Prevalence and clinical characteristics of elevated 1-alpha,25-dihydroxyvitamin D in pediatric nephrolithiasis and related disorders
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INTRODUCTION: The incidence of pediatric nephrolithiasis (kidney stones) has been increasing over the past several years. While environmental factors, such as poor fluid intake, high-salt diet, and obesity, can play a role, underlying metabolic factors account for at least one-third of cases of nephrolithiasis. Nephrolithiasis and related disorders, such as nephrocalcinosis and hypercalciuria, can lead to long-term kidney problems, including renal scarring, acute and chronic kidney disease, decreased renal function, or end-stage renal disease. The best treatment is prevention and is best guided by knowing the underlying cause. The majority of kidney stones are primarily comprised of calcium, and abnormal calcium metabolism and regulation can lead to nephrolithiasis, nephrocalcinosis, and hypercalciuria. Vitamin D is an important factor in calcium regulation in the body. The physiologically active form of vitamin D is 1α,25-dihydroxyvitamin D (1,25(OH)2D), which increases serum calcium by stimulating intestinal absorption of calcium, increasing renal calcium reabsorption, and mobilizing calcium from bone. Excess 1,25(OH)2D has been shown to be associated with hyperabsorption of calcium in the intestine, nephrolithiasis, hypercalcemia, and hypercalciuria. Production of 1,25(OH)2D requires hydroxylation of 25-hydroxyvitamin D by the kidney enzyme 1α-hydroxylase, which is regulated in turn by serum calcium, parathyroid hormone (PTH), and by 1,25(OH)2D itself. Tight control of 1,25(OH)2D levels is maintained in part by the breakdown of 1,25(OH)2D by the enzyme 24-hydroxylase, which is encoded by the gene CYP24A1. In the past few years, CYP24A1 mutations leading to decreased activity of 24-hydroxylase have been implicated in some cases of idiopathic infantile hypercalcemia as well as nephrolithiasis, nephrocalcinosis, and hypercalciuria. The prevalence of 24-hydroxylase deficiency is not known, and the spectrum of its clinical manifestations is not yet fully understood. Our study aims to describe the clinical characteristics of patients with laboratory findings suggestive of 24-hydroxylase deficiency, specifically high-normal or elevated serum 1,25(OH)2D. We aimed to determine the prevalence of elevated 1,25(OH)2D among pediatric patients with nephrolithiasis, and to compare clinical outcomes and biochemical findings in patients with normal versus elevated 1,25(OH)2D. PATIENTS AND METHODS: This study was a retrospective chart review. To determine the prevalence of high-normal (56-75 pg/mL) and high (>75 pg/mL) serum 1,25(OH)2D, we reviewed electronic medical records of patients seen in the Boston Children's Hospital Stone Clinic. We identified 346 patients who were evaluated for nephrolithiasis, were under 18 years of age at the time of presentation, and had at least one measurement of 1,25(OH)2D. Patients were classified based on their highest measured level of 1,25(OH)2D. To determine the clinical characteristics of patients with elevated 1,25(OH)2D, we reviewed clinical records and laboratory data of patients at Boston Children's Hospital with a diagnosis of nephrolithiasis, nephrocalcinosis, or hypercalciuria. We identified 83 patients who met our inclusion criteria: age of onset <18 years, at least one measurement of 1,25(OH)2D, and a pre-treatment urine solute analysis. Data collected included demographic information, diagnoses, family history of kidney disease, treatments, laboratory data, and urine solute analyses. We compared findings in patients with normal 1,25(OH)2D (≤55 pg/mL) versus elevated 1,25(OH)2D (>55 pg/mL). RESULTS: Of 346 children with nephrolithiasis in whom 1,25(OH)2D was measured, 100 (28.9%) had high 1,25(OH)2D, and an additional 120 (34.7%) had high-normal 1,25(OH)2D. To determine the clinical characteristics of elevated 1,25(OH)2D, we analyzed the data of 40 patients with normal 1,25(OH)2D and 43 patients with elevated 1,25(OH)2D who had a history of nephrolithiasis, nephrocalcinosis, or hypercalciuria. Seventy-five children had nephrolithiasis, and 25/37 (67.6%) of children with elevated 1,25(OH)2D had a recurrence of nephrolithiasis, compared to only 9/38 (23.7%) of children with normal 1,25(OH)2D (p < .001). Urine calcium/creatinine ratio did not differ between the two groups. However, linear regression analysis showed an association between 1,25(OH)2D levels and urine calcium/creatinine ratio. Important secondary findings included a younger age of onset, higher serum 25-hydroxyvitamin D, and lower parathyroid hormone levels in patients with elevated 1,25(OH)2D. CONCLUSIONS: Important clinical findings of this study were the increased rate of recurrence and the younger age of onset in patients with elevated 1,25(OH)2D. While we recognize that mutations in CYP24A1 do not account for the majority of cases of elevated 1,25(OH)2D, we do advocate for special consideration for these patients. In the absence of a commercially-available assay for 24-hydroxylase activity, children with nephrolithiasis, nephrocalcinosis, or hypercalciuria and elevated 1,25(OH)2D should be closely monitored for recurrence or worsening of symptoms. Furthermore, we advise caution in the use of vitamin D repletion in at-risk patients.