360 CHAPTER 8 Stone disease

Kidney stones: mechanisms of formation

Urine is said to be saturated with, for example, calcium and oxalate, when the product of the concentrations of calcium and oxalate exceeds the solubility product (Ksp). Below the solubility product, crystals of calcium and oxalate will not form and the urine is undersaturated. Above the solubility product, crystals of calcium and oxalate should form, but they do not because of the presence of inhibitors of crystal formation.

However, above a certain concentration of calcium and oxalate, inhibitors of crystallization become ineffective, and crystals of calcium oxalate start to form. The concentration of calcium and oxalate at which this is reached (i.e., at which crystallization starts) is known as the formation product (Kf), and the urine is said to be supersaturated with the substance or substances in question at concentrations above this level.

Urine is described as being metastable for calcium and oxalate at concentrations between the solubility product of calcium and oxalate and the formation product (see Box 8.1).

The ability of urine to hold more solute in solution than can pure water is due partly to the presence of various inhibitors of crystallization (e.g., citrate forms a soluble complex with calcium, preventing it from combining with oxalate or phosphate to form calcium oxalate or calcium phosphate stones). Other inhibitors of crystallization include magnesium, glycosaminoglycans, and Tamm–Horsfall protein.

Periods of intermittent supersaturation of urine with various substances can occur as a consequence of dehydration and following meals.

The earliest phase of crystal formation is known as nucleation. Crystal nuclei usually form on the surfaces of epithelial cells or on other crystals. Crystal nuclei form into clumps—a process known as aggregation. Citrate and magnesium inhibit not only crystallization but also aggregation.

KIDNEY STONES: MECHANISMS OF FORMATION 361

Box 8.1 Steps leading to stone formation

•Calcium and oxalate concentration < solubility product lNO STONE FORMATION

•Metastable calcium and oxalate concentrations lNO STONE FORMATION

•Calcium and oxalate concentrations > formation product lSTONE FORMATION

In the urine of subjects who do not form stones, the concentrations of most stone components are between Ksp and Kf.

362 CHAPTER 8 Stone disease

Factors predisposing to specific stone types

Calcium oxalate (~85% of stones)

Hypercalciuria

Excretion of >7 mmol of calcium per day in men and >6 mmol/day in women. A major risk factor for calcium oxalate stone formation is when it increases the relative supersaturation of urine. About 50% of patients with calcium stone disease have hypercalciuria. There are three types:

•Absorptive—increased intestinal absorption of calcium

•Renal—renal leak of calcium

•Resorptive—increased demineralization of bone (due to hyperparathyroidism)

Hypercalcemia

Almost all patients with hypercalcemia who form stones have primary hyperparathyroidism. Of hyperparathyroid patients, about 1% form stones (the other 99% do not because of early detection of hyperparathyroidism by screening serum calcium).

Hyperoxaluria

This is due to the following:

•Altered membrane transport of oxalate leading to increased renal leak of oxalate

•Primary hyperoxaluria—increased hepatic oxalate production; rare

•Increased oxalate absorption in short bowel syndrome or malabsorption (enteric hyperoxaluria)—the colon is exposed to more bile salts and this increases its permeability to oxalate.

Hypocitraturia

This is low urinary citrate excretion. Citrate forms a soluble complex with calcium and prevents complexing of calcium with oxalate to form calcium oxalate stones.

Hyperuricosuria

High urinary uric acid levels lead to formation of uric acid crystals, on the surface of which calcium oxalate crystals form.

Uric acid (~5–10% of stones)

Humans are unable to convert uric acid (which is relatively insoluble) into allantoin (which is very soluble). Human urine is supersaturated with insoluble uric acid. Uric acid exists in two forms in urine—uric acid and sodium urate. Sodium urate is 20 times more soluble than uric acid.

At a urine pH of 5, <20% of uric acid is present as soluble sodium urate. At urine pH 5.5, half the uric acid is ionized as sodium urate (soluble) and half is nonionized as free uric acid (insoluble). At a urine pH of 6.5, >90% of uric acid is present as soluble sodium urate.

Thus, uric acid is essentially insoluble in acid urine and soluble in alkaline urine. Human urine is acidic (because the end products of metabolism are acid) and this low pH, combined with supersaturation of urine with uric acid, predisposes to uric acid stone formation.

FACTORS PREDISPOSING TO SPECIFIC STONE TYPES 363

Approximately 20% of patients with gout have uric acid stones. Patients with uric acid stones may have the following:

-Gout. 50% of patients with uric acid stones have gout. The chance of forming a uric acid stone if you have gout is on the order of 1% per year from the time of the first attack of gout.

-Myeloproliferative disorders. Particularly following treatment with cytotoxic drugs, cell necrosis results in release of large quantities of nucleic acids that are converted to uric acid. A large plug of uric acid crystals may form in the collecting system of the kidney, in the absence of ureteric colic, causing oliguria or anuria.

-Idiopathic uric acid stones (no associated condition)

Calcium phosphate (calcium phosphate + calcium oxalate = 10% of stones)

These stones occur in patients with renal tubular acidosis (RTA), a defect of renal tubular H+ secretion resulting in impaired ability of the kidney to acidify urine. The urine is thus of high pH, and the patient has a metabolic acidosis. The high urine pH increases supersaturation of the urine with calcium and phosphate, leading to their precipitation as stones.

Types of renal tubular acidosis

-Type 1 or distal RTA: The distal tubule is unable to maintain a proton gradient between the blood and the tubular fluid. Of such patients, 70% have stones. Urine pH is >5.5, the patient has a metabolic acidosis and hypokalemia, urinary citrate is low, and hypercalciuria is present.

-Type 2 or proximal RTA is due to failure of bicarbonate resorption in the proximal tubule. There is associated increased urinary citrate excretion, which protects against stone formation.

-Type 3: A variant of type 1 RTA

-Type 4 is seen in diabetic nephropathy and interstitial renal disease. These patients do not make stones.

If urine pH is >5.5, use the ammonium chloride loading test. Urine pH that remains above 5.5 after an oral dose of ammonium chloride = incomplete distal RTA.

Struvite (infection or triple phosphate stones) (2–20% of stones)

These stones are composed of magnesium, ammonium, and phosphate. They form as a consequence of urease-producing bacteria that produce ammonia from breakdown of urea (urease hydrolyses urea to carbon dioxide and ammonium) and, in so doing, alkalinize urine as in the following equation:

NH2–O–NH2 + H2O l2NH3 + CO2

Under alkaline conditions, crystals of magnesium, ammonium, and phosphate precipitate.

364 CHAPTER 8 Stone disease

Cystine (1% of all stones)

These stones occur only in patients with cystinuria—an inherited (autosomal recessive) disorder of transmembrane cystine transport, resulting in decreased absorption of cystine from the intestine and in the proximal tubule of the kidney.

Cystine is very insoluble, so reduced absorption of cystine from the proximal tubule results in supersaturation with cystine and cystine crystal formation. Cystine is poorly soluble in acid urine (300 mg/L at pH 5, 400 mg/L at pH 7).

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