What causes hypercalciuria (increased urine calcium)?

Causes of Increased Urine Calcium (Hypercalciuria)

Hypercalciuria results from three primary mechanisms: increased intestinal calcium absorption (absorptive hypercalciuria), impaired renal tubular calcium reabsorption (renal hypercalciuria), or increased bone resorption (resorptive hypercalciuria), with dietary factors—particularly high sodium, animal protein, and paradoxically low calcium intake—playing critical modifying roles. 1, 2, 3

Primary Pathophysiologic Mechanisms

Absorptive Hypercalciuria (Most Common Form)

• Excessive intestinal calcium absorption is the predominant mechanism in idiopathic hypercalciuria, where absorbed calcium exceeds urinary calcium excretion 3
• Caused by increased calcitriol (1,25-dihydroxyvitamin D) production or enhanced sensitivity to calcitriol through upregulation of vitamin D receptors 4
• Characterized by normocalcemia, normal or low serum PTH, normal fasting urinary calcium, and normal bone density 3
• During calcium loading (1,700 mg/day), urinary calcium increases exaggeratedly to 453±154 mg/day (versus 211±42 mg/day in controls) with suppressed urinary cAMP 3

Renal Hypercalciuria

• Impaired renal tubular reabsorption of calcium causes primary renal calcium wasting 2, 5, 3
• Urinary calcium exceeds absorbed intestinal calcium, indicating the kidney as the primary defect 3
• Associated with elevated urinary cAMP or serum PTH despite normocalcemia 3
• May result from mutations in the CLCN5 chloride channel gene or calcium-sensing receptor (CaSR) 2

Resorptive Hypercalciuria

• Increased bone resorption drives calcium release into circulation and subsequent urinary excretion 2, 5
• Classic presentation in primary hyperparathyroidism: hypercalcemia, elevated serum PTH (normal <65 pg/mL), elevated urinary cAMP (8.58±3.63 vs. 4.02±0.70 μmol/g creatinine), fasting urinary calcium ≥0.2 mg/mg creatinine, and low bone density 3
• Urinary calcium exceeds absorbed intestinal calcium 3

Dietary and Medication-Induced Causes

High-Risk Dietary Factors

• High sodium intake directly increases urinary calcium excretion through competitive inhibition of calcium reabsorption in the proximal tubule 1
• Excessive animal protein increases urinary calcium and uric acid while reducing citrate excretion 1
• High carbohydrate and sucrose intake promotes calciuria 1
• Paradoxically, low dietary calcium (<400 mg/day) increases stone risk by 51% compared to normal calcium intake (1,200 mg/day) by failing to bind intestinal oxalate 1, 6

Medication-Induced Hypercalciuria

• Large doses of active vitamin D (calcitriol or alfacalcidol) increase intestinal calcium absorption and promote hypercalciuria, particularly when given during daytime with food 1
• Phosphate supplementation combined with vitamin D therapy increases calciuria risk 1
• Calcium supplements beyond age-appropriate requirements increase hypercalciuria risk 1
• Vitamin C supplementation increases oxalate generation and may indirectly affect calcium handling 1

Endocrine and Metabolic Disorders

Vitamin D Metabolism Abnormalities

• Overexpression of vitamin D receptors increases intestinal calcium absorption 2, 4
• Increased calcitriol production drives absorptive hypercalciuria 4
• Persistent abnormalities in calcium and vitamin D metabolism can occur lifelong, even when symptomatic hypercalcemia resolves 1

Hypophosphatemia

• Low serum phosphate can independently cause hypercalciuria through altered renal calcium handling 5

Williams Syndrome

• Increased intestinal calcium absorption from unknown mechanisms causes hypercalcemia and hypercalciuria, most severe in first 2 years but persisting lifelong 1

Diagnostic Approach

Essential Laboratory Evaluation

• Serum measurements: calcium (corrected for albumin), phosphorus, intact PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D 7, 5
• Urine measurements: 24-hour calcium (>0.1 mmol/kg/24h or >4 mg/kg/day defines hypercalciuria), calcium/creatinine ratio, phosphorus, cAMP 2, 5, 3
• Fasting urinary calcium ≥0.2 mg/mg creatinine suggests resorptive or renal hypercalciuria 3

Distinguishing Features

• Absorptive: normocalcemia, normal/low PTH, normal fasting urinary calcium, absorbed calcium > urinary calcium 3
• Renal: normocalcemia, elevated PTH/cAMP, urinary calcium > absorbed calcium 3
• Resorptive: hypercalcemia, elevated PTH, elevated cAMP, fasting urinary calcium ≥0.2 mg/mg creatinine, low bone density 3

Clinical Consequences

Nephrolithiasis and Nephrocalcinosis

• Hypercalciuria increases urinary saturation of calcium oxalate and calcium phosphate, promoting stone formation at all life stages 2, 6
• Nephrocalcinosis develops in 30-70% of patients receiving phosphate and vitamin D therapy 1

Bone Demineralization

• Bone mineral density is moderately decreased in idiopathic hypercalciuria, particularly the renal type 2
• Vertebral fracture risk appears increased despite only moderate BMD reduction 2
• Mechanisms include calcitriol-stimulated bone resorption and cytokine-mediated bone loss 2