Clinical Significance of Calcium-Creatinine Ratio
The urine calcium-to-creatinine ratio (Ca/Cr) is a convenient screening tool that estimates 24-hour urinary calcium excretion from a single spot urine sample, primarily used to diagnose hypercalciuria in children and adults, with age-specific upper normal limits ranging from 0.57 mol/mol in adults to 2.2 mol/mol in infants. 1
Definition and Purpose
The calcium-creatinine ratio corrects for variations in urine concentration by comparing calcium excretion to creatinine excretion in a single urine sample, eliminating the need for cumbersome 24-hour urine collections. 1, 2 This ratio provides a practical estimate of daily calcium excretion because creatinine excretion remains relatively constant throughout the day. 2
Normal Reference Ranges
Age-Specific Thresholds (mol/mol)
The upper normal limits vary significantly by age: 1
- <1 year: 2.2 mol/mol
- 1–3 years: 1.4 mol/mol
- 3–5 years: 1.1 mol/mol
- 5–7 years: 0.8 mol/mol
- 7–18 years: 0.7 mol/mol
- >18 years: 0.57 mol/mol
Alternative Units (mg/mg)
In clinical practice, a Ca/Cr ratio exceeding 0.23 mg/mg in children indicates hypercalciuria (corresponding to >4 mg/kg/day calcium excretion). 3
24-Hour Excretion Limits
For adults, the upper normal limit of 24-hour urinary calcium excretion is: 1
- 0.1 mmol (4 mg) per kg body weight for all adults, or
- 6.2 mmol (250 mg) in women
- 7.5 mmol (300 mg) in men
Clinical Applications
Primary Diagnostic Use: Hypercalciuria Screening
The Ca/Cr ratio serves as the first-line test for detecting hypercalciuria in patients with: 1, 3
- Recurrent kidney stones
- Unexplained hematuria
- Suspected metabolic bone disease
- X-linked hypophosphatemia evaluation
- Monitoring during long-term vitamin D therapy
Differential Diagnosis in Phosphate Disorders
In patients with rickets or osteomalacia, the Ca/Cr ratio helps distinguish FGF23-mediated diseases (which show normal or low urinary calcium) from primary tubular phosphate wasting disorders like NPT2a/NPT2c mutations (which show hypercalciuria and suppressed PTH). 1 This distinction is critical because FGF23-mediated diseases present with normal or low 1,25(OH)₂D and normal calcium excretion, whereas primary tubular defects show elevated 1,25(OH)₂D and increased calcium excretion. 1
Optimal Collection Method
Timing and Specimen Type
First-morning void specimens provide the most accurate results, with the highest correlation to 24-hour collections (r = 0.71) and lowest coefficient of variation. 4 Evening spot samples also perform well (r = 0.64), while second-morning samples are less reliable (r = 0.52). 4
Random urine samples collected 3 hours after breakfast show no significant difference from 24-hour Ca/Cr ratios and correctly diagnose hypercalciuria in 90% of cases. 3
Pre-Collection Instructions
Avoid testing when: 1
- Active urinary tract infection is present
- Patient has fever or acute illness
- During menstruation
- Within 24 hours of vigorous exercise
Diagnostic Accuracy and Limitations
Correlation with 24-Hour Collections
The Ca/Cr ratio shows significant correlation with 24-hour calcium excretion (r = 0.91, p = 0.001 in children; r = 0.57 in adults). 3, 5 However, in postmenopausal women, the spot urine calcium-to-creatinine ratio (SUCCR) underestimates 24-hour calcium excretion by a mean of 83 mg and has only 25% sensitivity for diagnosing hypercalciuria. 5
Factors Affecting Accuracy
The diagnostic accuracy improves when adjusted for: 5
- Body mass index (BMI)
- Parathyroid hormone (PTH) levels
- 1,25(OH)₂D levels
These adjustments can increase sensitivity from 25% to 100% in adults, though this correction formula requires validation before clinical implementation. 5
When to Use 24-Hour Collections Instead
Despite convenience, 24-hour urine collections remain the gold standard for diagnosing hypercalciuria in adults, particularly postmenopausal women and patients being evaluated for osteoporosis or nephrolithiasis. 5 The Ca/Cr ratio is most reliable in children and for screening purposes. 3, 6
Clinical Interpretation Algorithm
Step 1: Obtain Spot Urine Sample
Collect first-morning void or random sample 3 hours post-breakfast. 4, 3
Step 2: Compare to Age-Appropriate Threshold
Use the age-specific upper limits listed above. 1
Step 3: Confirm Abnormal Results
If elevated, repeat testing on a second day to confirm persistent hypercalciuria, as single measurements may not reflect chronic calcium excretion. 6
Step 4: Subclassify Hypercalciuria (if confirmed)
Perform fasting Ca/Cr and oral calcium tolerance test to distinguish: 6
- Absorptive hypercalciuria: Normal fasting Ca/Cr, increased response to calcium load
- Renal hypercalciuria: Elevated fasting Ca/Cr and increased response to load
- Dietary hypercalciuria: Normal fasting and post-load Ca/Cr, but increased sodium excretion
Common Pitfalls
Do not rely solely on spot Ca/Cr ratios in postmenopausal women or adults with suspected osteoporosis—the test significantly underestimates calcium excretion in this population and misses 75% of hypercalciuria cases. 5 Always confirm with 24-hour collection in these patients.
Do not interpret Ca/Cr ratios in patients on oral phosphate or active vitamin D therapy—these treatments alter calcium excretion patterns and invalidate the test. 1
Do not use adult reference ranges in children—age-specific thresholds are essential because calcium and creatinine excretion patterns change dramatically during growth. 1, 6