Utility of a Urine Screening Tool for Vitamin D Deficiency in Infants and Toddlers
Condition: Vitamin D Deficiency
MeSH terms: Vitamin D Deficiency
Study type: Observational

Summary: 
      Background:

      Vitamin D plays a key role in calcium absorption in the gut and in skeletal development.
      Vitamin D deficiency is common, affecting an estimated one billion people worldwide,
      including developed countries. Vitamin D deficiency causes rickets, the most common
      non-communicable disease of childhood. Rickets causes poor growth and skeletal deformities
      and, at its most severe, seizures and death. Recent data suggest that children with rickets
      have an increased risk for developing diabetes mellitus.

      Screening for vitamin D deficiency is not commonly done. It is generally diagnosed only after
      symptoms of rickets have developed. Prevention and treatment is simple and inexpensive.
      Hence, early detection of vitamin D deficiency through screening would be beneficial. Studies
      are urgently needed to validate such screening tests.

      Calcium balance is tightly regulated in the body and calcium loss in the urine (measured by
      the urine calcium-to-creatinine ratio) is a sensitive indicator of reduced calcium
      absorption, such as in vitamin D deficiency.

      Objective and Hypotheses. The objective of this study is to evaluate the urine
      calcium-to-creatinine ratio as a noninvasive and inexpensive screening test for vitamin D
      deficiency. Our hypotheses are 1) that the urine calcium-to-creatinine ratio correlates with
      blood vitamin D levels in infants and toddlers at risk for vitamin D deficiency and 2) that
      this test can be used to screen for vitamin D deficiency.

      Potential Impact. A validated screening tool would allow for the detection of vitamin D
      deficiency before the development of rickets, decreasing the morbidity and mortality of this
      common disease.
    

Detailed description: 
      Background:

      Insufficient circulating levels of vitamin D is a common problem in both developed and
      developing countries; it is estimated that over one billion people have vitamin D deficiency
      at this time. In children, vitamin D deficiency leads to nutritional rickets, which is
      considered the most common non-communicable disease of children worldwide. Rickets causes
      significant short term morbidity and mortality through hypocalcemic tetany and seizures, as
      well as long term morbidity from growth delay and skeletal deformities. Recent data also
      suggest that children who have had nutritional rickets are three times more likely to develop
      type 1 diabetes.

      There is wide agreement that screening for vitamin D deficiency would be highly beneficial.
      However, there is debate on how best to do this. Most screening efforts have included serum
      levels of 25-hydroxy-vitamin D and parathyroid hormone (PTH). However, these assays are
      complex and are neither available nor affordable for many of the most vulnerable populations.

      Calcium excretion in the kidney is a tightly regulated process involving metabolites of
      vitamin D and PTH. Renal calcium excretion, in the absence of primary renal or parathyroid
      gland disease, is a sensitive indicator of total body calcium balance. We have shown that
      renal calcium excretion correlates with blood levels of 25-hydroxy-vitamin D levels in older
      children and urine calcium-to-creatinine ratios have been shown to distinguish children with
      active rickets from healthy controls in one Nigerian study. This biomarker is noninvasive and
      the assays are straight forward and inexpensive. We believe that the urine
      calcium-to-creatinine ratio has excellent potential as a screening tool for vitamin D
      deficiency.

      Objective and Hypotheses. The objective of this study is to evaluate the urine
      calcium-to-creatinine ratio as a biomarker of vitamin D deficiency. Our hypotheses are 1)
      that urine calcium-to-creatinine ratio correlates with serum 25-hydroxy vitamin D level in
      infants and toddlers at risk for vitamin D deficiency and 2) that the urine
      calcium-to-creatinine ratio can be used to screen children for vitamin D deficiency. These
      hypotheses will be tested through two specific aims. Specific Aim 1 is to determine the
      correlation between the urine calcium-to-creatinine ratio with 25-hydroxy vitamin D levels
      and with biomarkers of rickets in infants and toddlers at increased risk for vitamin D
      deficiency. Specific Aim 2 is to determine the sensitivity, specificity, and positive and
      negative predictive values of one random urine calcium-to-creatinine ratio in relation to
      biochemical evidence of vitamin D deficiency.

      Design. This will be an observational study of infants and toddlers at increased risk for
      vitamin D deficiency. We will recruit 150 healthy children, 6 to 36 months of age, with risk
      factors for vitamin D deficiency (premature birth, breast feeding, dairy product avoidance,
      etc.). Based on previous studies in the US, we anticipate about 12% of these subjects will
      have vitamin D deficiency. Subjects will have a physical exam targeted to signs of rickets.
      Laboratories will include a random urine sample for calcium-to-creatinine ratio and blood for
      calcium, creatinine, alkaline phosphatase, phosphorus, magnesium, intact PTH, and 25-hydroxy
      vitamin D. Subjects with biochemical evidence of rickets will have x-rays done of the left
      wrist and knees that will be scored according to previously published rickets scores.

      Potential Impact. Vitamin D deficiency is increasingly recognized as a common source of
      morbidity in both developed and undeveloped countries. The validation of a noninvasive and
      inexpensive screening tool for vitamin D deficiency would allow for large scale screening of
      at risk populations and detect this problem early, preventing the morbidities of rickets.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Infants and Toddlers from 6 months to 3 years part of a group known to be in at least one
        high-risk group for vitamin D deficiency:

          1. child has been exclusively breast fedfor at least 1 month

          2. darkly pigmented children

          3. children born at a gestational age of 32 weeks or less

          4. recent immigrant from developed country

          5. child is underweight (wt/ht < 10%)

          6. children with bowed legs or wrist enlargement
      
Biospecimen description: 
      Whole Blood will be obtained from which we will collect serum and fresh urine which will be
      used for study labs. Urine and serum may be stored for future studies.
    
Keywords: Urine Calcium to Creatinine Ratio; Hypocalciuria; Infants; Toddlers