrix of struvite (Mg-NH4-PO4) and apatite (CaPO4) [2]. The most common mechanism resulting in calcium-containing stones is hypercalciuria. This may occur because of an increase in the delivery of calcium to the kidney, resulting from the use of enteral formulas high in calcium, vitamin D supplementation, or immobilization [5]. Increased renal losses of urinary calcium in the presence of a normal delivery load of calcium may occur in renal tubular acidosis, hypomagnesemia, hypocitraturia, hypophosphatemia, high protein diets, and a ketogenic diet [3,12,18]. The leading cause of secondary hypercalciuria in American children is immobilization [4]. Immobilization increases resorption from bone, causing both hypercalcemia and hypercalciuria [19].
Goyal et al: Urolithiasis With Topiramate 291
Table 2. Topiramate group: Demographic and clinical characteristics
Male/female Race: Caucasian (%) Mean age, yr (S.D.) Mean weight, kg (S.D.) Urinary tract infections Topiramate monotherapy Mean topiramate dose, mg/kg/day, range Mean duration of topiramate therapy, mo (S.D.) Range
Topiramate Group (n = 24)
Cohort With Stones (n = 13)
Cohort Without Stones (n = 11)
P-Value
11/13 20 (83%) 21.3 (6.4) 42.0 (9.5) 9 3/24 7.9, 3.2-25.7 36.4 (21.3) 1-84
8/5 11 (85%) 23.2 (6.8) 44.7 (10.9) 7 3/13 8, 3.2-25.7 31 (23.5) 1-84
3/8 9 (81%) 19.1 (5.5) 38.8 (6.7) 2 0/11 7.7, 4.2-17.5 42.9 (17.2) 17-72
0.12 0.80 0.12 0.40 0.10 0.22 0.54 0.12
In our nonambulatory patient population, diets are high in calcium, to optimize bone health and combat osteomalacia. There is also increased bone resorption because of immobility. This increased filtered calcium load is then passed through a presumed neurogenic bladder where there is urinary retention and stasis, an environment conducive to infection and stone formation. Antiepileptic drugs may cause osteomalacia by increasing bone resorption and augmenting hypercalciuria, especially in the context of polypharmacy [8-10]. Topiramate enhances this predisposition at multiple steps. First, it is a carbonic anhydrase inhibitor, which results in a reduction
of the reabsorption of filtered carbonate. This renal bicarbonate loss has a threefold effect, which includes an inability to form an appropriately acidified urine, metabolic acidosis, and the increased tubular reabsorption of citrate, with consequent hypocitraturia [9,20]. The rise in urinary pH increases the monohydrogen phosphate concentration, which then combines with calcium, forming the nidus for a subsequent crystallization of calcium stones [18]. Chronic metabolic acidosis, in turn, results in increased bone resorption, a risk factor for hypercalciuria [21]. Decreased urinary citrate, which normally forms a soluble complex with calcium, is also a risk factor for hypercalciuria. Hypocitraturia
Table 3. Topiramate group: Metabolic studies
Spot urine Calcium/Cr, mg/mg Uric acid/Cr, mg/dL GFR Oxalate/Cr, mol/mol Magnesium/Cr, mg/mg Citrate/Cr, g/g Phosphorus/Cr, mg/mg Fractional excretion of sodium Urinalysis pH Serum chemistries Bicarbonate, mmol/L Chloride, mmol/L Cr, mg/dL BUN, mg/dL Alk phos, U/L Parathyroid hormone, pg/mL
Topiramate Group (n = 24) n Median (Range)
Cohort With Stones (n = 13) n Median (Range)
Cohort Without Stones (n = 11) n Median (Range)
15 14 15 14 15 14 14
0.30 (0.06-1.0) 0.18 (0.09-0.33) 0.07 (0.01-0.1) 0.28 (0.08-3.08) 0.19 (0.02-1.25) 0.55 (0.01-1.09) 0.58 (0.28-1.61)
6 5 6 5 6 5 5
0.37 (0.09-1.0) 0.21 (0.12-0.33) 0.07 (0.01-0.07) 0.34 (0.08-0.74) 0.16 (0.02-1.25) 0.66 (0.27-1.09) 0.52 (0.37-1.61)
9 9 9 9 9 9 9
19
7 (5-8.5)
10
7 (5-8.5)
9
7.5 (6.5-8)
0.51
24 24 19 18 14 14
24 (19-29) 103 (96-110) 0.4 (0.2-1) 13 (5-24) 130 (66-285) 9.5 (3-42)
13 13 9 9 5 5
25 (19-29) 103 (96-110) 0.4 (0.2-1) 14 (5-24) 147 (88-285) 11 (7-42)
11 11 10 9 9 9
24 (19-27) 103 (97-109) 0.45 (0.3-0.8) 13 (6-20) 123 (66-243) 8 (3-41)
0.26 0.62 0.11 0.31 0.29 0.32
0.16 (0.06-0.59) 0.17 (0.09-0.25) 0.08 (0.03-0.1) 0.27 (0.12-3.08) 0.20 (0.08-0.34) 0.50 (0.01-0.83) 0.64 (0.28-1.27)
P-Value
0.14 0.59 0.77 0.69 0.68 0.42 0.70
Normal values of urinary solute: Cr ratios (ratios expressed as [mg/dL solute]/[mg/dL Cr], except as otherwise noted) [14,16,18]. Calcium, <0.21:1. Uric acid, <0.53 mg/dL GFR. Oxalate (mol/mol), <0.013:1. Citrate (g/g), 0.51:1. Magnesium, <0.09:1. Phosphorus, 0.38-1.26. FENA, 1-3%. Abbreviations: Alk phos = Alkaline phosphatase BUN = Blood urea nitrogen Cr = Creatinine FENA = Fractional excretion sodium [(urinary sodium)/serum sodium/(urine Cr/serum Cr)] GFR = Glomerular filtration rate PTH = Parathyroid hormone
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may also contribute directly to calcium phosphate crystallization, because citrate inhibits crystal growth and the agglomeration of preformed crystals [22]. This pattern of inadequate acidification of urine, metabolic acidosis, and hypocitraturia constitutes a strong risk factor for calcium urolithiasis [23], further exacerbated by other risk factors described with topiramate therapy such as hyperoxaluria. In our population, we found higher urinary pH and lower serum bicarbonate in the topiramate group, consistent with its known effects of decreased urinary acidification and metabolic acidosis [24]. Although the numbers are small, spot urine chemistries revealed increased urinary calcium excretion in topiramate patients who developed stones compared with stone-free patients, underscoring the role of hypercalciuria in stone predisposition in this subpopulation. Because there were no differences in environmental factors within the topiramate group, hypercalciuria in some may indicate either an inherent genetic predisposition, or more likely, a predisposition that was induced by topiramate exposure. The mechanism of topiramate-induced hypercalciuria likely results from systemic acidosis, which is implicated in impaired renal tubular calcium absorption [18]. Other spot urinary solute-to-creatinine ratios in the topiramate group were normal for uric acid (glomerular filtration rate, <0.53 mg/dL), elevated for oxalate (>0.013:1), and lower for citrate (<0.51:1) [14]. These findings are in agreement with other reports [24-26]. Magnesium and phosphorus are inhibitors of crystallization, and both the elevated magnesium and normal phosphorus ratios in our patients should have decreased the risk of urolithiasis. The important role of topiramate in the pathogenesis of stone formation is further highlighted by the observation that these patients developed stones despite exhibiting the lowest dietary intake of sodium and protein, which would be also be expected to reduce the risk of stone formation. The frequently cited incidence of stones in 1.5% of individuals exposed to topiramate was ascertained from clinical trials. However, the incidence with long-term topiramate therapy is not known, and small case series often cite higher percentages. Bootsma et al. reported a 1.1% incidence of kidney stones in adults. However, an additional 5.6% incidence of urogenital signs was evident [27]. In children, Coppola et al. reported incidences of 4.5-5.6%, with additional patients experiencing intermittent hematuria [28]. In our study, we defined urolithiasis (stone disease anywhere in the urinary tract system from the kidney to the urethra) according to evidence of stones either in radiologic studies or by the presence of stone fragments in diapers. An incidence of stones of 56% in our cohort reflects a markedly augmented risk with topiramate when there are preexisting risks for hypercalciuria and urinary stones. Our small cohort does not negate the possibility that this group was predisposed to stones because of chronic urinary tract infections. On the other hand, because this vulnerable subpopulation was already in a predisposing environment for urinary tract infections, it is quite possible that infection may tilt the environment in favor of stone formation with
the additive stress of metabolic changes induced by topiramate [16]. Alternatively, bacteriuria is not an uncommon finding in nonambulatory populations with neurogenic bladder [29,30], and stones may become secondarily infected or have a mixed composition of both struvite and calcium [31]. Poorly acidified urine associated with topiramate is conducive not only to calcium-containing stones but also to stones containing struvite [32]. This would explain the mixed composition of recurrent stones in one patient. This study has several limitations, including its retrospective data collection, small number of patients, and lack of metabolic and radiologic evaluations of all patients on topiramate therapy. Our study may also underestimate the prevalence of stone disease in this cohort, because radiologic studies were not performed in all patients treated with topiramate. Ideally, metabolic studies should have been performed before as well as during topiramate use. Stone analysis was also not performed in all individuals. However, patients at a center such as Hattie Larlham provide a unique opportunity to study the frequency of stones and associated morbidity in neurologically impaired individuals because of several controlled risk factors, including fixed dietary and fluid intake. Medication compliance is also not an issue. Our data indicate that this subpopulation has a much higher frequency of kidney stone formation when exposed to drugs such as topiramate than previously reported. This vulnerability increases because of preexisting risk factors for stone formation, including bladder stasis from immobility and neurogenic bladder, and a metabolic milieu predisposing to hypercalciuria from increased bone resorption and calcium supplementation. Urolithiasis has a high rate of recurrence, and is associated with significant expense and patient morbidity [30]. As seen in two of our patients, it may lead to serious complications, necessitating surgical treatment. Because the typical signs of flank and abdominal Table 4. Stone formation with topiramate: Risk factors and proposed screening/preventative measures Risk Factors
Screening Measures/Treatment
Dehydration Immobility
Increase in fluid intake Minimization of complications of immobility: Physical therapy Diagnosis and management of osteopenia Optimization of bladder function to minimize stasis and risk of infection
Chronic urinary tract infections; Neurogenic bladder Metabolic
Hypercalciuria Hypocitraturia Alkaline urine (pH >6.5-7) Metabolic acidosis Drugs
Biannual screening with spot urine studies for calcium and citrate; urinalysis; serum bicarbonate Restriction of total calcium intake and supplementation to <1500 mg/day Citrate supplementation if low urinary citrate Correction of metabolic acidosis
Goyal et al: Urolithiasis With Topiramate 293
pain and hematuria were not evident in our cohort and are difficult to ascertain in neurologically impaired children, clinicians must remain vigilant and adopt aggressively preventative measures. For a more complete list of risk factors and treatments of urolithiasis, the reader is referred to several excellent review articles [6,11,14,32]. A summary of the common risk factors in our population and our proposed screening and preventative measures is provided in Table 4. These include increasing fluid intake, reducing urine calcium excretion with thiazides, restricting sodium intake, minimizing complications from immobilization, and optimizing bladder function to minimize stasis and the risk of infection. We advocate spot urine studies as simple screening tools to assess predisposition for stones in high-risk subpopulations such as our group. Prospective studies using such screening tools and optimizing preventative measures will help substantiate our observations.
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[13] Stapleton FB, Noe HN, Jerkins GR, et al. Urinary excretion of calcium following an oral calcium-loading test in healthy children. Pediatrics 1982;69:594-7. [14] Santos-Victoriano M, Brouhard BH, Cunningham RJ. Renal stone disease in children. Clin Pediatr (Phila) 1998;37:583-600. [15] Matos V. Urinary oxalate and urate to creatinine rations in a healthy pediatric population. Am J Kidney Dis 1999;34:e1. [16] Polinsky MS, Kaiser KA, Baluarte HJ, et al. Renal stones and hypercalciuria. Adv Pediatr 1993;40:353-84. [17] Hoppe B, Langman CB. Hypocitraturia in patients with urolithiasis. Arch Dis Child 1997;76:174-5. [18] Vega D, Maalouf NM, Sakhaee K. Increased propensity for calcium phosphate kidney stones with topiramate use. Expert Opin Drug Saf 2007;6:547-57. [19] Mu¨ller CE, Bianchetti M, Kaiser G. Immobilization, a risk factor for urinary tract stones in children: A case report. Eur J Pediatr Surg 1994; 4:201-4. [20] Takeoka M, Holmes GL, Thiele E, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001;42:387-92. [21] Wiederkehr M, Krapf R. Metabolic and endocrine effects of metabolic acidosis in humans. Swiss Med Wkly 2001;131:127-32. [22] Pak C, Poindexter J, Adams-Huet B, et al. Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am J Med 2003;115:26-32. [23] Lamb E. Topiramate increases biochemical risk of nephrolithiasis. Ann Clin Biochem 2004;41:166-9. [24] Welch BJ, Graybeal D, Moe OW, et al. Biochemical and stonerisk profiles with topiramate treatment. Am J Kidney Dis 2006;48:555-63. [25] Gokce C, Gokce O, Baydine C, et al. Use of random urine samples to estimate total urinary calcium and phosphate excretion. Arch Intern Med 1991;151:1587-8. [26] Kuo R, Moran M, Kim D, et al. Topiramate-induced nephrolithiasis. J Endourol 2002;16:229-31. [27] Bootsma HP, Coolen F, Aldencamp AP, et al. Topiramate in clinical practice: Long term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav 2004;5:380-7. [28] Coppola G, Caliendo G, Veggiotti P, et al. Topiramate as add on drug in children, adolescents, and young adults with Lennox-Gastaut syndrome: An Italian multicentric study. Epilepsy Res 2002;51:147-53. [29] Sauerwein D. Urinary tract infection in patients with neurogenic bladder dysfunction. Int J Antimicrob Agents 2002;19:592-7. [30] Matlaga B, Kim S, Watkins S, et al. Changing composition of renal calculi in patients with neurogenic bladder. J Urol 2006;175: 1716-9. [31] Wilson D. Clinical and laboratory evaluation of renal stone patients. Endocrinol Metab Clin North Am 1990;19:773-803. [32] Pearle MS. Prevention of nephrolithiasis. Curr Opin Nephrol Hypertens 2001;10:203-9.
Introduction Pediatric urolithiasis occurs infrequently, with a prevalence varying from 1 in 1000 to 1 in 7600 hospital admissions in American children [1]. Male predominance was reported in some pediatric series, and stones occur most often in Caucasian children [2,3]. The recurrence of stones is common, and many predisposing factors often coexist in the pediatric age group [4,5].
From the *Pediatric Neurology Department, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio; and †Hattie Larlham Center for Children with Disabilities, Mantua, Ohio.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.11.004 0887-8994/09/$—see front matter
Stone formation results from supersaturation of urine, leading to crystallization. Biochemical factors pose an increased risk for stone formation, and include increased urinary excretion of calcium, uric acid, or oxalate. Inhibitors of stone crystal growth include increased urinary levels of magnesium or citrate. In addition, increased urinary sodium excretion is associated with increased urinary calcium excretion, whereas an alkaline urinary pH predisposes patients to the formation of calcium-containing stones. Over the past few decades, the etiology of stones has shifted from predisposing infections to metabolic causes [6]. Stones containing calcium account for 60-90% of all stones and indicate a metabolic etiology. Only 2-20% of analyzed stones are composed of struvite or ammonium-magnesium phosphate, and are associated with urinary tract infections. However, multiple factors may be prognostic of stone formation, including abnormal renal morphology, anatomic and functional abnormalities such as a neurogenic bladder, metabolic derangements, decreased activity level, and predisposing genetic factors. Diet and fluid intake may also influence the risk of kidney stones, with hypercalciuria as the common pathway leading to calcium stone formation [6]. Certain therapies, such as loop-diuretics (e.g., furosemide), a ketogenic diet, and carbonic anhydrase inhibitors (e.g., acetazolamide), are associated with an increased risk of nephrolithiasis. Topiramate, a broad-spectrum antiepileptic drug, is a weak carbonic anhydrase inhibitor. Although the incidence of kidney stones with topiramate was 1.5% in clinical trials [7], this incidence has not been assessed in subpopulations that may already manifest preexisting risk factors for stone formation, such as immobilization, a neurogenic bladder, and urinary tract infections. Our objective was to estimate the frequency of stones in nonambulatory, medically fragile children and young adults
Communications should be addressed to: Dr. Goyal; Pediatric Neurology Department, Rainbow Babies and Children’s Hospital; University Hospitals of Cleveland; 11100 Euclid Avenue, M/S 6090; Cleveland, OH 44106-6090. E-mail: [email protected] Received July 22, 2008; accepted November 3, 2008.
Goyal et al: Urolithiasis With Topiramate 289
receiving topiramate and with severe mental retardation and developmental disabilities. We also attempted to identify predisposing clinical factors for stone development in this patient population. Methods A retrospective chart review was performed of all individuals (n = 127) at the Hattie Larlham Center for Children with Disabilities, a long-term care facility for our population of interest. All individuals who had been treated with topiramate, alone or in combination with other antiepileptic drugs, comprised the topiramate group (n = 24). Patient data were collected from January 1, 2005 to December 31, 2007. Two control groups were created. The first (n = 22) consisted of all patients who were not on any antiepileptic medication for at least 2 years. Because the long-term use of some antiepileptic drugs was associated with osteomalacia and sometimes urolithiasis [8-10], a second control group (n = 23) was created from the remaining pool of 80 patients at the Hattie Larlham Center. This group included all patients who had characteristics similar to those in the topiramate group in regard to sex, race, pathology, mean ages within 4 years, and a similar number of antiseizure medications. Recorded parameters included sex, age, race, duration and dose of topiramate, concomitant medications, radiologic studies, diet (including calcium, vitamin D, sodium, protein, and fluid intake), and other risk factors, such as renal anomalies and urinary tract infections. We defined urolithiasis (i.e., a stone disease anywhere in the urinary tract system, from the kidney to the urethra) according to evidence of stones, either in radiologic studies or by the presence of stone fragments in diapers. Stones in diapers were initially identified by the direct-care staff, who change diapers on a regular basis at the facility, and were later confirmed by the nursing staff. Metabolic studies included serum electrolytes, urinalysis, alkaline phosphatase, and parathyroid hormone. Because our patient population was in diapers, random urine studies, rather than a 24-hour collection of urine from catheterized bladders, were collected and analyzed for calcium, creatinine, sodium, oxalate, citrate, uric acid, phosphorus, and magnesium. These urine studies were only performed in individuals with evidence of stone disease while on topiramate [11-15]. Urinary solute-to-creatinine ratios, including urate, oxalate, and citrate, were calculated as detailed elsewhere [11,14,16,17]. Treatment and any complications from stones were also recorded. This study was approved by the Institutional Review Boards of both the Hattie Larlham Center for Children with Disabilities and the University Hospitals of Cleveland.
Statistical Methods Variables are described overall and by relevant groups. Continuous variables are described with means and standard deviations when the departure form normality was not great. Medians and ranges are used when sample sizes are very small, and normality cannot be ascertained. Analysis of variance was used for continuous measures in three-group comparisons. The P value from the generalized F test is reported in the tables. Post hoc pairwise analyses were performed as appropriate. Fisher’s exact test was used for nominal variables. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC). The level of significance was set at 0.05.
Results The results are summarized in Table 1. Of 126 individuals (aged 4-45 years) residing at the Hattie Larlham Center for Children with Disabilities, 24 (19%) were treated with topiramate. The etiology of developmental disabilities varied from unknown to perinatal insults such as hypoxic-ischemic injury and stroke, and neurodevelopmental disorders such as Rett syndrome.
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All individuals were nonambulatory and had fixed dietary and fluid intake. Among the three groups, mean fluid intake ranged from 45-50.6 cm3/kg/day, mean protein intake ranged from 1.35-1.65 g/kg, mean total daily calcium intake (including diet and supplementation) varied between 17041809 mg, mean sodium intake was 43.7-58.6 mg/day, and vitamin D intake ranged from 787.5-876.3 IU/day. No patients were receiving diuretics, a ketogenic diet, or other carbonic anhydrase inhibitors such as zonisamide, which are associated with an increased risk for stones. Although statistical significance among the three groups was achieved in some dietary parameters (e.g., protein intake), this finding was not considered clinically significant. High protein intake is a risk factor for stone formation and, in fact, the highest protein intake was recorded in the first control group, on no antiepileptic drugs. Serum chemistries, however, revealed statistically significant higher serum chloride and lower serum bicarbonate values in the topiramate-treated group (P = 0.03 and < 0.001, respectively). Mean urinary pH was also nominally higher in this group compared with the two control groups, but did not reach statistical significance (P = 0.48). In the topiramate-treated group, one individual was previously diagnosed with a horseshoe kidney, without urinary outflow obstruction. Eight had a history of recurrent urinary tract infections, whereas each of the two control groups had only two individuals with urinary tract infections (P = 0.02). None had a family history or known genetic condition predisposing to urolithiasis. Stone fragments were evident in the diapers of 13 of 24 individuals (54%) on topiramate. No stone fragments occurred in any individuals in the two control groups. The incidence of stone fragments in the topiramate group was statistically significant (P < 0.001), compared with either control group. Radiologic confirmation with renal sonography or abdominal/pelvic computed tomography was achieved in 7 of 13 patients (54%). In four, stones were not evident according to ultrasound or computed tomography. Two of 13 did not undergo any radiologic studies because of unexpected death. Calcium-containing stones were evident in all four patients undergoing stone analysis. Calcium stones containing 90% calcium phosphate and 10% calcium oxalate were evident in two patients. In the other two patients, analysis revealed a mixed composition, including calcium phosphate (30%) and struvite (70%) in one patient. In the other patient, analysis on two different occasions showed calcium phosphate (95%) and struvite (5%) initially, and 3 years later, calcium phosphate (30%), calcium oxalate (10%), and struvite (60%). Data on the topiramate group are further summarized in Tables 2 and 3. Three of 13 individuals who developed stones were on topiramate monotherapy. Age at onset of stones ranged from 11-29 years. The average duration of topiramate therapy was 36.4 months (range, 1-84 months). The dose varied from 3.2-25.7 mg/kg/day (mean, 7.9 mg/kg). The topiramate dose is reported as mg/kg/day because many patients were in the adult age range, but their weight was more appropriate for the pediatric age group. Seven of
Table 1. Results: Demographic and clinical characteristics Control Group 1: No AEDs (n = 22)
Control Group 2: Nontopiramate AEDs (n = 23)
Topiramate Group (n = 24)
P-Value
12/10 20 (91%) 18.1 (5.6) 36.2 (12.1) 2 0
11/12 22 (96%) 21.0 (5.2) 41.9 (6.0) 2 0
11/13 20 (83%) 21.3 (6.4) 42.0 (9.5) 9 13
0.87 0.43 0.13 0.07 0.02 <0.001
50.6 (14.2) 32-82 1.65 (58) 1.0-3.3 1704 (498.9) 640-2475 58.6 (25.3) 27-106 876.3 (288.1) 256-1320
45 (11.4) 17.1-78.6 1.35 (0.28) 0.85-1.97 1765 (405) 775-2575 45 (24) 7-105 831 (183) 463-1156
46.7 (9.5) 31.7-70.8 1.35 (0.33) 0.86-2.5 1809 (451.7) 1245-2747 43.7 (16.7) 13.8-76.3 787.5 (236.1) 474-1345
0.27
101.9 (3.6) 91-110 26.2 (4) 19-43
101.9 (3.4) 95-107 26.3 (2.5) 20-31
100.6 (3.2) 91-105 28.3 (5.0) 20-43
103.4 (3.7) 96-110 23.9 (2.7) 19-29
0.03
n = 42 7 (8.2) 5-8.5
n = 11 6.9 (0.6) 6-8
n = 12 6.8 (0.9) 5-8
n = 19 7.2 (0.8) 5-8.5
Total (n = 69) Male/female Race: Caucasian (%) Mean age, yr (S.D.) Mean weight, kg (S.D.) Urinary tract infections Kidney stones Diet ad fluid intake Mean fluid, cm3/kg/day (S.D.) Range Mean protein, g/kg (S.D.) Range Mean calcium, mg (S.D.) Range Mean sodium, mEq (S.D.) Range Mean vitamin D, IU (S.D.) Range Serum chemistries Mean chloride, mmol/L (S.D.) Range Mean bicarbonate, mmol/L (S.D.) Range Urinalysis Mean pH (S.D.) Range
34/36 62 (90%) 20.2 (5.9) 40.1 (9.8) 13 13 47.4 (11.9) 17-82 1.5 (43) 0.85-3.3 1761.1 (448) 640-2747 48.9 (22.9) 7-106 830.3 (238) 256-1345
0.02 0.74 0.05 0.46
<0.001
0.48
Abbreviation: AEDs = Antiepileptic drugs
13 patients with stones had a history of urinary tract infections, compared with 1 of 11 patients without stones. Metabolic studies, as summarized in Table 3, were not performed in all patients in the topiramate-treated group. Seven died of complications from their underlying medical condition, and four were weaned off topiramate before all laboratory data were obtained. The fractional excretion of sodium and the median urine solute-to-creatinine ratios calculated for calcium, uric acid, oxalate, magnesium, citrate, and phosphorus are presented in Table 3. The difference in solute ratios within the topiramate-exposed group with and without stones did not reach statistical significance for any solute. However, the median calcium-to-creatinine ratio was higher than normal in the cohort with stones, consistent with hypercalciuria. The oxalate and magnesium ratios were elevated in all patients on topiramate (>0.013:1 and 0.09:1, respectively). Hypocitraturia with decreased median citrate-to-creatinine ratios was evident in both subgroups. Fractional excretion of sodium values of <1% were indicative of a prerenal etiology rather than renal or postrenal injury. Seven of 13 patients were weaned off topiramate, and two were treated with citrate supplementation. Two patients underwent lithotripsy for persistent stones. One failed lithotripsy, and needed two percutaneous nephrostomies for
stone removal. Urosepsis and retroperitoneal bleed requiring transfusion complicated lithotripsy in another patient.
Discussion Eighty percent of all urinary tract calculi in North America are calcium-containing stones, usually a mixture of calcium oxalate and calcium phosphate, and are associated with metabolic factors. Stones attributable to infection are the second most common form, typically comprising 2-20% of the total, and contain an organic matrix of struvite (Mg-NH4-PO4) and apatite (CaPO4) [2]. The most common mechanism resulting in calcium-containing stones is hypercalciuria. This may occur because of an increase in the delivery of calcium to the kidney, resulting from the use of enteral formulas high in calcium, vitamin D supplementation, or immobilization [5]. Increased renal losses of urinary calcium in the presence of a normal delivery load of calcium may occur in renal tubular acidosis, hypomagnesemia, hypocitraturia, hypophosphatemia, high protein diets, and a ketogenic diet [3,12,18]. The leading cause of secondary hypercalciuria in American children is immobilization [4]. Immobilization increases resorption from bone, causing both hypercalcemia and hypercalciuria [19].
Goyal et al: Urolithiasis With Topiramate 291
Table 2. Topiramate group: Demographic and clinical characteristics
Male/female Race: Caucasian (%) Mean age, yr (S.D.) Mean weight, kg (S.D.) Urinary tract infections Topiramate monotherapy Mean topiramate dose, mg/kg/day, range Mean duration of topiramate therapy, mo (S.D.) Range
Topiramate Group (n = 24)
Cohort With Stones (n = 13)
Cohort Without Stones (n = 11)
P-Value
11/13 20 (83%) 21.3 (6.4) 42.0 (9.5) 9 3/24 7.9, 3.2-25.7 36.4 (21.3) 1-84
8/5 11 (85%) 23.2 (6.8) 44.7 (10.9) 7 3/13 8, 3.2-25.7 31 (23.5) 1-84
3/8 9 (81%) 19.1 (5.5) 38.8 (6.7) 2 0/11 7.7, 4.2-17.5 42.9 (17.2) 17-72
0.12 0.80 0.12 0.40 0.10 0.22 0.54 0.12
In our nonambulatory patient population, diets are high in calcium, to optimize bone health and combat osteomalacia. There is also increased bone resorption because of immobility. This increased filtered calcium load is then passed through a presumed neurogenic bladder where there is urinary retention and stasis, an environment conducive to infection and stone formation. Antiepileptic drugs may cause osteomalacia by increasing bone resorption and augmenting hypercalciuria, especially in the context of polypharmacy [8-10]. Topiramate enhances this predisposition at multiple steps. First, it is a carbonic anhydrase inhibitor, which results in a reduction
of the reabsorption of filtered carbonate. This renal bicarbonate loss has a threefold effect, which includes an inability to form an appropriately acidified urine, metabolic acidosis, and the increased tubular reabsorption of citrate, with consequent hypocitraturia [9,20]. The rise in urinary pH increases the monohydrogen phosphate concentration, which then combines with calcium, forming the nidus for a subsequent crystallization of calcium stones [18]. Chronic metabolic acidosis, in turn, results in increased bone resorption, a risk factor for hypercalciuria [21]. Decreased urinary citrate, which normally forms a soluble complex with calcium, is also a risk factor for hypercalciuria. Hypocitraturia
Table 3. Topiramate group: Metabolic studies
Spot urine Calcium/Cr, mg/mg Uric acid/Cr, mg/dL GFR Oxalate/Cr, mol/mol Magnesium/Cr, mg/mg Citrate/Cr, g/g Phosphorus/Cr, mg/mg Fractional excretion of sodium Urinalysis pH Serum chemistries Bicarbonate, mmol/L Chloride, mmol/L Cr, mg/dL BUN, mg/dL Alk phos, U/L Parathyroid hormone, pg/mL
Topiramate Group (n = 24) n Median (Range)
Cohort With Stones (n = 13) n Median (Range)
Cohort Without Stones (n = 11) n Median (Range)
15 14 15 14 15 14 14
0.30 (0.06-1.0) 0.18 (0.09-0.33) 0.07 (0.01-0.1) 0.28 (0.08-3.08) 0.19 (0.02-1.25) 0.55 (0.01-1.09) 0.58 (0.28-1.61)
6 5 6 5 6 5 5
0.37 (0.09-1.0) 0.21 (0.12-0.33) 0.07 (0.01-0.07) 0.34 (0.08-0.74) 0.16 (0.02-1.25) 0.66 (0.27-1.09) 0.52 (0.37-1.61)
9 9 9 9 9 9 9
19
7 (5-8.5)
10
7 (5-8.5)
9
7.5 (6.5-8)
0.51
24 24 19 18 14 14
24 (19-29) 103 (96-110) 0.4 (0.2-1) 13 (5-24) 130 (66-285) 9.5 (3-42)
13 13 9 9 5 5
25 (19-29) 103 (96-110) 0.4 (0.2-1) 14 (5-24) 147 (88-285) 11 (7-42)
11 11 10 9 9 9
24 (19-27) 103 (97-109) 0.45 (0.3-0.8) 13 (6-20) 123 (66-243) 8 (3-41)
0.26 0.62 0.11 0.31 0.29 0.32
0.16 (0.06-0.59) 0.17 (0.09-0.25) 0.08 (0.03-0.1) 0.27 (0.12-3.08) 0.20 (0.08-0.34) 0.50 (0.01-0.83) 0.64 (0.28-1.27)
P-Value
0.14 0.59 0.77 0.69 0.68 0.42 0.70
Normal values of urinary solute: Cr ratios (ratios expressed as [mg/dL solute]/[mg/dL Cr], except as otherwise noted) [14,16,18]. Calcium, <0.21:1. Uric acid, <0.53 mg/dL GFR. Oxalate (mol/mol), <0.013:1. Citrate (g/g), 0.51:1. Magnesium, <0.09:1. Phosphorus, 0.38-1.26. FENA, 1-3%. Abbreviations: Alk phos = Alkaline phosphatase BUN = Blood urea nitrogen Cr = Creatinine FENA = Fractional excretion sodium [(urinary sodium)/serum sodium/(urine Cr/serum Cr)] GFR = Glomerular filtration rate PTH = Parathyroid hormone
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may also contribute directly to calcium phosphate crystallization, because citrate inhibits crystal growth and the agglomeration of preformed crystals [22]. This pattern of inadequate acidification of urine, metabolic acidosis, and hypocitraturia constitutes a strong risk factor for calcium urolithiasis [23], further exacerbated by other risk factors described with topiramate therapy such as hyperoxaluria. In our population, we found higher urinary pH and lower serum bicarbonate in the topiramate group, consistent with its known effects of decreased urinary acidification and metabolic acidosis [24]. Although the numbers are small, spot urine chemistries revealed increased urinary calcium excretion in topiramate patients who developed stones compared with stone-free patients, underscoring the role of hypercalciuria in stone predisposition in this subpopulation. Because there were no differences in environmental factors within the topiramate group, hypercalciuria in some may indicate either an inherent genetic predisposition, or more likely, a predisposition that was induced by topiramate exposure. The mechanism of topiramate-induced hypercalciuria likely results from systemic acidosis, which is implicated in impaired renal tubular calcium absorption [18]. Other spot urinary solute-to-creatinine ratios in the topiramate group were normal for uric acid (glomerular filtration rate, <0.53 mg/dL), elevated for oxalate (>0.013:1), and lower for citrate (<0.51:1) [14]. These findings are in agreement with other reports [24-26]. Magnesium and phosphorus are inhibitors of crystallization, and both the elevated magnesium and normal phosphorus ratios in our patients should have decreased the risk of urolithiasis. The important role of topiramate in the pathogenesis of stone formation is further highlighted by the observation that these patients developed stones despite exhibiting the lowest dietary intake of sodium and protein, which would be also be expected to reduce the risk of stone formation. The frequently cited incidence of stones in 1.5% of individuals exposed to topiramate was ascertained from clinical trials. However, the incidence with long-term topiramate therapy is not known, and small case series often cite higher percentages. Bootsma et al. reported a 1.1% incidence of kidney stones in adults. However, an additional 5.6% incidence of urogenital signs was evident [27]. In children, Coppola et al. reported incidences of 4.5-5.6%, with additional patients experiencing intermittent hematuria [28]. In our study, we defined urolithiasis (stone disease anywhere in the urinary tract system from the kidney to the urethra) according to evidence of stones either in radiologic studies or by the presence of stone fragments in diapers. An incidence of stones of 56% in our cohort reflects a markedly augmented risk with topiramate when there are preexisting risks for hypercalciuria and urinary stones. Our small cohort does not negate the possibility that this group was predisposed to stones because of chronic urinary tract infections. On the other hand, because this vulnerable subpopulation was already in a predisposing environment for urinary tract infections, it is quite possible that infection may tilt the environment in favor of stone formation with
the additive stress of metabolic changes induced by topiramate [16]. Alternatively, bacteriuria is not an uncommon finding in nonambulatory populations with neurogenic bladder [29,30], and stones may become secondarily infected or have a mixed composition of both struvite and calcium [31]. Poorly acidified urine associated with topiramate is conducive not only to calcium-containing stones but also to stones containing struvite [32]. This would explain the mixed composition of recurrent stones in one patient. This study has several limitations, including its retrospective data collection, small number of patients, and lack of metabolic and radiologic evaluations of all patients on topiramate therapy. Our study may also underestimate the prevalence of stone disease in this cohort, because radiologic studies were not performed in all patients treated with topiramate. Ideally, metabolic studies should have been performed before as well as during topiramate use. Stone analysis was also not performed in all individuals. However, patients at a center such as Hattie Larlham provide a unique opportunity to study the frequency of stones and associated morbidity in neurologically impaired individuals because of several controlled risk factors, including fixed dietary and fluid intake. Medication compliance is also not an issue. Our data indicate that this subpopulation has a much higher frequency of kidney stone formation when exposed to drugs such as topiramate than previously reported. This vulnerability increases because of preexisting risk factors for stone formation, including bladder stasis from immobility and neurogenic bladder, and a metabolic milieu predisposing to hypercalciuria from increased bone resorption and calcium supplementation. Urolithiasis has a high rate of recurrence, and is associated with significant expense and patient morbidity [30]. As seen in two of our patients, it may lead to serious complications, necessitating surgical treatment. Because the typical signs of flank and abdominal Table 4. Stone formation with topiramate: Risk factors and proposed screening/preventative measures Risk Factors
Screening Measures/Treatment
Dehydration Immobility
Increase in fluid intake Minimization of complications of immobility: Physical therapy Diagnosis and management of osteopenia Optimization of bladder function to minimize stasis and risk of infection
Chronic urinary tract infections; Neurogenic bladder Metabolic
Hypercalciuria Hypocitraturia Alkaline urine (pH >6.5-7) Metabolic acidosis Drugs
Biannual screening with spot urine studies for calcium and citrate; urinalysis; serum bicarbonate Restriction of total calcium intake and supplementation to <1500 mg/day Citrate supplementation if low urinary citrate Correction of metabolic acidosis
Goyal et al: Urolithiasis With Topiramate 293
pain and hematuria were not evident in our cohort and are difficult to ascertain in neurologically impaired children, clinicians must remain vigilant and adopt aggressively preventative measures. For a more complete list of risk factors and treatments of urolithiasis, the reader is referred to several excellent review articles [6,11,14,32]. A summary of the common risk factors in our population and our proposed screening and preventative measures is provided in Table 4. These include increasing fluid intake, reducing urine calcium excretion with thiazides, restricting sodium intake, minimizing complications from immobilization, and optimizing bladder function to minimize stasis and the risk of infection. We advocate spot urine studies as simple screening tools to assess predisposition for stones in high-risk subpopulations such as our group. Prospective studies using such screening tools and optimizing preventative measures will help substantiate our observations.
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