Association of hypercalciuria with vitamin D supplementation in patients undergoing ketogenic dietary therapy

Ketogenic dietary therapy (KDT) is used as an effective treatment for epilepsy. However, KDT carries the risk of bone health deterioration; therefore, vitamin D supplementation is required. Vitamin D replacement therapy in KDT has not been established because it may be related to hypercalciuria/urolithiasis, which are common adverse effects of KDT. Hence, this study aimed to evaluate the dose-dependent association between vitamin D₃ and hypercalciuria/urolithiasis in patients undergoing KDT and dose optimization for renal complications.

Overall, 140 patients with intractable childhood epilepsy started 3:1 KDT (lipid to non-lipid ratio) at the Severance Children's Hospital from January 2016 to December 2019. Regular visits were recommended after KDT initiation. Participants were assessed for height, weight, serum 25-hydroxyvitamin D (25-OH-D₃) level, parathyroid hormone level, and ratio of urinary excretion of calcium and creatinine (Uca/Ucr). Kidney sonography was conducted annually. Patients who already had urolithiasis and were taking hydrochlorothiazide before KDT, failed to maintain KDT for 3 months, did not visit the pediatric endocrine department regularly, did not take prescribed calcium and vitamin D3 properly, or needed hospitalization for > 1°month because of serious medical illness were excluded. Data from patients who started diuretic agents, e.g., hydrochlorothiazide, were excluded from that point because the excretion of calcium in the urine may be altered in these patients.

In total, 49 patients were included in this study. Uca/Ucr ratio significantly decreased with increasing levels of 25-OH-D₃ (p = 0.027). The odds ratio for hypercalciuria was 0.945 (95% confidence interval, 0.912-0.979; p = 0.002) per 1.0 ng/mL increment in 25-OH-D₃ level. Based on findings of receiver operating characteristic curve analysis and Youden's J statistic, the cut-off 25-OH-D₃ level for preventing hypercalciuria was > 39.1 ng/mL at 6 months. Furthermore, the vitamin D₃ supplementation dose cut-off was > 49.5 IU/kg for hypercalciuria prevention.

An inverse relationship between Uca/Ucr ratio and 25-OH-D₃ level was noted, which means that vitamin D supplementation is helpful for preventing hypercalciuria related to KDT. We suggest that the recommended 25-OH-D₃ level is > 40 ng/mL for hypercalciuria prevention and that KDT for children with epilepsy can be optimized by vitamin D₃ supplementation at 50 IU/kg.