What is the pathology of nephrolithiasis?

Pathology of Nephrolithiasis

Nephrolithiasis is a condition in which kidney stones form from crystals precipitating in the urine when the urinary concentration of crystal-forming substances is high or when inhibitors of stone formation are low. 1

Stone Composition and Prevalence

• Approximately 80% of kidney stones consist primarily of calcium oxalate, calcium phosphate, or both
• Other stone types include struvite, uric acid, and cystine 1
• Lifetime prevalence: 13% for men and 7% for women
• 5-year recurrence rate after an initial event: 35-50% without treatment 1

Pathophysiological Mechanism

The formation of kidney stones involves a complex multistep process:

1. Supersaturation: The initial step where stone-forming salts exceed their solubility in urine 2
2. Nucleation: Formation of crystal nidus when supersaturation reaches critical levels
3. Crystal growth: Enlargement of crystals through addition of constituents
4. Crystal aggregation: Clustering of crystals to form larger particles
5. Crystal retention: Adherence to renal epithelium and continued growth 2

Key Factors in Stone Formation

Promoters of Stone Formation

• Low urine volume: Increases concentration of stone-forming substances 1, 2
• Low urine pH: Particularly important for uric acid stones 2
• High urinary calcium (hypercalciuria): The greatest risk factor for calcium stone formation 3
• High urinary oxalate (hyperoxaluria): Contributes to calcium oxalate stone formation 1, 2
• High urinary sodium: Reduces renal tubular calcium reabsorption 1
• High urinary urate: Promotes calcium oxalate crystallization 2

Inhibitors of Stone Formation

• Citrate: Binds with calcium, reducing free calcium available for stone formation 1, 2
• Magnesium: Forms complexes with oxalate, reducing calcium oxalate supersaturation 2
• Organic substances: Including nephrocalcin, urinary prothrombin fragment-1, and osteopontin 2
• Potassium: Associated with citrate metabolism; hypokalemia decreases urinary citrate 1

Pathophysiological Subtypes

Calcium Stone Formation

• Hypercalciuria mechanisms 3:

  • Enhanced intestinal calcium absorption
  • Increased bone resorption
  • Altered renal tubular calcium transport

• Dietary factors:

  • Low dietary calcium paradoxically increases risk by reducing binding of oxalate in the gut 1
  • High sodium intake increases urinary calcium excretion 1
  • High animal protein intake increases urinary calcium and decreases citrate 1

Infection-Related Stones (Struvite)

• Caused by urease-producing bacteria (e.g., Proteus, Klebsiella)
• Urease splits urea into ammonia, raising urine pH and promoting struvite crystal formation
• These stones can grow rapidly and form "staghorn calculi" that fill the renal collecting system 4

Uric Acid Stones

• Form in persistently acidic urine (pH < 5.5)
• Associated with high purine intake and conditions with high cell turnover 5

Cystine Stones

• Result from genetic defect in renal tubular cystine transport
• Form in patients with cystinuria, a hereditary disorder 5

Environmental and Genetic Factors

• Stone formation results from an interaction between genetics and environmental exposure 1
• Dietary habits significantly influence stone risk 6
• Variations in intestinal oxalate absorption exist between individuals 1
• Some patients may have deficiency of Oxalobacter formigenes in the gut, which normally degrades oxalate 1

Clinical Implications

The pathophysiology of nephrolithiasis explains why certain preventive measures are effective:

• Increased fluid intake dilutes stone-forming substances 1
• Normal dietary calcium (not low) helps bind oxalate in the gut 1
• Limiting sodium and animal protein reduces urinary calcium 1
• Thiazide diuretics, citrate supplements, and allopurinol can be effective pharmacologic interventions based on stone type 1

Understanding the pathology of nephrolithiasis is essential for implementing appropriate preventive strategies and reducing the significant morbidity associated with this common condition.