What are the causes of nephrocalcinosia?

Causes of Nephrocalcinosis

Nephrocalcinosis results from calcium phosphate or calcium oxalate deposition in renal parenchyma, with causes broadly categorized into hereditary tubular disorders, metabolic abnormalities, iatrogenic factors, and prematurity-related mechanisms. 1

Primary Etiologic Categories

Hereditary Tubular Disorders

• Distal renal tubular acidosis represents one of the most common hereditary causes, characterized by impaired urinary acidification leading to alkaline urine and calcium precipitation 1
• Dent disease is a key X-linked tubular disorder causing hypercalciuria and progressive nephrocalcinosis 1
• Bartter syndrome types 1 and 2 characteristically present with hypercalciuria and nephrocalcinosis developing after 1-2 months of life, while types 3 and 4 typically show normocalciuria 2

Metabolic Disorders

• Idiopathic hypercalciuria is among the most frequent metabolic causes in children 1
• Primary hyperoxaluria must always be investigated as it leads to early-onset nephrocalcinosis and typically progresses to chronic kidney disease 1
• Hyperparathyroidism directly causes nephrocalcinosis through excess parathyroid hormone, which contributes to renal failure progression 3
• Williams Syndrome causes increased intestinal calcium absorption through unknown mechanisms, resulting in hypercalcemia and hypercalciuria most severe in the first 2 years but persisting lifelong 4

Iatrogenic and Medication-Related Causes

Diuretic Therapy

• Furosemide causes hypercalciuria leading to nephrocalcinosis, particularly in premature infants with chronic lung disease 2
• Loop and thiazide diuretics cause phosphaturia and magnesium depletion, which increases calcium excretion 2

Vitamin D and Phosphate Therapy

• Large doses of active vitamin D (calcitriol or alfacalcidol) increase intestinal calcium absorption and promote hypercalciuria, especially when given during daytime with food 4
• Phosphate supplementation combined with vitamin D therapy develops nephrocalcinosis in 30-70% of patients 4, 5
• Vitamin D intoxication is a recognized iatrogenic cause of medullary nephrocalcinosis 1

Nutritional Factors

• Calcium supplements beyond age-appropriate requirements increase hypercalciuria risk 4
• Vitamin C supplementation increases oxalate generation and may indirectly affect calcium handling 4

Prematurity-Related Mechanisms

• Hypercalciuria in very low birth weight infants has multifactorial pathogenesis, with extreme immaturity and underdevelopment of renal function as the most important variables 2
• Decreased glomerular filtration rate, low citrate excretion, and frequently alkaline urine result from renal functional immaturity 2
• Not all premature infants with hypercalciuria develop nephrocalcinosis, suggesting additional cofactors are required 2

Dietary and Metabolic Mechanisms

• High sodium intake directly increases urinary calcium excretion through competitive inhibition of calcium reabsorption in the proximal tubule 4
• Excessive animal protein increases urinary calcium and uric acid while reducing citrate excretion 4
• High carbohydrate and sucrose intake promotes calciuria 4
• Paradoxically, low dietary calcium (<400 mg/day) increases stone risk by 51% compared to normal intake by failing to bind intestinal oxalate 4

Intestinal Malabsorption

• Short bowel syndrome increases oxalate absorption because fatty acids sequester calcium and inhibit oxalate complexing 2
• Hypovolemia and dehydration in malabsorptive states contribute to renal stone and nephrocalcinosis formation 2
• Hypomagnesemia and metabolic acidosis increase the risk of renal precipitations including uric acid stones 2

Stone Composition Patterns

• Hydroxyapatite stone formers have nephrocalcinosis in 71.4% of cases without systemic disease 6
• Brushite stone formers demonstrate nephrocalcinosis in 57.9% of cases 6
• Calcium oxalate stone formers show dramatically lower frequency (17.6%) and extent of nephrocalcinosis 6
• Nephrocalcinosis presence positively correlates with higher urine calcium excretion (287 vs 224 mg/day) 6

Common Pitfalls

• Failure to investigate for primary hyperoxaluria can miss a progressive cause requiring early intervention 1
• Overlooking medication history particularly furosemide, vitamin D, and phosphate supplementation misses reversible causes 2, 4
• Inadequate evaluation of premature infants on chronic diuretic therapy for lung disease misses a high-risk population 2
• Assuming all nephrocalcinosis is medullary when cortical and diffuse patterns exist with different etiologies 1, 7