Renal stones in children, though rare, are associated with identifiable risk factors and carry a higher probability of recurrence than in adults. Children with renal stones require thorough evaluation to identify possible underlying metabolic conditions associated with an imbalance between stone inhibitors and promoters. Distal renal tubular acidosis (RTA) is a common cause of renal stones and nephrocalcinosis in children. Distal RTA usually occurs due to a
genetic defect. It can also develop secondary to diseases such as Sjogren syndrome, systemic lupus erythematosus, and medullary sponge kidney disease, or medications such as spironolactone, amiloride, ifosfamide, and acetazolamide.1

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited neurocutaneous syndrome with an estimated incidence of nearly 1 in 6000 births and a prevalence of 1 in 7000–20 000 people. This multisystem disorder causes tumors (mostly benign) in the brain, skin, lungs, eyes, heart, and kidneys.2 Renal manifestations include angiomyolipoma, renal cysts, and less commonly oncocytomas, which may lead to hypertension and chronic kidney disease.3

To our knowledge, no previous case report has confirmed a high frequency of renal stones in a patient with tuberous sclerosis. Intractable epilepsy is commonly associated with tuberous sclerosis and often requires treatment with multiple antiseizure medications. Patients using topiramate are at risk for nephrolithiasis because of hypocitraturia and a high urine pH. However, topiramate users are thought to have a low rate of symptomatic stone disease.4–8

In this report, we discuss a pediatric case of tuberous sclerosis with co-occurring renal stones and distal RTA and review cases in the literature.

Case Report

A six-year-old boy was diagnosed with TSC in his first year of life. Manifestations included seizures, cortical tubers, facial angiofibroma, retinal astrocytoma, gingival angiofibroma, shagreen patches, and hypopigmented macules. As part of routine surveillance, an ultrasound of the kidneys was conducted which showed a 7 mm renal stone in the interloper region and a 5 mm renal cyst in the right kidney. Owing to the nature of his illness, he had frequent seizures which were well-controlled with topiramate and carbamazepine. Urine cystine, calcium, and uric acid levels were all normal. Tables 1 and 2 list the results of laboratory investigations.

Further serum investigations revealed normal anion gap metabolic acidosis. Urine analysis showed an inappropriately high urine pH (6.5) with a positive urine anion gap, indicating impaired distal tubular acidification of urine. These tests were repeated twice, and the findings were consistent. The child was administered potassium citrate (10 mL twice daily), and the acidosis was corrected.

Discussion

Renal stones in children are associated with identifiable risk factors and carry a higher risk of recurrence than in adults. Therefore, it is the standard of care to evaluate children with renal stones for underlying precipitating factors.9,10 This child had distal RTA. Whether congenital or acquired, distal RTA may diminish the capacity of the kidney in removing the daily acid load, leading to nephrocalcinosis and renal stones.11,12 TSC is a multisystemic autosomal dominant disease characterized by the development of numerous benign tumors in different organs. It commonly affects the brain, skin, lungs, and kidneys.13 There is no known association between TSC and distal RTA. However, two cases of co-occurrence of TSC and distal RTA have been reported. Both patients were women aged 27 and 41 years. Notably, both had significant osteomalacia.14,15 There has been another report of two Saudi siblings with co-occurring TSC and Fanconi syndrome, a generalized proximal tubulopathy with a proximal RTA.16

A diagnosis of distal RTA is established by the presence of normal anion gap metabolic acidosis with the presence of inappropriately high urine pH. The impairment of urine acidification is further confirmed by the presence of a positive urine anion gap. The urine anion gap is calculated by subtracting the level of chloride ions from the sum of the levels of potassium and sodium ions. This enables the estimation of urinary ammonium (NH4+) ion levels. For the kidney to secrete protons (H+), a buffer is required to titrate the gradient and maintain urine pH within a tolerable range. Ammonia, the buffer, is generated by the proximal tubule and converted to NH4+ by adding H+ in the distal tubule. A positive anion gap indicates insufficient NH4+ (low secretion of H+).17,18

The mechanism of renal stones in distal RTA is multifactorial. A possible factor is increased absorption of citrate by the proximal tubule driven by acidemia resulting in low urine citrate, a natural stone inhibitor. Other factors include alkaline urine pH and hypercalciuria. The most common type of renal stone in distal RTA is calcium phosphate.11,19

The present patient was on topiramate, an antiseizure medication often prescribed for focal seizures and migraine prophylaxis. Several reports have suggested that topiramate can cause RTA by inhibiting carbonic anhydrase, the main enzyme driving bicarbonate absorption in the proximal tubule and H+ secretion in the distal tubule.4–8 This may lead to the formation of renal stones.

However, our patient had a renal stone prior to the initiation of topiramate; therefore, his distal RTA was likely caused by a different mechanism. Barone et al,20 described mice with TSC as having hyperproliferating intercalated cells. The intercalated cells are mainly responsible for H+ secretion in the distal tubule.21 The effect of the hyperproliferation of intercalated cells on their function is not yet known. Nevertheless, the presence of topiramate on board probably has an added effect on the process, increasing the risk of renal stone formation.22

Our patient had normal serum potassium, and his metabolic acidosis improved with a small dose of potassium citrate, indicating the mild nature of the disease. Some experts tend to label this spectrum as incomplete RTA, although it is not considered a separate entity.11 Even if acidosis is mild in nature and subclinical, failure to recognize the condition would result in bone demineralization; therefore, it is recommended to use oral alkalizers to maintain serum bicarbonate levels above 22 mEq/L .11,18,23

Conclusion

The association between TSC and distal RTA cannot be determined based on available case reports. Distal RTA in children with TSC and renal stones is worth investigating further.

Disclosure

The authors declared no conflicts of interest. A written consent was obtained from the patient's parent.

references

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