In Japan, the estimated annual incidence of first-episode upper urinary tract stones was 137.9 per 100,000 population in 201510. In our study, the incidence of TSC-associated urolithiasis was much higher than in the general population. The incidence of epileptic seizures was 80–90% in TSC patients11,12. Refractory epileptic seizures are often observed in TSC, and it is not uncommon to take three or more antiepileptic agents11,12. Topiramate and zonisamide have been widely used as antiepileptics. However, it has been reported that those drugs are associated with the development of acidosis and urolithiasis13,14. In some patients, topiramate and zonisamide lead to renal tubular acidosis through the inhibition of carbonic anhydrase in the renal tubules, which influences systemic metabolic acidosis and alkaline urine pH with a low urine citrate concentration. These metabolic changes result in calcium phosphate stone formation13,14. A study by Maalouf et al. showed that the prevalence of symptomatic urolithiasis among adult topiramate users was 10.7 %15. The median daily dose of topiramate was 300 mg and the median treatment period was 48 months15. Faught reported that the incidence of kidney stones associated with zonisamide was 2.7 % (15 of 549) 16. Most patients with refractory epileptic seizures need to take anti-epileptic agents for a long period. Longer administration of topiramate and zonisamide might result in a higher incidence of urolithiasis. In our study, the median antiepileptic treatment period was >80 months in both groups. We discontinued both drugs for all patients who had urolithiasis and switched to other agents.
In the urolithiasis group, the incidence of mental retardation and the urine specific gravity were higher than in the non-urolithiasis group. Patients with mental retardation are susceptible to dehydration because they cannot keep themselves hydrated. Thus, the daily urine volume decreased and the urine specific gravity increased. Increased urine specific gravity may promote stone development. We recommend to TSC patients and their families to drink >2 liters of water a day.
Medical expulsive therapy is recommended for urinary stones <10 mm in size17. Alpha blockers promote the spontaneous expulsion of urinary stones18. On the other hand, urinary stones ≥10 mm in size are not expelled spontaneously. Thus, surgical treatments such as TUL, ESWL, and percutaneous nephrolithotomy (PNL) are recommended19. AMLs are often comorbid with TSC20, 21. Unlike sporadic AML, TSC-associated AML develops at multiple sites on the bilateral sides.7 It develops at a younger age, and tends to exhibit a much faster growth rate over time than sporadic AML22, 23. When urolithiasis is comorbid with TSC-associated AML, ESWL and PNL cannot be performed because of the risk of bleeding from the AML. On the other hand, TUL does not damage the renal parenchyma and can be performed safely. Surgical options for the treatment of urolithiasis in patients with TSC-associated AML are limited. Furthermore, topiramate and zonisamide lead to the development calcium phosphate stones in some cases. In the present study, only one stone was composed of pure calcium oxalate; six were composed of mixed calcium phosphate and calcium oxalate. Urinary stones containing calcium phosphate are harder than calcium oxalate stones24. Otsuki et al. reported that stones containing calcium phosphate require more laser energy and a longer operating time, and that they are associated with a higher rate of perioperative complications24. Thus, prevention and early detection of urolithiasis are beneficial to TSC patients.
The present study has several limitations. First, this was a retrospective study and the urolithiasis group consisted of only 15 patients. The incidence of urolithiasis associated with TSC in this study does not reflect the overall prevalence of TSC in Japan. In addition, our hospital manages a large number of patients with refractory epileptic seizures; thus, the treatment period of patients receiving antiepileptic agents may be longer than in other medical institutions. Second, the urinary calcium and citrate concentrations were not measured in this study. The urine calcium to creatinine ratio and urine citrate to creatinine ratio change with diet and exercise. Spot urine examinations during early morning fasting, and 24-hour urine collection are difficult in TSC patients with mental retardation. There were no patients with hyperparathyroidism in the urolithiasis group.