Urolithiasis: Etiology and Pathogenesis

Introduction to Urolithiasis

• Urolithiasis affects 5% to 10% of people in the United States.
• Stones primarily arise in the kidney but form anywhere in the urinary tract.
• Men are affected more often than women.
• The peak age of onset is between 20 and 30 years.
• There is a familial and hereditary predisposition to stone formation.
• Inborn errors of metabolism lead to conditions like cystinuria and primary hyperoxaluria that cause excessive production and excretion of stone-forming substances.

Aetiology and Pathogenesis of Calculi

• There are four main types of calculi.
• Calcium stones account for about 70% of cases and consist of calcium oxalate or calcium oxalate mixed with calcium phosphate.
• Triple or struvite stones make up about 15% and comprise of magnesium ammonium phosphate.
• Uric acid stones account for approximately 5% to 10% of cases.
• Cystine stones make up 1% to 2% of cases.
• An organic mucoprotein matrix is present in all calculi, constituting 1% to 5% of the stone by weight.
• The most critical factor for stone formation is increased urinary concentration of stone constituents beyond their solubility, known as supersaturation.
• Low urine volume in metabolically normal patients can also promote supersaturation.

Calcium Oxalate Stones

• About 5% of patients diagnosed with calcium oxalate stones have hypercalcemia and hypercalciuria.
• Conditions associated with hypercalcemia or hypercalciuria include hyperparathyroidism, diffuse bone disease, and sarcoidosis.
• Approximately 55% of patients with calcium oxalate stones have hypercalciuria without hypercalcemia.
• Hypercalcuria without hypercalcemia can be caused by hyperabsorption of calcium from the intestine (absorptive hypercalcuria), intrinsic impairment in renal tubular reabsorption of calcium (renal hypercalcuria), or idiopathic fasting hypercalcuria with normal parathyroid function.
• As many as 20% of calcium oxalate stones are associated with increased uric acid secretion (hyperuricosuric calcium nephrolithiasis), with or without hypercalciuria.
• Increased uric acid secretion involves the nucleation of calcium oxalate by uric acid crystals in the collecting ducts.
• Around 5% of calcium oxalate stones are associated with hyperoxaluria, either hereditary (primary oxaluria) or, more commonly, acquired by intestinal overabsorption in patients with enteric diseases.
• Hypocitraturia, whether idiopathic or linked to acidosis and chronic diarrhea, can result in calcium stones.
• Some individuals with calcium stones have no identifiable cause, termed idiopathic calcium stone disease.

Magnesium Ammonium Phosphate Stones

• These stones form largely after infections caused by urea-splitting bacteria, such as Proteus and some Staph.
• These bacteria convert urea to ammonia, leading to alkaline urine and the precipitation of magnesium ammonium phosphate salts.
• These stones can become very large due to the high amount of urea normally excreted.
• Staghorn calculi, which occupy large portions of the renal pelvis, are frequently a result of infection.

Uric Acid Stones

• Uric acid stones are common in individuals with hyperuricemia, such as those with gout and diseases involving rapid cell turnover like leukemias.
• More than half of patients with uric acid calculi do not have hyperuricemia or increased urinary excretion of uric acid.
• A tendency to excrete urine with a pH below 5.5 may predispose individuals to uric acid stones.
• Uric acid is insoluble in acidic urine.
• Uric acid stones are radiolucent, while calcium stones are radiopaque.

Cystine Stones

• Genetic defects in the renal reabsorption of amino acids, including cystine, cause cystine stones and lead to cystinuria.
• Cystine stones also form at low urinary pH.

Factors Influencing Stone Formation

• Increased concentration of stone constituents, changes in urinary pH, decreased urine volume, and the presence of bacteria can influence stone formation.
• Calculi can occur even without these factors.
• Individuals with hypercalciuria, hyperoxaluria, and hyperuricosuria may not form stones.
• A deficiency in inhibitors of crystal formation in urine may enhance stone formation.
• Inhibitors of crystal formation include pyrophosphate, diphosphate, citrate, glycosaminoglycan, osteopontin, and a glycoprotein called nephrocalcin.

Morphology of Stones

• Urolithiasis is unilateral in about 80% of patients.
• Favored sites for stone formation are within renal calyces, pelves, and the bladder.
• Stones formed in the renal pelvis tend to remain small, with an average diameter of 2 to 3 mm.
• Stones may have smooth contours or an irregular, jagged mass of spicules.
• Many stones are often found within one kidney.
• Progressive accretion of salts can lead to the development of branching structures known as staghorn calculi, creating a cast of the pelvic and calyceal system.

Clinical Features of Urolithiasis

• Urolithiasis may be asymptomatic.
• It can produce severe renal colic and abdominal pain.
• It may cause significant renal damage.
• Larger stones often manifest with hematuria.
• Stones can predispose to superimposed infection due to their obstructive nature and the trauma they produce.